Cache Substituted 3-phenylpropionic acids and using them

Substituted 3-phenylpropionic acids and using them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 3-phenylpropionic acid derivatives of formula

wherein R1A represents hydrogen, methyl, ethyl, cyclopropyl or cyclobutyl, R1B is hydrogen or methyl, R2A represents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl, R2B is hydrogen or methyl or R1A and R2A are combined together, and in a combination to carbon atoms to which they are attached, form a cyclopropyl ring of formula

wherein R1B and R2B have the values as specified above, or R2A and R2B are combined together, and in a combination to a carbon atom, to which they are attached, form a cyclic group of formula or

wherein n means a number 1 or 2, R3 is hydrogen, fluorine or methyl, R4 represents hydrogen, fluorine, chlorine or a cyanogroup, R5A represents methyl, R5B is trifluoromethyl or R5A and R5B are combined together, and in a combination to a carbon atom, to which they are attached, form a difluorosubstituted cycloalkyl ring of formula or

R6 represents chlorine, alkyl with 1-4 carbon atoms, alkenyl with 2-4 carbon atoms, cyclopropyl or cyclobutyl; alkyl with 1-4 carbon atoms and alkenyl with 2-4 carbon atoms can contain up to three fluorine atoms, cyclopropyl and cyclobutyl up to three fluorine atoms as substitutes, and R7 represents hydrogen, fluorine, chlorine, methyl or a methoxy group. The invention also refers to a therapeutic agent containing the above compounds and to a method for producing the compounds of formula (I).

EFFECT: compounds of formula (I) activate the form of soluble haem-free guanylate cyclase and are applicable in the method of treating and/or preventing cardiac failure, angina, hypertension, pulmonary hypertension, ischemia, vascular diseases, disturbed microcirculation, thromboembolic diseases and arterial sclerosis.

6 cl, 4 tbl, 113 ex

 

This application relates to new derivatives of 3-fenilpropionovoy acid, process for their preparation, their use for the treatment and/or prophylaxis of diseases and their use for manufacturing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular diseases.

One of the major cellular systems transfer in mammalian cells is cyclic guanosinmonofosfat (cGMP). Together with nitric oxide (NO) that is released from the endothelium and tolerate hormonal and mechanical signals, it forms the NO/cGMP. Guanylyl cyclases catalyze the biosynthesis of cGMP from guanosine (GTP). Hitherto known representatives of this family can be classified as structural characteristics and in the type of ligands into two groups: guanylyl cyclases, having the form of particles that are able to be stimulated by natriuretic peptides and soluble guanylyl cyclases stimulated by NO. Soluble guanylyl cyclases consist of two subunits and probably contain one heme per heterodimer, which is part of the regulatory center. The latter is Central to the mechanism of activation. NO can bind to the iron atom of heme and thus markedly increase the activity of the enzyme. Formulations not containing�their heme, on the contrary, can not be stimulated under the action of NO. Carbon monoxide (CO) is also able to attach to the Central iron atom of heme, and this stimulation under the influence WITH noticeably smaller than the stimulation using a NO.

Due to the formation of cGMP and the resulting regulation phosphodieterase, ion channels and protein kinases plays guanilatziklazu a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, aggregation and adhesion of platelets and neuronal signal transmission, as well as diseases, which are based on the violation of the above processes. Under pathophysiological conditions, the NO/cGMP may be suppressed, which may lead to e.g. increased blood pressure, platelet activation, increased cellular proliferation, endothelial dysfunction, atherosclerosis, angina, heart failure, thromboses, stroke and myocardial infarction.

The possibility of treating diseases of this type, focused on the effects on cGMP signaling pathway in the organism, independent of NO, is a promising approach due to the high efficiency that should be expected, and slight side effects.

For therapeutic stimulation of soluble guanylyl cyclases to this�naszego day use only organic compounds as nitrates, the effect of which is based on NO. This NO is produced by bioconversion and activates soluble guanilatziklazu by attaching to the Central iron atom of heme. In addition to side effects, the decisive disadvantages of this method of treatment is the development of immunity [O. V. Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755].

In recent years, have been identified substances that stimulate soluble guanilatziklazu directly, i.e. without prior release of NO. Using indazole derivative YC-1 was first described NO-independent but gimzewski stimulator of soluble guanylyl cyclases (RGC) [Evgenov et al., ibid]. On the basis of YC-1 were detected other substances that have a higher capacity than YC-1 and do not have a significant suppression fosfodiesterasi (PDE). This led to the identification of Pirat-apyridine derivatives of BAY 41-2272, BAY 41-8543 and BAY 63-2521. These compounds, together with those in recent publications, structurally different substances CMF-1571 and A-350619 form a new class of stimulants RHC [Evgenov et al., ibid]. The common characteristic of this class of substances is NO-independent and selective activation of hem-comprising the TWG. In addition, these stimulants RHC in combination with N0 demonstrate a synergistic effect on the activation of the TWG, to�which is based on the stabilization of the complex narasimham. The exact binding site of these stimulants with the RHC RHC to date is a matter of debate. If the soluble guanylyl cyclases remove the heme group, this enzyme still shows detectivea catalytic basal activity, i.e., still cGMP is formed. Continuing basal catalytic activity of the enzyme that does not contain heme, can not be stimulated by any of the above stimulants [Evgenov et al., ibid.].

In addition, with the help of BAY 58-2667 as the prototype of this class were identified NO - and gamesanime activators RHC. Common attributes of these substances is that in combination with NO, they have only an additional effect on the activation of the enzyme, and that this activation is oxidized or not containing heme of the enzyme is markedly stronger in comparison with the enzyme containing heme [Evgenov et al., ibid; J. P. Stasch et al., Br.J.Pharmacol. 136 (2002), 773; J. P. Stasch et al., J. Clin. Invest. 116 (2006), 2552]. Spectroscopic studies give the opportunity to see that BAY 58-2667 displaces the oxidized heme group, which as a result of the weakening of the binding of iron with histidine only weakly connected to the TWG. It was also shown that the characteristic binding motif RHC-heme Tyr-x-Ser-x-Arg is indispensable for the interaction of the negatively charged propiononitrile heme group, and for the action of BAY 58-2667. In light of the above it is assumed that the center of the binding of BAY 58-2667 with the TWG is identical to the binding site of the heme group [J. P. Stasch et al., J. Clin. Invest. 116 (2006), 2552].

Thus, the compounds described in the present invention also able to activate soluble guanylyl cyclases that do not contain heme. This is also confirmed by the fact that these activators are of a new type, on the one hand, does not exhibit a synergistic effect in conjunction with N0 for the enzyme that contains heme, and, on the other hand, their action cannot be locked using gimzauskas inhibitor of soluble guanylyl cyclases 1H-1,2,4-oxadiazole[4,3-a]quinoxaline-1-one (ODQ), and even this substance increases [compare with O. V. Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755; J. P. Stasch et al., J. Clin. Invest. 116 (2006), 2552].

Therefore, an object of the present invention was to provide new compounds which act as described above as activators of soluble guanylyl cyclases, and as such can be used in particular for the treatment and prevention of cardiovascular diseases.

In the international application WO 00/64888-A1, European patent EP 1216980-A1, EP 1375472-A1, EP 1452521-A1, United States patent US 2005/0187266-A1 and US 2005/0234066-A1 describes various derivatives arylalkanolamine acids as agonists RAPP (receptor-activated proliferationresistant) for the treatment of diabetes, dyslipidemia, arteriosclerosis, General obesity and other diseases. In the European patents EP 1312601-A1 and EP 1431267-A1 shown replaced arylalkanolamine acid as receptor antagonists of prostaglandin PGE2for treatment, e.g., pain conditions, urological diseases, Alzheimer's disease and cancer. In addition, in the international application WO 2005/086661-A2 arylalkanolamine acid claimed as GPR40 modulators for the treatment of diabetes and dyslipidemia, and in international applications WO 2004/099170-A2, W02006/050097-A1 and WO 2006/055625-A2 describes phenylsilane carboxylic acids as inhibitors proteinkinase-phosphatase-1 (fog-1) for the treatment of diabetes, cancer and neurodegenerative diseases. In addition, international applications WO 96/12473-A1 and WO 96/30036-A1 is known to separate phenylacetylglutamine phenylalkylamine acids that form non-covalent mixtures improve the delivery of peptide biologically active substances inside the body. Recently in the international application WO 2009/127338-A1 were proposed derivatives carboxylic acids with oxytetracycline substituents that act as activators of soluble guanylyl cyclases.

The subject of this invention are compounds of the General formula (I)

,

in which

R1Arepresents hydrogen, �Thor, methyl, trifluoromethyl, ethyl, 1,1-deflorati, 2,2,2-trifluoroethyl, n-propyl, cyclopropyl or cyclobutyl,

R1Bis hydrogen or bromide

R2Arepresents hydrogen, methyl, trifluoromethyl, ethyl, 1,1-deflorati, 2,2,2-trifluoroethyl or n-propyl,

R2Bis hydrogen or bromide, or

R1Aand R2Aare linked together and together with the carbon atoms to which they are connected, form a cyclopropyl ring of formula

in which R1Band R2Bhave the meanings given above,

or

R2Aand R2Bare linked together and together with the carbon atom to which they are connected, form a cyclic group of the formula

,orwhere

n denotes the number 1, 2 or 3,

R3is hydrogen, fluorine, bromide or trifluoromethyl sulfide,

R4represents hydrogen, fluorine, chlorine, cyano group, methyl, trifluoromethyl or ethyl,

R5Ais methyl, trifluoromethyl or ethyl,

R5Bis a trifluoromethyl sulfide,

or

R5Aand R5Bare linked together and together with the carbon atom to which they are connected, form diversamente cycloalkyl ring formula

,, ,or,

R6represents hydrogen, fluorine, chlorine, bromine, cyano group, alkyl with 1-4 carbon atoms, alkenyl with 2-4 carbon atoms, cyclopropyl or cyclobutyl, and

alkyl with 1-4 carbon atoms and the alkenyl with 2-4 carbon atoms can contain up to three fluorine atoms as substituents

and

the cyclopropyl and cyclobutyl can contain up to two fluorine atoms as substituents

and

R7represents hydrogen, fluorine, chlorine, cyano group, methyl, trifluoromethyl, ethyl, methoxy or cryptometer,

and also their salts, solvates and solvates of salts.

Compounds according to the invention are compounds of formula (I) and their salts, solvates and solvates of these salts covered by formula (I) compounds of the formulae mentioned below and their salts, solvates and solvates of the salts and the compounds covered by formula (I), the following as examples of execution of the invention and their salts, solvates and solvates of the salts, if in a case covered by formula (I), the following compounds cannot speak about the salts, solvates and solvates of salts.

Compounds according to the invention, depending on their structure can exist in various stereoisomeric forms, i.e. in the form of configurational isomers or, if necessary, the�in the form of conformational isomers (enantiomers and/or diastereomers, including those in the case Atronach isomers). Therefore, the present invention includes enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereomers individual stereoisomeric components may be provided in a known manner; preferably, one uses chromatographic methods, especially HPLC (high performance liquid chromatography) on achiral or chiral phase.

Since the compounds according to the invention can exist in tautomeric forms, the present invention includes, without limitation, tautomeric form.

As salts in the present invention the preferred physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not themselves suitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention primarily include salts of conventional bases, such as cited as exemplary and preferred alkali metal salts (e.g. sodium and potassium salts), salts of alkaline earth metals (e.g. calcium and magnesium salts) and ammonium salts, which are derivatives of ammonia or body�ical amines with a carbon number from 1 to 16, like cited as exemplary and preferred ethylamine, diethylamine, triethylamine, ethyldiethanolamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, N-demerol, arginine, lysine and Ethylenediamine.

The solvates in the context of the invention are indicated by such forms of the compounds according to the invention, in which the solid or liquid state in coordination with solvent molecules form a complex. Hydrates are a private form of solvates in which the coordination is made with water. As solvates in the context of the present invention the preferred hydrates.

In addition, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrug" refers to compounds which themselves may be biologically active or inactive, but during their period of stay in the body are converted into compounds according to the invention (for example, as a result of metabolism or hydrolytically).

Particularly, the present invention includes able to the hydrolysis of ester derivatives of carboxylic acids of the formula (I) according to the invention. These esters understand that in physiological environments, in terms of biological tests, OPIE�data in the future, and above all, in tests on a living subject (in vivo) can be enzymatically or chemically hydrolyzed to free carboxylic acids mainly as biologically active compounds. As such esters prefer complex alkyl esters with 1-4 carbon atoms in the alkyl in which the alkyl group can be linear or branched. Especially preferred are complex methyl, ethyl or mpem-butyl esters.

In the present invention, the substituents, unless otherwise indicated, have the following meanings:

alkyl with 1-4 carbon atoms in the framework of the invention is a linear or branched alkyl residue with the number of carbon atoms from 1 to 4. As an illustrative and preferred may be mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, terbutyl and tert-butyl.

Of alkenyl with 2-4 carbon atoms and alkenyl of 2-3 carbon atoms in the framework of the invention represent a straight or branched alkenyl residue with one double bond and carbon atoms from 2 to 4 or 2 or 3 respectively. Preferred is a straight or branched alkenyl residue with 2 or 3 carbon atoms. As an illustrative and preferred may be mentioned: vinyl, allyl, n-prop-1-EN-1-yl, Isopropenyl, n-but-1-ene-1-yl, n-BU�-2-EN-2-yl, n-but-3-EN-2-yl, 2-methylprop-1-EN-1-yl and 2-methylprop-2-EN-1-yl.

In the framework of this invention it is true that for all of the residues that occur repeatedly, their values do not depend on each other. If residues in the compounds according to the invention are substituted, these residues can, if not stated otherwise, contain one or several deputies. Preferred is a substitution of one or two, or three identical or different substituents. Especially preferred is a substitution of one or two identical or different substituents.

In one particular form of execution of the present invention includes compounds of formula (I), in which

R1Arepresents hydrogen, fluorine, methyl, trifluoromethyl, ethyl, 1,1-deflorati, 2,2,2-trifluoroethyl or n-propyl,

R1Bis hydrogen or bromide

R2Arepresents hydrogen, methyl, trifluoromethyl, ethyl, 1,1-deflorati, 2,2,2-trifluoroethyl or n-propyl,

R2Bis hydrogen or bromide, or

R1Aand R2Aare linked together and together with the carbon atoms to which they are connected, form a cyclopropyl ring of formula

in which R13and R23have the meanings given above, or

R2Aand R2Bare linked together and together with the carbon atom, with Kotor�m they are connected, form a cyclic group of the formula

orwhere

n denotes the number 1, 2 or 3,

R3is hydrogen, fluorine, bromide or trifluoromethyl sulfide,

R4represents hydrogen, fluorine, chlorine, cyano group, methyl, trifluoromethyl or ethyl,

R5Ais methyl, trifluoromethyl or ethyl,

R5Bis a trifluoromethyl sulfide,

or

R5Aand R5Bare linked together and together with the carbon atom to which they are connected, form diversamente cycloalkyl ring formula

,,,or,

R6represents hydrogen, fluorine, chlorine, bromine, cyano group, alkyl with 1-4 carbon atoms or alkenyl with 2-4 carbon atoms, and alkyl with 1-4 carbon atoms and the alkenyl with 2-4 carbon atoms, for its part, can contain up to three fluorine atoms as substituents

and

R7represents hydrogen, fluorine, chlorine or methyl,

and also their salts, solvates and solvates of salts.

Preferred in the present invention are compounds of formula (I), in which

R1Arepresents hydrogen, methyl, trifluoromethyl, ethyl, n-propyl, cyclopropyl or cyclobutyl,

p> R1Bis hydrogen or bromide

R2Arepresents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl,

R2Bis hydrogen or bromide, or

R2Aand R2Bare linked together and together with the carbon atom to which they are connected, form a cyclic group of the formula

,orwhere

n denotes the number 1 or 2,

R3is hydrogen fluoride or bromide

R4represents hydrogen, fluorine, chlorine, cyano group, methyl or trifluoromethyl,

R5Ais methyl or ethyl,

R5Bis a trifluoromethyl sulfide,

or

R5Aand R5Bare linked together and together with the carbon atom to which they are connected, form diversamente cycloalkyl ring formula

,,or,

R6represents fluorine, chlorine, alkyl with 1-4 carbon atoms, alkenyl of 2-3 carbon atoms, cyclopropyl or cyclobutyl, and

alkyl with 1-4 carbon atoms and alkenyl of 2-3 carbon atoms can contain up to three fluorine atoms as substituents

and

the cyclopropyl and cyclobutyl can contain up to two fluorine atoms as substituents

<> and

R7represents hydrogen, fluorine, chlorine, methyl or methoxy group,

and also their salts, solvates and solvates of salts.

Another preferred embodiment of the present invention includes compounds of formula (I), in which

R1Arepresents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl,

R1Bis hydrogen or bromide

R2Arepresents hydrogen, methyl, trifluoromethyl or ethyl,

R2Bis hydrogen or bromide, or

R2Aand R2Bare linked together and together with the carbon atom to which they are connected, form a cyclic group of the formula

orwhere

n denotes the number 1 or 2,

R3is hydrogen or fluorine,

R4represents hydrogen, fluorine, chlorine, cyano group, methyl or trifluoromethyl,

R5Ais methyl or ethyl,

R5Bis a trifluoromethyl sulfide,

or

R5Aand R5Bare linked together and together with the carbon atom to which they are connected, form diversamente cycloalkyl ring formula

,,or,

R6represents fluorine, chlorine, alkyl with 1-4 carbon atoms or alkenyl of from -3 carbon atoms, moreover, alkyl with 1-4 carbon atoms and alkenyl of 2-3 carbon atoms, for its part, can contain up to three fluorine atoms as substituents

and

R7represents hydrogen, fluorine or chlorine,

and also their salts, solvates and solvates of the salts.

Particularly preferred in the present invention are compounds of formula (I), in which

R1Arepresents hydrogen, methyl or ethyl,

R1Bis hydrogen,

R2Arepresents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl,

R2Ais hydrogen or bromide

or

R2Aand R2Bare linked together and together with the carbon atom to which they are connected, form a cyclic group of the formula

,orwhere

n denotes the number 1 or 2,

R3is hydrogen,

R4represents a fluorine, chlorine or methyl,

R5Ais methyl,

R5Bis a trifluoromethyl sulfide, or

R5Aand R5Bare linked together and together with the carbon atom to which they are connected, form diversamente cyclopentenone ring formula

or,

R6represents fluorine, chlorine, methyl, trifluoromethyl, ethyl,1,1-deflorati, 2,2,2-trifluoroethyl, isopropyl, tert-butyl, 1,1,1-Cryptor-2-methylpropan-2-yl, vinyl, 1-forfinal, cyclopropyl, 2,2-divorcecare, cyclobutyl or 3.3-diversilobum,

and

R7represents hydrogen, fluorine, chlorine or methyl, and their salts, solvates and solvates of salts.

Another especially preferred embodiment of the present invention includes compounds of formula (I), in which

R1Arepresents hydrogen, methyl or ethyl,

R1Bis hydrogen,

R2Arepresents hydrogen or methyl,

R2Bis hydrogen,

or

R2Aand R2Bare linked together and together with the carbon atom to which they are connected, form a cyclic group of the formula

orwhere

n denotes the number 1 or 2,

R3is hydrogen,

R4represents a fluorine, chlorine or methyl,

R5Ais methyl,

R5Bis a trifluoromethyl sulfide, or

R5Aand R5Bare linked together and together with the carbon atom to which they are connected, form diversamente cyclopentenone ring formula

or ,

R6represents a chlorine atom, methyl, trifluoromethyl, ethyl, 1,1-deflorati, 2,2,2-trifluoroethyl, isopropyl,tert-butyl, 1,1,1-Cryptor-2-methylpropan-2-yl, vinyl or 1-forfinal,

and

R7represents hydrogen or fluorine,

and also their salts, solvates and solvates of salts.

A special form of execution of the present invention includes compounds of formula (I), in which

R1Arepresents hydrogen, methyl or ethyl,

and

R1A, R2Aand R2Brespectively are hydrogen atoms,

and also their salts, solvates and solvates of the salts.

Another special form of execution of the present invention includes compounds of formula (I), in which

R2Ais methyl, trifluoromethyl, ethyl or n-propyl,

and

R1A, R1Band R2Brespectively are hydrogen atoms,

and also their salts, solvates and solvates of the salts.

Another special form of execution of the present invention includes compounds of formula (I), in which

R1Aand R1Brespectively are hydrogen atoms,

and

R2Aand R2Brespectively represent a methyl group,

and also their salts, solvates and solvates of the salts.

Another special form of execution of the present invention includes compounds of formula (I), in which

R1Aand R1Bare respectively hydrogen atoms, and

R2Aand R2Bare linked together and together with the carbon atom to which they are connected, form a �ecoprofile or cyclobutyl ring formula

,or,

and also their salts, solvates and solvates of the salts.

Another special form of execution of the present invention includes compounds of formula (I), in which

R3is hydrogen,

and

R4represents fluorine or chlorine,

and also their salts, solvates and solvates of salts.

Another special form of execution of the present invention includes compounds of formula (I), in which

R5Ais bromide

and

R5Bis a trifluoromethyl sulfide,

and also their salts, solvates and solvates of salts.

Another separate embodiment of the present invention includes compounds of formula (I), in which

R5Aand R5Bare linked together and together with the carbon atom to which they are connected, form diversamente cyclopentenone ring formula

or ,

and also their salts, solvates and solvates of salts.

Another special form of execution of the present invention includes compounds of the formula (1-A)

in which the carbon atom marked with * contains phenylacetamido group presents S-configuration,

and

residues R1A, R1B, R2A, R2B, R3, R4, R5A, R5B, R6and R 7respectively have the meanings given above,

and also their salts, solvates and solvates of salts.

Determining residues shown separately in the respective combinations or preferred combinations of residues, regardless of these respective combinations specified residues also arbitrarily replaced by the residue definitions of other combinations.

Most preferred are combinations of two or more of the above preferred areas.

Another object of the invention is a method for producing compounds of formula (I) according to the invention, characterized in that the carboxylic acid of formula (II)

,

in which R5A, R5B, R6and R7have the above values,

in an inert solvent using a condensing agent or via the intermediate stage of the corresponding acid chloride of the carboxylic acid, in the presence of base is subjected to the combination with the amine of formula (III)

,

in which R1A, R1B, R2A, R2B, R3and R4have the above values,

and

T1represents alkyl with 1-4 carbon atoms or benzyl,

with the formation of carboxylic acid amide of the formula (IV)

,

in which R1A, R1B, 2A, R2B, R3, R4, R5A, R5B, R6, R7and T1have the meanings given above,

and then Hatshepsut the ester residue of the T1using basic or acidic solvolysis or, if T1represents benzyl, also using the experimental data showed, with obtaining carboxylic acids of the formula (I),

and, if necessary, the compound of formula (I) using methods known to those skilled separated into their enantiomers and/or diastereomers and/or converted into their solvates, salts and/or solvates of the salts with appropriate solvents (I) and/or reason (ii).

Inert solvents for the process phase (II)+(III)→(IV) [combination with the formation of the amide] are, for example, ethers, such as simple diethyl ether, simple tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, simple glycolytically ether or simple diethylethylenediamine ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, kalogeropoulou, such as dichloro methane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, acetonitrile, ethyl acetate, pyridine, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N'-dimethylpropyleneurea (DMPM) or N-methylpyrrolidone (NMP). As well� possible to use mixtures of these solvents. Preferably apply dichloro methane, tetrahydrofuran, dimethylformamide or mixtures of these solvents.

As condensing agents for this reaction combinations are suitable, for example, carbodiimide, such as N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl-, N,N'-dicyclohexylcarbodiimide (DCC) hydrochloride or N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide (EDK), phosgene derivatives such as N,N'-carbonyldiimidazole (CDI), 1,2-oxazoline connection such as 2-ethyl-5-phenyl-1,2-oxazole-3-sulfate or perchlorate, 2-tert-butyl-5-methylisoxazole, acylaminoacyl such as 2-ethoxy-1-ethoxy-1,2-dihydroquinoline or isobutylparaben, 1-chloro-2-methyl-1-dimethylamino-1-propene, anhydride papapostolou acid diethyl ether complex cyanophosphonate acid, bis(2-oxo-3-oxazolidinyl)phosphorylchloride, hexaflurophosphate the benzotriazole-1-yloxytris(dimethylamino)phosphonium, hexaflurophosphate the benzotriazole-1-yloxytris(pyrrolidino)phosphonium (Ru-THIEF), tetrafluoroborate O-(benzotriazole-1-yl)-N,N,N',N'-tetramethylurea (TBTU), hexaflurophosphate O-(benzotriazole-1-yl)-N,N,N',N'-tetramethylurea (gbtu), tetrafluoroborate 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethylurea (TBTU), hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (GATA) or tetrafluoroborate O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethylurea (TCTU), optionally in combination with others� - based adjuvants, such as 1-hydroxy-benzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and as grounds carbonates of alkali metals, for example, carbonates of sodium or potassium, or an organic base such as triethylamine, N-methylmorpholine, N-metapopulation, N,N-diisopropylethylamine, pyridine or 4-N,N-dimethylaminopyridine. Preferably hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (GATA) or tetrafluoroborate O-(benzotriazole-1-yl)-N,N,N',N'-tetramethylurea (TBTU), respectively, in combination with pyridine or N,N-diisopropylethylamine, hydrochloride or N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide (EHD) in combination with 1-hydroxybenzotriazole (HOBt) and triethylamine or 1-chloro-2-methyl-1-dimethylamino-1-propene together with pyridine.

Reaction (II)+(III)→(IV), usually conducted in the temperature range from 0°C to +60°C, preferably from +10°C to +40°C.

When you use one of the corresponding compound (II) anhydrides of carboxylic acids is combined with the amine component (III) is carried out in the presence of conventional organic auxiliary base, such as triethylamine, N-methylmorpholine, N-demerol, N,N-diisopropylethylamine, pyridine, 4-N,N-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preferably used triethylamine or N,N-dia's�appropiately.

The interaction of the amine (III) with the acid chloride of carboxylic acid, as a rule, is carried out in the temperature range from -20°C to +60°C, preferably in the range from -10°C to +30°C.

The receipt of the acid chloride of carboxylic acid is carried out in the usual way by treatment of the carboxylic acid (II) thionylchloride or oxaliplatin.

Cleavage of the ester group T1at the stage of the process (IV)→(I) is carried out by conventional methods, by an ester in an inert solvent is treated with acids or bases, and in the latter case, the formed first g, translates into a free carboxylic acid resulting from the acid treatment. In the case of complex mpem-butyl ether is the splitting of the ester is preferably carried out with acids. Complex benzyl esters preferably broken down by experimental data showed (hydrogenation) in the presence of a suitable catalyst such as e.g. palladium on charcoal.

As the inert solvent for this reaction, suitable water or normal to the cleavage of esters of organic solvents. To these preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or mpem-butanol, or ethers, such as simple diethyl ether, tetrahydro�furan, dioxane or simple glycolytically ether, or other solvents such as acetone, dichloro methane, dimethylformamide or dimethyl sulfoxide. It is also possible to use mixtures of these solvents. In the case of ester hydrolysis with substrate preferably mixtures of water with dioxane, tetrahydrofuran, methanol and/or ethanol. In the case of interaction with trifluoroacetic acid is preferably used dichloro methane, and in the case of interaction with hydrogen chloride, preferably tetrahydrofuran, simple diethyl ether, dioxane or water.

As grounds customary inorganic bases. These include, first of all, the hydroxides of alkaline or alkaline earth metals, such as, for example, the hydroxides of lithium, sodium, potassium or barium, or carbonates of alkali or alkaline earth metals, such as carbonates of sodium, potassium or calcium. Preferred are the hydroxides of lithium, sodium or potassium.

As acids for cleavage of esters, generally suitable are the sulfuric acid, hydrogen chloride/hydrochloric acid, promomadrid/bromatology acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluensulfonic acid, methanesulfonate or followed, or mixtures thereof, if necessary with added�of water. Preferred are hydrogen chloride or trifluoroacetic acid in the case of complex mpem-butyl ester and hydrochloric acid in the case of complex methyl esters.

This splitting of the ester, usually carried out at temperatures from -20°C to +100°C, preferably from 0°C to +60°C.

Intermediates of formula (II) can be obtained, for example, that complex ether carboxylic acids of the formula (V)

,

in which R5Aand R5Bhave the meanings given above,

and

T2represents alkyl with 1-4 carbon atoms or benzyl,

first deprotonated in an inert solvent using a base, then in the presence of a suitable palladium catalyst arriraw using panelbased of formula (VI)

,

in which R6and R7have the meanings given above, to produce a compound of formula (VII)

,

in which R5A, R5B, R6, R7and T2have the meanings given above,

and after that Hatshepsut ester residue T2by basic or acidic solvolysis, or if T2represents benzyl, also using the experimental data showed, to obtain the carboxylic acid (II).

The reaction of arilirovaniya at the stage of process (V)+(VI)→(VII) �predpochtitelno is carried out in toluene or mixtures of toluene/tetrahydrofuran in the temperature range from +20°C to +100°C. As the base for deprotonation of the ester (V) is preferably used bis(trimethylsilyl)amide lithium. Suitable palladiumii catalysts are, for example, palladium acetate (II) or Tris(dibenzylideneacetone)dipalladium, respectively, in combination with electron rich, spatially demanding phosphine ligands, such as 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl or 2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl [Ref. for example, W. A. Moradi and S. L. Buchwald, J. Am. Chem. Soc. 123. 7996-8002 (2001)].

Cleavage of the ester group T2at the stage of the process (VII)→(II) is carried out in the same manner as previously described for ester residue T1.

Intermediates of formula (II-A)

in which R6and R7have the meanings given above,

alternatively, can also happen as a result of an ester of phenylacetic acid of the formula (VIII)

,

in which R6, R7and T2have the meanings given above,

first use caused under the action of the base attaching 2-cyclopenten-1-she transferred to the compound of formula (IX)

,

in which R6, R7and T2have the meanings given above, then the compound of ftory�comfort with 1,1'-[(trifter-λ 4-sulfanyl)imino]bis(2-ethoxyethane) under the conditions of catalysis by boron TRIFLUORIDE to produce a compound of formula (VII-A)

,

in which R6, R7and T2have the meanings given above,

and then, in turn, Hatshepsut ester group T2with obtaining carboxylic acids (II-A).

At the stage of the process (VIII)→(IX) for deprotonation of the ester (VIII) is preferably used amide base, such as diisopropylamide lithium or bis(trimethylsilyl)amide lithium. For dioxaborinane in the conversion of (IX)→(VII-A) instead of the above 1,1'-[(trifter-λ4-sulfanyl)imino]bis(2-ethoxyethane) (deoxofluor reagent), if necessary, can also be used other known fluorinating reagents, such as TRIFLUORIDE, diethylaminoethyl (DAST) or TRIFLUORIDE, morpholinos (Morpho-DAST), [for the sequence of reactions (VIII)→(IX)→(VII-A) Ref., for example, T. Mase et al., J.Org. Chem. 66 (20), 6775-6786 (2001)].

Intermediates of formula (III) can be obtained, for example, in the result, or

[A] the ester phosphonooxy acid of formula (X)

in which R1Aand T1have the meanings given above,

and

R8represents alkyl with 1-4 carbon atoms,

in an inert solvent is subjected to conversion in the reaction of referirovanija, you�yuemei action Foundation, 3 nitrobenzoyl compound of formula (XI)

,

in which R2A, R3and R4have the meanings given above, with the formation of a compound of formula (XII)

,

in which R1A, R2A, R3, R4and T1have the meanings given above,

and this compound is then, in the presence of a suitable palladium or platinum catalyst is hydrogenated with obtaining ester 3-(3-Dapsone base)propionic acid of formula (III-A)

in which R1A, R2B, R3, R4and T1have the meanings given above,

or

[In] an ester of acrylic acid of formula (XIII)

,

in which R1A, R2A, R2Band T1have the meanings given above, in inert solvent is subjected to interaction in either conditions (i) catalysis by rhodium(1) with phenylboronic acid of formula (XIV)

,

in which R3and R4have the meanings given above,

PG as inert protective group on the amine is benzyl or p-methoxybenzyl,

or in the conditions (ii) catalysis by copper (I) with phenylmagnesium reagent of formula (XV)

,

in which R3/sup> , R4and PG have the meanings given above,

and

Hal1represents chlorine or bromine,

to produce a compound of formula (XVI)

,

in which R1A, R2A, R2B, R3, R4, PG and T1have the meanings given above,

and then remove the protective group on the amine PG in accordance with conventional methods by experimental data showed or oxidation process to produce ester 3-(3-Dapsone base)propionic acid of formula (III-B)

in which R1A, R2A, R2B, R3, R4and T1have the meanings given above,

or

[With] an ester of acrylic acid of formula (XVII)

,

in which R1A, R2Aand T1have the meanings given above,

in an inert solvent under conditions of palladium catalysis is introduced into the reaction combination with 3-amino - or 3-nitrophenylamino of formula (XVIII)

,

in which R3and R4have the meanings given above,

and

R9is amino or nitro group,

to produce a compound of formula (XIX)

,

in which R1A, R2A, R3, R4, R9and T1have the meanings given above,

and this compound in the presence of the appropriate palladi�vågå or platinum catalyst is hydrogenated with obtaining ester 3-(3-Dapsone base)propionic acid of formula (III-C)

in which R1A, R2A, R3, R4and T1have the meanings given above,

or

[D] the ester of formula (XX)

,

in which R1A, R1Band T1have the meanings given above,

in an inert solvent and after-deprotonation alkylate 3-bromobenzylamine of formula (XXI)

,

in which R3and R4have the meanings given above,

and

Hal2represents a chlorine, bromine or iodine,

to produce a compound of formula (XXII)

,

in which R1A, R1B, R3, R4and T1have the meanings given above,

then enter into interaction with benzylamine in the presence of base and palladium catalyst to produce a compound of formula (XXIII)

,

in which R1A, R1B, R3, R4and T1have the meanings given above,

and then N-benzyl group is removed by obtaining experimental data showed ester 3-(3-Dapsone base)propionic acid of formula (III-D)

in which R1A, R1B, R3, R4and T1have the meanings given above.

For deprotonation of complex phosphonic ester (X) in the reaction Oleinikova�I (X)+(XI)→(XII) are particularly suitable dinucleophiles strong bases, such as, for example, sodium hydride or potassium bis(trimethylsilyl)amide lithium, sodium or potassium or diisopropylamide lithium; preferably used sodium hydride.

The hydrogenation stage of the process (XII)→(III-A) or (XIX)→(III-C), usually carried out in an atmosphere of hydrogen at constant normal pressure. At the same time as the catalyst is preferably used palladium on activated carbon as the carrier material). The removal of protective group (or groups) to amine in the transformations (XVI)→(III-b) and (XXIII)→(III-D) is usually carried out by experimental data showed in a similar way, if PG (XVI) is p-methoxybenzyl, alternatively it can also occur by oxidation, e.g. with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or cerium (IV) ammoniumnitrate.

As the palladium catalyst for interaction (XVII)+(XVIII)→(XIX) [reaction Hyuk] preferably used palladium acetate(II) in combination with a phosphine ligand, such as, for example, triphenyl - or three-2-tolylphosphino [for the reaction (XIII)+(XIV)→(XVI) Ref., for example, N. Miyaura et al., Organometallics 16, 4229 (1997), and T. Hayashi, Synlett, Special Issue 2001, 879-887; for interaction (XIII)+(XV)→(XVI) Ref., for example, R. Knochel et al., Tetrahedron 56, 2727-2731 (2000), Angew. Chem. 120. 6907-6911 (2008)].

For α-deprotonation of the ester (XX) in the reaction of alquileres�of (XX)+(XXI)→(XXII) likewise particularly suitable are dinucleophiles strong bases, such as, for example, sodium hydride or potassium bis(trimethylsilyl)amide lithium, sodium or potassium or diisopropylamide lithium; preferably this is done with diisopropylamide lithium.

For the reaction of (XXII)+benzylamine→(XXIII) [combination of Buchwald-Hartwig] as the palladium catalyst is preferably used Tris(dibenzylideneacetone)dipalladium (0) in combination with (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphtyl as the phosphine ligand and tert-butylation sodium or potassium as the base [Ref., for example, J. P. WoIfe und S. L. Buchwald, Organic Syntheses, Coll. Vol.10, 423 (2004), Vol.78, 23 (2002)].

Described above stages of the process may be carried out at normal, elevated or at reduced pressure (e.g. from 0.5 to 5 bar); as a rule, in each case, working under normal pressure.

Separation of the compounds according to the invention on the corresponding enantiomers and/or diastereomers, if necessary, depending on expediency, may also be carried out at the stage of the compounds (II), (III), (IV), (VII), (XVI), (XXII) or (XXIII), which are then respectively subjected to transformations in the previously described sequence of processes in isolated form. This separation of stereoisomers can be carried out according to conventional, well-known specialist methods. Preferably used chromatographic SP�events on achiral or chiral separating the phases; in the case of carboxylic acids as intermediate or final products as an alternative can also be split using diastereomeric salt.

Compounds of formulas (V), (VI), (VIII), (X), (XI), (XIII), (XIV), (XV), (XVII), (XVIII), (XX) and (XXI) are either commercially available or described as such in the literature, or they can be obtained by analogy with the methods published in the literature, in ways apparent to those skilled. Many detailed techniques, as well as literature data to obtain the original substances are also found in the experimental part in the section relating to the receipt of parent compounds and intermediates.

Obtaining the compounds according to the invention as examples can be graphically represented using the following reactions schemes:

Scheme 1

Scheme 2

Figure 3

Scheme 4

Scheme 5

[PMB = p-methoxybenzyl; A=CH2or O; R=methyl or benzyl].

Scheme 6

[Bn = benzyl].

Scheme 7

Scheme 8

Scheme 9

Compounds according to the invention possess valuable pharmacologist�ical properties and can be used for the prevention and treatment of diseases in humans and animals.

Compounds according to the invention are potent activators of soluble guanylyl cyclases. They lead to relaxation of blood vessels, inhibition of platelet aggregation and to lower blood pressure and increase coronary blood flow. These effects contributes directly genetalia activation of soluble guanylyl cyclases and the increase in intracellular cyclic guanozinmonofosfata (cGMP).

In addition, the compounds according to the invention have good pharmacokinetic characteristics, especially in relation to their bioavailability and half-life in the body.

Thus, the compounds according to the invention can be used in medicinal products for the treatment and/or prophylaxis of cardiovascular diseases, such as, for example, high blood pressure (hypertension) and heart failure, stable and unstable angina, pulmonary arterial hypertension (LAS) and other forms of pulmonary hypertension (PH), renal hypertension, peripheral and cardiac vascular and arrhythmias, for the treatment of thromboembolic diseases and ischemia such as myocardial infarction, stroke, transistor and ischemic attacks, disturbances of peripheral circulation, prevention of restenoses, such as �donkey thrombolytic therapy, percutaneous transluminal angioplasty (!), percutaneous transluminal coronary angioplasty (PTCA) and bypass, for the treatment of arteriosclerosis, to stimulate the healing of wounds, and for treating osteoporosis, glaucoma and gastroparesis.

According to the present invention, the term heart failure includes both acute and chronic manifestations of heart failure, as well as specific or related nosological forms of this, such as acute decompensated heart failure, failure of right heart failure left heart, global heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart disease, valvular disease, congestive heart failure and heart valve disease, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, insufficiency of the aortic valve, tricuspid stenosis, tricuspid regurgitation, valve stenosis pulmonary artery valve insufficiency pulmonary artery, combined valvular heart disease, inflammation of the heart muscle (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, cardiac �nedostatocnosti, caused by diabetes, toxic, alcoholic cardiomyopathy, cardiac storage diseases, and systolic and diastolic heart failure.

In addition, the compounds according to the invention can be used for the treatment and/or prophylaxis of primary and secondary Raynaud's phenomenon, of microcirculation disorders, intermittent claudication, tinnitus, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic retinopathy, diabetic ulcers on the extremities, CREST syndrome, erythematosis, onychomycosis and rheumatic diseases.

Compounds according to the invention, in addition, is easily applied to prevent ischemic and/or reperfusion damage of organs or tissues, as well as added substances for perfusion or preservative solutions for organs, parts of organs, tissues or tissue parts of human or animal origin, especially during surgical procedures or in medical transplants.

In addition, the compounds according to the invention are suitable for treatment and/or prevention of diseases of the kidneys, especially in kidney failure and kidney failure. According to the present invention the concept of renal failure and kidney failure includes both acute and chronic forms of their manifestation, �well as underlying or related to these diseases of the kidneys, such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, the nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney transplant rejection, kidney disease caused by immune complex nephropathy induced by toxic substances nephropathy induced radiopaque substance, diabetic and nediabeticescoy nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, in which the diagnosis may be characterized by, for example, through an abnormally low excretion of creatinine and/or water, an abnormally elevated concentrations in the blood, urea, nitrogen, potassium and/or creatinine, altered activity of renal enzymes, such as, for example, glutamylcysteine, altered osmotic concentration of urine or the amount of urine, increased microalbuminuria, macroalbuminuria, the damage the glomeruli and arterioles, tubular dilatation, hyperphosphatemia and/or the need for dialysis. The present invention also includes the use of compounds according to the invention for the treatment and/or profile�Chiki secondary manifestations of renal failure, such as, for example, hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (e.g. hyperkalemia, hyponatremia) and disturbances in bone metabolism and carbohydrates.

In addition, the compounds according to the invention are suitable for treatment and/or prevention of diseases of the urogenital system such as, for example, overactive bladder, urinary incontinence, symptoms from the lower urinary tract (LUTS), incontinence, benign prostatic hyperplasia (BPH), erectile dysfunction and female sexual dysfunction.

In addition, the compounds according to the invention can be used for the treatment of asthmatic diseases, chronic obstructive pulmonary disease (COPD) and respiratory distress syndrome.

Compounds described in this invention are also active compounds for treating diseases in the Central nervous system that are characterized by dysfunctional system of NO/cGMP. They are especially suitable for improving perception, concentration, learning ability or memory after cognitive impairments like those that are found, in particular, in circumstances/diseases/syndromes such as "mild cognitive impairment", age-related delay proce�sa learning and memory impairment associated with age, memory loss, vascular dementia, craniocerebral trauma, brain hemorrhage, dementia, which occurs after strokes ("post-stroke dementia"), post-traumatic craniocerebral trauma, General difficulty in concentrating, difficulty in concentrating in children with problems of learning and memory, Alzheimer's disease, the disease is diffuse Taurus Levi, dementia with degeneration of the frontal lobes of the brain, including the syndrome of the Peak, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (als), Huntington's disease, multiple sclerosis, thalamic degeneration, a disease of Creutzfeld-Jakob disease, dementia caused by HIV, schizophrenia with dementia or psychosis Korsakov. They are also suitable for treating diseases of the Central nervous system, such as anxious, tense and depressive States, sexual dysfunctions and sleep disturbances caused by the condition of the Central nervous system, and for regulating pathological eating disorders, stimulants and narcotics.

In addition, the compounds according to the invention are also suitable for the regulation of the cerebral circulation and are an effective means to combat the migration�guys. They are also suitable for the prevention and combating the effects of cases of cerebral infarctions (heart beats), such as cerebral hemorrhage, cerebral ischemia and traumatic brain injury. Also the compounds according to the invention can be used to suppress pain conditions.

Along with this, the compounds according to the invention have anti-inflammatory effects and, thus, can be used as anti-inflammatory agents for the treatment and/or prevention of sepsis, multiple organ damage, inflammatory kidney disease, chronic intestinal inflammations, such as ulcerative colitis (Colitis ulcerosa and Crohn's disease (Morbus Crohn's disease), pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory eye diseases.

Due to its profile of action of the compounds according to the invention are particularly suitable for the treatment and/or prophylaxis of cardiovascular diseases such as heart failure, angina, hypertension, pulmonary hypertension, ischemia, vascular disease, disorders of microcirculation, thromboembolic disease and arteriosclerosis.

Another object of this invention is the use of compounds according to the invention for the treatment and/or prophylaxis of diseases, especially for�of olivani, the above.

Another object of this invention is the use of compounds according to the invention for the manufacture of a medicament for the treatment and/or prophylaxis of diseases, especially the diseases mentioned above.

Another object of this invention is the use of compounds according to the invention a method for the treatment and/or prophylaxis of diseases, especially the diseases mentioned above.

Another object of this invention is a method for the treatment and/or prophylaxis of diseases, especially the diseases mentioned above, with the use of an effective amount of at least one of the compounds according to the invention.

Compounds according to the invention can be used alone or if necessary in combination with other active substances. Another object of the present invention are medicinal products that contain at least one compound according to the invention and one or more other active substances, particularly for the treatment and/or prophylaxis of the abovementioned diseases. As suitable combinations of active substances as approximate and should be preferred:

- organic nitrates and NO donors such as, for example, sodium nitroprusside, nitroglycerin, isosorbide Mononitrate, isosorbide dinitrate, molsidomin� or SIN-1, and inhaled NO;

- compounds which inhibit the decomposition of cyclic guanozinmonofosfata (cGMP), such as, for example, inhibitors of phosphodiesterase (PDE) 1, 2 and/or 5, especially PDE inhibitors 5, such as sildenafil, vardenafil and tadalafil;

- NO-independent, but wasawesome guanylyl cyclases stimulators, such as compounds described in particular in international applications WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

- funds with antithrombotic action, for example and preferably from the group of suppressing platelet aggregation, anticoagulants or profibrinolytic substances;

- active substances, lowering blood pressure, for example and preferably from the group of calcium antagonists, antagonists of an angiotensin, angiotensin converting enzyme inhibitors (ACE), endothelin antagonists, renin inhibitors, alpha blockers-receptors, beta-receptor blockers, mineralocorticoid antagonists of the receptors, and of diuretics; and/or

active substances that modify lipid metabolism, for example and preferably from the group of agonists of receptors of thyroid hormones, inhibitors of cholesterol synthesis, such as cited as exemplary and preferred inhibitors of HMG-CoA reductase inhibitors, or of the synthesis of squalene, ACAT inhibitors, inhibitors of protein transfer holsteinborg� ether (SETR), inhibitors of microsomal protein that transports triglycerides (ICTR), agonists alpha-receptor proliferator-activated the peroxisome (RAPP), gamma-RAPP - and/or Delta-RAPP, means of suppressing the absorption of cholesterol, lipase inhibitors, polymeric bile acid adsorber, means of suppressing the reabsorption of bile acids and antagonist of lipoprotein (a).

Under tools, with antithrombotic action, preferably understand compounds from the group of suppressing platelet aggregation, anticoagulants or profibrinolytic substances.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an agent which inhibits platelet aggregation, which may be cited as an exemplary and preferred, aspirin, clopidogrel, ticlopidine or dipyridamole.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an inhibitor of thrombin, which may be cited as an exemplary and preferred, ximelagatran, melagatran, bivalirudin or Clexane.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an antagonist of GPIIb/IIIa, such as, cited as exemplary and preferred�found, tirofiban or abtsiksimab.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an inhibitor of factor Xa, such as given as an illustrative and preferred, rivaroxaban, apixaban, fidecaro, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with heparin or a derivative of low molecular weight heparin (LMWH).

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an antagonist of vitamin K, such as cited as exemplary and preferred coumarin.

Under tools, lower blood pressure and preferably understand compounds from the group of calcium antagonists, antagonists of an angiotensin, angiotensin converting enzyme inhibitors (ACE), endothelin antagonists, renin inhibitors, blockers alpha-receptor blockers, beta-receptor antagonists mineralocorticoid receptor, as well as diuretics.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with a calcium antagonist, t�as Kim cited as exemplary and preferred nifedipine, amlodipine, verapamil or diltiazem.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with a blocker of alpha-1-receptors, such as given as an illustrative and preferred, prazosin.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with a blocker of beta-receptors, such as given as an illustrative and preferred, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, daprela, landiolol, nebivolol, Espanola or bucindolol.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an antagonist of angiotensin aan, such as given as an illustrative and preferred, losartan, candesartan, valsartan, telmisartan or amberstar.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an inhibitor of angiotensin converting enzyme (ACE), such as given as an illustrative and preferred enalapril, �captopril, lisinopril, ramipril, delapril, fosinopril, quinapril, perindopril or trancopal.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an endothelin antagonist, such as cited as exemplary and preferred bosentan, darusentan, ambrisentan or sitaxsentan.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with a renin inhibitor, such as cited as exemplary and preferred aliskiren, SPP-600 or SPP-800.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an antagonist of the mineral corticoid receptors, such as cited as exemplary and preferred spironolactone or eplerenone.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with a diuretic, such as cited as exemplary and preferred furosemide.

Under the means of changing fat metabolism, preferably understand compounds from the group of inhibitors of protein transfer of cholesterol ester (SETR), receptor agonists, thyroid hormones, inhibitors of cholesterol synthesis, such as inhibitors gidroximetil�glutaryl-coenzyme A reductase (HMG-CoA) or the synthesis of squalene, the ACAT inhibitors, inhibitors of microsomal protein that transports triglycerides (ICTR), agonists of alpha, gamma and/or Delta-RAPP-receptors, of suppressing the absorption of cholesterol, polymeric bile acid adsorbers, of suppressing the reabsorption of bile acids, lipase inhibitors and antagonists of lipoprotein (a).

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an inhibitor of protein transfer of cholesterol ester (SYR), such as given as an illustrative and preferred torcetrapib (CP-529 414), JJT-705 or CETP vaccine-vaccine (Avant).

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an agonist of receptors of thyroid hormones, such as cited as exemplary and preferred D-thyroxine, 3,5,3'-triiodothyronin (T3), CGS 23425 or axiotron (CGS 26214).

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an inhibitor hydroxymethylglutaryl coenzyme a reductase (HMG-CoA) from the class of statins, such as cited as exemplary and preferred lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

In the case of one prefer�the diesel form of execution of the invention compounds according to the invention is administered in combination with an inhibitor of the synthesis of squalene, like cited as exemplary and preferred BMS-188494 or TAK-475.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an ACAT inhibitor, such as cited as exemplary and preferred avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an inhibitor of microsomal protein that transports triglycerides (ICTR), as cited as an exemplary and preferred implitapide, BMS-201038, R-103757 or JTT-130.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an agonist of gamma receptor proliferator-activated the peroxisome (RAPP), as cited as an exemplary and preferred pioglitazone or rosiglitazone.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an agonist of the Delta-RAPP, such as cited as exemplary and preferred GW 501516 or BAY 68-5042.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an agent which inhibits the absorption of cholesterol, such as �revtime as exemplary and preferred ezetimibe, tiqueside or pemaquid.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with a lipase inhibitor, such as cited as exemplary and preferred orlistat.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with a polymeric bile acid adsorber, such as cited as exemplary and preferred cholestyramine, colestipol, kresolver, cholestagel or colestimide.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an agent which inhibits the reabsorption of bile acids, such as cited as exemplary and preferred inhibitors of ASBT (=1 Wat), for example, AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In the case of one preferred form of execution of the invention compounds according to the invention is administered in combination with an antagonist of lipoprotein (a), such as given as an illustrative and preferred gemcabene calcium (C1-1027) or nicotinic acid.

Another object of the present invention are medicaments which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, no�bubbled, pharmaceutically suitable auxiliaries, and their use for the purposes specified above.

Compounds according to the invention can act systemically or topically. For this purpose they may be applied a suitable manner, such as, for example, orally, parenterally, pulmonale, nasal, sublingual, lingual, buccal, rectal, skin, transdermal, conjunctival, inside the ear or in the form of implants or stents, respectively.

For these applications the compounds according to the invention can be produced in suitable applications.

For oral administration according to the issues of the prior art are suitable existing applications that produce compounds according to the invention rapidly and/or vidoesseanna that contain these compounds according to the invention in crystalline and/or amorphized and/or dissolved form, such as, for example, tablets (uncoated or coated, for example, membranes, resistant to gastric juice or dissolve with a delay or are insoluble and which control the release of compounds according to the invention), tablets quickly disintegrating in the oral cavity, or film coating/wafers, film coating/lyophilization, capsules (e.g. hard or soft gelatin capsules), dragees, Gras�meaty, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral use may occur bypassing the stage of resorption (for example, intravenously, intra-arterially, vnutriarterialno, vnutripolostno or endolyumbalno) or with the inclusion of resorption (for example, intramuscularly, subcutaneously, intradermally, through the skin or into the peritoneum). For parenteral use as a form of application, among others, are suitable formulations for injection and intravenous injection in the form of solutions, suspensions, emulsions, or sterile freeze-dried powders.

For other methods of application are suitable, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, aerosols, drops, solutions or sprays for the nose, tablets, intended for the use of lingual, sublingual or buccal, films/wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, magmas), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, powders, implants or stents.

Preferred are oral and parenteral use, especially oral and intravenous use.

Compounds according to the invention may be converted into these forms of application. It can� be made by known methods by mixing with inert, non-toxic, pharmaceutically suitable excipients. These auxiliary substances is referred, inter alia, substances-carriers, for example, microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting means (for example, sodium dodecyl sulfate, polychiorinated), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colorants (e.g. inorganic pigments, such as, for example, iron oxide) and modifiers of taste and smell.

As a rule, were preferred for parenteral administration to achieve effective results, enter the amount from about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight. After oral administration the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and most preferably 0.1 to 10 mg/kg of body weight.

Despite this, if necessary, it may be necessary to deviate from these quantities, namely depending on body weight, method of application, individual tolerance to the active substance, type of the finished prepar�and the time or period respectively, in which it is applied. So, in some cases it may be sufficient to manage with less than the above minimum amount, while in other cases provided upper bounds to be exceeded. In the case of larger quantities may be recommended to distribute these quantities into several doses throughout the day.

The following examples explain in more detail the invention. The invention is not limited to these examples.

Percentages in the following tests and examples, unless otherwise indicated, represent mass percentages; parts are mass parts. The ratio of the solvents, the ratio of diluents and concentrations of solutions of liquid/liquid, respectively, relate to the volume.

A. Examples abbreviations and acronyms:

abs.absolute
ACacetyl
AEBN2,2'-azobis(2-methylpropionitrile)
water.water, aqueous solution
ATPadenosine-5'-triphosphate
Bnbenzyl
Brij®simple dodecyl ether of polyethylene glycol
BSAbovine serum albumin
approx.example
Bubutyl
cconcentration
approx.about, approximately
cat.catalytic

CIchemical ionization (in the case of MS)
dday (s)
DASTTRIFLUORIDE, diethylaminoethyl
thosethin-layer chromatography
DCIdirect chemical ionization (in the case of MS)
DDQ2,3-dichloro-5,6-dicyano-1,4-benzoquinone
dediastereomeric excess
ENTERdiisobutylaluminium
DMFAdimethylformamide
DMSOdimethyl sulfoxide
theory.theoretical (if)
RTIdithiotreitol
EDKhydrochloride N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide
enantiomeric excess
Elionization by electron impact (in the case of MS)
entenantiomerically pure enantiomer
EQ.equivalent (equivalents)
ESIionization electrospray (in the case of MS)
Etethyl
GCgas chromatography
us.saturated
GTP guanosine-5'-triphosphate
hhour (time)
GATAhexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea
HOBtthe hydrate of 1-hydroxy-1H-benzotriazole
HPLChigh performance liquid chromatography

iPrisopropyl
conc.concentrated
LC-MSliquid chromatography in conjunction with mass spectrometry
LDAsitedisability
LiHMDShexamethyldisilazide lithium [bis(trimethylsilyl)lithium amide]
Memethyl
minmin (minute)
MSmass spectrometry
NBSN-bromosuccinimide
NMRthe nuclear magnetic resonance spectroscopy
npara-
Pd/Cpalladium on charcoal
Phphenyl
MBPp-methoxybenzyl
Prpropyl
rat.racemic, racemate
Rfthe retention index (in the case of TLC)
PFreversed phase (in HPLC)
Tbrroom temperature
Rtretention time (in HPLC)
see abovesee above
Buttert-butyl
Theatriethanolamine
TPAtrifluoroacetic acid
T�f tetrahydrofuran
UVultraviolet spectroscopy

about/aboutthe ratio of volume to volume (solution)
collab.together, combined

GC-MS and LC-MS:

Method 1 (GC-MS):

Instrument: Micromass GCT, GC 6890; column: Restek RTX-35, 15 m×200 μm×0,33 mm; DC current of helium: 0,88 ml/min; heating chamber: 70°C; evaporator: 250°C; gradient: 70°C, 30°C/min→310°C (3 min exposure).

Method 2 (LC-MS):

Device type MS: Micromass ZQ; instrument type HPLC: HP 1100 Series; UV DAD; column: Phenomenex Gemini 3 µm 30 mm×3.00 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% A → a 2.5 min 30% A → a 3.0 min 5% A → 4.5 min 5% A; flow rate: 0,0 min 1 ml/min → 2.5 minutes/a 3.0 min/4.5 min 2 ml/min; heating chamber: 50°C; UV detection: 210 nm.

Method 3 (LC-MS):

Device type MS: Micromass ZQ; instrument type HPLC: Waters Alliance 2795; column: Phenomenex Synergi 2.5 µm MAX-RP 100A Mercury 20 mm×4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% A → a 0.1 min 90% A → a 3.0 min 5% A → a 4.0 min 5% A → 4,01 min 90% And the flow rate of the liquid: 2 ml/min; heating chamber: 50°C; UV detection: 210 nm.

Method 4 (LC-MS):

Instrument: Micromass Quattro Premier, equipped with a Waters UPLC Acquity; column: Thermo Hypersil GOLD of 1.9 µm, 50 mm×1 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% A → a 0.1 min 90% A → 1.5 min 10% A → a 2.2 min 10% A; flow rate: 0.33 ml/min; heating chamber: 50°C; UV detection: 210 nm.

Method 5 (LC-MS):

Device type MS: Waters Micromass Quattro Micro; instrument type HPLC: Agilent 1100 series; column: Thermo Hypersil GOLD 3 µm, 20 mm×4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 100% A → a 3.0 min 10% A → a 4.0 min 10% A → 4,01 min 100% A (flow rate 2.5 ml/min) → The 5.00 min 100% A; heating chamber: 50°C; flow rate: 2 ml/min; UV detection: 210 nm.

Method 6 (LC-MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 μm, 50 mm×1 mm; eluent A: 1 l of water + 0.25 ml 99% formic acid, eluent B: 1 l of acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 to min 90% A → a 1.2 min 5% A → a 2.0 min 5% A; flow rate: 0,40 ml/min; heating chamber: 50°C; UV detection: 210-400 nm.

Method 7 (LC-MS):

Device type MS: Waters ZQ; instrument type HPLC: Agilent 1100 Series; UV DAD; column: Thermo Hypersil GOLD 3 µm, 20 mm×4 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile+ 0.5 ml 50% formic acid; gradient range: 0.0 min 100% A → a 3.0 min 10% A → a 4.0 min 10% A → a 4.1 min 100% A (flow rate 2.5 ml/min); heating chamber: 55°C; flow rate: 2 ml/min; UV detection: 210 nm.

Method 8 (GC-MS):

Instrument: Micromass GCT, GC 6890; column: Restek RTX-35, 15 m ×200 μm×0,33 mm; DC current of helium: 0,88 ml/min; heating chamber: 70°C; evaporator: 250°C; gradient: 70°C, 30°C/min → 310°C (12 min excerpt).

Method 9 (LC-MS):

Instrument: Micromass Quattro Premier, equipped with a Waters UPLC Acquity; column: Thermo Hypersil GOLD of 1.9 µm, 50 mm×1 mm; eluent A: 1 l water + 0.5 ml 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml 50% formic acid; gradient: 0.0 to min 90% A → 0,3 min 90% A → a 3.0 min 10% A → 4,8 min 10% A; flow rate: 0.33 ml/min; heating chamber: 50°C; UV detection: 210 nm.

Method 10 (GC-MS):

Device: Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m×200 μm×0,33 mm; DC current helium: 1,20 ml/min; heating chamber: 60°C; evaporator: 220°C; gradient: 60°C, 30°C/min → 300°C (3,33 min exposure).

Starting compounds and intermediates:

Example 1A

Tert-butyl-3-(3-amino-2-methylphenyl)propanoate

In an argon atmosphere was pinned 201 ml (1,39 mol) of tert-boolprop-2-enoate to a solution of 100 g (463 mmol) of 1-bromo-2-methyl-3-nitrobenzene, 322 ml (2,31 mol) of triethylamine, 28,18 g (92,58 mmol) tri-2-tolylphosphino and 10,39 g (46,29 mmol) of palladium acetate(II) in 2 liters of DMF, and the mixture then was stirred 36 CPRI 125°C. After cooling to room temperature, this reaction mixture was stirred with a saturated aqueous solution of ammonium chloride and the organic phase separated. The aqueous phase three times were extracted with tert-butylmethylamine ether, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration the solvent was removed in vacuum to dryness. The obtained residue was purified using flash chromatography on silica gel (solvent petroleum ether/ethyl acetate 9:1). There was obtained 89 g (338 mmol, 73% of Theor.) the intermediate product tert-butyl(2E)-3-(2-methyl-3-nitrophenyl)prop-2-enoate in the form of a colorless solid substance. 88 g (334 mmol) of this solid was dissolved in 2 liters of ethanol at room temperature was mixed with 7 g of palladium on coal (10%) and gidrirovanie 18 h under normal pressure. Upon reaching complete conversion the reaction solution was filtered through kieselguhr, and the filtrate obtained was evaporated in a vacuum. Received 61,3 g (of 260.5 mmol, 78% of Theor.) target compound in the form of a colorless solid substance.

LC-MS (Method 2): Rt=A 1.84 min; m/z=236 (M+H)+.

1H-NMR (400 MHz, DMSO-d6d /M. D.): was 6.77 (1H, t), 6,47 (1H, d), 6,36 (1H, d), 4.72 in (2H, s), 2,14 (2H, t), a 2.36 (2H, t), of 1.95 (3H, s), of 1.39 (9H, s).

Example 2A

Ethyl-3-(3-amino-2-methylphenyl)propanoate

In a�the atmosphere of argon was pinned 10,844 g (108 mmol) itelpop-2-enoate to a solution of 7.8 g (36,1 mmol) 1-bromo-2-methyl-3-nitrobenzene, 20 ml (180,5 mmol) of triethylamine, 2,197 g (7,22 mmol) tri-2-tolylphosphino and 810 mg (3.6 mmol) of palladium acetate(II) in 200 ml of DMF, and the mixture then was stirred for 36 h at 125°C. After cooling to room temperature, this reaction mixture was stirred with a saturated aqueous solution of ammonium chloride and the organic phase separated. The aqueous phase three times were extracted with tert-butylmethylamine ether, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration the solvent was removed in vacuum to dryness. The obtained residue was purified using flash chromatography on silica gel (solvent petroleum ether/ethyl acetate 3:1). There was obtained 6.6 g (of $ 27.2 mmol, content 97%, 75% of Theor.) the intermediate product ethyl-(2E)-3-(2-methyl-3-nitrophenyl)prop-2-enoate in the form of a colorless solid substance. 6.6 g (of $ 27.2 mmol, content 97%) of this solid was dissolved in 200 ml of ethanol at room temperature was mixed with 500 mg of palladium on coal (10%) and during the night was gidrirovanie under normal pressure. Upon reaching complete conversion the reaction solution was filtered through kieselguhr, and the filtrate obtained was evaporated in a vacuum. Received 5,47 g (26,38 mmol, content 97%, 97% of Theor.) target compound in the form of a colorless solid substance.

LC-MS (Method 3): Rt=1,07 min; m/z=208 (M+H)+.

Example 3A

Tert-butyl(2E)-3-(4-fluoro-3-nitrophenyl)acrylate;

In an argon atmosphere of 0.65 g (16.3 mmol) of sodium hydride (60% suspension in mineral oil) was placed in 25 ml THF and cooled to 0°C. then slowly pinned 4,29 g (17 mmol) of a compound tert-butyl ether diethylphosphonoacetate acid. After 30 min was added 2.5 g (14.8 mmol) of 4-fluoro-3-nitrobenzaldehyde. The reaction mixture was stirred 3 h at Damn., then poured in 100 ml of water and three times were extracted with respectively 100 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (silica gel, solvent cyclohexane/ethyl acetate 50:1). Received 3.37 g (85% of theory.) target connection.

GC-MS (Method 1): Rt=6,45 min; m/z=211 (MtBu)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,49 (C, 9H), 6,69 (d, 1H), members, 7.59-7,76 (m, 2H), to 8.19 (DDD, 1H), and 8.50 (DD, 1H).

Example 4A

Complex tert-butyl ether 3-(3-amino-4-fluorophenyl)propane acid

535 mg (2.00 mmol) of complex mpem-butyl ether (2E)-3-(4-fluoro-3-nitrophenyl)prop-2-envoy acid was dissolved in 1 ml of ethanol and 1 ml of THF and mixed with 21.3 mg of palladium on coal (10%). When Damn. during the night was gidrirovanie in the hydrogen atmosphere at normal pressure. Then this reaction mixture was Phil�trevali with suction through kieselguhr, the residue was further washed with THF, and the filtrate was concentrated. Received 479 mg (100% of theory.) target connection.

LC-MS (Method 6): Rt=To 1.06 min; m/z=184 (M-C6H8)+.

1H-NMR (400 MHz, DMSO-d6): δ=at 6.84 (DD, 1H), to 6.58 (DD, 1H), 6,36-6,29 (m, 1H), 5,00 (s, 2H), 2,64 (t, 2H), 2,42 (t, 2H), of 1.36 (s, 9H).

Example 5A

tert-butyl(2E)-3-(4-chloro-3-nitrophenyl)prop-2-ENOAT

In an argon atmosphere 1.19 g (29,64 mmol, 60%) sodium hydride was suspended in 25 ml toluene and 25 ml of THF and cooled to 0°C. then slowly pinned to 7.28 ml (30,99 mmol) of tert-butyl(diethoxyphosphoryl)acetate and the mixture was stirred 30 min at 0°C. Then to the reaction mixture were added 5 g (26,94 mmol) 4-chloro-3-nitrobenzaldehyde and uploaded the reaction mixture was warmed to room temperature. This mixture was stirred for 2 h at room temperature and then was added 50 ml of water. After separating the organic phase the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration the solvent was removed in vacuum. The crude product was purified by chromatography on silica gel (solvent cyclohexane/ethyl acetate 9:1). Received was 6.77 g (of 23.86 mmol, 77% of Theor.) target connection.

MS (DCI): m/z=301 (M+NH4)+.

1H-NMR (400 MHz, DMSO-d6): δ=is 8.46 (d, 1H), 8,07 (DD, 1H), 771 (d, 1H), 7,51 (d, 1H), 6.75 in (d,1H), 1,49 (C, 9H).

Example 6A

Tert-butyl-3-(3-amino-4-chlorophenyl)propanoate

To a solution of 6,74 g (23,76 mmol) of tert-butyl(2E)-3-(4-chloro-3-nitrophenyl)prop-2-enoate in 200 ml of ethanol and 20 ml of THF at room temperature was added 500 mg of palladium on coal (10%) and 12 h were gidrirovanie under normal pressure. After a full course of the reaction (TLC control; eluent: cyclohexane/ethyl acetate 1:1) the reaction mixture was filtered through kieselguhr, and the filtrate was concentrated in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1→2:1). Was obtained 1.40 g (5,47 mmol, 23% of Theor.) target connection.

LC-MS (Method 6): Rt=1,14 min; m/z=256 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ=was 7.08 (d, 1H), 6,62 (s, 1H), 6,39 (DD, 1H), 5,22 (s, 2H), 2,66 (m, 2H), of 2.45 (t, 2H), of 1.37 (s, 9H).

Example 7A

Methyl-3-(3-amino-4-chlorophenyl)propanoate

To a solution of 1.0 g (of 3.91 mmol) tert-butyl-3-(3-amino-4-chlorophenyl)propanoate in 20 ml of methanol at boiling with reflux pinned 0,86 ml (11.7 mmol) of thionylchloride. The mixture was stirred for 1.5 h at reflux, and then after cooling was diluted with dichloromethane. This solution was poured into water, and after phase separation the organic phase was washed with saturated sodium bicarbonate solution and the saturation�aqueous solution of sodium chloride, dried over sodium sulfate and evaporated in vacuum. The residue was dried in high vacuum. Received 745 mg (90,3% of Theor.) target connection.

LC-MS (Method 6): Rt=0,91 min; m/z=213/215 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=2,52-2,60 (m, 2H), 2,62-2,77 (m, 2H), 5,22 (s, 2H), 6,39 (DD, 1H), 6,62 (d, 1H), 7,06 (d, 1H).

Example 8A

Methyl-{1-[3-(dibenzylamino)-4-fluorophenyl]cyclopropyl}acetate

Obtaining solution A: 688 mg (16,2 mmol) of lithium chloride in an argon atmosphere was dissolved in 50 ml of THF, and then mixed with 789 mg (32.5 mmol) of magnesium shavings and 23 μl (is 0.023 mmol) of a 1 M solution of Diisobutyl-minigrid in THF. The reaction solution was stirred 10 min at room temperature, and then cooled to -10°C. Then was added 5 g (13.5 mmol) of N,N-dibenzyl-5-bromo-2-foronline (registration number CAS 869529-97-5) and the solution was further stirred for approx. 1 h at -10°C.

Obtaining the solution In: 110 mg (2.6 mmol) of lithium chloride and 128 mg (1.3 mmol) of copper chloride(1) in an argon atmosphere at room temperature was suspended in 10 ml of THF, and then mixed with 1.65 ml (12,98 mmol) of chloro(trimethyl)silane and 1,46 g (12,98 mmol) methylcarbanilate (registration number CAS 110793-87-8). This solution is then stirred for another 1 h at Tbr.

The above solution And cooled to -40°C. Then slowly pinned a solution B. join�best now the solutions were slowly heated to -20°C and further stirred 1 h at this temperature. Then to the reaction mixture were added 50 ml of chilled on ice, half-saturation solution of ammonium chloride. After phase separation, the aqueous phase was extracted three more times with ethyl acetate, the combined organic phases were dried over magnesium sulfate and evaporated to dryness. The obtained crude product was purified chromatographically on silica gel (eluent: cyclohexane/ethyl acetate 10:1). Was allocated 2.1 g (5.2 mmol, 39% of Theor.) target connection.

1H-NMR (400 MHz, DMSO-d6d/M. D.): of 7.33-of 7.25 (8H, m), 7,25-to 7.18 (2H, m), 7,02-6,94 (1H, m), 6,78 was 6.69 (2H, m), 4,27 (4H, s), 3.43 points (ZN, s), 2,48 (2H, s), 0,78-0,73 (2H, m), 0,63-of 0.58 (2H, m).

LC-MS (Method 5): Rt=To 2.99 min; m/z=404 (M+H)+.

Example 9A

Methyl-[1-(3-amino-4-fluorophenyl)cyclopropyl]acetate

To a solution of 2.1 g (5.2 mmol) of methyl-{1-[3-(dibenzylamino)-4-fluorophenyl]cyclopropyl}acetate in 100 ml of ethanol at room temperature was added 200 mg of palladium on coal (10%) and gidrirovanie 12 h under normal pressure. After a full course of the reaction (TLC control; eluent: cyclohexane/ethyl acetate 1:1) the reaction mixture was filtered through kieselguhr, and the filtrate was concentrated in vacuum. The crude product was purified by chromatography through silica gel (eluent: cyclohexane/ethyl acetate 10:1). Received 647 mg (2.9 mmol, 56% of Theor.) target connection.

1H-NMR (400 MHz, DMSO-d6d/M. D.): to 6.88-6,78 (1H, m), 6,70-6,62 (1H, m), 6,44-635 (1H, m), to 4.98 (2H, ush. C), 3,51 (3H, C), by 2.55 (2H, C), 0,84-0,79 (2H, m), 0,78-0,73 (2H, m).

GC-MS (Method 1): Rt=5,67 min; m/z=224 (M+H)+.

Example 10A

5-Bromo-2-chloro-N,N-bis(4-methoxybenzyl)aniline

In an argon atmosphere 5,07 g (126,93 mmol, 60%) sodium hydride was suspended in 150 ml of THF and cooled to 0°C. then slowly pinned 10,70 g (51,81 mmol) 5-bromo-2-hornline dissolved in 10 ml of THF, and the mixture was stirred 30 min at 0°C. Then to the reaction mixture were added 25 g (124,34 mmol) 4-methoxybenzylamine and then the reaction mass was warmed to room temperature. This mixture was stirred for 2 h at Damn., and then was slowly poured into 150 ml of ice water. After separating the organic phase the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration the solvent was removed in vacuum. The crude product was purified by chromatography [column: Kromasil Si 6012, 350 mm×30 mm; eluent A: isohexane, eluent: ethyl acetate; gradient: 0 min 98% A → a 4.65 min 98% A → 13 min 87% A → 13,01 min 98% A → 13,28 min 98% A; flow rate: 70 ml/min; temperature: 20°C; UV detection: 265 nm]. Received of 12.37 g (27,69 mmol, 57% of Theor.) target connection.

1H-NMR (400 MHz, DMSO-d6d/M. D.): value of 7, 37 (1H, d), 7,26-of 7.19 (5H, m), of 7.19-7,14 (1H, m) 6,86 (4H, d), 4,11 (4H, s), 3,71 (6H, s).

LC-MS (Method 4): Rt=To 1.68 min; m/z=446 (M)+/sup> .

Example 11A

{3-[Bis(4-methoxybenzyl)amino]-4-chlorophenyl}boric acid

In an argon atmosphere at -78°C to a solution of 5.2 g (11,64 mmol) 5-bromo-2-chloro-N,N-bis(4-methoxybenzyl)aniline in 100 ml of a mixture THF/diethyl ether (1:1) slowly pinned to 6.1 ml (15,25 mmol) of a 2.5 M solution of n-utility in hexane. After the reaction solution was further stirred for 60 min at -78°C, slowly added with 4.3 ml (18,62 mmol) triisopropylsilane. This reaction solution is then further stirred for another 15 min at -78°C, then slowly warmed to room temperature and stirred for another 3 h at this temperature. Then added 150 ml of ice water. After separating the organic phase the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration the solvent was removed in vacuum. The crude product was purified by chromatography on silica gel (eluent: first cyclohexane/ethyl acetate 10:1→9:1→4:1, then dichloro methane/methanol 95:5). Thus was obtained to 2.54 g (6,17 mmol, 53% of Theor.) target connection.

LC-MS (Method 6): Rt=1,20 min; m/z=412 (M+H)+.

Example 12A

Benzyloxy-3-evidencethat

In an argon atmosphere at 0°C was dissolved 3.0 g (41,63 mmol) oxetan-3-she (registration number CAS 6704-31-0) 50 ml of dichloromethane, and then was mixed with 18.8 g (45,79 mmol) of benzyl(triphenyl-λ5-postenligaen)acetate. Thereafter, the reaction mixture was slowly warmed to room temperature and additionally stirred for another 15 min. the Reaction solution was then evaporated to dryness. The remainder were transferred to 25 ml of diethyl ether and stirred, and the mixture was stirred for 12 h at 4°C. the Precipitated triphenylphosphine was filtered, and the filtrate was evaporated to dryness. The obtained crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethylacetate:1→1:1). There was obtained 4.2 g (20,57 mmol, 49% of Theor.) target connection.

1H-NMR (400 MHz, DMSO-d6d/M. D.): of 7.42-7,30 (5H, m), of 5.85-5,80 (1H, m), 5,39-of 5.34 (2H, m), 5,27-with 5.22 (2H, m), 5,13 (2H, s).

MS (DCI): m/z=205 (M+H)+.

Example 13A

Benzyl-(3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}oxetan-3-yl)acetate

In an argon atmosphere at room temperature to a solution of 45 mg (0,09 mmol) chloride dimer (1 g,52)-cycloocta-1,5-wienrode(1) in 25 ml of dioxane are successively added 1.6 ml (2,37 mmol) of 1.5 M aqueous solution of potassium hydroxide, 272 mg (1.82 mmol) benzyloxy-3-evidencethat and 750 mg (1.82 mmol) {3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}boric acid. Then the reaction solution was stirred for 4 h at room temperature. After the last interaction the solution was evaporated to dryness, and �the STATCOM were transferred to 25 ml water and 25 ml of ethyl acetate. After phase separation, the aqueous phase was extracted three more times with ethyl acetate, the combined organic phases were dried over magnesium sulfate and evaporated to dryness. The obtained crude product was purified by chromatography on silica gel (eluent:cyclohexane/ethyl acetate 4:1→1:1). Was allocated 669 mg (1,17 mmol, 64% of Theor.) target connection.

1H-NMR (400 MHz, DMSO-d6d/M. D.): 7,34-7,26 (4H, m), 7,18-7,13 (4H, m), 7,12-7,07 (2H, m), 6,86-6,76 (6H, m), 4,90 (2H, s), 4.72 in (2H, d), is 4.57 (2H, d), 4,01 (6H, s), is 3.08 (2H, s).

LC-MS (Method 6): Rt=1,45 min; m/z=572 (M)+.

Analogously to example 13A synthesis has received the following connection:

ExampleName/Structure/starting compoundAnalytical data
14AMethyl-(1-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}cyclobutyl)acetate1H-NMR (400 MHz, DMSO-d6d/M. D.): 7,29 (1H, d), of 7.19 (4H, d), 6,83 (4H, d), of 6.79-6,74 (2H, m), of 4.04 (4H, s), 3,70 (6H, s), 3,35 (3H, s), 2,69 (2H, s), 2.26 and-2,17 (2H, m), 2,16-of 2.06 (2H, m), 2,03-of 1.89 (1H,m), 1,71-to 1.58 (1H, m).
LC-MS (Method 6): Rt=1,50 min; m/z=494 (M)+.
({3-[bis(4-methoxybenzyl)amino]-4-chlorphen�l}boric acid and methylcyclobutane [obtained in accordance with A. Goti et al., Tetrahedron 48 (25), 5283-5300(1992)])

Example 15A

Benzyl-[3-(3-amino-4-chlorophenyl)oxetan-3-yl]acetate

To a solution of 660 mg (1.15 mmol) benzyl-(3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}oxetan-3-yl)acetate in 30 ml of dichloromethane and 6 ml of water at room temperature was added 576 mg (2.54 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and stirred 2 h. After complete the reaction (TLC control; eluent: cyclohexane/ethyl acetate 2:1) to the reaction solution was added 25 ml of saturated sodium bicarbonate solution. After phase separation, the aqueous phase was extracted three more times with dichloromethane, the combined organic phases were dried over magnesium sulfate and evaporated to dryness. The obtained crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5:1). Was allocated 360 mg (0.98 mmol, content 90%, 85% of Theor.) target connection.

LC-MS (Method 4): Rt=1,18 min; m/z=332 (M+H)+.

Analogously to synthesis example 15A was obtained the following compound:

ExampleName/Structure/starting compoundAnalytical data
16AMethyl-[1-(3-amino-4-chlorophenyl)cyclobe�yl]acetate 1H-NMR (400 MHz, DMSO-d6d/M. D.): 7,06 (1H,d), 6,59 (1H, s),6,32(1H,d),5,21(2H,ush. C), 3.43 points (ZN, C), 2,73 (2H, s), 2,31-2,19 (4H,m), 2,09-to 1.94 (1 H, m), 1,82-to 1.67 (1H,m).
LC-MS (Method 4):Rt=1,20 min; m/z=254 (M+H)+.
(from methyl-(1-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}cyclobutyl)acetate)

Example 17A

3-Bromo-2-ftoranila

2.0 g (a 9.09 mmol) 3-bromo-2-peritrabecular was dissolved in 10 ml of dioxane and at Tbrmixed with 8.62 g (45,45 mmol) of tin chloride(And). After adding a few drops of 1 n hydrochloric acid the mixture was heated for 2 h at 70°C. After cooling, the reaction mixture was evaporated in vacuo, and the residue was transferred into ethyl acetate. The solution was then washed twice with 1 n aqueous sodium hydroxide solution, water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1). Received 997 mg (57.7% of theory.) target connection.

LC-MS (Method 6): Rt=0,88 min; m/z=189/191 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=5,43 (s, 2H), 6,66-of 6.85 (m, 3H).

Example 18A

Tert-butyl(2E)-3-(3-amino-2-fluorophenyl)acrylate;

A solution of 1.41 g (of 7.42 mmol) 3-bromo-2-foronline and 2.85 g (22,3 mmol) of a compound tert-butyl ester of acrylic acid in 8 ml of DMF was mixed with 5.2 ml (37,1 mmol) of triethylamine. From the flask three times evacuated and filled it with argon before it was added 451 mg (1,48 mmol) tri-2-tolylphosphino and of 166.6 mg (0,74 mmol) of palladium acetate (II). The reaction vessel again was twice evacuated and filled with argon, and then the mixture was heated to about 140°C. After 2 h of intensive mixing of the reaction mixture was cooled and poured into saturated sodium bicarbonate solution. This mixture three times were extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate and evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1). Was obtained 1660 mg of the target product (94,3% of Theor.).

LC-MS (Method 6): Rt=1,12 min; m/z=279 (M+H+CH3CN)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 1.48 (s, 9H), 5,27 (s, 2H), 6,45 (d, 1H), 6,73-7,02 (m, 3H), members, 7.59 (d, 1H).

Example 19A

Tert-butyl-3-(3-amino-2-fluorophenyl)propanoate

To a solution of 1660 mg (7.0 mmol) of tert-butyl(2E)-3-(3-amino-2-fluorophenyl)acrylate in a mixture of 5 ml of ethanol and 3 ml of THF was added palladium on charcoal (10%) and during the night was intensively stirred in hydrogen atmosphere at normal pressure. Then the reaction mixture f�ltravel through diatomaceous earth, and the residue on the filter was repeatedly washed with a mixture of ethanol/THF. The combined filtrate was evaporated in vacuo, and the residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1→10:1). Received 1350 mg of the target product (80,6% of Theor.).

LC-MS (Method 6): Rt=1,07 min; m/z=225.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,36 (s, 9H), of 2.45 (t, 2H), 2,74 (t, 2H), 5,00 (s, 2H), for 6.24-of 6.46 (m, 1H), is 6.51-to 6.66 (m, 1H), 6,66-about 6,82 (m, 1H).

Example 20A

Complex ethyl ester of (E/Z)-3-(4-fluoro-3-nitrophenyl)-2-methylprop-2-envoy acid

3.17 g of sodium hydride (60% suspension in mineral oil, 79,36 mmol) was suspended in 90 ml of THF/DMF (2:1). This mixture was cooled to 0°C and added dropwise a solution of 19,76 g (82,96 mmol) of complex createlogo ether 2-phosphonopropionic acid in 60 ml of a mixture THF/DMF (2:1). After 30 min at 0°C to this was pinned a solution of 12.2 g (72,14 mmol) 4-fluoro-3-nitrobenzaldehyde in 60 ml of a mixture THF/DMF (2:1). After finishing the addition the reaction mixture was slowly heated up to Tbrand stirred for 2 h at this temperature. Thereafter, the reaction mixture was poured into water. Three times were extracted with ethyl acetate, and the combined organic phases was evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1). There was obtained 15.2 g (83,2% of Theor.) target p�of keep this product as a mixture of isomers E/Z (E/Z 91:9).

LC-MS (Method 6): Z-isomer: Rt=1,11 min; m/z=254 (M+H)+; E-isomer: Rt=1,14 min; m/z=254 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): E-isomer: δ [M. D.]=1,28 (t, 3H), 4,22 (kV, 2H), members, 7.59-7,73 (m, 2H), 7,92 (DDD, 1H), 8,24 (DD, 1H).

Example 21A

Complex ethyl ester(+/-)-3-(3-amino-4-fluorophenyl)-2-methylpropanoic acid

15.2 g (60,02 mmol) of a compound ethyl ester of (E/Z)-3-(4-fluoro-3-nitrophenyl)-2-methylprop-2-envoy acid (E/Z 91:9) in a mixture of 100 ml of ethanol and 100 ml of THF was mixed with palladium on charcoal (10%) and during the night was intensively stirred in hydrogen atmosphere at normal pressure. The reaction mixture was then filtered through celite, the residue washed with a mixture of ethanol/dichloro methane, and the combined filtrate was evaporated in vacuum. The product was dried in a high vacuum. Received 13,34 g of the target product (98,7% of Theor.).

LC-MS (Method 6): Rt=0,98 min; m/z=226 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,04 (d, 3H), of 1.12 (t, 3H), 2,46-of 2.50 (m, 1H), 2,55-of 2.66 (m, 1H), 2,66-2,78 (m, 1H), 4,01 (kV, 2H), 5,00 (s, 2H), 6.18 of is 6.35 (m, 1H), 6,55 (DD, 1H), at 6.84 (DD, 1H).

The racemate obtained above was separated into the enantiomers by HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; injection volume: 0.15 ml; temperature: 30°C; eluent: 90% isohexane/10% ethanol; flow rate: 15 ml/min; detection: 220 nm]. Based on the 7.25 g of racemate was obtained 3,43 g of enantiomer 1 (Example 2A) and a 3.35 g of enantiomer 2 (Example 23A):

Example 22A

Complex ethyl ester of (+)-(2S)-3-(3-amino-4-fluorophenyl)-2-methylpropanoic acid

Output: 3,43 g

LC-MS (Method 6): Rt=Or = 0.97 min; m/z=226 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,04 (d, 3H), of 1.12 (t, 3H), 2,46-of 2.50 (m, 1H), 2,55-of 2.66 (m, 1H), 2,66-2,78 (m, 1H), 4,01 (kV, 2H), 5,00 (s, 2H), 6.18 of is 6.35 (m, 1H), 6,55 (DD, 1H), at 6.84 (DD, 1H).

[α]D20=+18.3°, C=of 0.465, chloroform.

Example 23A

Complex ethyl ester of (-)-(2R)-3-(3-amino-4-fluorophenyl)-2-methylpropanoic acid

Output: 3,35 g

LC-MS (Method 6): Rt=Or = 0.97 min; m/z=226 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,04 (d, 3H), of 1.12 (t, 3H), 2,46-of 2.50 (m, 1H), 2,55-of 2.66 (m, 1H), 2,68-to 2.79 (m, 1H), 4,01 (kV, 2H), 5,00 (ush. s, 2H), 6,30 (DD, 1H), 6,55 (DD, 1H), at 6.84 (DD, 1H).

[α]D20=-31.4°, c=0,520, chloroform.

Example 24A

Complex ethyl ester of (E/Z)-3-(4-chloro-3-nitrophenyl)-2-methylprop-2-envoy acid

4,74 g of sodium hydride (60% suspension in mineral oil, 118,56 mmol) was suspended in 93 ml of a mixture THF/DMF (1:1). This mixture was cooled to 0°C and dropwise added to 26.6 ml (123,92 mmol) of complex createlogo ether 2-phosphonopropionic acid. After 30 min at 0°C to this was pinned 20,0 g (107,78 mmol) 4-chloro-3-nitrobenzaldehyde. After finishing the addition the reaction mixture was slowly heated up to Tbrand stirred� another 3 h at this temperature. Thereafter, the reaction mixture was poured into water. Three times were extracted with ethyl acetate, and the combined organic phases was evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 70:1→50:1). Received of 26.7 g (91,9% of Theor.) the target product as a mixture of isomers E/Z (E/Z 91:9).

LC-MS (Method 4): Z-isomer: Rt=To 1.32 min; m/z=255; E - isomer: Rt=To 1.36 min; m/z=270 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): E - isomer: δ [M. D.]=1,28 (t, 3H), of 2.06 (d, 3H), 4,22 (kV, 2H), 7,56-7,67 (m, 1H), 7,75-a 7.87 (m, 2H), 8,17 (d, 1H).

Example 25A

Complex ethyl ester(+/-)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid

10.0 g (37,08 mmol) of a compound ethyl ester of (E/Z)-3-(4-chloro-3-nitrophenyl)-2-methylprop-2-envoy acid (E/Z 91:9) was dissolved in 25 ml of ethyl acetate and 25 ml of acetic acid was added palladium on charcoal (10%). The reaction mixture for a total of 6 h was intensively stirred in hydrogen atmosphere at normal pressure, and after 2 hours and thereto was added 25 ml of acetic acid and an additional portion of 10% palladium on coal. Then filtered through celite, and the residue was washed with a mixture of ethanol/dichloro methane. The combined filtrate was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuum. The crude product was purified by chromatography using n� silica gel (eluent: cyclohexane/ethyl acetate 30:1→10:1). Received 4,01 g of the target product (44,7% of Theor.).

LC-MS (Method 6): Rt=To 1.06 min; m/z=242 (M+H)+.

1H-NMR (400 MHz, DMSO-AE): 5 [M. D.]=of 1.05 (d, 3H), of 1.12 (t, 3H), 2,47-of 2.50 (m, 1H), 2,56-of 2.67 (m, 1H), 2,67-2,78 (m, 1H), was 4.02 (q, 2H), 5,23 (s, 2H), 6.35 mm (DD, 1H), to 6.58 (d,1H), 7,05 (d, 1H).

The racemate obtained above was separated into the enantiomers using preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm×20 mm; injection volume: 0.15 ml; temperature: 35°C; eluent: 50% of isohexane/50% isopropanol; flow rate: 15 ml/min; detection: 220 nm]. On the basis of 10.3 g of racemate was obtained 4.0 g of enantiomer 1 (Example 26A} and 3.7 g of enantiomer 2 (Example 27A):

Example 26A

Complex ethyl ester of (-)-(2R)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid

Yield: 4.0 g

LC-MS (Method 7): Rt=2,27 min; m/z=196/198.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=of 1.05 (d, 3H), of 1.12 (t, 3H), 2,47-of 2.50 (m, 1H), 2,54-of 2.66 (m, 2H), 2,68-2,80 (m, 1H), was 4.02 (q, 2H), 5,23 (s, 2H), 6.35 mm (DD, 1H), to 6.58 (d,1H), 7,05 (d, 1H).

[α]D20=-35,8°, c=0,560, chloroform.

Example 27A

Complex ethyl ester of (+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid

Yield: 3.7 g

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=of 1.05 (d, 3H), of 1.12 (t, 3H), 2,47-of 2.50 (m, 1H), 2,56-of 2.67 (m, 1H), 2,67-of 2.81 (m, 1H), was 4.02 (q, 2H), 5,23 (ush. s, 2H), 6.35 mm (DD, 1H), to 6.58 (d, 1H), 7,05 (d, 1H).

[α]D20=+35,1°, C=0,525, chloroform.

Example 28A

�Teal-(2E/Z)-2-(4-chloro-3-nitrobenzylidene)butanoate

1.19 g of sodium hydride (60% suspension in mineral oil, 29,64 mmol) was suspended in 50 ml of a mixture THF/DMF (1:1). This mixture was cooled to 0°C and dropwise added 7.3 ml (30,99 mmol) of complex createlogo ether 2-phosphonobutane acid. After 30 min at -10°With portions to this was added 5.0 g (26,94 mmol) 4-chloro-3-nitrobenzaldehyde. After finishing the addition the reaction mixture was stirred 5 h at 0°C and then slowly during the night was warmed to Damn. Thereafter, the reaction mixture was poured into water. Three times were extracted with ethyl acetate, and the combined organic phases was evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 6:1). Received 7,05 g (92,1% of Theor.) the target product as a mixture of isomers E/z

LC-MS (Method 6): Rt=1,24 min and 1.26 min; ionization is absent.

Example 29A

(+/-)-Ethyl-2-(3-amino-4-chlorbenzyl)butanoate

7,05 g (24.84 mmol) of ethyl-(2E/Z)-2-(4-chloro-3-nitrobenzylidene)butanoate was dissolved in 35 ml of ethyl acetate and 35 ml of acetic acid was added palladium on charcoal (10%). The reaction mixture for a total of 6 h was intensively stirred in hydrogen atmosphere at normal pressure, and after 4 h was added an additional portion of 10% palladium on coal. Then filtered through celite, and the mod�it was washed with a mixture of ethyl acetate/THF. The combined filtrate was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 30:1→10:1). Received of 4.12 g of the target product (64,9% of Theor.).

LC-MS (Method 6): Rt=1,14 min; m/z=210.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,84 (m, 3H), 1,10 (t, 3H), 1,42-1,59 (m, 2H), 2,40-2,80 (m, 4H), 4,01 (kV, 2H), 5,23 (s, 2H), system 6.34 (DD, 1H), to 6.58 (d, 1H),7,05(d,1H).

The racemate obtained above was separated into the enantiomers using preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 microns, 250 mm x 20 mm; injection volume: 0,43 ml; temperature: 30°C; eluent:ethanol; flow rate: 15 ml/min; detection: 220 nm]. On the basis of 3.22 g of racemate was obtained 1.22 g of enantiomer 1 (Example 30A) and 1.27 g Enan-timer 2 (Example 31A):

Example 30A

(-)-Ethyl-(2R)-2-(3-amino-4-chlorbenzyl)butanoate

Yield: 1.22 g LC-MS (Method 6): Rt=1,14 min; m/z=210.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,84 (m, 3H), 1,10 (t, 3H), 1,42-of 1.56 (m, 2H), 2,39-2,48 (m, 1H), 2,56-2,73 (m, 3H), 4,01 (kV, 2H), 5,11-5,27 (m, 2H), system 6.34 (DD, 1H), to 6.58 (d, 1H), 7,05 (d, 1H).

[α]D20=-28,1°, c=0,510, chloroform.

Example 31A

Output: 1,27 g LC-MS (Method 6): Rt=1,15 min; m/z=210.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,84 (m, 3H), 1,10 (t, 3H), 1.46 to 1.55 V (m, 2H), 2,42-2,49 (m, 1H), 2,54-2,69 (m, 3H), ,01 (kV, 2H), 5,22 (s, 2H), system 6.34 (DD, 1H), to 6.57 (d,1H), 7,05 (d,1H).

[α]D20=+34,1°, c=0,550, chloroform.

Example 32A

Tert-butyl(2E/Z)-3-(4-chloro-3-nitrophenyl)but-2-ENOAT

2,87 g of sodium hydride (60% suspension in mineral oil, 71,65 mmol) was suspended in 80 ml of THF. This mixture was cooled to 0°C and dropwise added to 17.6 ml (74,9 mmol) of tert-butyl(diethoxyphosphoryl)acetate. After 30 min at 0°C was added to 13.0 g (65,1 mmol) 4-chloro-3-nitroacetophenone. After finishing the addition the reaction mixture was slowly heated to Damn. and stirred for 1.5 h at Damn before then poured this mixture into the water. Three times were extracted with ethyl acetate, and the combined organic phases was evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1→10:1). Was received to control an additional 17.03 g (87,8% of Theor.) the target product as a mixture of isomers E/Z (E/Z approximately 1:1).

LC-MS (Method 5): isomer 1: Rt=2,61 min; m/z=255; isomer 2: Rt=2,77 min; m/z=224.

Example 33A

Complex tert-butyl ether(+/-)-3-(3-amino-4-chlorophenyl)butane acid

11.5 g (38,62 mmol) of tert-butyl(2E/Z)-3-(4-chloro-3-nitrophenyl)but-2-enoate (E/Z approximately 1:1) was dissolved in 60 ml of ethyl acetate and 60 ml of acetic acid was added palladium on charcoal (10%). The reaction mixture for 6 h was intensively stirred at �armelina the pressure in the hydrogen atmosphere. Then filtered through celite, and the residue was washed with ethyl acetate. The combined filtrate was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 30:1). Received 3,90 g (37,4% of Theor.) target product.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 1.14 (d, 3H), of 1.31 (s, 9H), of 2.38 (DD, 2H), 2,95 (kV, 1H), to 5.21 (ush. s, 2H), to 6.42 (DD, 1H), 6,65 (d, 1H), 7,06 (d, 1H).

The racemate obtained above was separated into the enantiomers using preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; injection volume: 0.15 ml; temperature: 30°C; eluent: 90% isohexane/10% ethanol; flow rate: 15 ml/min; detection: 220 nm]. Based on 5.0 g of racemate was obtained 2.1 g of enantiomer 1 (Example 34A) and 1.8 g of enantiomer 2 (Example 35A):

Example 34A

Complex tert-butyl ether(+)-(33)-3-(3-amino-4-chlorophenyl)butane acid

LC-MS (Method 4): Rt=To 1.34 min; m/z=270 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1.14 (d, 3H), of 1.31 (s, 9H), 2,19-of 2.45 (m, 2H), 2,95 (kV, 1H), 5,20 (s, 2H), to 6.42 (DD, 1H), 6,65 (d, 1H), 7,06 (d, 1H).

[α]D20=+20,9°, C=0,670, chloroform.

Example 35A

Complex tert-butyl ether (-)-(3R)-3-(3-amino-4-chlorophenyl)butane acid

LC-MS (Method 4): Rt=1,34 min; mz=214 (M+H-C 4H8)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 1.14 (d, 3H), of 1.31 (s, 9H), of 2.38 (DD, 2H), 2,95 (kV, 1H), 5,20 (ush. s, 2H), to 6.42 (DD, 1H), 6,65 (d, 1H), 7,06 (d, 1H).

[α]D20=-24,1°, C=0,570, chloroform.

Example 36A

To 4.81 g of sodium hydride (60% suspension in mineral oil, 120,13 mmol) was suspended in a mixture of 120 ml of THF and 120 ml of DMF. This mixture was cooled to 0°C and dropwise added 29.5 ml (125,59 mmol) of tert-butyl(diethoxyphosphoryl)acetate. After 30 min at 0°C to this was added 20.0 g (109,21 mmol) 4-fluoro-3-nitroacetophenone. After finishing the addition the reaction mixture was slowly heated up to Tbrand stirred for another 3.5 h at Tbrbefore then poured this mixture into the water. Three times were extracted with ethyl acetate, and the combined organic phases was evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 50:1). Received of 7.24 g (23.6% of theor.) the target product as a mixture of isomers E/Z (E/Z of about 1.2:1).

LC-MS (Method 4): isomer 1: Rt=To 1.34 min; m/z=208; isomer 2: Rt=1,42 min; m/z=208.

Example 37A

Complex tert-butyl ether(+/-)-3-(3-amino-4-fluorophenyl)butane acid

Of 7.24 g (25,74 mmol) of tert-butyl(2E/Z)-3-(4-fluoro-3-nitrophenyl)but-2-enoate (E/Z of about 1.2:1) was dissolved in 200 ml of ethanol and added palladi� on coal (10%). The reaction mixture during the night was intensively stirred in hydrogen atmosphere at normal pressure. Then filtered through celite, and the residue was twice washed with ethyl acetate. The combined filtrates were evaporated in vacuo, and the residue was dried in high vacuum. Received of 6.02 g of the target product (92,4% of Theor.).

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 1.14 (d, 3H), of 1.31 (s, 9H), is 2.37 (DD, 2H), 2,95 (kV, 1H), to 4.98 (s, 2H), 6,36 (DDD, 1H), 6,62 (DD, 1H), of 6.85 (DD, 1H).

The racemate obtained above was separated into the enantiomers using preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm×20 mm; injection volume: 0.15 ml; temperature: 35°C; eluent: 65% of isohexane/35% ethanol; flow rate: 15 ml/min; detection: 220 nm]. Based on 6.0 g of racemate was obtained 2,44 g of enantiomer 1 (Example 38A) and 1.92 g of enantiomer 2 (Example 39A):

Example 38A

Complex tert-butyl ether (+)-(3S)-3-(3-amino-4-fluorophenyl)butane acid

LC-MS (Method 6): Rt=1,11 min; m/z=254 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 1.14 (d, 3H), of 1.31 (s, 9H), 2,18-of 2.46 (m, 2H), 2,95 (kV, 1H), 4,99 (ush. s, 2H), 6,36 (DDD, 1H), 6,61 (DD, 1H), of 6.85 (DD, 1H).

[α]D20=+22,5°, C=0,570, chloroform.

Example 39A

Complex tert-butyl ether (-)-(3R)-3-(3-amino-4-fluorophenyl)butane acid

LC-MS (Method 6): Rt=1,11 min; m/z=254 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 1.14 (d, 3H), of 1.31 (s, 9H), 2.26 and-of 2.45 (m, 2H), 2,95 (kV, 1H), 4,99 (ush. s, 2H), 6,36 (DDD, 1H), 6,62 (DD, 1H), of 6.85 (DD, 1H).

[α]D20=-23,2°, C=0,510, chloroform.

Example 40A

Ethyl-3-(3-bromo-4-fluorophenyl)acrylate;

To a solution of 6.5 g (of 31.7 mmol) 3-bromo-4-fermentelos alcohol and 13,25 g (38 mmol) of ethoxycarbonylmethylene in 390 ml of toluene was added 9,65 g (111 mmol) of manganese dioxide. The reaction mixture was heated to reflux, after 1 h, added additional of 9.65 g of manganese dioxide and during the night was further heated to reflux. After cooling, the mixture was filtered through celite, and the filtrate was concentrated. The residue was purified using flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5:1). Received 7,05 g (81% of theory.) the target product in the form of a mixture of E/Z-isomers.

LC-MS (Method 4): Rt=1,33 min and 1.35 min; m/z=273/275 (M+H)+.

Example 41A

Rat-ethyl-2-(3-bromo-4-fluorophenyl)-TRANS-cyclopropanecarboxylic

In an argon atmosphere was placed 381 mg (9.52 mmol) of sodium hydride (60% suspension in paraffin oil) in 20 ml of DMSO and Damn. at one time there was added 2.1 g (9.52 mmol) of iodide trimethylsulfoxonium. After gassing slowly pinned 2.0 g (7.3 mmol) of ethyl-3-(3-bromo-4-fluorophenyl)acrylate, dissolved in 10 �l of DMSO. This reaction mixture was overnight heated at 50°C, then cooled to Tbrand without further treatment was purified using flash chromatography on silica gel (eluent:isohexane/ethyl acetate 100:1). Was obtained 907 mg (43% of Theor.) target product.

LC-MS (Method 6): Rt=1,20 min; m/z=289 (M+H)+.

GC-MS (Method 1): Rt=5,85 min; m/z=287/289 (M+H)+.

1H-NMR (500 MHz, CDCl3): δ [M. D.]=1,20-of 1.33 (m, 4H), 1.56 to to 1.63 (m, 1H), 1,80-of 1.88 (m, 1H), 2,43-2,52 (m, 1H), 4,17 (kV, 2H), 7,00-7,06 (m, 2H), 7,28 (d, 1H).

Example 42A

Rat-ethyl-2-[3-(benzylamino)-4-fluorophenyl]-TRANS-cyclopropane-carboxylate

In an argon atmosphere suspended 361,5 mg (3.8 mmol) mpem-butylate sodium in 12.9 ml of toluene and successively added 900 mg (3.1 mmol) (+/-)-TRANS-ethyl-2-(3-bromo-4-fluorophenyl)cyclopropanecarboxylate, 403 mg (3.8 mmol) of benzylamine, 28,7 mg (0.03 mmol) of Tris(dibenzylideneacetone)diplodia and 19.5 mg (0.03 mmol) rat.-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl. This mixture was stirred for 4 h was heated at 110°C. Then the reaction mixture was cooled to Damn, was added 100 ml of ethyl acetate and 50 ml of a saturated solution of ammonium chloride and filtered through celite.The organic phase was separated, washed with respectively 50 ml of a saturated solution of ammonium chloride and a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated. The crude product extra�whether using preparative HPLC. Received 262 mg of the target compound with a purity of 66% (18% of Theor.).

LC-MS (Method 6): Rt=1,28 min; m/z=314 (M+H)+.

Example 43A

Rat-ethyl-2-[3-amino-4-fluorophenyl]-TRANS-cyclopropanecarboxylic

262 mg (purity 66%, 0,55 mmol) (+/-)-ethyl-2-[3-(benzylamino)-4-fluorophenyl]-TRANS-cyclopropanecarboxylate was dissolved in 5 ml of a mixture ethanol/THF (1:1), was mixed with 26 mg of palladium on coal (10%) and Hidirova-whether for 24 h at Damn at a hydrogen pressure of 1 bar. Then the reaction mixture was filtered through celite, the residue was further washed with ethanol, and the filtrate was concentrated. The thus obtained crude product was purified using preparative HPLC. Was obtained 87 mg (69% of theory.) target connection.

LC-MS (Method 6): Rt=0,96 min; m/z=224 (M+H)+.

1H-NMR (400 MHz, DMSO-D6): δ [M. D.]=1,17-1,23 (m, 3H), 1,23-1,28 (m, 1H), 1,39 (dt, 1H), 1,67-of 1.81 (m, 1H), of 2.21-2,31 (m, 1H), of 4.09 (q, 2H), of 6.31 (DDD, 1H), 6,55 (DD,1H), 6,86 (DD, 1H).

Example 44A

3-Amino-4-peracetate

To a solution of 3 g (16.4 mmol) of 4-fluoro-3-nitroacetophenone 7.8 ml of 12 N hydrochloric acid at 0°C for 15 min pinned a solution of 11.1 g (89 mmol) of the dihydrate of tin chloride in 12 ml of water. Then the reaction mixture for 15 min was heated to reflux, and then further stirred over night at Tbr. After e�wow, the reaction mixture was poured onto ice, using 50% aqueous sodium hydroxide solution was adjusted to pH 12 and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Received 2,47 g (90% purity, 87% of Theor.) target connection.

LC-MS (Method 5): Rt=To 1.32 min; m/z=154 (M+H)+.

Example 45A and Example 46A

Ethyl(2E)-3-(3-amino-4-propenyl)-2-methylbut-2-ENOAT

and

ethyl(2Z)-3-(3-amino-4-propenyl)-2-methylbut-2-ENOAT

and

To a suspension of 1.29 g of sodium hydride (60% suspension in paraffin oil; of 32.3 mmol) 24.7 ml of THF at 0°C was slowly pinned at 6.92 ml (7,68 g; of 32.3 mmol) of complex createlogo ether 2-phosphonopropionic acid. The reaction mixture was stirred 30 min and then added 2,47 g (90% purity, 14,5 mmol) 3-amino-4-fortetienne. This reaction mixture was first stirred for 1 h at Tbrand then 2 h at reflux, then cooled to Tbrand further stirred overnight. Then this reaction mixture was poured into water and three times were extracted with respectively 100 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, was evaporated, and the residue was purified using flash chromatography on silica gel (eluent: toluene/ethyl acetate 5:1). In the form of individual�s isomers was obtained 612 mg (15% of Theor.) 2E-isomer (Example 45A) and 529 mg (13% of Theor.) 27-isomer (Example 46A).

2E-isomer (Example 45A):

LC-MS (Method 6): Rt=1,05 min; m/z=238 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,22-of 1.29 (m, 3H), 1,69 (d, 3H), 2,11 (d, 3H), 4,17 (d, 2H), 6,30 (DDD, 1H), 6,56 (DD, 1H), 6,97 (DD, 1H).

2 g-isomer (Example 46A):

LC-MS (Method 6): RtD =0.99 min; m/z=238 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,85 (t, 3H), 1,86-of 1.92 (m, 3H), 1,94 is 2.01 (m, 3H), 3,82 (kV, 2H), for 6.24 (DDD, 1H), is 6.51 (DD, 1H), 6,87 (DD, 1H).

Example 47A

To a solution of 48 mg (0.2 mmol) of ethyl-(2E)-3-(3-amino-4-fluorophenyl)-2-methylbut-2-enoate in 5 ml of methanol was added to 4.8 mg of palladium on coal (10%). The reaction mass was gidrirovanie overnight at a hydrogen pressure of 1 bar. Then filtered through celite, and the filtrate was concentrated. Received a 35.8 mg (74% of theory.) the target compound, which contained approximately 20% of erythrosora.

LC-MS (Method 6): Rt=To 1.02 min; m/z=240 (M+H)+.

An example of LVA

Rat-artpro-ethyl-3-(3-amino-4-fluorophenyl)-2-methylbutanoate

To a solution of 30 mg (0,13 mmol) ethyl-(2Z)-3-(3-amino-4-fluorophenyl)-2-methylbut-2-enoate 3.1 ml of methanol was added 3 mg of palladium on coal (10%). The reaction mass was gidrirovanie overnight at a hydrogen pressure of 1 bar. Then filtered through celite, and the filtrate was concentrated. Received 22,5 mg (74% of theory.) the target compound, which contained approximately 5% mpeo-isomer.

LC-MS (Method� 6): R t=1,04 min; m/z=240 (M+H)+.

Example 49A

Tert-butyl(2E)-3-(4-fluoro-3-nitrophenyl)acrylate;

In an argon atmosphere were placed 0.65 g of sodium hydride (60% suspension in paraffin oil; 16.3 mmol) in 25 ml THF and cooled to 0°C. Then slowly pinned 4,29 g (17 mmol) of complex mpem-butyl ether diethylphosphonoacetate acid. After 30 min stirring was added 2.5 g (14.8 mmol) of 4-fluoro-3-nitrobenzaldehyde. The reaction mixture was stirred 3 h at Tbrand then was poured into 100 ml water and three times were extracted with respectively 100 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 50:1). Received 3.37 g (85% of theory.) target product.

GC-MS (Method 1): Rt=6,45 min; m/z=211 (MtBu)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,49 (C, 9H), 6,69 (d, 1H), members, 7.59-7,76 (m,2H), to 8.19 (DDD, 1H), and 8.50 (DD, 1H).

Example 50A

RET-butyl(2E)-3-(4-cyano-3-nitrophenyl)acrylate;

To a solution of 500 mg (1,87 mmol) of tert-butyl(2E)-3-(4-fluoro-3-nitrophenyl)acrylate in 5.4 ml of DMF was added 134 mg (2,06 mmol) of potassium cyanide. After stirring over night at Tbrthe reaction mixture was directly purified using flash chromatography (eluent: CME�ü cyclohexane/ethyl acetate). There was obtained 57 mg (11% of Theor.) target connection.

LC-MS (Method 5): Rt=2,40 min; m/z=292 (M+NH4)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,39-1,58 (m, 9H), 6,91 (d, 1H), 7,73 (d, 1H), to 8.19 (d, 1H), of 8.26 is 8.38 (m, 1H), 8,72 (d, 1H).

Example 51A

tert-butyl-3-(3-amino-4-cyanophenyl)propanoate

To a solution of 48,9 mg (0.18 mmol) of tert-butyl(2E)-3-(4-cyano-3-nitrophenyl)acrylate in 4.4 ml of ethanol was added to 4.9 mg of palladium on coal (10%). The reaction mass was gidrirovanie when Damn. overnight at a hydrogen pressure of 1 bar. Then filtered through celite, and the filtrate was concentrated. Received a 43.5 mg (99% of theory.) the target compound with a purity of 85%.

LC-MS (Method 6): Rt=To 1.06 min; m/z=247 (M+H)+.

Example 52A

Ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate

To 287 g (of 1.65 mol) of (3R)-4,4,4-Cryptor-3-methylbutanoic acid [A. Gerlach and U. Schuiz, Speciality Chemicals Magazine 24 (4), 37-38 (2004); CAS Acc.-Nr. 142: 179196] in 580 ml of ethanol at room temperature was slowly added 133 ml (1.82 mole) of thionylchloride. Then the reaction solution was heated to 80°C and 2 h stirred at this temperature. After this was cooled to room temperature, was slowly added to 250 ml of water and three times were extracted with portions of 150 ml of methyl tert-butyl ether. The combined organic phases were dried over sodium sulfate. After filtration, the solvent was Udalov vacuum at 30°C and a pressure of 300 mbar. Then the crude product was distilled at 100 mbar and a temperature at the head of the column 65°C. Was allocated 225,8 g (113 mol, 74% of Theor.) target compound in the form of a colourless liquid.

1H-NMR (400 MHz, DMSO-d6d/M. D.): 4,10 (2H, kV), 2,88-of 2.72 (1H, m), 2,66-of 2.57 (1H, m), 2,46-a 2.36 (1H, m), 1,19 (3H, t), is 1.11 (3H, d).

GC-MS (Method 1): Rt=1,19 min; m/z=184 (M)+.

[α]D20=+16,1°, C=0,41, methanol.

Example 53A

Ethyl-4,4,4-Cryptor-3-methyl-2-(4-methylphenyl)butanoate (mixture of diastereomers)

In an argon atmosphere 196,9 mg (0.88 mmol) of palladium acetate(II) and 724,8 mg (1.84 mmol) of 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl were placed in 50 ml of anhydrous toluene. To this reaction solution was then slowly added to 43.8 ml (to 43.8 mmol) of a 1 M solution hexamethyldisilazide lithium in THF and was stirred 10 min at Tbr. Thereafter, the reaction solution was cooled to -10°C, was slowly added 7 g (38,0 mmol) (+/-)-ethyl-4,4,4-Cryptor-3-methylbutanoate and additionally stirred 10 min at -10°C. Then pinned 5 g (29,2 mmol) 4-bromthymol dissolved in 50 ml of toluene, and this reaction solution was first heated up to Tbrand then to 80°C. the Mixture was stirred 2 h at this temperature, then cooled to Tbrand further stirred overnight. After completing the reaction (TLC control; eluent: cyclohexan�/dichloro methane 2:1) the reaction mixture was filtered through diatomaceous earth, the residue was repeatedly washed with ethyl acetate and dichloromethane, and the combined filtrate was evaporated in vacuum. The obtained crude product was purified by chromatography on silica gel (eluent: petroleum ether/dichloro methane 4:1→3:1). Was allocated 3.91 g (of 14.3 mmol, 48.8 percent of theoretical.) target compound in the form of a colourless liquid.

1H-NMR (400 MHz, DMSO-D6d/M. D.): 7,26 (2H, d), 7,20-7,12 (2H, m), 4,17-3,95 (2H, m), 3,74 (0.25 H, d), 3.66 m (0.75 H, d), 3,35-of 3.07 (1H, m), 2,29 (2.25 H), 2,28 (0.75 H, s), of 1.17 (0.75 H, d), is 1.11 (3H, t) 0,76 (2.25 N, d).

GC-MS (Method 1): Rt=4,20 min; m/z=275 (M+H)+(diastereoisomer 1); Rt=To 4.23 min; m/z=275 (M+H)+(diastereoisomer 2).

Example 54A

Ethyl-(3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoate

Preparation of solution A: 163,9 ml of a 1 M solution hexamethyldisilazide lithium in toluene in an argon atmosphere was cooled to a temperature of from -10°C to -20°C (cooling with a bath of acetone/dry ice) and was slowly added 20 g (108,6 mmol) ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate dissolved in 150 ml of toluene, and drew attention to the fact that the temperature did not exceed -10°C. This solution is then further stirred for 10 minutes at a temperature not more than -10°C.

Preparation of solution B: 27,03 g (141,2 mmol) 1-bromo-4-chlorobenzene in an argon atmosphere at T"STP. was dissolved in 100 ml of toluene and added 731 mg (3,26 mmol) of palladium acetate (II) and 2,693 g (6,84 MMO�b) 2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine. This solution was further stirred for 10 min at Tbr.

First, the cooling bath was removed from the solution A. Then to the cold solution And slowly pinned a solution V. United now solutions were slowly heated up to Tbrand stirred 1 h at this temperature. Then the reaction solution was heated to 80°C (internal temperature) and stirred at this temperature for 3 h. then the reaction solution was slowly cooled to Tbrand additionally stirred for another 12 h. Then the reaction mixture was filtered through kieselguhr, the residue repeatedly was further washed with toluene and the combined filtrate was evaporated in vacuum. The obtained crude product was purified by chromatography on silica gel (eluent: cyclohexane/dichloro methane 4:1). Was allocated to 27.4 g (92,98 mmol, 86% of Theor.) target compound in the form of a yellow oil with a ratio of diastereomers of 3:1.

GC-MS (Method 1): Rt=4,45 min; m/z=294 (M)+(diastereoisomer 1); Rt=4,48 min; m/z=294 (M)+(diastereoisomer 2).

Analogously to examples of synthesis 53A and 54A were obtained the following compounds:

ExampleTrade name/Structure/starting compoundAnalytical data
55A Ethyl-(3R)-4,4,4-Cryptor-2-(4-isopropylphenyl)-3-methylbutanoateGC-MS (Method 1): Rt=4,61 min; m/z=302 (M)+(diastereoisomer 1); Rt=A 4.64 min; m/z=302 (M)+(diastereoisomer 2).
(from 1-bromo-4-isopropylbenzene and ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate)
56AEthyl-(3R)-2-(4-tert-butylphenyl)-4,4,4-Cryptor-3-methylbutanoateGC-MS (Method 1): Rt=A 4.83 min; m/z=3-(M+H)+(diastereoisomer 1); Rt=4,85 min; m/z=317 (M+H)+(diastereoisomer 2).
MC (DCI): m/z=334 (M+NH)+.
(from 1-bromo-4-tert-butylbenzene and ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate)

ExampleName/Structure/starting compoundAnalytical data
57AEthyl-(3R)-4,4,4-Cryptor-3-methyl-2-[4-(trifluoromethyl)phenyl]butanoateGC-MS (Method 1):Rt=3,38 min; m/z=328 (M)+(diastereoisomer 1); Rt=3,42 min; m/z=328 (M)+(diastereoisomer 2).
from 1-bromo-4-(trifluoromethyl)benzene and ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate)
58AEthyl-(3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butanoateGC-MS (Method 1): Rt=4,68 min; m/z=370 (M)+.
(from 1-bromo-4-(1,1,1-Cryptor-2-methylpropan-2-yl)benzene and ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate)

Example 59A

Ethyl-2-[4-(methyl bromide)phenyl]-4,4,4-Cryptor-3-methylbutanoate

2.25 g (8.2 mmol) of ethyl-4,4,4-Cryptor-3-methyl-2-(4-methylphenyl)butanoate, 1.53 g (8,6 mmol) of N-bromosuccinimide and 67 mg (0,41 mmol) 2,2'-azobis-2-methylpropionitrile in 36 ml of trichloromethane was stirred over night while boiling to reflux. After completed conversion filter out succinimide, the residue on the filter was further washed with dichloromethane, and the filtrate was concentrated in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 40:1). Was allocated 2,667 g (7.5 mmol, 92% of Theor.) yellow oil.

GC-MS (Method 1): Rt=5,72 min; m/z=373 (M-Br)+(diastereoisomer 1); Rt=5,74 min; m/z=373 (-Br) +(diastereoisomer 2).

Example 60A

Ethyl-4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoate

To of 3.77 g (of 10.67 mmol) ethyl-2-[4-(methyl bromide)phenyl]-4,4,4-Cryptor-3-methylbutanoate in 40 ml of 1-methylpyrrolidine-2-she added 529 mg (2,78 mmol) of copper iodide(1) and 4 g (20,82 mmol) of methyl-2,2-debtor-2-(persulfuric)acetate and during the night stirred at 80°C. After the last interaction, the reaction solution was slowly poured into 100 ml of ice water. The resulting mixture was then three times was extracted with diethyl ether. The combined organic phases were dried over magnesium sulfate. After filtration the solvent was removed in vacuum. The obtained crude product was purified by chromatography on silica gel (eluent: cyclohexane/dichloro methane 4:1). Was allocated to 1.48 g (4,32 mmol, 41% of Theor.) target compound in the form of a yellowish oil.

GC-MS (Method 1): Rt=4,06 min; m/z=342 (M)+(diastereoisomer 1); Rt=Of 4.09 min; m/z=342 (M)+(diastereoisomer 2).

MS (DCI): m/z=360 (M+NH4)+.

Example 61A

1-Bromo-4-(2-bromo-1-fluoroethyl)benzene

5.0 g (27,31 mmol) 4-rostirolla was dissolved in 40 ml of dichloromethane, cooled to 0°C and was mixed with 13,21 g (81,94 mmol) trihydrated of triethylamine. After that, three reception added of 5.83 g (32,78 mmol) of N-bromosuccinimide. The mixture was stirred over night at Tto�mn . After dilution with dichloromethane the reaction mixture was poured into ice water. The organic phase was sequentially washed with 1 n hydrochloric acid, water and saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: pentane). Was allocated 4.14 g (53.8% of theory.) target connection.

GC-MS (Method 1): Rt=4,94 min; m/z=277/281/283 (M+H)+.

1H-NMR (400 MHz, DMSO-D6): δ [M. D.]=3,75-of 4.04 (m, 2H), 5,84 (dt, 1H), 7,31-7,51 (m, 2H), 7,55-7,78 (m, 2H).

Example 62A

1-Bromo-4-(1-forfinal)benzene

To a cooled to 0°C solution of 1.0 g (3,55 mmol) 1-bromo-4-(2-bromo-1-fluoroethyl)benzene in 10 ml of pentane in several portions was added 796 mg (to 7.09 mmol) of tert-butylate potassium. The resulting suspension was stirred 30 min at 0°C and then 1 h at TbrFiltered the solids, and the filtrate was washed with a saturated solution of ammonium chloride, dried over magnesium sulfate and carefully evaporated in a vacuum. Received 0,61 g (85.6% of theoretical.) target connection.

GC-MS (Method 1): Rt=3,14 min; m/z=200/202 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=5,10 (DD, 1H), 5,47 (DD, 1H), of 7.48-7,61 (m, 2H), 7,62-7,72 (m, 2H).

Example 63A

Complex ethyl ester of (3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoic acid (mixture of diastereomers)

24,4 ml (24,4 mmole) of a 1 M solution hexamethyldisilazide lithium in toluene was cooled to -10°C and dropwise added a solution of 3.0 g (16,29 mmol) ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate in 15 ml of abs. toluene. This mixture was additionally stirred for 10 min Then at -10°C was pinned pre-prepared solution of 3.92 g (21,18 mmol) 1-bromo-4-ethylbenzene, 110 mg (0.49 mmol) of palladium acetate (II) and 404 mg (1.03 mmol) of 2'-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl in 20 ml of abs. toluene. The resulting reaction mixture was stirred first for 1 h at Tbrthen 3 h at 80°C. thereafter, the mixture was evaporated in vacuo, and the residue was transferred into ethyl acetate and poured into water. The aqueous phase was re-extracted with ethyl acetate, and the combined organic phases were washed with saturated solution of ammonium chloride and a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. From the residue after chromatography on silica gel (eluent: first cyclohexane, then a gradient of cyclohexane/ethyl acetate 200:1→50:1) received 3,051 g of target compound (64,9% of Theor., the ratio of diastereomers of about 3:1).

LC-MS (Method 4): Rt=1,52 min; m/z=289 (M+H)+(side diastereoisomer); Rt=A 1.54 min; m/z=289 (M+H)+(major diastereoisomer).

1H-NMR (400 MHz, DMSO-d6): core diaster�Omer: δ [M. D.]=0,76 (d, 3H), of 1.13 (t, 3H), of 1.17 (t, 3H), 2,55-2,63 (m, 2H), 3,21-of 3.31 (m, 1H), to 3.67 (d, 1H), 3,95-4,16 (m, 2H), 7,15-of 7.23 percent (m, 2H), 7,25-7,31 (m, 2H).

Similarly, on the basis of ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate and the corresponding panelbased, were obtained both of the following connections:

Example 64A

Complex ethyl ester of (3R)-4,4,4-Cryptor-3-methyl-2-(4-vinylphenol)butane acid (mixture of diastereomers)

GC-MS (Method 1): Rt=A 4.64 min and of 4.66 min; m/z=286 (M)+.

1H-NMR (400 MHz, DMSO-d6): the major diastereoisomer: δ [M. D.]=0,79 (d, 3H), of 1.12 (t, 3H), 3,22-of 3.32 (m, 1H), 3,73 (d, 1H), 3,99-4,17 (m, 2H), 5,28 (d, 1H), 5,84 (d, 1H), 6,72 (DD, 1H), 7,34-7,40 (m, 2H), 7,45-7,51 (m, 2H).

Example 65A

Complex ethyl ester of (3R)-4,4,4-Cryptor-2-[4-(1-forfinal)phenyl]-3-methylbutanoic acid

GC-MS (Method 1): Rt=4,60 4,63 min and min; m/z=304 (M)+LC-MS (Method 6); Rt=1,29 1,30 min and min; m/z=279.

1H-NMR (400 MHz, DMSO-d6): the major diastereoisomer: δ [M. D.]=0,79 (d, 3H), of 1.12 (t, 3H), 3,34-to 3.38 (m, 1H), 3,81 (d, 1H), 3,99-4,17 (m, 2H), 4,97 (DD, 1H), 5,42 (DD, 1H), of 7.46-7,49 (m, 2H), 7,63 (d, 2H).

Example 66A

Methyl-(4-chlorophenyl)-(3-oxocyclopentyl)acetate;

In an argon atmosphere of 14.8 ml (105,6 mmol) of Diisopropylamine were placed in 150 ml of THF, cooled to -30°C and slowly added 42,3 ml (105,75 mmol) of a 2.5 M solution of n-utility in hexane. Then the reaction solution was warmed to -20°C, m�long added 15 g (RB 81.25 mmol) methyl-(4-chlorophenyl)acetate, dissolved in 90 ml of THF, and 2 hours and further stirred at this temperature. Then the reaction solution was cooled to -78°C and slowly added to 7.2 ml (86.1 mmol) of 2-cyclopenten-1-one dissolved in 60 ml THF. After completed addition, the solution was further stirred 1 h at this temperature. After TLC monitoring (eluent: cyclohexane/ethyl acetate 9:1) to reaction mass was added a saturated solution of ammonium chloride and transferred to the ethyl acetate. The aqueous phase was twice extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate. After filtration the solvent was removed in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1). Was allocated 15,65 g (58,67 mmol, 72% of Theor.) target compound in the form of a yellowish oil.

GC-MS (Method 1): Rt=7,02 min; m/z=266 (M)+(diastereoisomer 1); Rt=7,04 min; m/z=266 (M)+(diastereoisomer 2).

MC (DCI): m/z=284 (M+NH4)+.

Example 67A

Methyl-(4-chlorophenyl)-(3,3-diverticulitis)acetate

In an argon atmosphere loaded 82,5 ml (82,14 mmol) of a 50% solution of 1,1'-[(trifter-λ4-sulfanyl)imino]bis(2-ethoxyethane) (deoxofluor reagent) in THF, diluted with 200 ml of toluene, cooled to 5°C and slowly added 744 µl (5,87 mmol) of a 1 M solution of the complex of boron TRIFLUORIDE of diet�charger ether. This mixture was additionally stirred for 2 h at 5°C. Then to the reaction solution was slowly added 15,65 g (58,67 mmol) methyl-(4-chlorophenyl)-(3-oxocyclopentyl)acetate, dissolved in 200 ml of toluene, then heated to 55°C and 60 h was further stirred at this temperature. Thereafter, the reaction mixture was poured into a cooled to 0°C, a mixture consisting of 100 ml of toluene and 100 ml of 2 M aqueous solution of sodium hydroxide. The organic phase was separated, and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration the solvent was removed in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:1). Was allocated 13,24 g (45,86 mmol, 78% of Theor.) target compound in the form of a colorless oil.

MS (DCI): m/z=306 (M+NH4)+.

GC-MS (Method 1): Rt=Of 5.83 min; m/z=288 (M)+(diastereoisomer 1); Rt=5,86 min; m/z=288 (M)+(diastereoisomer 2).

Example 68A

(+/-)-Ethyl-(2,2-diverticulitis)acetate

To a solution of 52.8 ml (399,5 mmol) of the TRIFLUORIDE diethylaminoethyl (DAST) in 150 ml of abs. dichloromethane at Tbrpinned 17.0 g (of 99.88 mmol) of (+/-)-ethyl-2-oxacyclopentane. This mixture was heated over night to reflux. After cooling, to this was added to 13.2 ml (9988 mmol) of the TRIFLUORIDE diethylaminoethyl (DAST), and the mixture is again stirred for 36 h at boiling with reflux. After cooling, diluted with dichloromethane, was carefully added saturated sodium bicarbonate solution and then intensively stirred. The organic phase was sequentially washed with saturated sodium bicarbonate solution, twice with 1 n hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuum. From the dark-brown residue the product was isolated using column chromatography on silica gel (eluent: pentane/dichloro methane 10:1→1:1). Received 7,52 g (39% of theory.) target connection.

GC-MS (Method 1): Rt=2,88 min; m/z=172.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=factor of 1.18 (t, 3H), 1,33-of 1.48 (m, 1H), 1,61-to 1.77 (m, 2H), 1,92-of 2.20 (m, 3H), 2,24-of 2.38 (m, 1H), 2,43-2,60 (m, 2H), 4,07 (kV, 2H).

Example 69A

Complex ethyl ester (4-chlorophenyl)-(2,2-diverticulitis)acetic acid (mixture of diastereomers)

To 22.6 ml (22.6 mmol) of a 1 M solution hexamethyldisilazide lithium in toluene was cooled to -20°C and dropwise added a solution 2,90 g (15,09 mmol) (+/-)-ethyl-(2,2-diverticulitis)acetate in 20 ml of abs. toluene. This mixture was stirred 10 min at -20°C. After removing the cooling pinned pre-prepared solution of 3.75 g (19,61 mmol) 4-bromchlorenone, 110 mg (0.49 mmol) of palladium acetate (II) and 374 mg (0.95 mmol) 2'-di�ilovelilwayne-2-(N,N-dimethylamino)biphenyl in 20 ml of abs. toluene. The resulting reaction mixture was stirred first for 1 h at Damn., and then 2 h at 90°C. After cooling, the reaction mixture was poured into water. The aqueous phase three times were extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate and evaporated in vacuum. From the residue after chromatography on silica gel (eluent: cyclohexane/ethyl acetate 50:1) obtained 2.70 g of the target compound (59,1% of Theor., the ratio of diastereomers of approximately 1:4,3).

GC-MS (Method 1): Rt=6,09 mines and of 6.20 min.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,01-of 1.27 (m, 3H), 1,37-of 1.50 (m, 1H), 1,51-of 1.75 (m, 3H), 1,94-of 2.23 (m, 3H), 2,84-of 3.07 (m, 1H), 3,55-with 3.79 (m, 1H), 3,93-4,20 (m, 2H), 7,29-7,53 (m, 4H).

Example 70A

(+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoate acid

5,086 g (17,26 mmol) ethyl-(3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoate was dissolved in 68 ml of dioxane and was added 34 ml of a 1 n aqueous solution of sodium hydroxide. This reaction mixture was stirred 2 h at 50°C. Then the reaction mixture was acidified with 1 n hydrochloric acid to pH 1 and several times was extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuum. There was obtained 3.9 g (14,63 mmol, 85% of theoretical., 83% de) of the target connection.

1H-NMR (400 MHz, DMSO-d6 d/M. D.): 12,95-of 12.73 (1H, ush.C), 7,49-7,34 (4H, m), 3,68 (1H, d), 3,31-3,18 (1H, m), 1,20 (0,25 N, d), 0,78 (2,75 N, d).

GC-MS (Method 1): Rt=4,85 min; m/z=266 (M)+.

[α]D20=+57,2°, c=0,41, methanol.

Analogously to synthesis example 70A were obtained the compounds shown in the following table:

ExampleName/Structure/Initial connectionAnalytical data
71A4,4,4-Cryptor-3-methyl-2-(4-methylphenyl)butane acidGC-MS (Method 1): Rt=4,48 min; m/z=246 (M)+.
(from ethyl 4,4,4-Cryptor-3-methyl-2-(4-methylphenyl)butanoate)
72A(2S,3R)-4,4,4-Cryptor-2-(4-isopropylphenyl)-3-methylbutanoate acid1H-NMR (400 MHz, DMSO-de, δ/M. D.): 12,56 (1H, ush.C), 7,25 (4H, q), 3,56(1H, d), or 3.28-3,16 (1H, m), 2,94-of 2.81 (1H, m), 1,19 (6H, d), and 0.75 (3H, d).
GC-MS (Method 1): Rt=4,93 min; m/z=274 (M)+.
(from ethyl(3R)-4,4,4-Cryptor-2-(4-isopropylphenyl)-3-methylbutanoate)
73A(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-Cryptor-3-methylbutanoate acidGC-MS (Method 1): Rt=5,15 min; m/z=288 (M)+.
(from ethyl(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-Cryptor-3-methylbutanoate)

ExampleName/Structure/Initial connectionAnalytical data
74A(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(trifluoromethyl)phenyl]butane acidGC-MS (Method 1): Rt=3,85 min; m/z=300 (M)+.
(from ethyl(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(trifluoromethyl)phenyl]butanoate)
75A(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butane acid1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,90-12,40 (1H, ush.C), 7,53 (2H, d), 7,40 (2H, d), of 3.69 (0,11 N, d), to 3.64 (0,89 N, d), 3,30-3,20 (1H, m), of 1.55 (6H, s) to 1.21 (0,33 N, d),0,76 (2,67 N, d).
LC-M� (Method 6):R t=1,19 min; m/z=341 (M-H)-.
(from ethyl(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butanoate)

ExampleName/Structure/Initial connectionAnalytical data
76A4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butane acid1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,95-of 12.59 (1H,UII. C) value of 7, 37 (4H, q), 3,70 is 3.57 (3H, m), 3,30-3,18 (1H,m), of 0.76 (3H, d).
GC-MS (Method 8): Rt=4,45 min. m/z=315 (M+H)+.
(from ethyl 4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoate)
77A(4-Chlorphen yl)-(3,3-diverticulitis)acetic acid1H-NMR (400 MHz, DMSO-d6d/M. D.): of 12.59(1H,ush.C), 7,38 (4H, q), 3,51 (0.5 N, d), 3,48 (0.5 N,d), 2,77-2,60 (1H,m), 2,42-of 2.27 (0,5 H,m), 2.26 and-of 1.20 to 5.5 H, m).
GC-MS (Method 1): Rt=6,33 min; m/z=274 (M)+(diastereoisomer 1);
from methyl-(4-chlorophenyl)-(3,-diverticulitis)acetate) Rt=6,38 min; m/z=274 (M)+(diastereoisomer 2).

Example 78A

(3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoate acid (mixture of diastereomers)

3.0 g complex ethyl ester of (3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoic acid (approximately 88% purity, approximately 9,16 mmol; mixture of diastereomers) was dissolved in the mixture, respectively, and 12.4 ml each of methanol, THF and water and the portions was added 5.49 g (137,35 mmol) of sodium hydroxide. The reaction mixture was stirred 9 h at 40°C. After cooling, the volatile solvents were largely removed in vacuo, and the residue was diluted with water. Was using acidified with hydrochloric acid, and the aqueous phase three times were extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, was evaporated in vacuum, and the residue was dried in high vacuum. Received 2,61 g of target compound in the form of a crude product, which was not subjected to further purification (ratio of diastereoisomers about 9:1).

LC-MS (Method 6): Rt=1,08 min; m/z=259 (M-H)-(side diastereoisomer); Rt=1,11 min; m/z=259 (M-H)-(major diastereoisomer).

1H-NMR (400 MHz, DMSO-d6): the major diastereoisomer: δ [M. D.]=0,76 (d, 3H), of 1.17 (t, 3H), 2,54-of 2.66 (m, 4H), 3,10-3,29 (m, 1H), 3,56 (d, 1H), 7,14-7,22 (m, 2H), 7,22-7,32 (m, 2H), is 12.58 (ush. s, 1H).

Similarly, those�of tempera ture of the reaction: from T brto 40°C; reaction time: 9-12 hours) from the corresponding esters were obtained both of the following carboxylic acid derivatives:

Example 79A

(3R)-4,4,4-Cryptor-3-methyl-2-(4-vinylphenol)butane acid (mixture of diastereomers)

The ratio of diastereomers of approximately 10:1.

LC-MS (Method 6): Rt=1,04 min; m/z=257 (M-H)-(side diastereoisomer); Rt=To 1.06 min; m/z=257 (M-H)-(major diastereoisomer).

1H-NMR (400 MHz, DMSO-d6): the major diastereoisomer: δ [M. D.]=0,78 (d, 3H), 3,18-of 3.31 (m, 1H), 3,62 (d, 1H), 5,28 (d, 1H), 5,84 (d, 1H), 6,73 (DD, 1H), 7,31-7,39 (m, 2H), 7,40-7,54 (m, 2H), by 12.74 (ush.s, 1H).

Example 80A

(3R)-4,4,4-Cryptor-2-[4-(1-forfinal)phenyl]-3-methylbutanoate acid (mixture of diastereomers)

The ratio of diastereomers of about 9:1.

GC-MS (Method 1): Rt=4,97 min; m/z=276.

1H-NMR (400 MHz, DMSO-d6): the major diastereoisomer: δ [M. D.]=0,78 (d, 3H), 3,16-3,29 (m, 1H), 3,70 (d, 1H), 4,96 (DD, 1H), of 5.34 (d, 1H), 5,47 (d, 1H), 7,39-7,51 (m, 2H), 7,58-7,69 (m, 2H), 12,83 (ush.s, 1H).

Example 81A

(4-Chlorophenyl)-(2,2-diverticulitis)acetic acid (mixture of diastereomers)

2.70 g (8,92 mmol) of a compound ethyl ester (4-chlorophenyl)-(2,2-diverticulitis)acetic acid (mixture of isomers) was dissolved in 10 ml of methanol, 10 ml THF and 5 ml of water and at Tbradded 7,13 g (89,18 mmol) of 50% aqueous sodium hydroxide solution. This reaction mixture was stirred over night at TbrThen was diluted with water and with hydrochloric acid set acid pH. The aqueous phase three times were extracted with ethyl acetate, and the combined organic phases were dried over sodium sulfate, was evaporated in vacuum and the residue was dried in high vacuum. Got 2,39 g of target compound (97.6% of theoretical., the ratio of diastereomers in about 1:1).

LC-MS (Method 6): Rt=1,05 1,07 min and min; m/z=273 (M-H)-.

Example 82A

(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoate

To 19.5 g (73,13 mmol) (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid was dissolved in 860 ml of dichloromethane and mixed with 0.5 ml of DMF. Then, at a temperature from -5°C to -10°C (cooling bath of ice/acetone) was slowly pinned 73 ml (146,26 mmol) of 2 M solution of oxalicacid in dichloromethane and the mixture is further stirred 1 h at this temperature. After completing the reaction, the reaction solution was evaporated in vacuum and the obtained residue was extracted in 200 ml of dichloromethane and then again evaporated to dryness. Was obtained 20.1 g (70,5 mmol, 96% of Theor.) target compound in the form of a colorless oil. The thus obtained product was used in subsequent reactions without further purification and without additional spectroscopic characterization.

EN�logical manner were obtained the compounds in the following table:

ExampleName/StructureThe original substance
83A(2S,3R)-4,4,4-Cryptor-2-(4-isopropylphenyl)-3-methylbutanoate(2S,3R)-4,4,4-Cryptor-2-(4-isopropylphenyl)-3-methylbutanoate acid

ExampleName/StructureThe original substance
84A(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-Cryptor-3-methylbutanoate(2S,3R}-2-{4-tert-butylphenyl)-4,4,4-Cryptor-3-methylbutanoate acid
85A(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(trifluoromethyl)phenyl]butanoate(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(trifluoromethyl)phenyl]-butane acid
86A(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butanoate(2S,3R)-4,4,4-Cryptor-3-m�Teal-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butane acid

ExampleName/StructureThe original substance
87A4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoate4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]-butane acid
88A(4-Chlorophenyl)-(3,3-diverticulitis)acetyl chloride(4-Chlorophenyl)-(3,3-diverticulitis)-acetic acid

Example 89A

Tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propanoate

18 g (70,38 mmol) (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoate was dissolved in 500 ml of THF, was added to 18.4 ml (105,57 mmol) of N,N-diisopropylethylamine and cooled to -10°C. Then slowly added 20,07 g (70,38 mmol) tert-butyl-3-(3-amino-4-chlorophenyl)propanoate dissolved in 500 ml of THF, and it was noticed so while adding the temperature did not exceed 0°C. then the mixture is further stirred for another 1 h. Then to the reaction solution was added water and ethyl acetate, the organic phase was separated, and the aqueous phase still �Reidy was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in a rotary evaporator. The residue was purified using chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1). Got 30,13 g (59,74 mmol, 85% of Theor.) target connection.

1H-NMR (400 MHz, DMSO-d6d/M. D.): 9,82 (1H, s), 7,50-of 7.42 (4H, m), 7,39-7,32 (2H, m), 7,07-7,01 (1H, m), of 4.12 (1H, d), 3,42-3,29 (1H, m) of 2.75 (2H, t), 2,46 (2H, t), of 1.31 (9H, s), to 0.80 (3H, d).

LC-MS (Method 7): Rt=3,03 min; m/z=502/504 (M-H)+.

Similarly, there were obtained the compounds shown in the following table:

ExampleName/Structure/starting compoundAnalytical data
90ATert-butyl-3-(4-chloro-3-{[(2S,3R)-4,4,4-Cryptor-2-(4-isopropylphenyl)-3-methylbutanoyl]amino}phenyl)propanoate1H-NMR (400 MHz, DMSO-d6d/M. D.): 9,70 (1H, c), 7,47-of 7.42 (1H, m), 7,34 (3H, t), 7.23 percent (2H, d), 7,04 of 6.99 (1H, m), 4,07 (1H, d), 3,40-3,26 (1H, m), 2,94-of 2.81 (1H, m) of 2.75 (2H, t), of 2.45 (2H, t), of 1.31 (9H, s), 1,19 (6H, d), Of 0.78 (3H, d).
LC-MS (Method 4): Rt=1,72 min; m/z=510/512 (M-N)-.
(from (2S,3R)-4,4,4-Cryptor-2-(4-isopropylphenyl)-3-�of ethylbutylamine and tert-butyl-3-(3-amino-4-chlorophenyl)propanoate)

ExampleName/Structure/starting compoundAnalytical data
91ATert-butyl-3-(3-{[(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-chlorophenyl)propanoate1H-NMR (400 MHz, DMSO-d6d/M. D.): 9,71 (1H, c), 7,49-the 7.43 (1H, m), 7,41-of 7.35 (4H, m), 7,34 (1H, d), 7,04-6,98 (1H, m), 4,08 (1H, d), 3,39-of 3.25 (1H, m) of 2.75 (2H, t), of 2.45 (2H, t), of 1.31 (9H, s) of 1.27 (9H, s), to 0.78 (3H, d).
LC-MS (Method 6): Rt=1,52 min; m/z=524/526 (M-H)-.
(from (2S,3R)-2-(4-tert-butylphenyl)-4,4,4-Cryptor-3-methylbutanoate and tert-butyl-3-(3-amino-4-chlorophenyl)propanoate)
92ATert-butyl-3-[4-chloro-3-({(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(trifluoromethyl)phenyl]butanoyl}amino)-phenyl]propanoate1H-NMR (400 MHz, DMSO-d6d/M. D.): of 9.89 (1H,c), 7,76 (2H, d), 7,69 (2H, d), value of 7, 37 (1H, d), 7,35 (1H, d), to 7.04 (1H, DD), 4,24 (1H, d), 3,48-3,36 (1H, m) of 2.75 (2H, t), of 2.45 (2H, t), of 1.29 (9H, s), to 0.80 (3H, d).
LC-MS (�method 6): R t=1,43 min; m/z=536 (M-H)-.
(from(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(trifluoromethyl)phenyl]butanolide and tert-butyl-3-(3-amino-4-chlorophenyl)propanoate)

ExampleName/Structure/starting compoundAnalytical data
93Atert-butyl-3-[4-chloro-3-({(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butanoyl}amino)phenyl]propanoateLC-MS (Method 6): Rt=1,48 min; m/z=579 (M-H)-.
(from (2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butanolide and tert-butyl-3-(3-amino-4-chlorophenyl)propanoate)
ATert-butyl-3-[4-chloro-3-({4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-triflora-Teal)phenyl]butanoyl}amino)phenyl]propane t1H-NMR (400 MHz, DMSO-d6d/M. D.): 9,78 (1H, c), of 7.46 (2H, d), 7,41 (1H, d), 7,35 (3H, t), 7,02 (1H, DD), 4,11 (1H, d), 3,63 (2H, kV), 3,42-or 3.28 (1H, m) of 2.75 (2H, t), of 2.45 (2H, t), of 1.30 (9H, s), 0.79 in (3H, d).
LC-MS (Method 6): Rt=1,41 min; m/z=550 (M-H)-.
(from 4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanolide and tert-butyl-3-(3-amino-4-chlorophenyl)propanoate)

ExampleName/Structure/starting compoundAnalytical data
95ATert-butyl-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}phenyl)-propanoicLC-MS (Method 5): Rt=3,01 min; m/z=510/512(M-N)-.
(from (4-chlorophenyl)-(3,3-diverticulitis)acetyl chloride and tert-butyl-3-(3-amino-4-chlorophenyl)propanoate)
96AEthyl-(2S)-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}phenyl)-2-methylpropanoateLC-MS (Method 7): Rt=2,94 min; m/z=498 (M)+.
(from (4-chlorophenyl)-(3,3-diverticulitis)acetyl chloride and ethyl-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate)

ExampleName/Structure/starting compoundAnalytical data
97AEthyl-(2R)-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}phenyl)-2-methylpropanoateLC-MS (Method 7): Rt=2,94 min; m/z=498 (M)+.
(from (4-chlorophenyl)-(3,3-diverticulitis)acetyl chloride and ethyl-(2R)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate)
AMethyl-[1-(4-chloro-3-{[(ZR)-2-(4-chlorphen yl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)cyclobutyl]-acetate1H-NMR (400 MHz, DMSO-de, δ/M. D.): 9,95 (0,33 N, C), 9,81 (0,66 H, s), 7,54-7,30 (6H, m), 7,02-6,93 (1H, m), 4,14 (1H,d), 3,41-or 3.28 (1H, m), 3,37 (3H, s), 2,80-to 2.74 (2H, m), 2,35-to 2.19 (4H, m), 2,11-of 1.97 (1H, m), 1,82-to 1.69 (1H, m), 1,25 (1H, d), 0,80 (2H, d).
LC-MS (Method 7): Rt=2,96 min; m/z=500/502 (M-N)-.
(from (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoate and methyl-[1-(3-amino-4-chlorophenyl)cyclobutyl]acetate)

ExampleName/Structure/starting compoundAnalytical data
99ABenzyl-[3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)oxetan-3-yl]acetate1H-NMR (400 MHz, DMSO-d6d/M. D.): for 9.88 (1H, c), 7,51 (1H, d), was 7.45 (4H, q), 7,38 (1H, d), to 7.33-7.23 percent (3H, m), 7,17-7,10 (2H,m), 7,03 (1H, DD), to 4.92 (2H, s), 4,78-the 4.67 (4H, m), 4,17 (1H, d), 3,42-or 3.28 (1H, m), 3,18 (2H, s), Of 0.80 (3H, d).
LC-MS (Method 7): Rt=2,87 min; m/z=578 (M-H)-.
(from (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoate and benzyl-[3-(3-amino-4-chlorophenyl)oxetan-3-yl]acetate)

Example 100A

Methyl-[1-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]-amino}-4-fluorophenyl)cyclopropyl]acetate

A solution of 70 mg (0,31 mmol) (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid, 84 mg (0,31 mmol) of methyl[1-(3-amino-4-fluorophenyl)cyclopropyl]acetate, 179 mg (0.47 mmol) of hexaflurophosphate 2-(1H-7-asobancaria-1-yl)-1,1,3,3-tetramethylurea (GATA) and 0.6 ml of pyridine in 2.4 ml of DMF was stirred overnight at room temperature. After the reaction, the reaction mass without additional�th processing directly separated using preparative HPLC. Were obtained 106 mg (0,22 mmol, 72% of Theor.) target compound in the form of a colorless oil.

1H-NMR (400 MHz, DMSO-d6d/M. D.): of 10.02 (1H, s), 7,71 (1H, DD), 7,52-7,38 (4H, m), 7,15-7,06 (1H, m), 7,05-6,98 (1H, m), 4,11 (1H, d), 3,48 (3H, s), 3,42-of 3.25 (1H, m), of 2.57 (2H, s), of 0.90 is 0.84 (2H, m), 0,81-0,74 (5H, m).

LC-MS (Method 6): Rt=1,33 min; m/z=472 (M+H)+.

Similarly, it was obtained the following compound:

ExampleName/Structure/starting compoundAnalytical data
101AMethyl-[1-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)cyclopropyl]acetate1H-NMR (400 MHz, DMSO-d6d/M. D.): 9,96 (1H, s), 7,74 (1H, DD), 7,34 (2H, d), 7,20 (2H, d), 7,12-7,05 (1H, m), 7,03-of 6.96 (1H, m), of 4.04 (1H, d), 3,47 (3H, C), 3,41-of 3.25 (1H, m), 2,63-2,52 (4H, m), of 1.17 (3H, t), 0,89 is 0.84 (2H, m)That 0,81-0,73 (5H,m).
LC-MS (Method 4): Rt=1,53 min; m/z=466 (M+H)+.
(from (2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoic acid and methyl-[1-(3-amino-4-fluorophenyl)cyclopropyl]acetate)

General method 1: Amide combination of derivatives of 4,4,4-Cryptor-3-methyl-2-phenylbuta�acid type with aniline with the use of "GATA"

To a solution of the appropriate derived 4,4,4-Cryptor-3-methyl-2-phenylbutanoate acid (approximately from 0.8 to 1.5 EQ., from 0.15 to 1.5 mol/l) and aniline (approximately from 0.8 to 1.5 EQ., from 0.15 to 1.5 mol/l) in a mixture of DMF and pyridine (ratio in the mixture is from about 3:1 to 1.5:1) at Tbradd GATA (1.0 to 2.0 EQ.). Alternatively, instead of pyridine can also be used N,N-diisopropylethylamine (from 2.0 to 5.0 EQ.). The resulting mixture was stirred 4 h to 48 h at a temperature of Tbrto 60°C., If necessary after 24 h additional part is added aniline or carboxylic acids and GATA. After the reaction, the crude product after removal of the solvent in vacuum can be purified using preparative reverse phase HPLC (eluent: gradient acetonitrile/water) or alternatively, after aqueous workup of the reaction mixture using chromatography on silica gel (eluent: a mixture of cyclohexane/ethyl acetate or dichloro methane/methanol).

The following examples were obtained in accordance with the General method 1:

ExampleName/StructureAnalytical data
102AComplex tert-butyl ether(+/-)-3-(3-{[2-(4-chlorine�enyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-fluorophenyl)propane acid (diastereoisomer 1) LC-MS (Method 4): Rt=Of 1.64 min; m/z=487 (M-H)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 1,32 (s, 9H), 2,48 (m, 2H), of 2.81 (t, 2H), 3,34-3,45 (m, 1H), 4,12 (d, 1H), to 6.88-7,12 (m, 2H), of 7.36-7,52 (m, 4H), 7,63 (TD, 1H), 10,03 (s, 1H).

ExampleName / StructureAnalytical data
103AComplex /npem-butyl ether(+/-)-3-(3-{[2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-fluorophenyl)propane acid (diastereoisomer 2)1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,22 (d, 3H), 1,32 (s, 9H), 2.49 USD (m, 2H), 2,82 (t, 2H), 3,21 (DD, 1H),4,15(d, 1H), 6,93-7,12 (m, 2H), 7,35-the 7.43 (m, 2H), 7,43-7,52 (m, 2H), 7,54-7,74 (m, 1H), 10,12 (s, 1H).
104AComplex mpem-butyl ether(+/-)-3-(3-{[2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)propane acid (diastereoisomer 1)LC-MS (Method 4): Rt=Ratio of 1.63 min; m/z=486 (M-H)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,78 (d, 3H), of 1.31 (m,9H), Of 2.44 (t, 2H), 2,74 (t, 2H), 3,33-3,48 (m, 1H), 4,11(d,1H), at 6.92-to 7.04 (m, 1H), 7,12 (DD, 1H), 7,35-7,52 (m, 4H), 7,65 (DD, 1H), 10,02 (s, 1H).

ExampleName/StructureAnalytical data
105AComplex tert-butyl ether(+/-)-3-(3-{[2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)propane acid (diastereoisomer 2)LC-MS (Method 4): Rt=Ratio of 1.63 min; m/z=486 (M-H)-.
1H-NMR (400 MHz, DMSO-d6: δ [M. D.]=1,21 (d, 3H), of 1.31 (s, 9H), of 2.45 (t, 2H), 2,74 (t, 2H), 3,21 (DD, 1H), 4,13 (d, 1H), 6,89-7,06 (m, 1H), 7,14 (DD, 1H), of 7.36-7,44 (m, 2H), 7,45-to 7.55 (m, 2H), 7.62 mm (DD, 1H), 10,12 (s, 1H).
AComplex tert-butyl ether(+)-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)propane acidLC-MS (Method 6): Rt=1,43 min; m/z=486 (M-H)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,78 (d, 3H), of 1.31 (s, 9H), of 2.44 (t, 2H), 2,74 (t, 2H), 3,34-3,4 (m, 1H), 4,11 (d, 1H), 6,87-7,02 (m, 1H), 7,12 (DD, 1H), of 7.36-7,51 (m, 4H), 7,65 (DD, 1H), 10,03 (s, 1H).
[α]D20+127°, c=0,52, chloroform.

ExampleName/StructureAnalytical data
107Complex tert-butyl ether (+)-3-(4-fluoro-3-{((2S,3R)-4,4,4-Cryptor-3-methyl-2-(4-vinylphenol)butanoyl]amino}phenyl)-propane acidLC-MS (Method 6): R,=1,39 min; m/z=478 (M-H)".
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), of 1.31 (s, 9H), of 2.44 (t, 2H), 2,74 (t, 2H), 3,35-of 3.43 (m, 1H), 4,08 (d, 1H), 5,26 (d, 1H), of 5.83 (d, 1H), 6,72 (DD, 1H), 6,97 (TD, 1H), 7,11 (DD, 1H), 7,32-7,51 (m, 4H), 7,66 (DD, 1H), 9,99 (s, 1H).
[α]D20=+119.4 p°, C=0,455, chloroform.
108AEthyl-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoate (mixture of diastereomers)LC-MS (Method 6): Rt=1,35 min; m/z=474 (M+H)+.
1H-NMR (400 MHz, DMSO-d6: δ [M. D.]=0,78 (d, 3H), 1,01-1,11 (m, 6H), 2,56-2,69 (m, 2H), 2,69-2,83 (m, 1H), 3,34-3,44 (m, 1H), a 3.87-3,99 (m, 2H), 4,11 (d, 1H), to 6.88-7,00 (m, 1H), 7,12 (DD, 1H), 7,39-of 7.48 (m, 4H), 7,55-7,66 (m, 1H), 10,03 (s, 1H).
109AComplex tert-butyl ether (+)-3-(4-chloro-3{[(2S,3R)-4,4,4-Cryptor-3-methyl-2-(4-vinylphenol)butanoyl]amino}phenyl)-propane acidLC-MS (Method 6): Rt=1,43 min; m/z=496 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.31 (s, 9H), of 2.45 (t, 2H), 2,75 (t, 2H), 3,34-of 3.43 (m, 1H), of 4.09 (d, 1H), 5,27 (d, 1H), 5,84 (d, 1H), 6,72 (DD, 1H), 7,03 (DD, 1H), 7,29-7,53 (m, 6H), 9,78 (s, 1H).
[α]D20=+105,2°, C=0,315, chloroform.

ExampleName/StructureAnalytical data
110AComplex tert-butyl ether(+)-3-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-propane acidLC-MS (Method 6): R,=1,46 min; m/z=480 (M-H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,77 (l,
3H), of 1.17 (t, 3H), of 1.31 (s, 9H), 244 (t, 2H), 2,60 (kV, 2H), 2,74 (t, 2H), 3,29-to 3.34 (m, 1H), 4,05 (d, 1H), 6,86-7,00 (m, 1H), 7,11 (DD, 1H), made 7.16 interest-7,26 (m, 2H), 7,28-7,41 (m, 2H), 7,69 (DD, 1H), 9,96 (s, 1H).
[α]D20=+108,7°,=0,500, chloroform.
111AComplex tert-butyl ether (+)-3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-propane acidLC-MS (Method 6): Rt=1,51 min; m/z=496 (M-H)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,78 (d, 3H), of 1.17 (t, 3H), of 1.31 (s, 9H), of 2.45 (t, 2H), 2,59 (kV, 2H), 2,75 (t, 2H), 3,34-3,40 (m, 1H), 4,06 (d, 1H), 7,02 (DD, 1H), 7,20 (d, 2H), 7,34 (DD, 3H), of 7.42 (d, 1H), 9,73 (s, 1H).
[α]D20=+62,7°, C=0,475, chloroform.

ExampleName/StructureAnalytical data
112AComplex ethyl ester 3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoic acid (mixture of diastereomers)LC-MS (Method 4): Rt=To 1.61 min; m/z=484 (M+H)+.
1H-NMR (400 MHz, DMSO- 6): δ [M. D.]=0,78 (d, 3H), 1,03-1,07 (m, 5H), of 1.17 (t, 3H), 2,55-2,69 (m, 4H), to 2.74-2,83 (m, 1H), 3,27-3,40 (m, 2H), 3,96 (square d, 2H), 4,03-4,12 (m, 1H), 6,97 (DD, 1H), 7,20 (d, 2H), to 7.33-7,41 (d, 4H), The 9.73 (s, 1H).
AComplex ethyl ester 3-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoic acid (mixture of diastereomers)LC-MS (Method 4): Rt=1,57 min; m/z=468 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,77 (d, 3H), 0,99-1,11 (m,6H), 1,11-1,23 (m, 3H), 2,52-of 2.68 (m, approx. 5H), 2,70-to 2.85 (m, 1H), or 3.28-of 3.32 (m, approx. 1H), 3,90-4,00 (m, 2H), 4,00-4,08 (m, 1H), about 6,82-of 6.96 (m, 1H), 7,11 (DD, 1H), made 7.16 interest-7,25 (m, 2H), 7,27-7,41 (m, 2H), 7,65 (DD, 1H), 9,96 (s, 1H).

ExampleName/StructureAnalytical data
114AComplex ethyl ester 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoic acid (mixture of diastereomers)LC-MS (Method 5): Rt=2,95 min; m/z=490/492 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 1,00-1,12 (m, 6H), 2,59-of 2.72 (m, 2H), 2,74-2,86 (m, 1H), 3,34-of 3.42 (m,1H), 3,96 (square d, 2H), 4,12 (d, 1H), 6,99 (DD, 1H), 7,26-7,39 (m,2H), 7,39-7,54 (m, 4H), to 9.81 (s, 1H).
115AComplex tert-butyl ether 3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)butane acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,55 min; m/z=510 (M-H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 1,10-1,19 (m, 6H), of 1.24/1.26 in (2, collab, 9H), 2,32-2,46 (m, 2H), 2,59 (kV, 2H), 2,97-3,11 (m, 1H), 3,33-3,40 (m, 1H), was 4.02-to 4.14 (m, 1H), 7,06 (d, 1 H), 7,20 (d, 2H), 7,35 (d, 3H), Of 7.48 (DD, 1H), 9,72 (s, 1H).

ExampleName/StructureAnalytical data
AMethyl ester (+)-3-[4-chloro-3-({(2S,3R)-4,4,4-Cryptor-2-[4-(1-forfinal)phenyl]-3-methylbutanoyl}-amino)phenyl]propane acidLC-MS (Method 6): Rt=1,30 min; m/z=472/474 (M+H)+.
H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 2,54-2,60 (m, 2H), 2,73-is 2.88 (m, 2H), 3,35 is-3.45 (m, 1H), 4,15 (d, 1H), 4,96 (DD, 1H), of 5.40 (DD, 1H), to 7.04 (DD, 1H), 7,28-7,40 (m, 2H), 7,45-to 7.55 (m, 2H), members, 7.59-7,71 (m, 2H), 9,84 (s, 1H).
[α]D20=+66,3°, C=0,455, chloroform.
117AComplex tert-butyl ether 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-chlorophenyl)butane acid (mixture of diastereomers)LC-MS (Method 4): Rt=Of 1.66 min; m/z=516/517 (M+H)+.
1H-NMR (400 MHz, DMSO-d6: δ [M. D.]=0,80 (d, 3H), of 1.16 (d, 3H),1,24/1,26(2, joint., 9H), 2,34-2,47 (m, 2H), 3,01-3,14 (m, 1H), 3,33-of 3.42 (m, 1H), 4,10-4,18 (m, 1H), was 7.08 (d, 1H), of 7.36 (d, 1H), 7,40-7,51 (m, 5H), 9,80 (s, 1H).

ExampleName/StructureAnalytical data
118AComplex tert-butyl ether (3S)-3-(4-chloro-3-{[(4-chlorophenyl)-(2,2-diverticulitis)acetyl]amino}phenyl)-butane acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,45 min; m/z=524/526 (M-N)-and Rt=1,46 min; m/z=524/526 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,16 (d, 3H), 1,24/1.26 in (2, joint., 9H), 1,48-1,78 (m, 3H), 1,96-of 2.25 (m, 3H), 2,33-2,47 (m, 2H), 2,89-3,18 (m,2H), 4,06 (DDD, 1H), 7,07 (DDD, 1H), 7,30-of 7.50 (m, 6H), 9,60/9,81 (2, joint., 1H).
AComplex tert-butyl ether 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)butane acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,45 min; m/z=500 (M-H)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (D, 3H), of 1.16 (d, 3H), 1,23/1,24 (2s, joint., 9H), 1,58-1,72 (m, 1H), 2,30-2,47 (m, 2H), 2,99-3,10 (m, 1H), 3,32-of 3.43 (m, 1H), 4,12 (d, 1H), 6,97-7,06 (m, 1H), 7,13 (DD, 1H), 7,38-7,54 (m, 4H), 7.62 mm-7,79 (m, 1H), 10,02 (s, 1H).

ExampleName/StructureAnalytical data
120AComplex tert-butyl ether 3-(4-chloro-3-{[(4-chlorophenyl)-(2,2-divertikulitis)acetyl]amino}phenyl)-propane acid (mixture of diastereomers)LC-MS (Method 6): Rt=To 1.44 min; m/z=510/512 (M-N)-and Rt=1,45 min; m/z=510/512 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,07-1,25 (m, 1H), 1,31 (s, 9H), 1,46-of 1.75 (m, 3H), 1,95-of 2.25 (m, 2H), 2,42-2,47 (m, 2H), 2,70-of 2.81 (m, 2H), 2,87-3,20 (m, 1H), 4,03/4,06 (2D, collab, 1H), 6,97-7,12 (m, 1H), 7,29-7,54 (m, 6H), 9,63/9,84 (2s, joint., 1H).
AComplex ethyl ester of (2S)-3-(4-chloro-3-{[(4-chlorophenyl)-(2,2-diverticulitis)acetyl]amino}phenyl)-2-methylpropanoic acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,40 min; m/z=498/500 (M+H)+and Rt=1,41 min; m/z=498/500 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,98-1,08 (m, 6H), 1,10-1,24 (m, 1H), 1,48-of 1.80 (m, 3H), 1,96 and 2.26 (m, 2H), 2,57-2,70 (m, 2H), 2,70-2,86 (m, 1H), 2,90-up 3.22 (m, 1H), 3,90-4,10 (m, 3H), 6,98 (DDD, 1H), 7,30-7,51 (m, 6H), 9,63/case 9.83 (2s, joint., 1H).

ExampleName/StructureAnalytical data
122AComplex ethyl ester 2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)butane acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,45 min; m/z=504 (M+H)+.
1H-NMR (400 MHz, DMSO-de): δ [M. D.]=0,77-0,88 (m, approx. 6H), 0,98-of 1.07 (m, approx. 3H), 1,44-of 1.56 (m, 2H), 2,42-2,48 (m, 1H), 2,72 (d, 2H), 3,33-of 3.43 (m, 1H), 3,88-4,01 (m, 2H), 4,12 (d, 1H), 6,98 (DD, 1H), 7,30-value of 7, 37 (m, 2H), 7,40-7,51 (m, 4H), to 9.81 (s, 1H).

Primera

Ethyl-(2R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate

500 mg (2.07 mmol) of a compound ethyl ester of (-)-(2R)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid and 607 mg (2,28 mmol) (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid was dissolved in a mixture of 2.0 ml of DMF and 1.0 ml of pyridine and at Tbrmixed with 1022 mg (2,69 mmol) GATA. The reaction mixture was stirred over night at Tbr. Then was diluted with ethyl acetate, and this solution was sequentially washed with 1 n hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 40:1). Thus was obtained 998 mg (98.4% of theory.) target connection.

LC-MS (Method 6): Rt=1,41 min; m/z=490/492 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 0,99-of 1.09 (m, 6H), 1,54-of 1.74 (m, 1H), 2,59-2,73 (m, 2H), 2,74-2,88 (m, 1H), 3,97 (kV, 2H), 4,12 (d, 1H), 6,99 (DD, 1H), 7,25-value of 7, 37 (m, 2H), 7,40-to 7.55 (m, 4H), 981 (s, 1H).

Example 124A

(+)-Ethyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate

Method A:

1,50 g (6.21 mmol) of a compound ethyl ester of (+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid and of 1.82 g (6,83 mmol) (3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid (as a mixture of diastereomers of about 9:1) was dissolved in a mixture of 6.3 ml of DMF and 3.2 ml of pyridine and at Tbrmixed with 2,83 g (7,45 mmol) GATA. The reaction mixture was stirred over night at Tbr. Then was diluted with ethyl acetate, and this solution was sequentially washed with a saturated solution of ammonium chloride and a saturated solution of sodium chloride. The organic phase was dried over magnesium sulfate and evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 50:1→40:1). The thus obtained mixed fraction (which contained the side diastereoisomer) were separated using repeated chromatography on silica gel (eluent: cyclohexane/ethyl acetate 40:1). In total got of 2.46 g (80.8% of theor.) target connection.

Method:

To and 7.60 g (28,50 mmol) (3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid (as a mixture of diastereomers of about 9:1) was added 30 ml of dichloromethane and 1 drop of DMF. To a solution, cooled to -10°C,was added dropwise from 4.48 ml (to 51.3 mmol) oxalicacid, so that the temperature did not exceed -5°C. the Reaction mixture was stirred 1 h at a temperature of from -5°C to 0°C and then about 30 min without cooling when raising the temperature to Tbrbefore it was evaporated in vacuum. The remainder were transferred to dichloro methane, and the solution was again evaporated in vacuo. After re-conducting this process, the obtained acid chloride briefly dried in a high vacuum and directly injected in further transformation without further purification.

To a solution of 6,05 g (25,03 mmol) of a compound ethyl ester of (+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid in 25 ml of abs. THF was added to 6.1 ml (35,04 mmol) of N,N-diisopropylethylamine. The resulting solution was cooled to -10°C and added dropwise a solution of the above acid chloride (7.85 g, 27.5 mmol) in about 10 ml of abs. THF, and the temperature was maintained below 0°C. Then the reaction mixture was stirred 1 h at a temperature of from -10°C to 0°C and then added three drops of ethyl acetate and water. After 10 minutes, the mixture is optionally diluted with ethyl acetate, sequentially washed with 1 n hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuum. The crude product is in a period of 4 h was stirred in 50 ml of diisopropyl ether. After filtration �must register the solid is again stirred with 40 ml of diisopropyl ether. This obtained solid was thoroughly dried in a high vacuum. Thus was obtained 8,32 g of the target compound. Obtained above the filtrates were combined and evaporated in vacuo. From the residue using chromatography on silica gel (eluent: cyclohexane/ethyl acetate 50:1) has been added to 1.75 g of the product. In total thus received 10,07 g (82,1% of Theor.) target connection.

LC-MS (Method 7): Rt=2,95 min; m/z=490 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 1,00-1,10 (m, 6H), 2,58-of 2.72 (m, 2H), 2,72-2,83 (m, 1H), 3,34-3,44 (m, 1H), 3,96 (kV, 2H), 4,12 (d, 1H), 6,99 (DD, 1H), 7,27-7,38 (m, 2H), of 7.42-7,51 (m, 4H), 9,82 (s, 1H).

[α]D20=+94°, C=0,58, chloroform. Example 125

Complex ethyl ester of (+)-(2S)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)butane acid

To 3.3 g (12,38 mmol) (3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid (as a mixture of diastereomers of about 9:1) was added 13 ml of dichloromethane and 1 drop of DMF. To a solution, cooled to -10°C, was added dropwise to 1.94 ml (22,28 mmol) oxalicacid, so that the temperature did not exceed -5°C. Then the reaction mixture was stirred 1 h at a temperature of from -5°C to 0°C before it was evaporated in vacuum. The remainder were transferred to dichloro methane, and the solution was again evaporated in vacuo. After re-conducted�of this process, the obtained acid chloride briefly dried in a high vacuum and directly injected in further transformation without further purification.

To a solution of 1.22 g (4.77 mmol) of (+)-ethyl-(2S)-2-(3-amino-4-chlorbenzyl)butanoate in 4.8 ml of abs. THF was added 1.2 ml (6,68 mmol) of N,N-diisopropylethylamine. The resulting solution was cooled to -10°C and added dropwise a solution of acid chloride obtained above (1.5 g, the 5.25 mmol) in 2 ml of abs. THF, and the temperature was maintained below 0°C. Then the reaction mixture was stirred 1 h at a temperature of from -10°C to 0°C and then added three drops of ethyl acetate and water. After 10 minutes, the mixture is optionally diluted with ethyl acetate, sequentially washed with 1 n hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuum. The desired product was isolated by chromatography of the residue on silica gel (eluent: cyclohexane/ethyl acetate 40:1). Was obtained 2.13 g (88,5% of Theor.) target connection.

LC-MS (Method 6): Rt=1,46 min; m/z=504 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,76-0,88 (m, 6H), of 1.02 (t, 3H), 1,45-of 1.56 (m, 2H), 2,47 (d, 1H), 2,72 (d, 2H), 3,34-of 3.43 (m, 1H), 3,93 (square d, 2H), 4,12 (d, 1H), 6,98 (DD, 1H), 7,29-7,38 (m, 2H), 7,40-7,52 (m, 4H), 9,81 (C, 1H).

[α]D20=+And 62.6°, C=0,515, chloroform.

In accordance with the same method it was received the following connection:

Example 126A

Complex ethyl ester of (+)-(2R)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzylmalonate acid

LC-MS (Method 6): Rt=1,46 min; m/z=504/506 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), from 0.84 (t, 3H), was 1.04 (t, 3H), 1,46-of 1.56 (m, 2H), of 2.45-2.49 USD (m, 1H), 2,70-to 2.74 (m, 2H), 3,34-of 3.42 (m, 1H), 3,95 (kV, 2H), 4,12 (d, 1H), 6,98 (DD, 1H), 7,30-value of 7, 37 (m, 2H), Of 7.42-7,50 (m, 4H), to 9.81 (s, 1H).

[α]D20=+52,3°, C=0,485, chloroform.

Example 127A

Ethyl-2-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-lrans-cyclopropanecarboxylate

To a solution of 90 mg (0.34 mmol) (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid in 1.5 ml of a mixture of 4:1 from DMF and pyridine was added 167 mg (0,44 mmol) GATA. After 30 minutes of mixing at Tbrto this was added 83 mg (from 0.37 mmol) RAC.-ethyl-2-[3-amino-4-fluorophenyl]-TRANS-cyclopropanecarboxylate. The reaction mixture was stirred over night at Tbrthen was diluted with ethyl acetate (about 50 ml) and washed with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated, and the residue was purified using preparative HPLC. Was obtained 123 mg (77% of theory.) target connection.

LC-MS (Method 6): Rt=1,35 min; m/z=472 (M+H)+.

1H-NMR (400 MHz, DMSO-d5): δ [M. D.]=0,79 (d, 3H), 1,19 (t, 3H), 1,25-1,34 (m, 1H), of 1.42 (dt, 1H), 1,73-of 1.91 (m, 1H), 2,31-of 2.45 (m, 1H), 3,96-4,20 (m, 3H), 6,83-7,00 (m, 1H), 7,13 (DD, 1H), 7,45 (s, 4H), EUR 7.57-to 7.68 (m, 1H), To 10.06 (s, 1H).

Example 128�

Ethyl-threo-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylbutanoate

To a solution of 35.5 mg (0,13 mmol) (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid and 0.98 ml of DMF was added to 0.15 ál (0,19 mmol) of pyridine and 75.8 mg (0.2 mmol) GATA. The reaction mixture was stirred 30 min at Damn., and then there was added 35 mg (0.15 mmol) of RAC.-the threo-ethyl-3-[3-amino-4-fluorophenyl]-2-methylbutanoate. After stirring over night the reaction mixture was directly purified using preparative HPLC. There was obtained 34 mg (52% of theory.) target connection.

LC-MS (Method 5): Rt=2,89 min; m/z=488 (M+H)+.

Example 129A

Ethyl Erythro-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylbutanoate

To a solution of 22.3 mg (84 μmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid 0,62 ml of DMF was added to 9.5 ál (117 mmol) of pyridine and 47.7 mg (125 μmol) GATA. The reaction mixture was stirred 30 min at Damn., and then there was added 22 mg (92 μmol) of RAC.-Erythro-ethyl-3-[3-amino-4-fluorophenyl]-2-methylbutanoate. After stirring over night the reaction mixture was directly purified using preparative HPLC. Received of 10.7 mg (24% of Theor.) target connection.

LC-MS (Method 4): Rt=1,57 min; m/z=488 (M+H)+.

Example 130A

tert-butyl-3(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-cyanophenyl)propanoate

To a solution of 41,3 mg (0,16 mmol) (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid of 1.16 ml of dichloromethane at 0°C was added 155 μl (0,31 mmol) of 2 M solution of oxalicacid in dichloromethane and a drop of DMF. After 1 h stirring at 0°C the reaction mixture was evaporated, the remaining residue was dissolved in 1 ml THF was added 32 μl (0,19 mmol) of N,N-diisopropylethylamine, cooled to 0°C and added a solution of 42 mg (0.17 mmol) of tert-butyl-3-(3-amino-4-cyanophenyl)propanoate in 2 ml of THF. The reaction mixture was stirred over night at Tbr. Then this mixture was poured in 10 ml of water and was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated. The residue was purified using preparative HPLC. There was obtained 16.5 mg (22% of Theor.) target connection.

LC-MS (Method 7): Rt=2,86 min; m/z=439 (MtBu)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,81 (d, 3H), 1,27-of 1.35 (m, 9H), 2,83 (m, 2H), 4,01 (d, 1H), 7,21 (DD, 1H), 7,30 (s, 1H), 7,40-7,52 (m, 4H), 7,69 (d, 1H), 10,47 (s, 1H).

Example 131A

Methyl-(2E)-3-(2-methyl-3-nitrophenyl)acrylate;

In an argon atmosphere was pinned achieved sales of 119.5 g (of 1.39 mol) of a compound methyl ester of acrylic acid to a mixture of 100 g (0,463 mol) of 2-bromo-6-nitrotoluene, 323 ml (2,31 mol) of triethylamine, 28,2 g (92,6 mmol) tri-2-tolylphosphino and 10.4 g (46.3 mmol) of palladium acetate (II) in 2.0 if�RAH DMF and then the mixture was stirred for 36 h at 125°C. After cooling to room temperature the reaction mixture was stirred with 4 liters of a saturated aqueous solution of ammonium chloride and three times was extracted with a total of 5 liters of diethyl ether. The combined organic phases were washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration the solvent was removed in vacuum to dryness. The obtained residue was purified using flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate 6:1). The product was stirred with heptane, and the precipitated solid was filtered with suction and dried in a high vacuum. Received of 48.7 g of target compound (46,6% of Theor.).

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=2,41 (s, 3H), 3,76 (s, 3H), 6,63 (d, 1H), of 7.48 (t, 1H), 7,84-to 7.95 (m, 2H), 8,00 (d, 1H).

Example 132A

Methyl-3-(3-amino-2-methylphenyl)propanoate

Of 48.7 g (220,1 mmol) of methyl-(2E)-3-(2-methyl-3-nitrophenyl)acrylate was dissolved in 2.2 liters of methanol, and the solution was gidrirovanie apparatus for continuous hydrogenation of ("H-Cube midi" company Thales Nano, Budapest) at a flow rate of 6-10 ml/min and reaction temperatures of 35-40°C and at a maximum pressure of hydrogen. After finishing the interaction of a solution containing the product was evaporated in vacuum. Received 40,0 g of the target product in the form of solids (92,1% of Theor.).

1-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,97 (s, 3H), of 2.45 (t, 2H), 2,78 (t, 2H), 3,58 (s, 3H), 4.75 in (s, 2H), 6,37 (d, 1H), 6,50 (d, 1H), of 6.79 (t, 1H).

Example 133A

Methyl-3-(3-amino-4-chloro-2-methylphenyl)propanoate

To a solution of 2.0 g (10.3 mmol) of methyl-3-(3-amino-2-methylphenyl)propanoate in 10 ml of acetonitrile at Damn. added to 1.38 g of 10.3 mmol) N-chlorosuccinimide. The reaction mixture was stirred 30 min, then was diluted with ethyl acetate. This mixture is then washed us. the sodium bicarbonate solution and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. From the crude product after chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1) identified 279 mg of the desired product (11.8% of Theor.).

LC-MS (Method 4): Rt=1,11 min; m/z=228 (M+H)+.

1H-NMR (500 MHz, DMSO-d6): δ [M. D.]=2,06 (s, 3H), 2,46 (m, 2H), 2,78 (t, 2H), 3,58 (s, 3H), 4,94 (s, 2H), to 6.42 (d, 1H), 6,98 (d, 1H).

Primera

3-Bromo-6-chloro-2-methylaniline

To a solution of 12.0 g (for 64.5 mmol) 3-bromo-2-methylaniline in 150 ml of acetonitrile at Damn. added 8,61 g (for 64.5 mmol) N-chlorosuccinimide. The reaction mixture was stirred 7 h at 60°C, and after cooling was evaporated in vacuum. The remainder were transferred to dichloro methane, and the mixture was successively washed with us. the sodium bicarbonate solution and us. a solution of sodium chloride, dried over sodium sulfate and UPA�ivali in a vacuum. From the crude product after chromatography on silica gel (eluent: cyclohexane/ethyl acetate 40:1 to 20:1) allocated to 3.78 g of the target product (26.6% of theor.).

GC-MS (Method 1): Rt=5,07 min; m/z=218/220 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=2,24 (s, 3H), 5,39 (s, 2H), 6,80 (d, 1H), 7,03 (d, 1H).

Example 135A

tert-butyl(2E)-3-(3-amino-4-chloro-2-methylphenyl)-2-methyl

and

tert-butyl-2-(3-amino-4-chloro-2-methylbenzyl)acrylate;

and

1,50 g (6,80 mmol) 3-bromo-6-chloro-2-methylaniline, 2,90 g (20,4 mmol) of tert-butyl methacrylate and 4.74 ml (34,0 mmol) of triethylamine was dissolved in 10.0 ml of DMF. The reaction solution was vacuumed three times and each time was purged with argon. After adding 152,7 mg (0,68 mmol) of palladium acetate(II) and 414,1 mg (1,36 mmol) tri-2-tolylphosphino again was twice evacuated and purged with argon. Then the reaction mixture was stirred for 2 h at 150°C. After cooling, the mixture was filtered through celite, and the residue was further washed with DMF. The filtrate was concentrated in vacuum and the residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 100:1). Received 1.59 g of a mixture of both compounds (a ratio of about 2:1, 83% of Theor.).

LC-MS (Method 4): Rt=1,45 min; m/z=226 (M-C4H8) and Rt=1,49 min; m/z=282 (M+H)+.

1H-NMR (400 MHz, D�WITH-d 6): tert-butyl(2E)-3-(3-amino-4-chloro-2-methylphenyl)-2-methyl acrylate: δ [M. D.]=1,49 (C, 9H), of 1.75 (d, 3H), 2,02 (s, 3H), 5,12 (s, 2H), 6,44 (d, 1H), 7,11 (d, 1H), 7,51 (s, 1H).

1H-NMR (400 MHz, DMSO-d6): tert-butyl-2-(3-amino-4-chloro-2-methylbenzyl)acrylate, δ [M. D.]=of 1.42 (s, 9H), of 1.98 (s, 3H), of 3.45 (s, 2H), 4,97 (s, 2H), further 5.15 (d, 1H), 6,01 (d, 1H), 6,38 (d, 1H), 7,02 (d, 1H).

Example A

(+/-)-tert-butyl-3-(3-amino-4-chloro-2-methylphenyl)-2-methylpropanoate

To 354 mg (14.6 mmol) of magnesium turnings and a few crystals of iodine was added a solution of 1.58 g (5,61 mmol) of a mixture of tert-butyl(2E)-3-(3-amino-4-chloro-2-methylphenyl)-2-methyl acrylate and tert-butyl-2-(3-amino-4-chloro-2-methylbenzyl)acrylate (Example 135A) in 5,0 ml of methanol. This mixture was stirred at Tbr(first cooling) during the night. Then when cooled with ice was added 50 ml of 1 n hydrochloric acid. Then, through the addition of 10% aqueous sodium hydroxide solution the pH of the mixture was set approximately equal to 10. The mixture three times were extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated in vacuum. From the crude product after chromatography on silica gel (eluent: cyclohexane/ethyl acetate from 50:1 to 40:1) identified 962 mg of the target product (60.5% of theory.).

LC-MS (Method 9): Rt=2,30 min; m/z=284 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 1.02 (d, 3H), 1,32 (s, 9H), of 2.06 (s, 3H), 246 (DD, 1H), 2,80 (DD, 1H), 4,94 (ush. s, 2H), 6,38 (d, 1H), 6,97 (d, 1H).

The racemate obtained above was separated into the enantiomers using preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm×20 mm; flow: 20 ml/min; detection: 220 nm, injection volume: 0,28 ml; temperature: 22°C; eluent: 93% of isohexane/7% isopropanol]. Based on 962 mg of the racemate was obtained 434 mg of enantiomer 1 (Example 137A) and 325 mg of enantiomer 2 (Example A):

Example 137A

(-)-Tert-butyl-(2R)-3-(3-amino-4-chloro-2-methylphenyl)-2-methylpropanoate

Output:434 mg

LC-MS (Method 4): Rt=To 1.44 min; m/z=284 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,03 (d, 3H), 1,32 (s, 9H), of 2.06 (s, 3H), 2,46 (DD, 1H), 2,80 (DD, 1H), is 4.93 (s, 2H), 6,38 (d, 1H), 6,97 (d, 1H).

[α]D20=-37,3°, C=0,455, chloroform.

Primera

Output: 325 mg

LC-MS (Method 4): Rt=To 1.44 min; m/z=284 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,03 (d, 3H), 1,32 (s, 9H), of 2.06 (s, 3H), 2,46 (DD, 1H), 2,80 (DD, 1H), is 4.93 (s, 2H), 6,38 (d, 1H), 6,97 (d, 1H).

[α]D20=+35,0°, C=0,455, chloroform.

Example A

Ethyl-4,4,4-Cryptor-3-(4-fluoro-3-nitrophenyl)but-2-ENOAT

It chilled in an ice bath suspension of 1.86 g (60% suspension in mineral oil, to 46.4 mmol) of sodium hydride in a mixture of 70 ml of THF and 20 ml of DMF was slowly pinned to 10.9 g (to 48.5 mmol) of complex etiolog� ether diethylphosphonoacetate acid. After the addition the mixture was stirred for another 30 min at 0°C before it was added 10.0 g (42.2 per mmol) 2,2,2-Cryptor-1-(4-fluoro-3-nitrophenyl)ethanone. This reaction mixture was stirred over night at Tbrand then poured into water. Three times were extracted with ethyl acetate, and the combined organic phases was evaporated in vacuum. From the crude product after chromatography on silica gel (eluent: cyclohexane/ethyl acetate from 20:1 to 10:1) provided of 9.23 g of the target product (71,2% of Theor.).

GC-MS (Method 1): Rt=4,51 min; m/z=262 (M-C2H5O)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,04 (t, 3H), 4,03 (kV, 2H), of 6.96 (d, 1H), 7.67 per-7,76 (m, 1H), 7,78-7,86 (m, 1H), 8,16 (DD, 1H).

Example 140A

(+/-)-Ethyl-3-(3-amino-4-fluorophenyl)-4,4,4-triptoreline

5.0 g (16.3 mmol) of ethyl-4,4,4-Cryptor-3-(4-fluoro-3-nitrophenyl)but-2-enoate was dissolved in 133 ml of ethanol in an argon atmosphere was added 866 mg of palladium on coal (10%). The reaction mixture was intensively stirred over night at Tbrin hydrogen atmosphere (normal pressure). After this was filtered through celite, and the residue was further washed with ethyl acetate. The filtrate was concentrated in vacuo, and the resulting product was purified using chromatography on silica gel (eluent: cyclohexane/ethyl acetate 50:1). Got 3.91 g of the target product (85.9% of theor.).

LC-MS (Method 6): Rt+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,08 (t, 3H), 2,85 (DD, 1H), 2,99 (DD, 1H), 3,81-3,92 (m, 1H), 3,94-4,07 (m, 2H), to 5.21 (s, 2H), 6,40-to 6.58 (m, 1H), was 6.77 (DD, 1H), of 6.96 (DD, 1H).

Example 141A

Tert-butyl-2-methylbutanoate

15.0 g (124,4 mmol) of acid chloride of 2-metilmaslyanaya acid was dissolved in 150 ml of abs. THF, cooled to 0°C and dropwise added 114 ml (114 mmol) of a 1 M solution of tert-butylate potassium in THF. After the addition was stirred 1 h at 0°C, then 5 h at Tbrbefore the vacuum was removed about half of the solvent. After addition of diethyl ether with vigorous stirring was added dropwise us. the sodium bicarbonate solution. After phase separation, the aqueous phase was extracted with diethyl ether and the combined organic phases were washed with us. the sodium carbonate solution, dried over sodium sulfate and evaporated in vacuum. The crude product was purified by distillation in vacuum (19 mm Hg.CT., 40-45°C). In total, he received a 6.35 g of the target product (32,3% of Theor.).

GC-MS (Method 1): Rt=1,53 min; m/z=85.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,84 (m, 3H), 1,01 (d, 3H), 1,33-of 1.41 (m, 1H), of 1.39 (s, 9H), 1,48-of 1.55 (m, 1H), 2,13 and 2.26 (m, 1H).

Example 142a is

2-Bromo-4-(methyl bromide)-1-chlorobenzene

Stage 1:

199,0 g (0,845 mol) of 3-bromo-4-chlorobenzoic acid was dissolved in 2.5 lit�Oh THF, was cooled to -10°C and at this temperature was added 1,69 liters (1,69 mol) of a 1 M solution of borane in THF. The reaction mixture was overnight heated to Tbrbefore added a saturated aqueous solution of ammonium chloride. After adding water, was extracted with twice with ethyl acetate, the combined organic phases were dried over magnesium sulfate and evaporated in vacuum. Was obtained in the form of a crude product 206 g of (3-bromo-4-chlorophenyl)methanol, which was used in next step without further purification.

Stage 2:

260 g (approximately 1.05 mol) of crude (3-bromo-4-chlorophenyl)methanol was dissolved in 2.86 liters of dichloromethane, cooled to -5°C and slowly added 127,1 g (of 44.6 ml, 460 mmol) of tribromide phosphorus. After the addition was stirred for another 1 h at -5°C before it was diluted with dichloromethane and water. The organic phase was separated, dried over magnesium sulfate and evaporated in vacuum. Received in the form of raw product to 280.5 g (approximately 84% of Theor.) 2-bromo-4-(methyl bromide)-1-chlorobenzene.

GC-MS (Method 1): Rt=And 5.36 min; m/z=281/283/285 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=4,71 (s, 2H), 7,49 (DD, 1H), 7,63 (d, 1H), to 7.89 (d, 1H).

Example 143A

(+/-)-Tert-butyl-2-(3-bromo-4-chlorbenzyl)-2-methylbutanoate

Of 5.8 ml (to 41.6 mmol) of Diisopropylamine in an argon atmosphere was dissolved in 50 ml dry THF and cooled to -30°C. the Pinned�Ali of 16.6 ml (to 41.6 mmol) solution of n-utility (2.5 M solution in hexane), and the resulting mixture was warmed to 0°C before it was cooled to -70°C. was Added a solution of 5.06 g (32,0 mmol) tert-butyl-2-methylbutanoate in 20 ml of THF, and the reaction temperature maintained below -60°C. After 4 h stirring at -60°C was added a solution of 10.0 g (35,2 mmol) 2-bromo-4-(methyl bromide)-1-chlorobenzene in 30 ml of THF, and again temperature was maintained below -60°C. Then the reaction mixture during the night was slowly heated up to Tbrbefore this was added a saturated aqueous solution of ammonium chloride and ethyl acetate. After phase separation, the aqueous phase was twice extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 100:1). Got the 7.62 g (65,9% of Theor.) target connection.

GC-MS (Method 1): Rt=6,52 min; m/z=306 (M-C4H7)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,83 (t, 3H), 0,93 (s, 3H), 1,32-of 1.45 (m, 10H), 1,60-of 1.73 (m, 1H), 2,62 (d, 1H), 2,91 (d, 1H), 7,18 (DD, 1H), 7,47-7,56 (m, 2H).

Example 144A

(+/-)-Gret-butyl-2-[3-(benzylamino)-4-Chlorobenzyl]-2-methylbutanoate

In an argon atmosphere in dried flask was weighed 1.59 g (16,6 mmol) of tert-butylate sodium and added 34.6 per ml of abs. toluene. To that one after another was added 5.0 g (13,8 mmol) (+/-)-tert-butyl-2-(3-bromo-4-chlorobenzo�)-2-methylbutanoate, 1.8 ml (16,6 mmol) of benzylamine, 633 mg (0.69 mmol) of Tris(dibenzylideneacetone)diplodia and 344 mg (0,55 mmol) (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl. Then the reaction mixture was stirred for 2.0 hours at 110°C. After cooling, this reaction mixture is added saturated aqueous solution of ammonium chloride and ethyl acetate and filtered with suction through kieselguhr. After phase separation, the organic phase was washed with us. solution of ammonium chloride and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 80:1). Received of 4.44 g of the target compound in a little more cleaned (about 83% of Theor.).

LC-MS (Method 6): Rt=1,57 min; m/z=388 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,70 (t, 3H), of 1.13-1,22 (m, 1H), of 1.35 (s, 9H), of 1.39 (s, 3H), of 1.39-1,50 (m, 1H), 2,42 (d, 1H), 2,66 (d, 1H), 4,26-to 4.46 (m, 2H), 6,00 (t, 1H), of 6.26-6.35 mm (m, 1H), 7,11 (d, 1H), made 7.16 interest-7.23 percent (m, 1H), 7,28-7,34 (m,4H), was 7.45 and 7.55 (m, 1H).

Example 145A

(+/-)-tert-butyl-2-(3-amino-4-chlorbenzyl)-2-methylbutanoate

2.20 g (approximately 5,67 mmol) (+/-)-tert-butyl-2-[3-(benzylamino)-4-Chlorobenzyl]-2-methylbutanoate was dissolved in 130 ml of ethyl acetate was added 100 mg of palladium on coal (10%). The reaction mixture was stirred over night at Tbrin the hydrogen atmosphere at normal pressure. �this autumn, the reaction mixture was filtered with suction through kieselguhr, the residue was thoroughly washed with ethyl acetate, and the combined filtrate was evaporated. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate from 50:1 to 30:1). Received 924 mg (54,7% of Theor.) target connection.

LC-MS (Method 6): Rt=To 1.34 min; m/z=298 (M+H)+.

The racemate obtained above was separated into the enantiomers using preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm×20 mm; flow: 20 ml/min; detection: 220 nm, injection volume: 0,30 ml; temperature: 35°C; eluent: 70% of isohexane/30% ethanol]. On the basis of 924 mg of racemate was obtained 405 mg of enantiomer 1 (Example 146A) and 403 mg of enantiomer 2 (Example 147A):

Example 146A

(-)-RET-butyl-2-(3-amino-4-chlorbenzyl)-2-methylbutanoate (enantiomer 1)

Yield: 405 mg

LC-MS (Method 6): Rt=To 1.32 min; m/z=298 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,81 (t, 3H), 0,93 (s, 3H), 1,28-of 1.37 (m, 1H), 1,38 (s, 9H), 1,59-1,71 (m, 1H), 2,45 (d, 1H), 2,74 (d, 1H), 5,14-5,22 (m, 2H), of 6.31 (DD, 1H), to 6.57 (d, 1H), to 7.04 (d, 1H).

[α]D20=-11,8°, C=0,50, chloroform.

Example 147A

(+)-tert-butyl-2-(3-amino-4-chlorbenzyl)-2-methylbutanoate (enantiomer 2)

Output:403 mg LC-MS (Method 6): Rt=To 1.32 min; m/z=298 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,75-0,85 (m, 3H), 0,93 (s, 3H), 1,30-1,37 (m, 1H), of 1.39 (s, 9H), 1,58-1,70 (m, 1H), 2,45 (d, 1H), 2,74 (d, 1H), 5,09-5,2 (m, 2H), of 6.31 (DD, 1H), to 6.57 (d, 1H), to 7.04 (d, 1H).

[α]D20=+12,0°, C=0,420, chloroform.

Example A

2,2,2-Cryptor-1-(3-nitrophenyl)alanon

20,0 g (USD 114.9 mmol) of 2,2,2-triptoreline was placed in 80 ml of conc. sulfuric acid and cooled to -10°C. To this mixture was pinned pre-cooked at -10°C a solution of 4.8 ml (114,8 mmol) of nitric acid in 20 ml of conc. sulfuric acid so that the reaction temperature did not exceed -5°C. Upon completion of addition the reaction mixture was stirred 1 h at a temperature between -10°C and 0°C, and then carefully poured into ice water. By adding 50% aqueous sodium hydroxide solution was set the pH of the mixture of about 9-10. Three times were extracted with ethyl acetate, the combined organic phases were dried over magnesium sulfate and evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: first cyclohexane/dichloro methane from 2:1 to 1:1, pure dichloro methane). Was obtained 19.2 g of the target product (76.2% of theor.).

LC-MS (Method 6): Rt=0,81 min; m/z=236.

GC-MS (Method 1): Rt=3,19 min; m/z=150 (M-CF3)+.

Example 149A

To a cooled to 0°C suspension 4,41 g (60% suspension in mineral oil, of 110.4 mmol) of sodium hydride in a mixture of 37.2 ml THF and 37,2 ml of DMF was dripped 25,9 ml (of 110.4 mmol) of tert-b�Teal(diethoxyphosphoryl)acetate. After 30 min, to this was added 18.6 g (to 84.9 mmol) of 2,2,2-Cryptor-1-(3-nitrophenyl)ethanone, the cooling bath was removed, and the reaction mixture was stirred 2 h at Tbr. Then the reaction mixture was poured into water and after saturation with sodium chloride three times were extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate from 100:1 to 20:1). Got 18,0 g of the desired product as a mixture of E/Z-isomers (66,8% of Theor.).

LC-MS (Method 6): Rt=1,25 min; ionization is absent.

MS (DCI): m/z=335 (M+H2O)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,17/1,50 (2, collab, 9H), 6,93/7,14 (2D, joint., 1H), 7,74-7,94 (m, 2H), 8,16/8,23 (2s, joint., 1H), 8,30-to 8.42 (m, 1H).

Example 150A

(+/-)-Tert-butyl-3-(3-Dapsone base)-4,4,4-triptoreline

18,0 g (56,7 mmol) of tert-butyl(2E/Z)-4,4,4-Cryptor-3-(3-nitrophenyl)but-2-enoate was dissolved in 100 ml of ethanol and removed the oxygen with argon. After adding 1.21 g of palladium on coal (10%) the mixture was intensively stirred at Tbrovernight in a hydrogen atmosphere at normal pressure. Then the reaction mixture was filtered through celite, the residue washed thoroughly with ethanol, the filtrate was concentrated in vacuo, and the resulting product over night dried in high�commercial vacuum. Received of 13.7 g of the desired product (83,7% of Theor.).

LC-MS (Method 6): Rt=To 1.02 min; m/z=290 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,27 (s, 9H), 2,70 (DD, 1H), 2,89 (DD, 1H), 3,62-with 3.79 (m, 1H), 5,11-5,17 (m, 2H), 6,43-6,56 (m, 3H), of 6.99 (t, 1H).

Example 151A

(+/-)-tert-butyl-3-(3-amino-4-chlorophenyl)-4,4,4-triptoreline

13.6 g (47,0 mmol) (+/-)-tert-butyl-3-(3-Dapsone base)-4,4,4-tricorporate was placed in 100 ml of acetonitrile and at Tbradded 6.28 g (47,0 mmol) N-chlorosuccinimide. The reaction mixture was first stirred for 12 h at 60°C and then was allowed to stand 3 days at Tbr. After evaporation in vacuum the residue was purified using chromatography on silica gel (eluent: cyclohexane/ethyl acetate 100:1) and furnish the desired target product. Got 4,49 g of target compound (29.5% of Theor.).

LC-MS (Method 6): Rt=1,17 min; m/z=324 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,27 (s, 9H), of 2.72 (DD, 1H), of 2.91 (DD, 1H), 3,74-3,86 (m, 1H), 5,43 (s, 2H), 6,55 (DD, 1H), of 6.79 (d, 1H), 7,17 (d, 1H).

The racemate obtained above was separated into the enantiomers using preparative HPLC on a chiral phase [column: Daicel Chiralpak OJ-H, 5 μm, 250 mm×20 mm; flow rate: 15 ml/min; detection: 220 nm, injection volume: 0.20 ml; temperature: 35°C; eluent: 70% of isohexane/30% ISO-propanol]. Based on 4,49 g of racemate was obtained 2,02 g of enantiomer 1 {Example 152A) and 2.04 g of enantiomer 2 (Example 153�):

Example 152A

(-)-Tert-butyl-(3R)-3-(3-amino-4-chlorophenyl)-4,4,4-triptoreline

Output: 2,02 g

LC-MS (Method 6): Rt=1,17 min; m/z=324 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,27 (s, 9H), of 2.72 (DD, 1H), of 2.91 (DD, 1H), 3.75 to of 3.85 (m, 1H), 5.40 to-5,46 (m, 2H), 6,55 (DD, 1H), of 6.79 (d, 1H), 7,17 (d, 1H).

[α]D20=-69,4°, C=0,520, chloroform.

Example 153A

Output: 2,04 g

LC-MS (Method 6): Rt=1,17 min; m/z=324 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,27 (s, 9H), 2,71 (DD, 1H), of 2.91 (DD, 1H), 3,74-3,86 (m, 1H), 5,38-5,46 (m, 2H), 6,55 (DD, 1H), 6,73-6,80 (m, 1H), 7,17 (d, 1H).

[α]D20=+66,3°, C=0,495, chloroform.

Example 154

4.0 g (35,0 mmol) cyclobutylamine acid was dissolved in 20 ml of dichloromethane, was added a drop of DMF and, after cooling to 0°With added dropwise 4.0 ml (45,6 mmol) dichlorohydrin oxalic acid. The reaction mixture was stirred 2 h at a temperature between 0°C and 10°C and then was evaporated in vacuum on the cold. The residue was extracted in abs.dichloro methane and running in the cold was evaporated in vacuum. This process was repeated one more time before the acid chloride obtained a short time, for 5 min, dried in a high vacuum. Then the precipitate was transferred to a 20 ml abs. THF, cooled to 0°C and dropwise added 28 ml (28 mmol) of a 1 M solution of tert-butylate� potassium in THF. Upon completion of the addition the cooling was removed and was further stirred for 1 h at Tbrbefore it was poured into water. Three times was extracted with dichloro-methane, and the combined organic phases were dried over magnesium sulfate and evaporated in vacuum. Received 3,88 g of crude desired product (approximately 65% of Theor.).

GC-MS (Method 1): Rt=2,29 min; m/z=97 (M-C3H5O2)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,38 (s, 9H), 1,60-1,89 (m, 5H), 1,95-2,11(m,2H), 2,28 (d,2H).

Example 155A

Tert-butylcyclopentadienyl

10.0 g (99.9 mmol) cyclopropylacetic acid was dissolved in 50 ml of dichloromethane, was added a drop of DMF and after cooling to 0°C was dropwise added to 9.6 ml (109,9 mmol) dichlorohydrin oxalic acid. The reaction mixture was stirred 2 h at a temperature between 0°C and 10°C and then was evaporated in vacuum on the cold. Balance a short time (approximately 5 min) was dried in a high vacuum, then transferred to 20 ml of abs. THF, cooled to 0°C and dropwise added 89,9 ml (89,9 mmol) of a 1 M solution of tert-butylate potassium in THF. Upon completion of the addition the cooling was removed and was further stirred for 2 h at Tbrbefore was largely removed in vacuo THF (pressure to 150 mm Hg.CT., water bath of about 30°C). To the residue was added diethyl ether and 0.5 N aqueous solution �Drago soda. After phase separation, the organic phase was dried over magnesium sulfate, was evaporated in vacuo, and the residue was briefly dried in a high vacuum. Received 8.38 g of the crude target product (about 53% of Theor.).

GC-MS (Method 1): Rt=1,80 min; m/z=100 (M-C4H8)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,05-0,14 (m, 2H), 0,38-0,51 (m, 2H), 0,81-0,99 (m, 1H), 1,40 (s, 9H), and 2.10 (d, 2H).

Example 156A

(+/-)-Tert-butyl-3-(3-bromo-4-chlorophenyl)-2-cyclobutylamine

2.9 ml (20.8 mmol) of Diisopropylamine in an argon atmosphere was dissolved in 30 ml dry THF and cooled to -20°C. was Pinned to 8.3 ml (20.8 mmol) solution of n-utility (2.5 M solution in hexane) and the resulting mixture was stirred 30 min at -20°C before it was cooled to -78°C. At this temperature, was added a solution of 2,60 g (approximately 15.3 mmol, crude) of tert-butylacetoacetate in 10 ml of THF. After 4 h stirring at -78°C was added a solution of 3.95 g (13,9 mmol) 2-bromo-4-(methyl bromide)-1-chlorobenzene in 10 ml of THF. This reaction mixture during the night was slowly heated up to Tbrbefore added a saturated aqueous solution of ammonium chloride. Three times were extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated in vacuum. The residual solid stirred in 30 ml of a mixture of cyclohexane/dichlormid�n (1:1) and filtered. It is solid again stirred in 10 ml of a mixture of cyclohexane/dichloro methane (1:1) and again filtered, this process was repeated one more time. All the filtrates were collected, combined and evaporated under vacuum. Then, this precipitate was further purified by chromatography on silica gel (eluent: from pure cyclohexane to cyclohexane/dichloro methane from 20:1 to 10:1). Thus received 2,24 g of target compound (43,2% of Theor.).

GC-MS (Method 1): Rt=At 6.92 min; m/z=318 (M-C4N7)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,27 (s, 9H), 1,71-of 1.84 (m, 4H), 1,90-1,94 (m, 1H), 1,96-2,04 (m, 1H), 2,33-of 2.44 (m, 1H), 2,53-2,60 (m, 1H), 2,61-2,71 (m, 1H), 7,22 (DD, 1H), 7,52 (d, 1H), EUR 7.57 (d, 1H).

In a similar manner was obtained the following example:

Example 157A

Tert-butyl-3-(3-bromo-4-chlorophenyl)-2-cyclopropylamino

Based on tert-BUTYLCARBAMATE and 2-bromo-4-(methyl bromide)-1-chlorobenzene, received 3,13 g of target compound (45% of theory.).

GC-MS (Method 1): Rt=6,41 min; m/z=301/304 (M-C4H8)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,22 (TT, 2H), 0,40-0,50 (m, 2H), of 0.82 with 0.93 (m, 1H), of 1.28 (s, 9H), 1,82-of 1.88 (m, 1H), 2,81-2,89 (m, 2H), 7,24 (DD, 1H), 7,52 (d, 1H), 7,60 (d, 1H).

Primera

(+/-)-Tert-butyl-3-[3-(benzylamino)-4-chlorophenyl]-2-cyclobutylamine

To a dry flask in an argon atmosphere was weighed RUB 848.6 mg (8,83 mmol) tre�-butylate sodium, 337 mg (0,39 mmol) of Tris(dibenzylideneacetone)diplodia and 183 mg (0,29 mmol) rat.-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, kept 10 min in a high vacuum, and then filed argon. To that one after another was added 5 ml of abs.toluene, 0,96 ml (8,83 mmol) benzylamine and the solution of 2.75 g (of 7.36 mmol) (+/-)-tert-butyl-3-(3-bromo-4-chlorophenyl)-2-cyclobutylamine in 5 ml of abs. toluene. The reaction mixture was evacuated three more times and, accordingly, each time again filed argon, and then 3 h stirred at 110°C. After cooling, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride. Three times were extracted with ethyl acetate. Organic phases were combined, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/dichloro methane from 4:1 to 2:1, then pure dichloro methane). Got 1.95 g of the target compound (65,1% of Theor.).

LC-MS (Method 4): Rt=A 1.90 min; m/z=400 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1.26 in (s, 9H), 1,54-of 1.76 (m, 4H), 1,78-to 1.86 (m, 2H), 2,19-of 2.38 (m, 2H), 2,38-of 2.45 (m, 2H), 4,33-of 4.44 (m, 2H), 5,95 (m, 1H), 6,25-6,40 (m, 2H), 7,11 (d, 1H), 7.23 percent (TD, 1H), 7,27-value of 7, 37 (m, 4H).

In a similar manner was obtained the following example:

Primera

Tert-butyl-3-[3-(benzylamino)-4-chlorophenyl]-2-cyclopropylamino

Based on tert-butyl-3-(3-bromo-4-chlorophenyl)-2-cyclopropylamino� and benzylamine received 2,51 g of target compound (74,7% of Theor.).

LC-MS (Method 6): Rt=1,55 min; m/z=386 (M+H)+.

Example 160A

1.85 g (4,63 mmol) (+/-)-tert-butyl-3-[3-(benzylamino)-4-chlorophenyl]-2-cyclobutylamine was dissolved in 10 ml of ethyl acetate, removed the oxygen with argon and was added 98 mg (0,093 mmol) of palladium on coal (10%). The reaction mixture was stirred for 4 h at Tbrin the hydrogen atmosphere at normal pressure, and then allowed to stand on the weekend. The mixture was filtered through celite, the residue was further washed with ethyl acetate, the filtrate was concentrated in vacuo, and the resulting filtrate from the residue dried in a high vacuum. This residue (a mixture of approximately 1:1 from the starting materials and the desired product) was re-dissolved in about 10 ml of ethyl acetate, removed the oxygen with argon, and again was added 98 mg (0,093 mmol) of palladium on coal (10%). This reaction mixture was stirred for 4 h at Tbrin the hydrogen atmosphere at normal pressure. Then filtered through celite, optionally washed with ethyl acetate, the filtrate was concentrated in vacuo, and the residue was dried in high vacuum. After chromatographic purification on silica gel (eluent: cyclohexane/ethyl acetate 20:1) was obtained 1.12 g of the desired product (78.2% of theor.).

LC-MS (Method 6): Rt=To 1.34 min; m/z=310 (M+H)+254 (M-C4H7)+.

1H-NMR (400 MHz, DMSO-d 6): δ [M. D.]=1,29 (s, 9H), 1,68-to 1.86 (m, 4H), 1,87-of 1.95 (m, 1H), 1,96-2,07 (m, 1H), 2,32-2,48 (m, 4H), to 5.21 (s, 2H), 6,33 (DD, 1H), to 6.57 (d,1H), to 7.04 (d, 1H).

The racemate obtained above was separated into the enantiomers using preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; flow: 20 ml/min; detection: 230 nm injection volume: 0,80 ml; temperature: 25°C; eluent: 95% of isohexane/5% ethanol]. On the basis of 790 mg of the racemate was obtained 318 mg of enantiomer 1 (Example A) and 339 mg of enantiomer 2 (Example he 162a):

Example A

Tert-butyl-3-(3-amino-4-chlorophenyl)-2-cyclobutylamine (enantiomer 1)

Yield: 318 mg

LC-MS (Method 4): Rt=1,70 min; m/z=254 (M-C4H7)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,29 (s, 9H), 1,68-of 1.85 (m, 4H), 1,87-1,94 (m, 1H), 1,96-of 2.06 (m, 1H), 2,31-2,48 (m, 4H), to 5.21 (s, 2H), 6,33 (DD, 1H), to 6.57 (d, 1H), to 7.04 (d, 1H).

The example he 162a

Tert-butyl-3-(3-amino-4-chlorophenyl)-2-cyclobutylamine (enantiomer 2)

Yield:339 mg

LC-MS (Method 4): Rt=1,71 min; m/z=254 (M-C4H7)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,29 (s, 9H), 1,67-of 1.84 (m, 4H), 1,87-1,94 (m, 1H), 1,95-2,05 (m, 1H), 2,32-2,48 (m, 4H), 5,22 (s, 2H), 6,33 (DD, 1H), to 6.57 (d, 1H), to 7.04 (d, 1H).

Example 163A

(+/-)Tert-butyl-3-(3-amino-4-chlorophenyl)-2-cyclopropylamino

2,50 g (4,63 mmol) (+/-)-tert-butyl-3-[3-(benzylamino)-4-chlorophenyl]-2-cyclopropyl�of propanoate was dissolved in 160 ml of ethyl acetate, removed the oxygen with argon and added 150 mg of palladium on coal (10%). The reaction mixture was stirred 8 h at Tbrin the hydrogen atmosphere at normal pressure. Then the mixture was filtered through celite, optionally washed with ethyl acetate, the filtrate was concentrated in vacuo, and the residue was dried in high vacuum. This residue was purified using chromatography on silica gel (eluent: from pure cyclohexane to cyclohexane/ethyl acetate 20:1). Got 1.41 g of the desired product (73,6% of Theor.).

LC-MS (Method 6): Rt=1,28 min; m/z=240 (M-C4H7)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,10-0,18 (m, 1H), 0,19-0,26 (m, 1H), from 0.37 to 0.52 (m, 2H), 0.79, which is 0.92 (m, 1H), 1,30 (C, 9H), 1,73 (TD, 1H), 2,65-to 2.74 (m, 2H), 5,10-a 5.25 (m, 2H), 6.35 mm (DD, 1H), 6,59 (d, 1H), 6,99-7,06 (m, 1H).

Example 164A

Methyl-3-(3-amino-4-chlorophenyl)hex-2-ENOAT

and

methyl-3-(3-amino-4-chlorophenyl)hex-3-ENOAT

and

To a mixture of 10.0 g (48.4 mmol) of 5-bromo-2-Chloroaniline and 8,69 g (67,8 mmol) of methyl-(2E)-hex-2-enoate in 100 ml of DMF was added to 33.8 ml (of 242.2 mmol) of triethylamine. The mixture was vacuumed three times and each time again filed argon. After the addition of 1.09 g (4,84 mmol) of palladium acetate (II) and 2,95 g (9,69 mmol) tri-2-tolylphosphino again was twice evacuated and filled with argon before then this reaction mixture was stirred for 4 h at 150°C. After cooled�I this mixture was poured onto water, saturated with sodium chloride and three times were extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated in vacuo, finally at high vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 50:1). Got 7,70 g of a mixture of both target compounds (62,7% of theoretical., the ratio of approximately 1.5:1 in favor of α,β-unsaturated isomer).

LC-MS (Method 6): methyl-3-(3-amino-4-chlorophenyl)hex-2-ENOAT: Rt=1,04 min, m/z=254 (M+H)+; methyl-3-(3-amino-4-chlorophenyl)hex-3-ENOAT: Rt=1,12 min, m/z=254(M+H)+.

1H-NMR (400 MHz, DMSO-d6): methyl-3-(3-amino-4-chlorophenyl)hex-2-ENOAT: δ [M. D.]=0,85 (t, 3H), 1,29-of 1.41 (m, 2H), 2,92-3,00 (m, 2H), 3.46 in (s, 3H), of 5.45 (s, 2H), 5,98 (s, 1H), 6,69 (DD, 1H), 6,94 (d, 1H), 7,20 (d, 1H).

1H-NMR (400 MHz, DMSO-d6): methyl-3-(3-amino-4-chlorophenyl)hex-3-ENOAT: δ [M. D.]=1,00 (t, 3H), of 2.15 (Quint, 2H), 3,56 (s, 3H), 3,66 (s, 2H), 5,26-5,31 (m, 2H), 5,84 (t, 1H), 6,54 (DD, 1H), of 6.79 (d, 1H), to 7.09 (d, 1H).

Example A

(+/-)-Methyl-3-(3-amino-4-chlorophenyl)hexanoate

7,70 g (30,3 mmol) of a mixture of methyl-3-(3-amino-4-chlorophenyl)hex-2-enoate and methyl-3-(3-amino-4-chlorophenyl)hex-3-enoate (about 1.5:1, Example 164A) was dissolved in 45 ml of ethyl acetate was added 646 mg (to 0.303 mmol) of palladium on charcoal (5%) and stirred at Tbrin the hydrogen atmosphere at normal pressure. After 10 h, the reaction mixture was filtered �through celite, was further washed with ethyl acetate, and the filtrate was concentrated. The residue was translating about 50 ml of ethyl acetate was again added about 650 mg of palladium on charcoal (5%) and stirred at Tbrin the hydrogen atmosphere at normal pressure. After an additional 36 h, the reaction mixture was filtered again through celite, optionally washed with ethyl acetate, and the filtrate was concentrated. The remainder were transferred to 800 ml of ethyl acetate was again added about 650 mg of palladium on charcoal (5%) and stirred 24 h at Tbrin the hydrogen atmosphere at normal pressure. The reaction mixture was filtered again through celite, optionally washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate from 50:1 to 10:1). In total, got 4,79 g of a mixture of desired product and starting materials. This mixture was dissolved in 180 ml of ethyl acetate was again added 603 mg (0,566 mmol) of palladium on coal (10%) and stirred over night at Tbrin the hydrogen atmosphere at normal pressure. The reaction mixture was filtered through celite, optionally washed with ethyl acetate, the filtrate was concentrated, and the residue was dried in high vacuum. It was obtained of 4.45 g (approximately 57% of Theor.) target product.

LC-MS (Method 4): Rt=1,50 min; m/z=256 (M+H)+.

1/sup> H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 0.80 (t, 3H), of 1.03-of 1.15 (m, 2H), 1,39-of 1.56 (m, 2H), 2,46 (DD, 1H), 2,59 (DD, 1H), 2,78-2,89 (m, 1H), 3,50 (s, 3H), 5,22 (ush. s, 2H), 6,39 (DD, 1H), 6,61 (d, 1H), 7,06 (d, 1H).

Example 166A and Example A

Methyl-3-(3-amino-4-chlorophenyl)pent-2-ENOAT

and

methyl-3-(3-amino-4-chlorophenyl)pent-3-ENOAT

and

To a mixture of 5.0 g (24.2 mmol) of 5-bromo-2-Chloroaniline and 5,53 g (48.4 mmol) IU-Teal-2-pentenoate in 50 ml of DMF was added to 16.9 ml (121 mmol) of triethylamine. The mixture was vacuumed three times and each time again filed argon. After adding 544 mg (2,42 mmol) of palladium acetate(II) and 1.47 g (4,84 mmol) tri-2-tolylphosphino again was twice evacuated and filled with argon, and then the reaction mixture was stirred 6 h at 150°C. After cooling, this mixture was held overnight at Tbrand then poured into water. Three times were extracted with ethyl acetate. Organic phases were combined, dried over magnesium sulfate, was evaporated in vacuum, and the residue was dried in high vacuum. From this residue using chromatography on silica gel (eluent: cyclohexane/ethyl acetate from 50:1 to 10:1) were allocated to both the isomer of the desired product in divided form. Received 0.85 g of methyl-3-(3-amino-4-chlorophenyl)pent-2-enoate (14.6% of Theor.), and of 3.05 g of methyl-3-(3-amino-4-chlorophenyl)pent-3-enoate (52.5% of theory.).

Methyl-3-(3-amino-4-chlorophenyl)pent-2-ENOAT(Example 166A):

LC-MS (Method 6): Rt=1,09 min; m/z=240 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,97 (t, 3H), 2,98 (kV, 2H), 3,66 (s, 3H), of 5.45 (s, 2H), 5,96 (s, 1H), 6,70 (DD, 1H), 6,95 (d, 1H), 7,21 (d, 1H).

Methyl-3-(3-amino-4-chlorophenyl)pent-3-ENOAT (Example A):

LC-MS (Method 6): Rt=1,00 min; m/z=240 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,75 (d, 3H), 3,47 (s, 2H), 3,56 (s, 3H), 5,28 (s, 2H), 5,94 (kV, 1H), 6,54 (DD, 1H), was 6.77 (d, 1H), to 7.09 (d, 1H).

Example 168A

(+/-)-Methyl-3-(3-amino-4-chlorophenyl)pentanoate

3,05 g (12.7 mmol) of methyl-3-(3-amino-4-chlorophenyl)pent-3-enoate and 0.85 g (3,55 mmol) methyl-3-(3-amino-4-chlorophenyl)pent-2-enoate together was dissolved in 500 ml of ethyl acetate was added 346 mg (0,325 mmol) of palladium on coal (10%) and stirred over night at Tbrin the hydrogen atmosphere at normal pressure. Thereafter, the reaction mixture was filtered through celite, optionally washed with ethyl acetate and the filtrate was evaporated. After drying the residue in a high vacuum received 3,73 g of the target product (94,8% of Theor.).

GC-MS (Method 1): Rt=6,07 min; m/z=242 (M)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,71 (t, 3H), 1,42-1,49 (m, 1H), 1,55-to 1.61 (m, 1H), 2,42-2,48 (m, 1H), 2,60 (DD, 1H), 2,68-2,78 (m, 1H), 3,50 (s, 3H), 5,22 (s, 2H), 6,39 (DD, 1H), 6,61 (d, 1H), 7,05-was 7.08 (m, 1H).

Example 169A

Complex ethyl ester of (3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid (a mixture of diastereomer�)

81,5 ml (to 81.5 mmol) of a 1 M solution hexamethyldisilazide lithium in toluene was cooled to -20°C and dropwise added a solution of 10.0 g (of 50.3 mmol) of ethyl(3R)-4,4,4-Cryptor-3-methylbutanoate in 50 ml of abs. toluene. This mixture was additionally stirred for 10 min and Then at -20°C was pinned pre-prepared solution of 14.8 g (70,6 mmol) 1-bromo-4-chloro-2-fervently, 366 mg (1,63 mmol) of palladium acetate (II) and 1.35 g (3,42 mmol) 2-dicyclohexylphosphino-2'-(N,N-Dimethylamino)biphenyl in 50 ml of abs. toluene. Upon completion of the addition the cooling was removed, and the resulting reaction mixture was stirred first for 1 h at Tbrthen over night at 80°C. After cooling, the mixture was filtered through celite, several times, further washed with toluene, and the obtained filtrate was concentrated under vacuum. From the residue after chromatography on silica gel (eluent: cyclohexane/ethyl acetate 100:1→100:4) was obtained 4.26 g of the target compound (25,1% of theor.).

230 GC-MS (Method 1): Rt=4.21 min; m/z=312 (M)+.

In a similar manner was obtained the following example:

Example 170 ╟

Complex ethyl ester of (3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid (mixture of diastereomers)

On the basis of 2.0 g ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate and of 2.96 g of 1-bromo-4-chloro-3-torbenson, received 2,47 g of the target compound�deposits.

GC-MS (Method 1): Rt=4,33 min+4,36 min; both m/z=312 (M)+.

1H-NMR (400 MHz, DMSO-d6): primary diastereoisomer δ [M. D.]=0,80 (d, 3H), of 1.08-1,19 (m, 3H), 3,34-to 3.41 (m, 1H), 3,88 (d, 1H), 4,01-4,18 (m, 2H), 7,28-7,34 (m, 1H), 7,51-of 7.64 (m, 2H).

Example 171À

Ethyl-(3R)-2-(4-chloro-2-methylphenyl)-4,4,4-Cryptor-3-methylbutanoate (mixture of diastereomers)

22,5 ml (22,5 mmol) of a 1 M solution hexamethyldisilazide lithium in toluene was cooled to -20°C and dropwise added a solution of 2,76 g (of 50.3 mmol) of ethyl(3R)-4,4,4-Cryptor-3-methylbutanoate in 15 ml of abs. toluene. This mixture was additionally stirred for 10 min and Then at -20°C was pinned pre-prepared solution of 4.0 g (19.5 mmol) of 2-bromo-5-chlorotoluene, 101 mg (0.45 mmol) of palladium acetate(II) and 371 mg (0.94 mmol) 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl in 15 ml of abs. toluene. Upon completion of the addition the cooling was removed, and the resulting reaction mixture was stirred first for 1 h at Tbrthen over night at 100°C. After cooling, the mixture was filtered through celite, several times, further washed with toluene, and the obtained filtrate was concentrated under vacuum. Got 3,10 g of target compound in the form of a crude product, which was directly subjected to further transformations.

GC-MS (Method 1): Rt=4,72 min; m/z=308 (M)+.

Example A

Ethyl-(3R)-2-(4-chloro-3-methylphenyl-4,4,4-Cryptor-3-methylbutanoate (mixture of diastereomers)

29,2 ml (29,2 mmol) of a 1 M solution hexamethyldisilazide lithium in toluene was cooled to -10°C and dropwise added a solution of 4.30 g (23.4 mmol) of ethyl(3R)-4,4,4-Cryptor-3-methylbutanoate in 26 ml of abs. toluene. This mixture was additionally stirred for 10 min Then at -10°C was pinned pre-prepared solution of 5.0 g (19.5 mmol, 80%) of 5-bromo-2-chlorotoluene, 131 mg (of 0.58 mmol) of palladium acetate(II) and 483 mg (1,23 mmol) 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl in 26 ml of abs. toluene. The resulting reaction mixture was stirred first for 1 h at Tbrthen 4 h at 80°C. After cooling, the mixture was diluted with ethyl acetate, washed twice with an aqueous sodium hydrogencarbonate solution and once with us. a solution of sodium chloride, dried over sodium sulfate and evaporated in vacuum. Got 7,80 g of target compound in the form of a crude product, which was directly subjected to further transformations.

LC-MS (Method 4): Rt=1,55 min; m/z=309 (M+H)+.

In a similar manner was obtained the following example:

Example 173A

Ethyl-(3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoate (mixture of diastereomers)

On the basis of 3.91 g of ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate and 5.0 g of 4-bromo-1,2-dichlorobenzene, received 7,54 g of target compound in the form of a crude product.

LC-MS (�method 4): R t=A 1.54 min; m/z=329 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,80/1,17 (2D, joint., 3H), 1,10-1,15 (m, 3H), 3,30-to 3.41 (m, 1H), 3,89/3,94 (2D, joint., 1H), 4,01-4,18 (m, 2H), 7,38-of 7.48 (m, approx. 1H), members, 7.59-to 7.68 (m, approx. 1H), 7,74/the 7.75 (2D, joint., 1H).

Example A

(3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoate acid (mixture of diastereomers)

4.26 g (13.6 mmol) of a compound ethyl ester of (3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid (mixture of diastereomers) was dissolved in a mixture of 22 ml of methanol, 22 ml of THF and 11 ml of water and at 0°C was added to 10.9 g of 50% aqueous sodium hydroxide solution. The reaction mixture was stirred over night at Tbr. Then the vacuum was removed a significant portion of organic solvents. The remaining mixture was diluted with water and extracted with diethyl ether. After phase separation, the organic phase was discarded, and the aqueous phase was acidified with polukoertsitivnoi hydrochloric acid (pH approximately 2) and several times was extracted with ethyl acetate. The combined ethyl acetate phase was dried over sodium sulfate and evaporated in vacuum. Got 3,38 g (76,7% of Theor.) the target product as a mixture of diastereomers, which could be used in subsequent reactions without further purification.

LC-MS (Method 4): Rt=1,25 min; m/z=283 (M-H)-.

1H-NMR (400 MHz, DMSO-dsub> 6): primary diastereoisomer δ [M. D.]=0,87 (d, 3H), 3,27-3,37 (m, 1H), was 4.02 (d, 1H), 7,35 (DD, 1H), 7,45-7,52 (m, 2H), 13,02 (ush. s, 1H).

Similarly, there were obtained the following carboxylic acids:

Example 175A

(3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoate acid (mixture of diastereomers)

The ratio of diastereomers in about 1:1.

GC-MS (Method 1): Rt=4,79 min; m/z=284 (M)+.

1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,80/1,19 (2D, joint., 3H), 3,18-3,29 (m, 1H), 3,74/3,77 (DD, joint., 1H), 7,28 (d, 1H), 7,43-7,65 (m, 2H), 12,91/13,24 (2 ush. with, joint., 1H).

Example ulitsa 176a

(3R)-2-(4-chloro-3-methylphenyl)-4,4,4-Cryptor-3-methylbutanoate acid (mixture of diastereomers)

The ratio of diastereomers of about 5:1.

1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,78/1,11 (2D, joint., 3H), 2,31/2,32 (2s, joint., 3H), 3,24-3,30 (m, 1H), 3,61/3,64 (2D, joint., 1H), 7,20-7,50 (m, 5H), 12,80 (ush. s, 1H).

Example A

(3R)-2-(4-chloro-2-methylphenyl)-4,4,4-Cryptor-3-methylbutanoate acid (mixture of diastereomers)

3,10 g (crude, about 10,04 mmol) ethyl-(3R)-2-(4-chloro-2-methylphenyl)-4,4,4-Cryptor-3-methylbutanoate (mixture of diastereomers) was dissolved in a mixture of 10 ml of methanol, 10 ml THF and 5 ml of water and at 0°C was added 8,03 g of 50% aqueous sodium hydroxide solution. The reaction mixture was stirred for but�and at T br. Then made acidic with 1 n hydrochloric acid (pH approximately 2), and three times were extracted with ethyl acetate. The combined organic phases were washed with us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate from 50:1 to 4:1). Got 1,46 g (51.8% of Theor.) the target product as a mixture of diastereomers (approximately 5:1).

GC-MS (Method 1): Rt=5,14 min; m/z=280 (M)+.

1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,76/1,11 (2D, joint., 3H), 2,34/2,36 (2s, joint., 3H), 3,33-to 3.38 (m, approx. 1H, overlapped), 3,81/3,88 (2D, joint., 1H), 7,27-7,41 (m, 3H), 12,81 (ush. s, 1H).

Example A

(3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoate acid (mixture of diastereomers)

Of 3.77 g (untreated, approximately 11,5 mmol) ethyl-(3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoate (mixture of diastereomers) was dissolved in a mixture of 14 ml of methanol, 14 ml of THF and 5 ml of water and at 0°C was added 9,16 g of 50% aqueous sodium hydroxide solution. The reaction mixture was stirred for about 6 h at 40°C. Then acidified with 1 n hydrochloric acid (pH approximately 2), and three times were extracted with ethyl acetate. The combined organic phases were washed with us. a solution of sodium chloride, dried over sodium sulfate and evaporated in vacuum. Poluchil,94 g of target compound in the form of crude product which could be used in subsequent reactions without further purification.

1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,80/1,19 (2D, joint., 3H), 3,21-3,30 (m, 1H), 3,69-3,82 (m, 1H), of 7.42 (DD, 1H), 7,63-to 7.67 per (m, 1H), 7,70-7,73 (m, 1H), 12,97 (ush. s, 1H).

Example 179A

(3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoate (mixture of diastereomers)

660 mg (2,32 mmol) (3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid (mixture of diastereomers) was dissolved in 2 ml of dichloromethane. After you add one small drop of DMF, the reaction solution was cooled to a temperature of from -5°C to 0°C and added dropwise 0.4 ml (a 4.64 mmol) oxalicacid. The cooling was removed, and the reaction mixture was stirred 1 h at Damn. before the end of gas evolution. Thereafter, the reaction mixture was evaporated in vacuum. The residue was twice extracted the abs. dichloromethane, each time again was evaporated under vacuum and finally the residue was dried in high vacuum. Received 640 mg of the desired product, which was directly subjected to further transformations without additional purification.

The following examples were obtained in accordance with the General method 1 (Amide a combination of derivatives 4,4,4-Cryptor-3-methyl-2-phenylbutanoate acid with aniline with the use of GATA in DMF with pyridine or N,N-diisopropylethylamine as based�I):

ExampleName/Structure/starting compoundAnalytical data
180A(+)-Tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propanoateLC-MS (Method 6): Rt=to 1.44 min; m/z=520 (M-H)".
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,83 (d, 3H), of 1.30 (s, 9H), 2,42-2,48 (m, 2H), to 2.76 (t, 2H), 3,35-of 3.46 (m, 1H), of 4.09-4,19 (m, 1H), 7,05 (DD, 1H), 7,26-7,41 (m, 3H), 7,49 (DD, 1H), a 7.62 (t, 1H), 9,86 (s, 1H).
(from tert-butyl-3-(3-amino-4-chlorophenyl)propanoate and (3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid (mixture of diastereoisomers))[α]D20=+66,9°, C=0,46, chloroform.
A(+)-Ethyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoateLC-MS (Method 6): Rt=1,40 min; m/z=508 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,83 (d, 3H), 1,01-1,10 (m,6H), 2,60-2,71 (m, 2H), 2,74-2,84 (m, 1H), 3,35-3,49 (m,1H),3,96 (kV, 2H), 4,15 (d, 1H), 7,00 (DD, 1H), 7,24-7,39 (m, 3H), 7,49 (DD, 1H),7,62 (t, 1H), 9,87 (s, 1H).
F(of complex ethyl ester of (+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid and (3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid (mixture of diastereoisomers))[α]D20=+98,6°, C=0.45, and chloroform.

ExampleName / Structure / starting compoundAnalytical data
A(+)-Ethyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-2-methylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoateLC-MS (Method 6): Rt=1,46 min; m/z=504 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=of 0.75 (d, 3H), 1,02-1,12 (m, 6H), 2,61-of 2.72 (m, 2H), 2,77-2,84 (m, 1H), 3,33-of 3.42 (m, 1H), 3,98 (kV, 2H), 4,15 (d, 1H), 7,02 (DD, 1H), 7.24 to 7,30 (m, 2H), 7,32-7,38 (m, 2H), 7,52 (d, 1H), For 9.88 (s, 1H).
(of complex ethyl ester of (+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid and (3R)-2-(4-chloro-2-methylphenyl)-4,4,4-Cryptor-3-methylbutanoic acid (mixture of diastereoisomers))[α]D2=+112,3°, C=0,40, chloroform.
ATert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propanoateLC-MS (Method 4): Rt=To 1.69 min; m/z=516/518 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.31 (s, 9H), of 2.33 (s, 3H), 2,46 (m, 2H), 2,75 (t, 2H), 3,34-to 3.41 (m, 1H), 4,07 (d, 1H), 7,03 (DD, 1H), 7,27 was 7.45 (m, 5H), 9,80 (s, 1H).
(from tert-butyl-3-(3-amino-4-chlorophenyl)propanoate and (3R)-2-(4-chloro-3-methylphenyl)-4,4,4-Cryptor-3-methylbutanoic acid)

ExampleName/Structure/starting compoundAnalytical data
AEthyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoateLC-MS (Method 4): R,=of 1.64 min; m/z=502/504 (M-H)".
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 1,02-of 1.09 (m, 6H), of 2.33 (s, 3H), 2,59-of 2.72 (m, 2H), 2,74-to 2.85 (m, 1H), 3,34-3,44 (m, 1H), 3,96 (kV, 2H), 4,04-4,11 (m, 1H), 6,99 (DD, 1H), 7,26-7,38 (m, 3H), 7,39-7,44 (m, 2H), 9,80 (s, 1H).
(with�one of the ethyl ester of (+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid and (3R)-2-(4-chloro-3-methylphenyl)-4,4,4-Cryptor-3-methylbutanoic acid)
AEthyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoateLC-MS (Method 6): Rt=To 1.44 min; m/z=524/526 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,83 (d, 3H), 1,01-1,08 (m, 6H), 2,60-2,70 (m, 2H), 2,75-2,83 (m, 1H), 3,35-3,48 (m, 1H), 3,96 (kV, 2H), of 4.09-4,16 (m, 1H), 7,01 (DD, 1H), 7,30-7,38 (m, 2H), 7,45 (DD,1H), 7,67 (d, 1H), 7,72 (d, 1H), 9,87 (s, 1H).
(of complex ethyl ester of (+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid and (3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)

ExampleName/Structure/starting compoundAnalytical data
ATert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propanoateLC-MS (Method 6): Rt=1,48 min; m/z=536/538 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): δ (M. D.]=0,83 (d, 5H), 1,30 (C, 9H), 2,42-2,48 (m, 2H), 2,72 is 2.80 (m, 2H), 3,34-3,48 (m, 1H), 4,7-4,17 (m, 1H), 7,05 (DD, 1H), 7,31-7,39 (m, 2H), 7,45 (DD, 1H), 7,67 (d, 1H), 7,72 (d, 1H), 9,87 (s, 1H).
(from tert-butyl-3-(3-amino-4-chlorophenyl)propanoate and (3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)
ATert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)-2-methylpropanoate (mixture of diastereomers)LC-MS (Method 6): Rt=1,45 min; m/z=530/532 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.03(ush. s, approx., 3H), of 1.29 (s, approx., 9H), 1,51 (ush. s, approx., 1H), 1,56 (ush. s, approx., 1H), 2,15 (ush. s, 1H), 2,77 (ush. s, 1H), 3,34-of 3.43 (m, 1H), 3,86-was 4.02 (m, 1H), 6,97-was 7.08 (m, 1H), 7,15 (ush. s, 1H), 7.23 percent (ush. s, 1H), 7,38-7,53 (m, 5H), 9,87 (ush. s, 1H) [sounds strongly broadened due to the presence of rotamers].
(from (+/-)-tert-butyl-3-(3-amino-4-chloro-2-methylphenyl)-2-methylpropanoate and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)

ExampleName/Structure/starting compoundAnalytical data
AEthyl-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-t�iftar-3-methylbutanoyl]amino}-4-fluorophenyl)-4,4,4-triptoreline LC-MS (Method 4): Rt=1.65 V min; m/z=526 (M-H)-.
1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,79 (d, 3H), of 1.03 (t, 3H), of 2.91 (DD, 1H), 3,03 (DD, 1H), 3,34-of 3.46 (m, 1H), 3,89-4,00 (m, 2H), 4,04-4,18 (m, 2H), 7,15-7,32 (m, 2H), of 7.42 and 7.55 (m, 4H), a 7.85-8,06 (m, 1H), 10,17 (s, 1H).
(from (+/-)-ethyl-3-(3-amino-4-fluorophenyl)-4,4,4-tricorporate and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)
ATert-butyl-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-2-methylbutanoate (mixture of diastereomers)LC-MS (Method 6): Rt=Of 1.64 min; m/z=544/546 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,74-0,84 (m, 6H), 0,88/0,91 (2D, joint., 3H), 1,22/1,32 (2, joint.,9H), 1,32-of 1.40 (m, 1H), 1,58-1,68 (m, 1H), of 2.57 (d, 1H), 2,84/2,85 (2D, joint., 1H), 3,35-of 3.43 (m, 1H),4,03-4,08/4,10 (2D, joint., 1H), to 6.95 (DD, 1H), 7,26-7,38 (m, 2H), 7,39-7,52 (m, 4H), 9,81/case 9.83 (2, joint., 1H).
F(from (+/-)-tert-butyl-2-(3-amino-4-chlorbenzyl)-2-methylbutanoate and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)

ExampleName/Structure/starting compoundAnalytical data
190ATert-butyl-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-2-methylbutanoate (diastereoisomer B)LC-MS (Method 6): Rt=1,57 min; m/z=544/546 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,75-of 0.82 (m, 6H), 0.88 to (s, 3H), 1,22 (s, 9H), 1,27-to 1.38 (m, 1H), 1.56 to of 1.70 (m, 1H), 2,54 (l, approx. 1H, overlapped), 2,84 (d, 1H), 3,35-of 3.43 (m, 1H), 4,01-to 4.14 (m, 1H), 6,95 (d, 1H), 7,17-7,32 (m, 1H), 7,35 (d, 1H), 7,41-EUR 7.57 (m, 4H), case 9.83 (s, 1H).
(from (+)-tert-butyl-2-(3-amino-4-chlorbenzyl)-2-methylbutanoate (enantiomer 2) and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)[α]D20=+68,0°, C=0,280, chloroform.
ATert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-triptoreline (mixture of diastereomers)LC-MS (Method 6): Rt=1,50 min; m/z=570/572 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): both diatereo�EPA δ [M. D.]=0,80 (l, 3H), 1,21 (s, 9H), 2,74-of 2.81 (m, 1H), 2,88-to 2.99 (m, 1H), 3,34-of 3.46 (m, 1H), 3,95-4,10 (m, 1H), 4,11-4,19 (m, 1H), 7,25 (DD, 1H), 7,40-7,54 (m, 5H), 7,58-7,72 (m, 1H), to 9.93/9,94 (2s, joint., 1H).
(from (+/-)-tert-butyl-3-(3-amino-4-chlorophenyl)-4,4,4-tricorporate and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)

ExampleName/Structure/starting compoundAnalytical data
ATert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclobutylamine (mixture of diastereomers)LC-MS (Method 4): Rt=1,97 min; m/z=556 (M-H)-.
1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,79 (d, 3H), of 1.18/1.22 m (2C, collab, 9H), 1,66-of 1.85 (m, 4H), 1,86-2,02 (m, 2H), 2,28-of 2.45 (m, 2H), 2,55-of 2.64 (m, 1H), 3,34-of 3.42 (m, 1H), 4,11/4,12 (2D, joint., 1H), 6,97/6,99 (2D, joint., 1H), 7,30-value of 7, 37 (m, 2H), 7,40-7,51 (m, 4H), 9,80/9,81 (2D, collab, 1H).
(from (+/-)-tert-butyl-3-(3-amino-4-chlorophenyl)-2-cyclobutylamine and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)
A(+)-Tert-�the scrap-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclobutyl (diastereoisomer A) LC-MS (Method 6): Rt=To 1.67 min; m/z=556(M-H)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 1,22 (s, 9H), 1,68-to 1.82 (m, 4H), 1,86-of 1.93 (m, 1H), 1,94-2,03 (m, 1H), 2,31-2,47 (m, 2H), 2,56-2,63 (m, 2H), 3,36-of 3.43 (m, 1H), 4,12 (d, 1H), 6,98 (DD, 1H), 7,31-value of 7, 37 (m, 2H), 7,41-7,51 (m, 4H), to 9.81 (s, 1H).
(from tert-butyl-3-(3-amino-4-chlorophenyl)-2-cyclobutylamine (enantiomer 1) and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)[α]D20=+51,3°, C=0,445, chloroform.

ExampleName/Structure/starting compoundAnalytical data
A(+)-Tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclobutylamine (diastereoisomer B)LC-MS (Method 6): Rt=1,58 min; m/z=556 (M-H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0.79 in (l,
3H), of 1.18 (s, 9H), 1,67-of 1.83 (m, 4H), 1,84-of 1.93 (m, 1H), 1,94-2,02 (m, 1H), 2,31-of 2.44 (m, 2H), 2,57-of 2.64 (m, 1H), 3,35-of 3.42 (m, 1H), 4,08-to 4.14 (m, 1H), 6,98 (DD, 1H), 7,29-value of 7, 37 (m, 2H), of 7.42-7,49 (m, 4H), To 9.81 (s, 1H).
(from tert-butyl-3-(3-amino-4-chlorophenyl)-2-cyclobutylamine (enantiomer 2) and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)[α]D20=+81,8°, C=0,475, chloroform.
ATert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclopropylethanol (mixture of diastereomers)LC-MS (Method 4): Rt=1,80 min; m/z=542 (M-H)-.
1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,12-0,26 (m, 2H), 0.43 in (kV, 2H), 0.79 in (d, 3H), 0,81-0,90 (m, 1H), 1,20/1,24 (2s, joint., 9H), 1,67-of 1.81 (m, 1H), 2,76-2,83 (m, 2H), 3,36-of 3.43 (m, 1H), 4,11/4,12 (2D, joint., 1H),7,01 (DD, 1H), 7,30-7,39 (m, 2H), 7,41-7,51 (m, 4H), 9,78-9,85 (m, 1H).
(from (+/-)-tert-butyl-3-(3-amino-4-chlorophenyl)-2-cyclopropylethanol and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)

Example 196A

(+)-Ethyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate

280,7 mg (1,16 mmol) of a compound ethyl ester of (+)-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoic acid was dissolved in 1.5 ml abs. THF was added to 0.26 ml (1,48 mmol) of N,N-Diisopropylamine�in and after cooling to -10°With added dropwise a solution of 320 mg (raw, approximately 1,06 mmol) prepared in situ (3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoate in 0.5 ml of abs. THF. The reaction mixture after the addition for 30 min was stirred at a temperature between -10°C and 0°C. Then, after adding a few drops of water diluted with dichloromethane. This mixture was washed with 1 n hydrochloric acid and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The crude product was first purified using preparative reverse phase HPLC (eluent: methanol/water), then with the help of chromatography on silica gel (eluent: cyclohexane/ethyl acetate 40:1). Received 144 mg of the target compound (26.9% of Theor.).

LC-MS (Method 6): Rt=1,42 min; m/z=508 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,86 (d, 3H), 1,02-1,12 (m, 6H), 2,63-of 2.72 (m, 2H), 2,76-2,86 (m, 1H), 3,34-3,44 (m, 1H), 3,93-was 4.02 (m, 2H), 4,36 (d, 1H), 7,03 (DD, 1H), 7,25-7,29 (m, 1H), 7,32-7,38 (m, 2H), 7,51 (DD, 1H), 7,61 (t, 1H), 10,02 (s, 1H).

[α]D20=+90°, C=0,30, chloroform.

Example 197A

Methyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)propanoate

265 mg (1,16 mmol) methyl-3-(3-amino-4-chloro-2-methylphenyl)propanoate was dissolved in 1.5 ml abs. THF was added to 0.28 ml (1,63 mmol) of N,N-diisopropylethylamine and after cooling to -10°With added dropwise a solution of 398 mg (raw, approx 1,40 mmol) prepared�CSOs in situ (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoate in 0.5 ml of abs. THF. The reaction mixture after the addition during 1 h was heated from -10°C to Tbrand then was diluted with ethyl acetate. This mixture was washed with 1 n hydrochloric acid and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified using preparative reverse phase HPLC (eluent: methanol/water). Got 485 mg of the target compound (87.5% of theor.).

LC-MS (Method 6): Rt=1,25 min; m/z=476 (M+H)+.

Example 198A

(+)-Tert-butyl-(2R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)-2-methylpropanoate

200 mg (0,705 mmol) of (-)-tert-butyl-(2R)-3-(3-amino-4-chloro-2-methylphenyl)-2-methylpropanoate was dissolved in 1 ml abs. THF was added to 0.17 ml (0,987 mmol) of N,N-diisopropylethylamine and after cooling to -10°With added dropwise a solution of 241 mg (crude, about 0,846 mmol) prepared in situ (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoate in 0.2 ml of abs. THF. The reaction mixture after the addition to the 2 hours was heated from -10°C to Tbrand then poured into water. The aqueous phase three times were extracted with ethyl acetate and the combined organic phases were washed with 1 n hydrochloric acid and us. a solution of sodium chloride, dried over magnesium sulfate, was evaporated in vacuum, and the residue was dried in high vacuum. Received 282 mg target soy�of inane (75,2% of Theor.).

LC-MS (Method 6): Rt=1,45 min; m/z=530 (M-H)-.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.03 (ush. s, 3H), of 1.30 (s, 9H), of 1.50 (ush. s, 1H), 2,15 (ush. s, 1H), 2,42 (ush. s, 1H), 2,69-of 2.92 (m, 1H), 3,34-3,45 (m, 1H), 3,94 (d, 1H), 7,03 (d, 1H), 7.23 percent (ush. s, 1H), 7,45 (s, 4H), case 9.83/9,91 (2 ush. with, joint., 1H) [sounds significantly broadened due to the presence of rotamers}.

[α]D20=+68,9°, C=0,50, chloroform.

In a similar manner was obtained the following example:

Example A

(+)-Tert-butyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)-2-methylpropanoate

On the basis of 200 mg (+)-tert-butyl-(2S)-3-(3-amino-4-chloro-2-methylphenyl)-2-methylpropanoate and 241 mg of freshly prepared (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoate, received 287 mg of the target product (75,2% of Theor.).

LC-MS (Method 6): Rt=1,51 min; m/z=530 (M-H)-.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), was 1.04 (ush. s, 3H), of 1.29 (s, 9H), 1,51 (ush. s, 1H), 2,15 (ush. s, 1H), 2,56-of 2.68 (m, 1H), 2,79 (ush. s, 1H), 3,34-3,45 (m, 1H), 3,94 (ush. d, 1H), 7,03 (d, 1H), 7,15 (ush. s, 1H), 7.23 percent (ush. s, 1 H), 7,45 (s, 4H), 9,87 (ush. s, 1H) [sounds significantly broadened due to the presence of rotamers].

[α]D20=+116,1°, C=0,520, chloroform.

Example 200A

(+)-Tert-butyl-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-2-methylbutanoate (diastereoisomer A)

225 mg (0,756 mm�l) (-)-tert-butyl-2-(3-amino-4-chlorbenzyl)-2-methylbutanoate (enantiomer 1) and 231 mg (0,907 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid was dissolved in 0.9 ml of pyridine and 2.7 ml of DMF and at T bradded 345 mg (0,907 mmol) HA-TU. The reaction mixture during the night was stirred at 45°C before added an additional 0.5 EQ. (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid and 0.6 EQ. GATA. The reaction mixture was again stirred for 3 h at 45°C and then after cooling was diluted with ethyl acetate. This mixture was washed with 1 n hydrochloric acid and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified using preparative reverse phase HPLC (eluent: acetonitrile/water) and subsequent chromatography on silica gel (eluent: cyclohexane/ethyl acetate 40:1). Received 177 mg of the desired product (35.6% of Theor.).

LC-MS (Method 4): Rt=1,97 min; m/z=544 (M-H)-.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,76-0,83 (m, 6H), of 0.91 (s, 3H), of 1.31 (s, 9H), 1,33-of 1.40 (m, 1H), 1,57-to 1.67 (m, 1H), of 2.57 (d, 1H), 2,85 (d, 1H), 3,35-of 3.43 (m, 1H), 4,07-4,13 (m, 1H), 6,95 (DD, 1H), 7,30-of 7.36 (m, 2H), 7,41-of 7.48 (m, 4H),9,82(s, 1H).

[α]D20=+63,2°, C=0,365, chloroform.

Example A

Methyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)hexanoate (mixture of diastereomers)

1.45 g (5,67 mmol) (+/-)-methyl-3-(3-amino-4-chlorophenyl)hexanoate and 1.81 g (6,80 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid was dissolved in 5.0 ml of pyridine and 10.0 ml of DMF and at Tbradded 2,80 g (value of 7, 37 mmol) GATA. Reactionary cm�camping during the night stirred at T brand then was diluted with ethyl acetate. This mixture was washed with 1 n hydrochloric acid and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified using chromatography on silica gel (eluent: first cyclohexane, then cyclohexane/ethyl acetate 50:1). In the two fractions obtained in total 2,02 g of the target product (70,6% of Theor.).

LC-MS (Method 6): Rt=1,43 min; m/z=504 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,74-0,85 (m, 6H), 0,98-of 1.16 (m, 2H), 1,42-to 1.61 (m, 2H), 2.49 USD (DD, CA, 1H, overlap), of 2.64 (DD, 1H), 2,84-3,02 (m, 1H), 3,37-of 3.42 (m, 1H), 3,47/3,48 (2, joint., 3H), 4,12 (d, 1H), 7,05 (DD, 1H), 7,31-7,38 (m, 2H), 7,41-to 7.55 (m, 4H), case 9.83 (s, 1H).

Example 202A

Methyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)pentanoate (mixture of diastereomers)

500 mg (2.07 mmol) of (+/-)-methyl-3-(3-amino-4-chlorophenyl)pentanoate and 668,9 mg (2.48 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid was dissolved in 1.7 ml of pyridine and 3.3 ml of DMF and at Tbradded to 1.02 g (2,69 mmol) GATA. The reaction mixture during the night was stirred at Tbrand then was diluted with ethyl acetate. This mixture was washed with 1 n hydrochloric acid and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified using chromatography on forces�the Kagel (eluent: first cyclohexane, then cyclohexane/ethyl acetate 50:1). Received 675 mg of the target product (66,6% of Theor.).

257 LC-MS (Method 6): Rt=To 1.39 min; m/z=490 (M-H)-.

1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,65-0,74 (m, 3H), of 0.80 (d, 3H), 1,43-to 1.67 (m, 2H), 2.49 USD (DD, approx., 1H, overlap), to 2.65 (DD, 1H), 2,80-of 2.92 (m, 1H), 3,35-of 3.43 (m, 1H), 3,47/3,48 (2s, joint., 3H), of 4.13 (d, 1H), 7,05 (DD, 1H), of 7.36 (DD, 2H), 7,43-7,51 (m, 4H), 9,84 (s, 1H).

Example A

(+)-Tert-butyl-(3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-triptoreline

2.0 g (6.18 of mmol) of (+)-tert-butyl-(3S)-3-(3-amino-4-chlorophenyl)-4,4,4-tricorporate and 1,98 g (7.41 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid was dissolved in 5.0 ml of pyridine and 10.0 ml of DMF and at Tbradded 3,05 g (8,03 mmol) GATA. The reaction mixture during the night was stirred at Tbrbefore we added additional 1,98 g (7.41 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid and 3.05 g (8,03 mmol) GATA. The reaction mixture was again stirred for 8 h at 40°C and then after cooling was diluted with ethyl acetate. This mixture was washed with 1 n hydrochloric acid and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified using chromatography on silica gel (eluent: first cyclohexane, then cyclohexane/ethyl acetate 50:1). Semi�enny thus the product (2.7 g) was further purified by repeated chromatography on silica gel (eluent: cyclohexane/ethyl acetate 100:1). Got 1.80 g of the desired product (50,9% of Theor.).

LC-MS (Method 4): Rt=Of 1.74 min; m/z=570 (M-H)-.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 1,21 (s, 9H), 2,77 (DD, 1H), to 2.94 (DD, 1H), 3,36-of 3.46 (m, 1H), 3,99-of 4.09 (m, 1H), 4,15 (d, 1H), 7,17-7,29 (m, 1H), of 7.42-7,52 (m, 5H), members, 7.59-7,65 (m, 1H), 9,94 (s, 1H).

[α]D20=+84,0°, C=0,48, chloroform. In a similar manner was obtained the following example:

Example A

(+)-Tert-butyl-(3R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-triptoreline

On the basis of 1.0 g (3,09 mmol) of (-)-tert-butyl-(3R)-3-(3-amino-4-chlorophenyl)-4,4,4-tricorporate and 988 mg (3,71 mmol) of (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid, there was obtained 1.2 g (68% of Theor.) target product.

LC-MS (Method 4): Rt=To 1.75 min; m/z=570 (M-H)-.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 1,21 (s, 9H), 2,78 (DD, 1H), 2,93 (DD, 1H), 3,35-3,47 (m, 1H), 3,99-4,10 (m, 1H), 4,15 (d, 1H), of 7.19-7,28 (m, 1H), 7,40-7,52 (m, 5H), 7,60-7,66 (m, 1H), to 9.93 (s, 1H).

[α]D20=+42,7°, C=0,48, chloroform.

Example 205A

In an argon atmosphere was pinned 201 ml (1,39 mol) of tert-boolprop-2-enoate to a solution of 100 g (463 mmol) of 1-bromo-2-methyl-3-nitrobenzene, 322 ml (2,31 mol) of triethylamine, 28,18 g (92,58 mmol) tri-2-tolylphosphino and 10,39 g (46,29 mmol) of palladium acetate (II) in 2 liters of DMF and then the mixture was stirred for 36 h at 125°C. After cooling�message to room temperature, this reaction mixture was stirred with a saturated aqueous solution of ammonium chloride and the organic phase is separated. The aqueous phase three times were extracted with tert-butylmethylamine ether, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration the solvent was removed to dryness under vacuum. The obtained residue was purified using flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate 9:1). Got 89 g (338 mmol, 73% of Theor.) the intermediate product tert - butyl(2E)-3-(2-methyl-3-nitrophenyl)prop-2-enoate in the form of a colorless solid substance.

88 g (334 mmol) of this solid was dissolved in 2 liters of ethanol at room temperature was added 7 g of palladium on coal (10%) and gidrirovanie 18 h under normal pressure. After a full course of the reaction was filtered through diatomaceous earth and the filtrate obtained was evaporated in a vacuum. Got 61,3 g (of 260.5 mmol, 78% of Theor.) target compound in the form of a colorless solid substance.

LC-MS (Method 2): Rt=A 1.84 min; m/z=236 (M+H)+.

1H-NMR (400 MHz, DMSO-d6d/M. D.): was 6.77 (1H, t), 6,47 (1H, d), 6,36 (1H, d), 4.72 in (2H, s), 2,14 (2H, t), a 2.36 (2H, t), of 1.95 (3H, s), of 1.39 (9H, s).

Example 206A

Tert-butyl-3-(3-bromo-4-chlorophenyl)-2,2-dimethylpropanoate

4.0 ml (28.8 mmol) of Diisopropylamine in an argon atmosphere was dissolved in 50 ml dry THF and cooled to -30°C. was Pinned to 11.5 ml (28.8 mmol) of a solution of n-utility (2.5 M solution in hexane�). The resulting mixture was warmed to 0°C and then cooled to -70°C. Then was added a solution of 2.77 g (19.2 mmol) of tert-butyl-2-methylbutanoate in 20 ml of THF, and the reaction temperature maintained below -60°C. After 4 h stirring at -60°C was added a solution of 6.0 g (21.1 per mmol) 2-bromo-4-(methyl bromide)-1-chlorobenzene in 30 ml of THF, moreover, the reaction temperature is again maintained below -60°C. the Reaction mixture during the night was stirred with slow warming up to Tbrand then added a saturated aqueous solution of ammonium chloride and ethyl acetate. After phase separation, the aqueous phase was twice extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1→4:1). Received 5.6 g (84% of theory.) target connection.

GC-MS (Method 1): Rt=6,16 min; m/z=290/292 (M-C4H8)+.

Example 207A

Tert-butyl-3-[3-(benzylamino)-4-chlorophenyl]-2,2-dimethylpropanoate

In an argon atmosphere in a dry flask was weighed to 1.73 g (17,95 mmol) of tert-butylate sodium and mixed with 40 ml of abs. toluene. To this were successively added to 5.2 g (14,96 mmol) tert-butyl-3-(3-bromo-4-chlorophenyl)-2,2-dimethylpropanoate, with 1.96 ml (17,95 mmol) of benzylamine, 685 mg (0.75 mmol) of Tris(dibenzylideneacetone)diplodia and�e 373 mg (0,60 mmol) (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl. The reaction mixture for 2 h stirred at 110°C, then cooled to Tbrand additionally stirred at this temperature over night. Then to the reaction mixture were added saturated aqueous solution of ammonium chloride and ethyl acetate and filtered through kieselguhr with suction. After phase separation, the organic phase was washed with a saturated solution of ammonium chloride and a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified by means of preparative HPLC (eluent: acetonitrile/water). Got 2,78 g of target compound (50% of theory.).

LC-MS (Method 6): Rt=1,53 min; m/z=374/376 (M+H)+.

Example 208A

Tert-butyl-3-(3-amino-4-chlorophenyl)-2,2-dimethylpropanoate

2.7 g (about 7,22 mmol) tert-butyl-3-[3-(benzylamino)-4-chlorophenyl]-2,2-dimethylpropanoate was dissolved in 150 ml of ethyl acetate was added 100 mg of palladium on coal (10%). The reaction mixture was stirred at Tbrovernight in a hydrogen atmosphere at normal pressure. Then the mixture was filtered through kieselguhr with suction, the residue washed thoroughly with ethyl acetate, and the combined filtrate was evaporated. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1→7:1). Got to 1.49 g (72.7% of theory.) target connection.

LC-MS (IU�od 4): R t=1,46 min; m/z=284/286 (M+H)+.

1H-NMR (400 MHz, DMSO-d6d/M. D.): 7,05 (1H, d), to 6.57 (1H, d), 6.32 per (1H, DD), 5,20 (2H, s), 2,60 (2H, s), of 1.38 (9H, s), of 1.05 (6H, s).

Example A

N,N-dibenzyl-5-bromo-2-chloraniline

In an argon atmosphere 9,69 g (242,16 mmol, 60% suspension in mineral oil) of sodium hydride was suspended in 100 ml of THF and cooled to 0°C. then slowly pinned 20,0 g (96,86 mmol) 5-bromo-2-Chloroaniline dissolved in 50 ml of THF, and the mixture was stirred 30 min at 0°C. then to the reaction mixture was slowly added 39,76 g (232,47 mmol) bromide, dissolved in 150 ml of THF, and then the reaction mixture was warmed to room temperature. This mixture was stirred over night at Tbrand then carefully poured into 150 ml of ice water. After separating the organic phase the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration the solvent was removed in vacuum. To the resulting crude product was added isopropanol, and the crystals formed were filtered off with suction and dried in a high vacuum at 40°C. 14 g of target compound. The filtrate was concentrated and the obtained residue was purified using chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1). Thus received additional�e EUR 7.57 g of target compound (total yield: 21,57 g, 58% of Theor.).

LC-MS (Method 6): Rt=1,53 min; m/z=386/388 (M+H)+.

Analogously to example I received the following connection:

ExampleName/Structure/Initial connectionAnalytical data
210AN,N-dibenzyl-2-chloro-5-stanlinLC-MS (Method 4): Rt=To 1.86 min; m/z=433/435 (M+H)+.
(2-chloro-5-godonline and bromide)

Example 211A

[4-Chloro-3-(dibenzylamino)phenyl]boric acid

In an argon atmosphere at -78°C to a solution of 15 g (38,79 mmol) N,N-dibenzyl-5-bromo-2-Chloroaniline in 350 ml of a mixture THF/diethyl ether (1:1) slowly pinned of 20.2 ml (50,42 mmol) of a 2.5 M solution of n-utility in hexane. After the reaction solution was further stirred for 60 min at -78°C, thereto was slowly added to 14.3 ml (62,1 mmol) triisopropylsilane. The reaction solution was then stirred an additional 15 min at -78°C, then slowly warmed to room temperature and during the night stirred even at this temperature. After this was added 150 ml of ice water. After �of delenia organic phase the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration the solvent was removed in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1→4:1). Received 9 g (66% of theory.) target connection.

LC-MS (Method 6): Rt=To 1.21 min; m/z=352 (M+H)+.

Example 212A

Tert-butylcyclopentadienyl

In an argon atmosphere at room temperature was dissolved 3.0 g (42.8 mmol) of cyclobutanone in 160 ml of dichloromethane, and then added of 20.95 g (55,64 mmol) of tert-butyl(triphenyl-λ5-postenligaen)acetate and 0.68 g (the 5.56 mmol) of benzoic acid. The reaction mixture was stirred over night at room temperature and then evaporated to dryness. The residue was stirred with 25 ml of diethyl ether and the mixture was stirred for 12 h at 4°C. the Precipitated triphenylphosphine was filtered and the filtrate was evaporated to dryness. The obtained crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1). Got 9.3 g (99% of theory.) target connection.

1H-NMR (400 MHz, DMSO-d6d/M. D.): δ,47-5,41 (1H, m), 3,05-2,95 (2H, m), 2,82-to 2.74 (2H, m), 2,06-of 1.95 (2H, m), of 1.50 (9H, s).

GC-MS (Method 1): Rt=3,01 min; m/z=112 (M-C4H8)+.

Example 213A

Tert-butylcyclopentadienyl

To a solution of 9.65 g (55,34 �mol) [(1-amoxicilpin)oxy](trimethyl)silane, 25 g (66,41 mmol) of tert-butyl(triphenyl-λ5-postenligaen)acetate and 8.11 g (66,41 mmol) of benzoic acid in 240 ml of THF at room temperature was pinned 55 ml (55 mmol) of a 1 M solution of Tetra-n-butylammonium in THF. After 1 h stirring, the reaction mixture was heated to 80°C and further stirred for 2 h at this temperature. Then using a rotary evaporator the solvent was distilled (200 mbar, the temperature of the bath 40°C). The remainder were transferred to diethyl ether, cooled to 4°C and left to stand for 1 h at this temperature. The precipitate was (triphenylphosphine) was filtered. Then, using a rotary evaporator from the filtrate the solvent was removed. The obtained crude product was purified chromatographically on silica gel (eluent: cyclohexane/ethyl acetate 20:1). Got 3,58 g (42% of theory.) target connection.

GC-MS (Method 1): Rt=2,45 min; m/z=98 (M-C4H8)+.

1H-NMR (400 MHz, DMSO-d6d/M. D.): of 1.18-1.26 in (m, 2H), 1,34-of 1.41 (m, 3H), of 1.44 (s, 9H), 6,06-6,13 (m, 1H).

Example A

Ethyl-(3,3-di methoxycinnamaldehyde)acetate

The solution 3,93 g (44,59 mmol) 1,1-dimethoxyethane and 5 g (44,59 mmol) of ethyl buta-2,3-dienoate in 50 ml of toluene was heated to reflux and stirred for 24 h. After cooling to room temperature from the reaction mixture the solvent was removed, and the floor�enny crude product was purified chromatographically on silica gel (eluent: cyclohexane/ethyl acetate 20:1). Received 1.9 g (21% of Theor.) target compound in the form of a colorless liquid which was used in subsequent reactions without further characterization.

Example 215A

Tert-butyl{1-[4-chloro-3-(dibenzylamino)phenyl]cyclopropyl}acetate

Obtaining solution A: 300 mg (0.69 mmol) of N,N-dibenzyl-2-chloro-5-godonline in an argon atmosphere was dissolved in 3 ml of THF and cooled to -78°C. Then slowly pinned 0.4 ml (up to 0.80 mmol) of 2 M solution of isopropylacrylamide in THF. After this reaction solution was slowly warmed to -40°C and 30 min, further stirred at this temperature.

Receiving solution: 6 mg (0.14 mmol) of lithium chloride and 13 mg (0.07 mmol) of copper chloride(1) in an argon atmosphere at room temperature was suspended in 12 ml of THF and then added 84 μl (0.66 mmol) of chloro(trimethyl)silane, and 102 mg (0,66 mmol) of tert-butylcyclopentadienyl. The solution is still 1 hour and further stirred at Tbr.

The solution was cooled to -40°C and slowly pinned to a solution A. Then, the resulting reaction mixture for another 1 hour and further stirred at -40°C. Then to the reaction mixture were added 20 ml of chilled on ice, half-saturation of an aqueous solution of ammonium chloride. After phase separation, the aqueous phase was extracted three more times with ethyl acetate, and the combined organic FA�s were dried over magnesium sulfate, was filtered and was evaporated to dryness. The obtained crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1). Received 135 mg (42% of theory.) target connection.

LC-MS (Method 6): Rt=1,73 min; m/z=462/464 (M+H)+.

Analogously to Example 13A were obtained the following compounds:

ExampleName/Structure/starting compoundAnalytical data
216ATert-butyl{1-[4-chloro-3-(dibenzylamino)phenyl]cyclobutyl}acetateLC-MS (Method 4): Rt=1,96 min; m/z=476/478 (M+H)+.
(from [4-chloro-3-(dibenzylamino)phenyl]boric acid and tert-butylacetoacetate)
217AEthyl-{1-[4-chloro-3-(dibenzylamino)phenyl]-3,3-dimethoxycinnamoyl}acetateLC-MS (Method 6): Rt=1,53 min; m/z=508/51 (M+H)+.
(from [4-chloro-3-(dibenzylamino)phenyl]boric acid and ethyl-(3,3-dimethoxycinnamoyl)acetate)

P�emer 218A

Ethyl-{1-[4-chloro-3-(dibenzylamino)phenyl]-3-oxacyclobutane}acetate

770 mg (1.52 mmol) of ethyl-{1-[4-chloro-3-(dibenzylamino)phenyl]-3,3-dimethoxycinnamoyl}acetate was dissolved in 10 ml of THF, mixed with 2 ml of 1 M hydrochloric acid and 1 h stirred at 50°C. Then the reaction solution was diluted with 10 ml water and 10 ml of ethyl acetate. After phase separation, the organic phase was dried over magnesium sulfate, was filtered and was evaporated to dryness using a rotary evaporator. Got 607 mg of the target compound (87% of theory.).

LC-MS (Method 6): Rt=To 1.44 min; m/z=462/464 (M+H)+.

Example 219A

Ethyl-{1-[4-chloro-3-(dibenzylamino)phenyl]-3,3-diversilobum}acetate

In argon atmosphere, to 2 ml of dichloromethane was added 0.3 ml (2,27 mmol) of [ethyl(trifter-λ4-sulfonyl)amino]ethane. The reaction solution was cooled to 0°C and slowly added 175 mg (0.38 mmol) of ethyl-{1-[4-chloro-3-(dibenzylamino)phenyl]-3-oxacyclobutane}acetate in 3 ml of dichloromethane. The solution was then slowly heated to room temperature and during the night additionally stirred at this temperature. Thereafter, the reaction mixture was poured into 50 ml of ice water, and the organic phase separated. The aqueous phase was extracted three more times with dichloromethane. The combined organic phases were dried over magnesium sulfate. After filtration, the solvent� was removed under vacuum, and the obtained crude product was purified by means of preparative HPLC (eluent: methanol/water 8:2). 59 mg of the target compound (32% of theory.).

LC-MS (Method 6): Rt=1,53 min; m/z=484/486 (M+H)+.

Example A

135 mg (0.29 mmol) of tert-butyl{1-[4-chloro-3-(dibenzylamino)phenyl]-cyclopropyl}acetate was dissolved in 10 ml of ethyl acetate was added 15 mg of palladium on coal (10%) and 2 h stirred at Tbrin the hydrogen atmosphere at normal pressure. Thereafter, the reaction mixture was filtered through celite, the residue was further washed with ethyl acetate, and the filtrate was concentrated. Got 73 mg of the target compound (89% of theory.).

LC-MS (Method 6): Rt=1,15 min; m/z=282/284 (M+H)+.

Analogously to example A were obtained the following compounds:

ExampleName/Structure/starting compoundAnalytical data
ATert-butyl-[1-(3-amino-4-chlorophenyl)cyclobutyl]acetateLC-MS (Method 6): Rt=1,24 min; m/z=296 (M+H)+.
(from tert-butyl{1-[4-chloro-3-(dibenzylamino)phenyl]cyclobutyl}aceta�a)

ExampleName/Structure/starting compoundAnalytical data
AEthyl-[1-(3-amino-4-chlorophenyl)-3,3-diversilobum]acetateLC-MS (Method 4): Rt=To 1.36 min; m/z=304/306 (M+H)+.
(ethyl-{1-[4-chloro-3-(dibenzylamino)phenyl]-3,3-diversilobum}acetate)

Example A

Tert-butyl(2E)-3-(3-amino-4-cyanophenyl)-2-methyl

In argon atmosphere, a mixture of 2.0 g (10,15 mmol) 2-amino-4-bromobenzonitrile, 2,165 g (2.5 ml, 15,23 mmol) tert-butyl-2-methyl acrylate, 93 mg (0.10 mmol) of Tris(dibenzylideneacetone)diplodia, 41 mg (0.20 mmol) of tri-tert-butylphosphine and 2.4 ml (11,17 mmol) of N,N-dicyclohexylamine in 20 ml of dioxane was heated to 120°C and during the night stirred at this temperature. The control results of the reaction (TLC, eluent: cyclohexane/ethyl acetate 9:1) was added 10 mg of Tris(dibenzylideneacetone)diplodia, 10 mg of tri-tert-butylphosphine and 500 µl tert-butyl-2-methyl acrylate and the mixture was stirred for additional 4 h at 120°C. Then the reaction mixture was filtered che�ez target and the filtrate was concentrated in vacuum. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 9:1→4:1). Received 1,375 g of target compound (52% of theory.).

LC-MS (Method 4): Rt=1,33 min; m/z=259 (M+H)+.

Example A

Tert-butyl-3-(3-amino-4-cyanophenyl)-2-methylpropanoate

1370 mg (5.3 mmol) of tert-butyl(2E)-3-(3-amino-4-cyanophenyl)-2-methyl acrylate was dissolved in 30 ml of ethyl acetate, was added 282 mg of palladium on coal (10%) and at Tbrwas stirred for 3 days under a hydrogen atmosphere at normal pressure. Then the reaction mixture was filtered through celite, the residue on the filter was further washed with ethyl acetate, and the combined filtrate was evaporated. The crude product was purified by means of preparative HPLC (eluent: acetonitrile/water). Got 870 mg of the target compound (63% of theory.).

LC-MS (Method 6): Rt=1,04 min; m/z=261 (M+H)+.

Analogously to example 54A was obtained the following compound:

ExampleName/Structure/starting compoundAnalytical data
AEthyl-(3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoateGC-MS (M�TOD 1): R t=5,34 min; m/z=324/326 (M)+.
(4-bromo-1-chloro-2-methoxybenzoyl and ethyl-(3R)-4,4,4-Cryptor-3-methylbutanoate)

Example A

Ethyl-(3R)-2-[4-(2,2-dichloro-3-oxacyclobutane)phenyl]-4,4,4-Cryptor-3-methylbutanoate

3,83 g (13,38 mmol) ethyl-(3R)-4,4,4-Cryptor-3-methyl-2-(4-vinylphenol)-butanoate was dissolved in 50 ml of diethyl ether and was added 2.67 g (20,74 mmol) of zinc-copper couple and 6.5 ml of 1,2-dimethoxyethane. Then to the resulting suspension was slowly pinned 4 ml (36,1 mmol) trichloroacetamide. Then the reaction solution was heated at reflux and stirred overnight. After addition of dichloromethane the reaction mixture was then washed with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, was filtered and was evaporated in vacuum. The obtained crude product was purified chromatographically on silica gel (eluent: cyclohexane/ethyl acetate 4:1). Got 4,57 g (86% of Theor.) target compound in the form of a yellowish oil which was used in further reactions without additional characterization.

Example A

Ethyl-(3R)-4,4,4-Cryptor-3-methyl-2-[4-(3-oxocyclopent)phenyl]butanoate

It is 4.57 g (11,51 mmol) these�-(3R)-2-[4-(2,2-dichloro-3-oxacyclobutane)phenyl]-4,4,4-Cryptor-3-methylbutanoate and 3.76 g (of 57.5 mmol) of zinc dust in 100 ml of THF was added 100 ml of a saturated aqueous solution of ammonium chloride, and then was stirred 5 h at 75°C. After cooling to room temperature and addition of dichloromethane the reaction mixture was washed with water. After phase separation, the aqueous phase further three times was extracted with dichloromethane. Then the combined organic phases were dried over magnesium sulfate, was filtered and was evaporated in vacuum. Got 1.21 g of the target compound (32% of theory.).

GC-MS (Method 1): Rt=6,52 min, m/z=286 (M-C2H2O)+(diastereoisomer 1); Rt=6,55 min, m/z=286 (M-C2H2O)+(diastereoisomer 2).

MS (DCI): m/z=346 (M+NH4)+.

Example A

Ethyl-(3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoate

In an argon atmosphere was charged 7.3 ml (5,16 mmol) of a 50% solution of 1,1'-[(trifter-λ4-sulfanyl)imino]bis(2-ethoxyethane) (deoxo-ferragina) in THF, diluted with 20 ml of toluene, cooled to 5°C and slowly added 47 μl (0,37 mmol) of a 1 M solution of the complex of boron TRIFLUORIDE with diethyl ether. This mixture was additionally stirred for 2 h at 5°C. Then to the reaction solution was slowly added 1.21 g (of 3.69 mmol) ethyl-(3R)-4,4,4-Cryptor-3-methyl-2-[4-(3-oxocyclopent)phenyl]butanoate dissolved in 20 ml of toluene, then heated to 55°C and was stirred for a further 48 h at this temperature. Thereafter, the reaction mixture was poured into a cooled to 0°C mixture�, consisting of 20 ml toluene and 20 ml of 2 M aqueous solution of sodium hydroxide. The organic phase was separated, and the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration the solvent was removed in vacuum. The crude product was purified chromatographically on silica gel (eluent: cyclohexane/ethyl acetate 10:1). Allocated 558 mg (43% of Theor.) target compound in the form of a yellowish liquid.

GC-MS (Method 1): Rt=5,40 min, m/z=350 (M)+(diastereoisomer 1); Rt=5,44 min, m/z=350 (M)+(diastereoisomer 2).

MC (DCI): m/z=368 (M+NH4)+.

Example 229A

Ethyl-(3R)-2-[4-(2,2-diversicolor)phenyl]-4,4,4-Cryptor-3-methylbutanoate

1.58 g (5,52 mmol) ethyl-(3R)-4,4,4-Cryptor-3-methyl-2-(4-vinylphenol)butanoate, 23 mg (0,55 mmol) of sodium fluoride and 24 mg (0.11 mmol) of 2,6-detrol-butyl-4-METHYLPHENOL was heated to 110°C and stirred 5 min. Then slowly pinned to 1.9 ml (at 9.38 mmol) trimethylsilyltriflate(persulfuric)acetate and the mixture was further stirred for 60 minutes at 110°C (caution: gas evolution after about 30 min). After cooling to room temperature and add ethyl acetate and saturated aqueous sodium bicarbonate solution and the organic phase separated, dried over magnesium sulfate, was filtered and was evaporated to dryness. The crude product was purified by chromatography�raficheskih on silica gel (eluent: cyclohexane/dichloro methane 4:1). Received 1.5 g of target compound (81% of theory.).

GC-MS (Method 1): Rt=4,99 min, m/z=336 (M)+(diastereoisomer 1); Rt=5,01 min, m/z=336 (M)+(diastereoisomer 2).

MC (DCI): m/z=354 (M+NH4)+.

Analogously to example 70A were obtained the compounds shown in the following table:

ExampleName/Structure/Initial connectionAnalytical data
230A(2S,3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoate acidGC-MS (Method 1): Rt=5,76 min; m/z=322 (M)+MC (EI): m/z=322 (M)+
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,76 (d, 3H), 2,58 is 2.76 (m, 2H), 2,91-3,05 (m, 2H), 3,17-or 3.28 (m, 1H), 3,34-3,45 (m, 1H),3,60 (d, 1H), 7,27-of 7.36 (m, 4H), 12,63-12,81 (ush. s, 1H).
(from ethyl(3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoate)

ExampleName/Structure/Initial connectionAnalytical data
A2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoate acid 1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,91-12,71 (1H, ush. C), 7,41 (1H, d), 7,18 (1H, d), 6,98 (1H, DD), 3,86 (3H, s), 3,66 (1H, d), 3,40-3,19 (1H, m, partially overlapped with a signal of H2O), 0,79 (3H, d).
LC-MS (Method 5): Rt=2,20 min; m/z=295/297 (M-N)-.
F(from ethyl(3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoate)
A(2S,3R)-2-[4-(2,2-diversicolor)phenyl]-4,4,4-Cryptor-3-methylbutanoate acidLC-MS (Method 6):Rt=1,09 min; m/z=307 (M-H)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,76 (d, 3H), 1,86-2,04 (m, 2H), 2,92-3,06 (m, 1H), 3,18-3,29 (m, 1H), 3,61 (d, 1H), 7,27 (d, 2H), 7,34 (d, 2H), 12,72 (ush. s, 1H).
(from ethyl(2S,3R)-2-[4-(2,2-diversicolor)phenyl]-4,4,4-Cryptor-3-methylbutanoate)

Analogously to example 82A were obtained the compounds shown in the following table:

ExampleName/StructureSource connection
233A (2S,3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoate(2S,3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoate acid
234A(2S,3R)-2-[4-(2,2-diversicolor)phenyl]-4,4,4-Cryptor-3-methylbutanoate(2S,3R)-2-[4-(2,2-diversicolor)phenyl]-4,4,4-Cryptor-3-methylbutanoate acid

Example A

Tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2,2-dimethylpropanoate

400 mg (1,50 mmol) (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid was dissolved in 24 ml of dichloromethane was added 320 mg (2,40 mmol) 1-chloro-N,N,2-trimethylpropane-1-EN-1-amine and was stirred 30 min at room temperature. Then to this was added 364 μl (4.5 mmol) of pyridine, and 510 mg (1,80 mmol) tert-butyl-3-(3-amino-4-chlorophenyl)-2,2-dimethylpropanoate and the mixture is further stirred for 2 h at room temperature. Thereafter, the reaction mixture was evaporated in vacuum and the obtained crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1). Received 462 mg of the target compound (58% of theory).

LC-MS (Method 6): Rt=1,53 min; m/z=530/532 (M-N)-.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), of 1.02 (s, 3H), of 1.05 (s, 3H), of 1.26 (s, 9H), 2,65-2,78 (m, 2H), 3,27-3,44 (m, 1H, partially overlapped with a signal of H2O), 4,10 (d, 1H), of 6.96 (DD, 1H), 7,31 (d, 1H), 7,35 (d, 1H), 7,41-7,51 (m, 4H), case 9.83 (s, 1H).

Similarly, there were obtained the compounds shown in the following table:

ExampleName/Structure/starting compoundAnalytical data
ATert-butyl-[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)cyclobutyl]-acetateLC-MS (Method 6): Rt=1,52 min; m/z=542/544 (M-N)-.
(from tert-butyl-[1-(3-amino-4-chlorophenyl)cyclobutyl]acetate and (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)
AEthyl-(2S)-3-[4-chloro-3-({(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butanoyl}amino)phenyl]-2-methylpropanoateLC-MS (Method 6): Rt=1,46 min; m/z=564 (M-H)-.
(from ethyl(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate and (2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butane acid)

ExampleName/Structure/starting compoundAnalytical data
AEthyl-(2S)-3-[4-chloro-3-({4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoyl}amino)phenyl]-2-methylpropanoateLC-MS (Method 6): Rt=To 1.37 min; m/z=536/538 (M-N)+.
(from ethyl(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate and 4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butane acid)
AEthyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoateLC-MS (Method 6): Rt=To 1.37 min; m/z=520/522 (M+H)+.
1H-NMR (400 MHz, DMSO-d6d/M. D.): 9,80 (1H, s), of 7.42 (1H, d), 7,35 (2H, d), 7,25-7,20 (1H, m),7,06-6,96 (2H, m), 4,10 (1H, d), 3,95 (2H, kV), a 3.87 (3H, s), 3,49-to 3.34 (1H, m), 2,84-to 2.74 (1H, �), 2,72-of 2.58 (2H, m), 1,11-of 1.00 (6H, m), and 0.83 (3H, d).
(from ethyl(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate and (2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoic acid)

ExampleName/Structure/starting compoundAnalytical data
ATert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propanoateLC-MS (Method 6): Rt=1,43 min; m/z=532/534 (M+H)+.
1H-NMR (400 MHz, DMSO-d6d/M. D.): 9,80 (1H, c), of 7.42 (1H, d), 7,38 (1H, d), of 7.36 (1H, d), 7.23 percent (1H, d), 7,07-of 6.99 (2H, m), of 4.09 (1H, d), a 3.87 (3H, s), 3,50-to 3.34 (1H, m) to 2.76 (2H, t), 2,46 (2H, t), of 1.30 (9H, s), and 0.83 (3H, e).
(from tert-butyl-3-(3-amino-4-chlorophenyl)propanoate and (2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoic acid)
ATert-butyl-[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)cyclopropyl] acetateLC-MS (Method 6): Rt=1,48 min; m/z=528/530 (M-NG.
(from tert-butyl-[1-(3-amino-4-chlorophenyl)cyclopropyl]acetate and (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)

ExampleName/Structure/starting compoundAnalytical data
AEthyl-[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-3,3-diversilobum]acetateLC-MS (Method 6): Rt=To 1.39 min; m/z=550/552 (M-H)-.
from ethyl-[1-(3-amino-4-chlorophenyl)-3,3-diversilobum]acetate and (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)
ATert-butyl-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-cyanophenyl)-2-methylpropanoateLC-MS (Method 6): Rt=To 1.39 min; m/z=507/509 (M-N)-.
(from tert-butyl-3-(3-amino-4-cyanophenyl)-2-methylpropanoate and (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid)

Analogously to example 89A were receiving�s connection in the following table:

ExampleName/Structure/starting compoundAnalytical data
244ATert-butyl-3-[4-chloro-3-({(2S,3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoyl}amino)phenyl]propanoate1H-NMR (400 MHz, DMSO-d6d/M. D.): of 9.75 (1H, s), 7,44-value of 7, 37 (3H, m), of 7.36-7,27 (3H, m), 7,02 (1H, DD) 4,10 (1H, d), 3.46 in-3,27 (2H, m, partially overlapped with a signal of H2O), 3,06-of 2.91 (2H, m) of 2.75 (2H, t), 2,71 at 2.59 (2H, m), of 2.45 (2H, t), of 1.31 (9H, s), 0.79 in (3H, d).
(from (2S,3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoate and tert-butyl-3-(3-amino-4-chlorophenyl)propanoate)LC-MS (Method 4): Rt=Of 1.64 min; m/z=558/560 (M-H)-.
AEthyl-(2S)-3-[4-chloro-3-({(2S,3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoyl}amino)phenyl]-2-methylpropanoate1H-NMR (400 MHz, DMSO-d6d/M. D.): of 9.75 (1H, s), 7,40 (3H, t), 7,32 (3H, t), 6,97 (1H, DD), 4,10 (1H, d) to 3.96 (2H, q), 3.46 in-or 3.28 (2H, m, partially overlapped with a signal of H2O), 3,06-of 2.91 (2H, m), 2,84-of 2.58 (5H, m), 1,1-1,01 (6H, m), 0,79 (3H, d).
LC-MS (Method 6): Rt=1,43 min; m/z=544/546 (M-N)-.
(from (2S,3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoate and ethyl-(2S)-3-(3-amino-4-chlorophenyl)-2-methylpropanoate)

ExampleName/Structure/starting compoundAnalytical data
ATert-butyl-3-[4-chloro-3-({(2S,3R)-2-[4-(2,2-diversicolor)phenyl]-4,4,4-Cryptor-3-methylbutanoyl}amino)phenyl]propanoate1H-NMR (400 MHz, DMSO-d6d/M. D.): 9,77 (1H, c), of 7.42 (3H, d), 7,34 (1H, d), 7,27 (2H, d), 7,02 (1H, DD), of 4.09 (1H, d), 3.43 points-or 3.28 (1H, m, partially overlapped with a signal of H2O), 3,05-to 2.94 (1H, m) of 2.75 (2H, t), of 2.45 (2H, t), 2,04-to 1.86 (1H, m), of 1.31 (9H, s), to 0.78 (3H, d).
LC-MS (Method 7): Rt=To 2.99 min; m/z=544/546 (M-N)-.
(from (2S,3R)-2-[4-(2,2-diversicolor)phenyl]-4,4,4-Cryptor-3-methylbutanoate and tert-butyl-3-(3-amino-4-chlorophenyl)propanoate)

Example A

Tert-butyl-3-(3-{[(2S,3R)-2-(4-chlorp�Neal)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)propanoate

A mixture of 100 mg (0.38 mmol) (2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoic acid, 88 mg (0.38 mmol) of tert-butyl-3-(3-amino-2-methylphenyl)propanoate, 213 mg (0,56 mmol) hexaphosphate 2-(1H-7-asobancaria-1-yl)-1,1,3,3-tetramethylurea (GATA) and 1 ml of pyridine in 4 ml of DMF was stirred overnight at room temperature. After this interaction, the reaction mixture was directly separated into its components without any additional processing using preparative HPLC (eluent: acetonitrile/water). Received 151 mg (83% of Theor.) target compound in the form of a colorless oil.

1H-NMR (400 MHz, DMSO-d6d/M. D.): 9,68 (1H, s), of 7.46 (4H, s), to 7.09-6,93 (3H, m), 3,94 (1H, d), 3.43 points-or 3.28 (1H, m, partially overlapped with a signal of H2O), 2,78 (2H, t), is 2.41 (2H, t), 1.91 a (ZN, C), of 1.35 (9H, s), to 0.80 (3H, d).

LC-MS (Method 4): Rt=1,57 min; m/z=482 (M-H)-.

Similarly, it was obtained the following compound:

ExampleName/Structure/starting compoundAnalytical data
ATert-butyl-3-(3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)propanoated6-NMR (400 MHz, LCA�-d 6d/M. D.): 10,00 (1H, s), of 7.64 (1H, d), 7,41 (1H, d), 7,20 (1H, s), 7,13 (1H, t), 7,03-6,94 (2H, m), 4,07 (1H, d), a 3.87( 3H, s), 3,48-to 3.34 (1H, m), is 2.74 (2H, t), of 2.45 (2H, t), of 1.30 (9H, s), of 0.82 (3H, e).
LC-MS (Method 6): Rt=1,38 min; m/z=516/518(M-H)-.
(from (2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoic acid and tert-butyl-3-(3-amino-4-fluorophenyl)propanoate)

Example 249A

Diethyl-[2-(4-chlorophenyl)propan-2-yl]malonate

In an argon atmosphere to 254 mg (10,45 mmol) magnesium turnings in 5 ml of diethyl ether was slowly added 1 g (5,23 mmol) 1-bromo-4-chlorobenzene (2.5 ml diethyl ether. After reaction start to the reaction mixture were added 1 g (5,23 mmol) 1-bromo-4-chlorobenzene (2.5 ml diethyl ether. This reaction mixture was further stirred for 30 min at room temperature, was added 103 mg (1.05 mmol) of copper chloride(1), and then cooled to -10°C. Then it was slowly pulled of 2.09 g (10,45 mmol) diethylpropane-2-eldermount. Next, the reaction mixture was heated to reflux and was further stirred for 3 h at this temperature. Then very slowly added 20 ml of ice-cold 1 M hydrochloric acid. After phase separation, the aqueous phase was extracted three more times, dietro�th ether. The combined organic phases were dried over magnesium sulfate and then evaporated to dryness. The crude product was purified by means of preparative HPLC (eluent: methanol/water 70:30). Thus received 800 mg of the target compound (25% of Theor.).

MS (DCI): m/z=330 (M+NH4)+.

GC-MS (Method 1): Rt=6.19 min; m/z=312 (M)+.

Example 250A

Ethyl-3-(4-chlorophenyl)-3-methylbutanoate

A solution of 796 mg (2,55 mmol) diethyl-[2-(4-chlorophenyl)propan-2-yl]malonate, 216 mg (5,10 mmol) of lithium chloride and 46 μl (2,55 mmol) of water in 5 ml of DMSO was heated to reflux and was stirred for 4 h at this temperature. After cooling to room temperature, to the reaction mixture were added 20 ml of diethyl ether and 20 ml of water. After phase separation, the organic phase was washed three more times with water, and dried organic phase over magnesium sulfate and then evaporated to dryness. The crude product was purified by means of preparative HPLC (eluent: methanol/water 70:30). Received 276 mg of the target compound (45% of theory.).

MS (DCI): m/z=258 (M+NH4)+.

GC-MS (Method 1): Rt=4.99 min; m/z=240/242 (M)+.

Example A

Ethyl-3-(4-chloro-3-nitrophenyl)-3-methylbutanoate

276 mg (1,45 mmol) ethyl-3-(4-chlorophenyl)-3-methylbutanoate was dissolved in 10 ml of dichloromethane and cooled to 0°C. Then portions were added 278 mg (1,38 mm�l) tetrafluoroborate nitrone and the mixture was stirred for 4 h at a temperature between 0°C and 10°C. Then added 10 ml of water and 10 ml of dichloromethane and the phases were separated. The organic phase was dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ ethyl acetate 10:1). Received 223 mg of the target compound (68% of Theor.).

MS (DCI): m/z=303 (M+NH4)+.

GC-MS (Method 1): Rt=6,39 min; m/z=285 (M)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,00 (t, 3H), 1,38 (C, 6N), to 2.74 (s, 2H), 3,89 (kV, 2H), 7,66-7,76 (m, 2H), 8,03 (d, 1H).

Example A

Ethyl-3-(3-amino-4-chlorophenyl)-3-methylbutanoate

To a solution of 213 mg (0.75 mmol) ethyl-3-(4-chloro-3-nitrophenyl)-3-methylbutanoate in 10 ml of ethyl acetate was added 40 mg of palladium on coal (10%). The reaction mixture was gidrirovanie over night at Tbrwith a hydrogen pressure of 1 bar. Then filtered through celite, and the filtrate was concentrated. Received 166 mg (87% of theory.) target compound in the form of a yellowish oil.

LC-MS (Method 6): Rt=1,05 min; m/z=256/258 (M+H)+.

Analogously to example I received the following connection:

ExampleName/Structure/starting compoundAnalytical data
AEthyl-3-(4-chloro-3-{[(2S,3R)-2-(4-Chlo�phenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-3-methylbutanoate LC-MS (Method 6): Rt=1,42 min; m/z=504/506 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), and 0.98 (t, 3H), 1,32 (s, 6H), 2,58 (s, 2H), 3,30-of 3.43 (m, 1H, partially overlapped with a signal of H2O), 3,86 (kV, 2H), 4,14 (d, 1H), 7,20 (DD, 1H), 7,35 (d, 1H), 7,43-of 7.50 (m, 4H), 7,55 (d, 1H), 9,82 (s, 1H).
(from ethyl-3-(3-amino-4-chlorophenyl)-3-methylbutanoate and(23,3^?)-2-(4-chlorophenyl)" 4,4,4-Cryptor-3-methylbutanoic acid)

Application examples:

General method 2: the Breakdown of complex tert-butyl esters to the corresponding carboxylic acids using trifluoroacetic acid

To a solution of the appropriate complex tert-butyl ester in dichloromethane (concentration of from about 0.1 to 2.0 mol/l; additionally, if desired, with a drop of water) at a temperature from 0°C to Tbrdropwise added trifluoroacetic acid (TFA), has not yet achieved the ratio of dichloro methane/terephthalic acid of about 2:1 to 1:2 (V/V). The mixture is stirred for 1-24 h at Tbrif necessary, this mixture is heated to 40°C, until achieving a complete transformation. Thereafter, the reaction mixture pariveda in a vacuum. The crude product can be purified using chromatography on silica gel (elution with mixtures of dichloro methane/ethyl acetate or qi�lovekin/ethyl acetate, if necessary with the addition of minor amounts of acetic acid, or mixtures of dichloro methane/methanol) using a crystallization from acetonitrile or mixtures of water/acetonitrile, or by preparative reverse phase HPLC (eluent: gradient acetonitrile/water).

The following examples were obtained in accordance with the General method 2:

ExampleName/Structure/Initial connectionAnalytical data
1(+)-3-(4-Chloro-3-{[(2S,3R)-4,4,4-Cryptor-2-(4-isopropylphenyl)-3-methylbutanoyl]amino}phenyl)propane acid1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,65-11,44 (1H, ush. C), 9,72 (1H, s), 7,45 (1H, d), 7,35 (3H, t), 7,24 (2H, d), 7,03 (1H, DD), 4,07 (1H, d), 3,39-3,24 (1H, m), 2,94-of 2.81 (1H, m) to 2.76 (2H, t), 2,48 (2H, t), 1,19 (6H, d), 0,79 (3H, d).
LC-MS (Method 5): Rt=2.69 min; m/z=456 (M+H)+.
[α]D20=+102,5°, C=0,44, methanol.
(from tert-butyl-3-(4-chloro-3-{[(2S,3R)-4,4,4-Cryptor-2-(4-isopropylphenyl)-3-methylbutanoyl]amino}phenyl)propanoate)
2(+)--(3-{[(25,3/?)-2-(4-tert-butylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-chlorophenyl)propane acid 1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,11 (1H, c), 9,72 (1H, s), 7,47 (1H, d), 7,41-of 7.35 (4H, m), to 7.33 (1H, d), 7,03 (1H, DD), 4,08 (1H, d), 3,39-3,24 (1H, m) to 2.76 (2H, t), 2,48 (2H, t), of 1.27 (9H, s), 0.79 in (3H, d).
LC-MS (Method 4): Rt=1,47 min; m/z=470 (M+H)+.
[α]D20=+94,9°, C=0,42, methanol.
(from tert-butyl-3-(3-{[(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-chlorophenyl)propanoate)

ExampleName/Structure/Initial connectionAnalytical data
33-[4-Chloro-3-({(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(trifluoromethyl)phenyl]butanoyl}amino)-phenyl]propane acid1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,49-11,83 (1H, ush. (C), of 9.89 (1H, s), to 7.77 (2H, d), 7,69 (2H, d), 7,39 (1H, d), 7,35 (1H, d), 7,05 (1H, DD), 4,24(1H, d), 3,59-3,26 (1H, m) to 2.76 (2H, t), 2,48 (2H, t), to 0.80 (3H, d).
LC-MS (Method 4): Rt=To 1.34 min; m/z=482 (M+H)+.
(istrat-butyl-3-[4-chloro--({(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(trifluoromethyl)-phenyl]butanoyl}amino)phenyl]propanoate)
4(+)-3-[4-Chloro-3-({(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butanoyl}amino)phenyl]-propane acid1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,11 (1H, s), 9,78 (1H, s), 7,54 (2H, d), 7,51-of 7.42 (3H, m), 7,34 (1H, d), 7,03 (1H, DD), 4,14 (1H, d), 3,42-3,26 (1H, m) to 2.76 (2H, t), 2,48 (2H, t), of 1.55 (6H, s), 0.79 in (3H, d).
LC-MS (Method 6): Rt=1,24 min; m/z=524 (M+H)+.
[α]d20=+72,1°, C=0,43, methanol.
(from tert-butyl-3-[4-chloro-3-({(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butanoyl}-amino)phenyl]propanoate)

ExampleName/Structure/Initial connectionAnalytical data
53-[4-Chloro-3-({4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoyl}amino)-phenyl]propane acid1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,11 (1H, c), 9,79 (1H, s), of 7.46 (2H, d), 7,41 (1H, d), 7,35 (3H, t) to 7.04 (1H, DD), 4,11 (1H, d), to 3.64 (2H, kV), 3,44-3,26 (1H, m) to 2.76 (2H, t), 2,48 (2H, t), 0,79 (3H, d).
LC-MS (Method 4): Rt=1,33 min; m/z=496 (M+H)+.
(from tert-butyl-3-[4-chloro-3-({4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]-butanoyl}amino)phenyl]propanoate)
63-(4-Chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}phenyl)-propane acid1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,13 (1H, s), 9,79 (0.5 N, C), 9,75 (0.5 N, C), of 7.48-7,34 (6H, m), 7,07 (1H, d), of 3.78 (0.5 N, d), of 3.75 (0.5 N, d), 3,58-3,45 (0,5 H, m), 3.43 points-3,26 (0,5 H, m), 2,92-of 2.81 (1H, m), 2,77 (2H, t), 2,57-of 2.45 (2H, t), 2,44-of 1.80 (3H, m), 1,71-of 1.45 (1.5 N, m), 1,35-of 1.20 (0.5 N, m).
LC-MS (Method 6): Rt=1,15 min; m/z=456/458 (M+H)+.
(istrat-butyl-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}-phenyl)propanoate)

ExampleName/Structure/Initial connectionAnalytical data
73-(4-Chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-butane acid (mixture of diastereomers)1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 1,12-to 1.21 (m, 6H), of 2.45 (d, 2H), 2,59 (kV, 2H), 3,03-3,13 (m, 1H), 3,32 (d, 1H), 4,07 (d, 1H), 7,06 (d, 1H), 7,20 (d, 2H), 7,31-7,38 (m, 3H), 7,47 (d, 1H), 9,69 (s, 1H), A 12.03 (ush. s, 1H).
83-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-chlorophenyl)-butane acid (mixture of diastereomers)LC-MS (Method 4): Rt=1,45 min; m/z=462 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.16 (d, 3H), of 2.45 (d, 2H), 3,01-3,14 (m, 1H), 3,34-of 3.42 (m, 1H), 4,13 (d, 1H), was 7.08 (DD, 1H), of 7.36 (d, 1H), 7,40-of 7.50 (m, 5H), to 9.81 (s, 1H), 12,06 (s, 1H).

ExampleName/Structure/Initial connectionAnalytical data
93-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-butane acid (mixture of diastereomers)LC-MS (Method 5): Rt=2,47 min; m/z=446 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 1,15/1,16 (2D, joint., 3H), 2,44 (d, 2H), 3,02-3,13 (m, 1 H), 3,34-of 3.42 (m, 1H), 4,12 (d, 1H), 6,97-7,06 (m, 1H), 7,13 (DD, 1H), 7,40-7,49 (m, 4H), 7,67 (d, 1H), 10,03 (s, 1H), 12,05 (ush. s, 1H).
10(35)-3-(4-Chloro-3-{[(4-chlorophenyl)(2,2-diverticulitis)acetyl]amino}phenyl)-butane acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,17 min; m/z=470(M+H)+and Rt=1,19 min; m/z=470 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,11-1,19 (m, 3H), 1,45-1,78 (m, 3H), from 2.00 and 2.26 (m, 2H), 2,45/2,46 (2D, joint., 2H), 2,88-3,17 (m, 2H), 4,04/4,07 (2D, joint., 1H), 6,99-7,13 (m, 1H), 7,30-7,44 (m, 3H), 7,44-7,52 (m, 2H), a 9.64/9,84 (2s, joint., 1H), 12.07 (br. s, 1H).

ExampleName/Structure/Initial connectionAnalytical data
113-(4-Chloro-3-{[(4-chlorophenyl)-(2,2-diverticulitis)acetyl]amino}phenyl)-propane acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,16 min; m/z=456(M+H)+and Rt=1,18 min; m/z=456 (M+H)+.
1H-NMR (40 MHz, DMSO-d6): δ [M. D.]=1,11-of 1.81 (m, 3H),1,96-2,26 (m, 2H), 2,48 (m, 2H), to 2.76 (t, 2H), 2,86-3,20 (m, 1H), 4,03/4,07 (2D, joint., 1H), 6,98-to 7.09 (m, 1H), 7,29-7,54 (m, 6N), a 9.64/9,85 (2s, joint., 1H), 12,09 (ush. s, 1H).

Example 12

(+)-3-(4-Fluoro-3-{[(28,3/?)-4,4,4-Cryptor-3-methyl-2-(4-vinylphenol)-butanoyl]amino}phenyl)propane acid

283 mg (0,590 mmol) of a compound tert-butyl ether (+)-3-(4-fluoro-3-{[(2S,3R)-4,4,4-Cryptor-3-methyl-2-(4-vinylphenol)butanoyl]amino}phenyl)-propane acid was dissolved in 5.9 ml of a 4N solution of hydrogen chloride in dioxane and 24 h was stirred at Tbr. Then the vacuum was removed volatile components. The residue was purified using the ongoing double-preparative reverse phase HPLC (eluent: gradient acetonitrile/water). Received 48 mg (19.2% Theor.) target connection.

LC-MS (Method 6): Rt=1,14 min; m/z=424 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 2,63-2,82 (m, 4H), 3,58-3,66 (m, 1H), 4,08 (d, 1H), 5,27 (d, 1H), of 5.83 (d, 1H), 6,72 (DD, 1H), 6,89-7,03 (m, 1H), 7,12 (DD, 1H), 7,41 (d, 2H), 7,47 (d, 2H), 7,65 (DD, 1H), 10,00 (s, 1H), 12,12 (ush. s, 1H).

[α]D20=+At 149.5°, C=0,310, chloroform.

Example 13

(+)-3-(4-Chloro-3-{[(2S,3R)-4,4,4-Cryptor-3-methyl-2-(4-vinylphenol)-butanoyl]amino}phenyl)propane acid

249,0 mg (0,502 mmol) of a compound tert-butyl ether (+)-3-(4-chloro-3-{[(2S,3R)-4,4,4-Cryptor-3-methyl-2-(4-vinylphenol)butanoyl]amino}phenyl)-propane acid was dissolved in 3.8 ml of 4N R�the target of hydrogen chloride in dioxane and 24 h was stirred at T br. The reaction mixture was frozen (-78°C) and then subjected to freeze drying in a high vacuum. The residue was purified using preparative reverse phase HPLC (eluent: gradient acetonitrile/water). Got 167,4 mg (75.8% of theory.) target connection.

LC-MS (Method 6): Rt=1,16 min; m/z=440 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 2,48 (m, 2H), to 2.76 (t, 2H), 3,35-of 3.42 (m, 1H), of 4.09 (d, 1H), 5,27 (d, 1H), 5,84 (d, 1H), 6,73 (DD, 1H), to 7.04 (DD, 1H), 7,34 (d, 1H), 7,39-7,52 (m, 5H), 9,79 (s, 1H), 12,14 (ush. s, 1H).

[α]D20=+88,8°, C=0,325, chloroform.

Example 14

(+)-3-[4-Chloro-3-({(2S,3R)-4,4,4-Cryptor-2-[4-(1-forfinal)phenyl]-3-methylbutanoyl}amino)phenyl]propane acid

To a cooled to 0°C a solution of 212 mg (0,449 mmol) of a compound methyl ester (+)-3-[4-chloro-3-({(2S,3R)-4,4,4-Cryptor-2-[4-(1-forfinal)phenyl]-3-methylbutanoyl}amino)phenyl]propane acid in a mixture of, respectively, 1.0 ml each of methanol, THF and water was added to 16.1 mg (0,674 mmol) of lithium hydroxide. This mixture is then heated to Tbrand 3 h stirred at Tbr, then diluted with water and with 1 n hydrochloric acid was set acidic (pH about 2). Three times were extracted with ethyl acetate. The organic phases were combined and evaporated in vacuo. The crude product is first pre-purified by reverse phase HPLC (eluent: gradient acetonitrile/water). Education�, which aimed at the main hydrolysis 2R-diastereoisomer was then separated using a preparative HPLC on a chiral phase [column: Daicel ChiralpakAD-H, 5 µm, 250 mm×20 mm; injection volume: 0.25 ml; temperature: 35°C; eluent: 90% isohexane/10% ethanol, flow rate: 15 ml/min; detection: 220 nm]. Thus was obtained and 74.0 mg (36,0% of Theor.) target connection.

LC-MS (Method 4): Rt=1,33 min; m/z=458 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,81 (d, 3H), 2,47 (t, 2H), to 2.76 (t, 2H), 3,35-of 3.43 (m, 1H), 4,15 (d, 1H), of 4.95 (DD, 1H), 5,39 (DD, 1H), to 7.04 (DD, 1H), 7,26-7,44 (m, 2H), 7,44-members, 7.59 (m, 2H), members, 7.59-to 7.68 (m, 2H),9,82 (s, 1H), 12,11 (ush. s,1H).

[α]D20=+69,2°, C=0,405, chloroform.

Example 15

(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propane acid

30,13 g (59,74 mmol) tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propanoate was dissolved in 1000 ml of dichloromethane and Damn. added 92 ml of trifluoroacetic acid. The reaction mixture was stirred 3.5 h at Tbr. Then add dichloro methane and water. The organic phase was separated, dried with magnesium sulfate and evaporated in vacuum. The residue is carefully dried in a high vacuum. Got 26,31 g (98.3% of theoretical.) target connection.

LC-MS (Method 7): Rt=2,51 min; m/z=446/448 (M-N)-.

1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,14 (1H, s), case 9.83 (1H, s), 7,50-the 7.43 (4H, m), 7,39 (1H, d), 7,35 (1H, d), 7,05 (1H, DD), of 4.12 (1H, d), 3.43 points-or 3.28 (1H, m) to 2.76 (2H, t), 2,48 (2H, t), to 0.80 (ZN, d).

[α]D20=+100,1°, C=0,42, methanol.

P�emer 16

(+)-(2R)-3-(4-chloro-3-[[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate acid

990 mg on 2.02 mmol) of ethyl-(2R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate was dissolved in 5.7 ml of acetic acid was added to 2.7 ml of concentrated hydrochloric acid. The mixture was stirred for 1 h at 100°C. After cooling, the reaction mixture was evaporated in vacuum. The residue is transferred into ethyl acetate and washed several times with water with a few drops of a saturated solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and evaporated in vacuum. The residue was purified by chromatography on silica gel (eluent: first, dichloro methane, dichloro methane/ethyl acetate 10:1). Received 652 mg (69.9% of theor.) target connection.

LC-MS (Method 6): Rt=To 1.21 min; m/z=462 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.02 (d, 3H), 2,55-2,62 (m, 2H), 2,78-2,88 (m, 1H), 3,35-of 3.43 (m, 1H), 4,12 (d, 1H), 7,01 (DD, 1H), 7,32-7,39 (m, 2H), of 7.42-7,50 (m, 4H), case 9.83 (s, 1H), 12,16 (ush. s, 1H).

[α]D20=+60,56°, C=0,530, chloroform.

Example 17

(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate acid

Method A:

A mixture of 2.45 g (5,0 mmol) ethyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]�Mino}phenyl)-2-methylpropanoate, 6.0 ml of acetic acid and 20 ml of 20% aqueous sulfuric acid was stirred for 7 hours under reflux. After cooling, the reaction mixture was poured into water. The aqueous phase three times were extracted with ethyl acetate, and the combined organic phases was evaporated in vacuum. The residue is again transferred into ethyl acetate and washed several times with water with a few drops of a saturated solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and evaporated in vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1→4:1). Received 1.88 g (81,4% of Theor.) target connection.

LC-MS (Method 6): Rt=1,22 min; m/z=462 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.02 (d, 3H), 2,55-2,61 (m, 2H), 2,78-2,88 (m, 1H), 3,35-of 3.43 (m, 1H), 4,12 (d, 1H), 7,01 (DD, 1H), 7,32-7,39 (m, 2H), 7,43-of 7.50 (m, 4H), case 9.83 (s, 1H), 12,16 (ush. s, 1H).

[α]D20=+101,2°, C=0,590, chloroform.

Method:

A mixture of 12,99 g (26,49 mmol) of (+)-ethyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate, 60 ml of acetic acid and 60 ml of 30% aqueous sulfuric acid was stirred 3 h at reflux (temperature of the bath 140°C). After cooling, the reaction mixture was poured into water. The aqueous phase three times were extracted with ethyl acetate, and the combined organic phases were washed with us�saturated solution of sodium chloride, dried over sodium sulfate and evaporated in vacuum. The remainder of the overnight dried in a high vacuum. The thus obtained crude product was stirred with 90 ml of diisopropyl ether first 1 h at 50°C and then 4 h at Tbr. After filtration, the solid is dried in a high vacuum. Got 7,84 g (64% of theory.) the target compound (fraction 1). From the filtrate after evaporation and re-treatment 30 ml of diisopropyl ether was allocated additional portion. After drying in a high vacuum was obtained 1.65 g (13.5% of Theor.) slightly contaminated target compound (fraction 2).

LC-MS (Method 4): Rt=To 1.39 min; m/z=461/463 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.02 (d, 3H), 2,55-2,61 (m, 2H), 2,77-2,88 (m, 1H), 3,34-of 3.43 (m, 1H), 4,12 (d, 1H), 7,01 (DD, 1H), 7,31-7,39 (m, 2H), 7,41-7,51 (m, 4H), case 9.83 (s, 1H), 12,15 (s, 1H).

[α]D20=+To 127.6°, C=0,575, chloroform. Example 18

(+)-[1-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)cyclopropyl]acetic acid

106 mg (0,23 mmol) of methyl-[1-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)cyclopropyl]acetate was dissolved in 4 ml of glacial acetic acid and 2 ml of concentrated hydrochloric acid and stirred 1 h at 100°C. Then the reaction mixture was diluted with 10 ml of water and then this aqueous solution was three times extracted with respectively �orciani 10 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated in vacuum. The obtained crude product was purified using preparative reverse phase HPLC (eluent: gradient acetonitrile/water). Received 64 mg of the target compound (0.14 mmol, 89% of Theor.).

LC-MS (Method 4): Rt=To 1.34 min; m/z=458 (M+H)+.

1H-NMR (400 MHz, DMSO-d6d/M. D.): 10,03 (1H, s), 7,69-members, 7.59 (1H, m), 7,52-7,34 (4H, m), 7,11-7,00 (2H, m), 4,11 (1H, d), 3.43 points-3,27 (1H, m), a 2.36 (2H, s), 0,88-0,82 (2H, m), to 0.78 (3H, d), of 0.72 and 0.64 (2H, m).

[α]D20=+108,7°, C=0,36, methanol.

General method 3: the Breakdown of complex ethyl or methyl esters to the corresponding carboxylic acids using a mixture of hydrochloric acid or sulfuric acid with acetic acid

A solution of the appropriate complex ethyl or methyl ester in a mixture of acetic acid and concentrated hydrochloric acid or acetic acid and 10% or polukoertsitivnoi sulfuric acid is stirred at a temperature of from 80°C to 130°C (if necessary at reflux) for a period of time from 30 min to 12 h. After cooling, this reaction mixture or directly evaporated in vacuum or pour into water, the aqueous phase extracted with ethyl acetate or dichloromethane, and the combined organic phase is evaporated in vacuum. The crude product can be purified using chromatography on silica gel (elution �Masami dichloro methane/ethyl acetate or cyclohexane/ethyl acetate, if necessary with the addition of minor amounts of acetic acid, or mixtures of dichloro methane/methanol), by crystallization from acetonitrile or mixtures of water/acetonitrile or via preparative reverse phase HPLC (eluent: gradient acetonitrile/water).

The following examples were obtained in accordance with the General method 3:

ExampleName/Structure/Initial connectionAnalytical data
19(+)-[1-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)cyclopropyl]acetic acid1H-NMR (400 MHz, DMSO-d6d/M. D.): 11,97 (1H, c), 9,96 (1H, s), of 7.75 (1H, DD), 7,34 (2H, d), 7,20 (2H, d), to 7.09 (1H, t), 7,05-of 6.99 (1H, m), of 4.05 (1H,d), 3,40-3,27 (1H, m), 2,59 (2H, kV), 2,55-of 2.48 (2H, m), of 1.17 (3H, t), 0,88-0,82 (2H, m), 0.79, which is 0,74 (5H, m).
LC-MS (Method 5): Rt=2,58 min; m/z=452 (M+H)+.
[α]D20=+125,2°, C=0,35, methanol.
(from methyl-[1-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)cyclopropyl]acetate)
20 (2S)-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}phenyl)-2-methylpropanoate acidLC-MS (Method 6): Rt=To 1.21 min; m/z=470/472 (M)+.
(from ethyl(2S)-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}phenyl)-2-methylpropanoate)

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.02 (d, 3H), 2,55-2,61 (m, 2H), 2,77-2,89 (m,1H), 3,33-of 3.42 (m, 1H), 4,12 (d, 1H), 7,01 (DD, 1H), 7,30-7,40 (m, 2H), 7,41-7,51 (m, 4H), 9,82 (s, 1H), 12,14 (ush. s, 1H).
ExampleName/Structure/Initial connectionAnalytical data
21(2R)-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}phenyl)-2-methylpropanoate acidLC-MS (Method 6): Rt=To 1.21 min; m/z=470/472 (M)+.
(from ethyl(2R)-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-divertikulitis)acetyl]amino}phenyl)-2-methylpropanoate)
223-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate (mixture of diastereomers)LC-MS (Method 5): Rt=2,57 min; m/z=462 (M+H)+.

ExampleName/Structure/Initial connectionAnalytical data
233-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoate acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,22 min; m/z=440 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,77 (d, 3H), 1,01 (d, 3H), of 1.17 (t, 3H), 2,53-2,62 (m, about 4H), 2,77-2,87 (m, 1H), 3,27-to 3.38 (m, about 1H), 4,05 (d, 1H), 6,86-6,98 (m, 1H), 7,11 (DD, 1H), made 7.16 interest-7.23 percent (m, 2H), 7,29-value of 7, 37 (m, 2H), With 7.66 (dt, 1H), becomes 9.97 (s, 1H), 12,14 (ush. s, 1H).
243-(4-Chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate acid (mixture of diastereomers)LC-MS (Method 6): Rt=1.27 mm min; m/z=456 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), of 1.02 (d, 3H), 1,1 (t, 3H), 2,55-of 2.64 (m, about 4H), 2,77-2,88 (m, 1H), 3,27-to 3.38 (m, about 1H), 4,06 (d, 1H), 6,99 (DD, 1H), 7,21 (d, 2H), 7,34 (DD, 3H), 7,41 (d, 1H), of 9.74 (s, 1H), 12,20 (ush. s, 1H).

ExampleName/Structure/Initial connectionAnalytical data
25(2S)-3-(4-chloro-3-{[(4-chlorophenyl)-(2,2-diverticulitis)acetyl]amino}phenyl)-2-methylpropanoate acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,17 min; m/z=470(M+H)+and Rt=1,19 min; m/z=470 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 1.02 (d, 3H), 1,11-of 1.26 (m, 1H), 1,48-1,78 (m, 3H), 1,99-of 2.24 (m, 2H), 2,55-2,62 (m, about 2H), 2,77-2,86 (m, 1H), 2,87-3,20 (m, 1H), was 4.02/4,06 (2D, joint., 1H), 6,99/7,01 (DD, joint., 1H), 7,30 was 7.45 (m, 4H), 7,45-7,51 (m, 2H), a 9.64 (s, 1H), 12,14 (ush. s, 1H).
262-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-butane acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,26 min; m/z=476 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=range 0.74-0.89 (m, 6H), 1,40-of 1.53 (m, 2H), 2,30-2,45 (m, 1H), 2,46-by 2.55 (m, about 1H), 2,57-2,68 (m, 1H), 2,68-of 2.81 (m, 1H), 3,36-3,44 (m, about 1H), 4,12 (d, 1H), 7,00 (DD, 1H), 7,29-7,40 (m, 2H), 7,41-7,51 (m, 4H), 9,82 (s, 1H), 12,15 (ush. s, 1H).

Example 27

(+)-[3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)oxetan-3-yl]acetic acid

A solution of 120 mg (0,21 mmol) benzyl[3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)oxetan-3-yl]acetate in 15 ml of ethyl acetate was mixed with 25 mg of palladium on coal (10%). In the hydrogen atmosphere was gidrirovanie under normal pressure for 2 h. then the reaction mixture was filtered through tonsil, the residue on the filter was further washed with ethyl acetate, and the combined filtrate was evaporated on a rotary evaporator. Got 98 mg (0.2 mmol, 97% of Theor.) target connection.

LC-MS (Method 4): Rt=1,28 min; m/z=488/490 (M-H)-.

1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,76-to 11.52 (1H, ush. C) for 9.88 (1H, s), 7,52 (1H, d), 7,50-7,39 (5H, m), 7,10 (1H, DD), 4,79-4,71 (2H, m), 4,71-a 4.64 (2H, m), 4,14 (1H, d), 3,42-or 3.28 (1H, m), 3,03 (2H, C) to 0.80 (3H, d).

[α]D20=+88,4°, C=0,355, methanol.

Example 28

[1-(4-Chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)cyclobutyl]acetic acid

38 mg (0.08 mmol) of methyl[1-(4-chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}Hairdryer�l)cyclobutyl]acetate was dissolved in 9.5 ml of dioxane and was added 0.15 ml of 1 n aqueous solution of sodium hydroxide. The reaction mass was stirred over night at 80°C. Then the reaction mixture was acidified with 1 n hydrochloric acid to pH 1 and several times was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuum. The crude product was purified using preparative HPLC. Received 22 mg (0.05 mmol, 60% of Theor.) target connection.

LC-MS (Method 6): Rt=1,28 min; m/z=488/490 (M+H)+.

1H-NMR (400 MHz, DMSO-d6d/M. D.): 11,88 (1H, ush. (C), 9,95 (0.5 N, C), 9,81 (0.5 N, s), 7,54-7,31 (6H, m), 7,06-of 6.96 (1H, m), 4,14 (1H, d), 3.43 points-3,27 (0,5 H, m), 3,27-3,14 (0.5 H, m), 2,70 (1H, s), 2,69 (1H, s), 2,34-of 2.17 (4H, m), 2,10-of 1.95 (1H, m), Of 1.81 and 1.66 (1H, m), 1,25 (1.5 N, d), 0,80 (1.5 N, d).

Example 29

(+)-(2R)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)butane acid

To 1,96 g (3,89 mmol) of a compound ethyl ester of (+)-(2R)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-butane acid was added to 15.2 ml of acetic acid and 7.6 ml of concentrated hydrochloric acid. The reaction mixture was stirred 5 h at reflux (temperature of the bath 140°C). After cooling, water was added. Several times was extracted with dichloromethane and the combined organic phases were washed with saturated solution of sodium chloride�I, dried over sodium sulfate and evaporated in vacuum.

After chromatography of the residue on silica gel (eluent: cyclohexane/ethyl acetate 10:1→2:1) received a 1.46 g (78.6% of theor.) target connection.

LC-MS (Method 6): Rt=1,25 min; m/z=476 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 0,82-0,89 (m, 3H), 1,42-of 1.54 (m, 2H), 2,41 (m, 1H), of 2.64 (DD, 1H), 2,75 (DD, 1H), 4,12 (d, 1H), 7,00 (DD, 1H), 7,31-7,39 (m, 1H), of 7.42-7,50 (m, 3H), 9,82 (s, 1H), 12,16 (ush. s, 1H).

[α]D20=+92,7°, C=0,380, methanol. In a similar way the following compound:

Example 30

(+)-(2S)-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)butane acid

325 LC-MS (Method 5): Rt=2,66 min; m/z=476 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 0.85 (t, 3H), 1,43-of 1.52 (m, 2H), 2.26 and-2,47 (m, 1H), 2,59-2,69 (m, 1H), 2,70-2,82 (m, 1H), 3,34-3,44 (m, 1H), 4,12 (d, 1H), 7,00 (DD, 1H), 7,30-7,39 (m, 2H), 7,40-7,52 (m, 4H), 9,82 (s, 1H), 12,13 (ush. s, 1H).

[α]D20=+143,1°, C=0,380, chloroform.

Example 31 and Example 32

3-[4-Chloro-3-({4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]-butanoyl}amino)phenyl]propane acid (enantiomers 1 and 2)

120 mg (0,24 mmol) of racemic 3-[4-chloro-3-({4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoyl}amino)phenyl]propane acid (example 5) was separated into the enantiomers using preparative HPLC on Hira�encourages creativity phase [column: Daicel Chiralpak AD-H, 5 µm, 250 mm×20 mm; eluent: isohexane/ethanol 85:15 (V/V); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 35°C].

Example 31

(+)-3-[4-Chloro-3-({(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)-phenyl]butanoyl}amino)phenyl]propane acid (enantiomer 1)

Yield: 48 mg

Rt=5,75 min; chemical purity > 99%; > 99% EE

[column: Daicel Chiralpak AD-H, 5 μm, 250 mm×4.6 mm; eluent: isohexane/ethanol of +0.2% TFA +1% water) 85:15 (V/V); flow rate: 1 ml/min; temperature: 35°C; UV detection: 220 nm].

[α]D20=+91,8°, C=0,405, methanol.

LC-MS (Method 4): Rt=1,33 min; m/z=496 (M+H)+.

1H-NMR (400 MHz, DMSO-d6d/M. D.): 12,24-12,02 (1H, ush. C), 9,80 (1H, s), of 7.46 (2H, d), the 7.43-7,39 (1H, m), 7,35 (3H, t) to 7.04 (1H, DD), 4,11 (1H, d), to 3.64 (2H, kV), 3,44-3,27 (1H, m) to 2.76 (2H, t), 2,48 (2H, t), 0,79 (3H, d).

Example 32

(-)-3-[4-Chloro-3-({(2R,3S)-4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)-phenyl]butanoyl}amino)phenyl]propane acid {enantiomer 2)

Yield:52 mg

Rt=Of 6.85 min; chemical purity > 97,4%; > 99%

[column: Daicel Chiralpak AD-H, 5 μm, 250 mm×4.6 mm; eluent: isohexane/(ethanol + 0.2% of TFA + 1% water) 85:15 (V/V); flow rate: 1 ml/min; temperature: 35°C; UV detection: 220 nm].

[α]D20=-94,3°, C=0,40, methanol.

LC-MS (Method 4): Rt=1,33 min; m/z=496 (M+H)+.

Examples 33-36

3-(4-Chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]Amin�}-phenyl)propane acid (isomers 1-4)

44 mg (0,096 mmol) of a mixture of diastereomers of 3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}phenyl)propane acid (Example 6) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm×20 mm; eluent: isohexane/ethanol 70:30 (V/V); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 35°C].

Thus were obtained the four different fractions, which consisted respectively of a mixture of two isomers. These fractions were separated with a preparative HPLC on a chiral phase into individual isomers [Faction 1 and 2: column: Daicel Chiralpak AS-H, 5 μm, 250 mm×20 mm; eluent: isohexane/isopropanol 75:25 (V/V); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 35°C. Fraction 3 and 4: column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; eluent: isohexane/ethanol 80:20 (V/V); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 35°C]:

Example 33 (isomer 1):

Yield:8 mg

Rt=6,49 min; chemical purity > 99%

[column: Daicel Chiralpak AS-H, 5 μm, 250 mm×4.6 mm; eluent: isohexane/isopropanol 75:25 (V/V); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 35°C].

Example 34 (isomer 2):

Yield: 11 mg

Rt=Remaining 9.08 min; chemical purity > 98.5% of

[column: Daicel Chiralpak AS-H, 5 μm, 250 mm×4.6 mm; eluent: isohexane/isopropanol 75:25 (V/V); flow rate: 1 ml/min; UV detection: 220 nm; �emperature: 35°C].

Example 35 (isomer 3):

Yield: 12 mg Rt=Of 7.19 min; chemical purity > 99%

[column: Daicel Chiralpak AD-H, 5 μm, 250 mm×4.6 mm; eluent: isohexane/ethanol 80:20 (V/V); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30°C].

Example 36 (isomer 4):

Yield: 9 mg

Rt=8,58 min; chemical purity > 97.5% of the

[column: Daicel Chiralpak AD-H, 5 μm, 250 mm×4.6 mm; eluent: isohexane/ethanol 80:20 (V/V); flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30°C].

Example 37

3-(3-{[(3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoate acid (mixture of diastereomers)

300 mg (0,633 mmol) ethyl-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoate (mixture of diastereomers) was dissolved in a mixture of respectively each in 1.0 ml of methanol, THF and water at 0°C was added 265.5 mg (6,33 mmol) of lithium hydroxide. The mixture was first stirred 1 h at 0°C and then 1 h at Tbr. After this, the solution was diluted with water and installed acidic with 1 n hydrochloric acid (pH about 2). The aqueous phase three times were extracted with diethyl ether and once with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuum. Received 294 mg (99.7% from Theor.) target compound in the form of a mixture of four diastereomers.

LC-MS (Method 6): Rt =1,18 min; m/z=446 (M+H)+.

Example 38 and Example 39

3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoate acid (diastereomers 1 and 2)

The above diastereomeric mixture of 3-(3-{[(3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoic acids (Example 37) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralpak AS-H, 5 μm, 250 mm×20 mm; injection volume: 0.25 ml; temperature: 40°C; eluent: 90% isohexane/10% (ethanol + 0.2% of TFA + 1% water); flow rate: 15 ml/min; detection: 220 nm]. On the basis of 260 mg of a mixture of diastereoisomers, in addition to the other two isomers was obtained 52 mg of isomer 1 (Example 38) and 54 mg of isomer 2 (Example 39):

Example 38 (diastereoisomer 1Y

(+)-(2S)-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]-amino}-4-fluorophenyl)-2-methylpropanoate acid

Isomer 1 using preparative reverse phase HPLC (eluent: acetonitrile/water) was purified again advanced. Received 32 mg.

LC-MS (Method 6): Rt=1,18 min; m/z=446 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 1,01 (d, 3H), 2,51-of 2.58 (m, 2H), 2,76-2,86 (m, 1H), 3,35 (DD, 1H), 4,11 (d, 1H), 6,87-7,00 (m, 1H), 7,12 (DD, 1H), 7,41-7,49 (m, 4H), 7,63 (DD, 1H), 10,04 (s, 1H), 12,11 (ush. s, 1H).

[α]D20=+150,4°, C=0,50, chloroform.

Example 39 (diastereoisomer 2):

(+)-(2R)-3-(3-{[(2S,3R)-2-(4-harfe�yl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoate acid

Isomer 2 again was further purified using preparative reverse phase HPLC (eluent: acetonitrile/water). Received 21 mg.

LC-MS (Method 6): Rt=1,18 min; m/z=446 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), of 1.02 (d, 3H), 2,53-of 2.58 (m, 2H), 2,77-2,87 (m, 1H), 3,30-to 3.41 (m, 1H), 4,11 (d, 1H), 6,89-7,00 (m, 1H), 7,12 (DD, 1H), 7,41-of 7.48 (m, 4H), 7,63 (DD, 1H), 10,04 (s, 1H), 12,12 (ush. s, 1H).

[α]D20=+131,6°, C=0,530, chloroform.

Example 40 and Example 41

3-(4-Chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]-amino}phenyl)-2-methylpropanoate acid (diastereomers 1 and 2)

The above diastereomeric mixture of 3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoic acid (Example 24) was further separated using preparative HPLC on a chiral phase [column: chiral phase silica gel based on the selector poly(N-methacryloyl-1--isoleucine-3-pentylamine), 430 mm×40 mm; injection volume: 2.0 ml; temperature: 24°C; eluent: 40% of isohexane/60% ethyl acetate; flow rate: 80 ml/min; detection: 265 nm]. On the basis of 514 mg of a mixture of diastereomers, received 178 mg of diastereoisomer 1 (Example 40) and 218 mg of diastereoisomer 2 (Example 41):

Example 40 (diastereoisomer 1):

(+)-(2R)-3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate acid

<> LC-MS (Method 6): Rt=1,25 min; m/z=456 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 0,98-1,05 (m, 3H), of 1.17 (t, 3H), 2,55 - 2,63 (m, 4H), 2,78-2,88 (m, 1H), or 3.28-3,37 (m, 1H), 4,06 (d, 1H), 6,99 (DD, 1H), 7,20 (d, 2H), 7,34 (DD, 3H), 7,41 (d, 1H), 9,73 (s, 1H), 12,15 (s, 1H).

[α]D20=+52°,=0,500, chloroform.

Example 41 (diastereoisomer 2):

(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate acid

LC-MS (Method 6): Rt=1,27 min; m/z=456 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,78 (d, 3H), of 1.02 (d, 3H), of 1.17 (t, 3H), 2,54-of 2.64 (m, 4H), 2,77-2,87 (m, 1H), or 3.28-3,37 (m, 1H), 4,06 (d, 1H), 6,99 (DD, 1H), 7,21 (d, 2H), 7,34 (DD, 3H), 7,41 (d, 1H), of 9.74 (s, 1H), 12,16 (ush.s, 1H).

[α]D20=+75,0°, C=0,640, chloroform.

Example 42 and Example 43

3-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoate acid (diastereomers 1 and 2)

The above diastereomeric mixture of 3-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoic acid (Example 23) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralpak AS-H, 5 μm, 250 mm×20 mm; injection volume: 0,30 ml; temperature: 30°C; eluent: 92% of isohexane/8% (ethanol + 0.2% of TFA + 1% water); flow rate: 15 ml/min; detection: 220 nm]. On the basis of 509 mg of the mixture of diastereoisomers, received 209 mg diaster�Omer 1 (Example 42) and 220 mg of diastereoisomer 2 (Example 43):

Example 42 (diastereoisomer 1):

(+)-(2S)-3-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoate acid

LC-MS (Method 6): Rt=1,22 min; m/z=440 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,77 (d, 3H), 1,01 (d, 3H), of 1.17 (t, 3H), 2,55-2,63 (m, 4H), 2,76-2,86 (m, 1H), 3,25-3,39 (m, 1H), 4,05 (d, 1H), to 6.88-6,98 (m, 1H), 7,11 (DD, 1H), 7,17-7,24 (m, 2H), 7,29-7,38 (m, 2H), 7,66 (DD, 1H), becomes 9.97 (s, 1H), 12,13 (ush.s, 1H).

[α]D20=+162,1°,=0,500, chloroform.

Example 43 (diastereoisomer 2):

(+)-(2R)-3-(3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylpropanoate acid

LC-MS (Method 6): Rt=1,22 min; m/z=440 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,77 (d, 3H), 1,01 (d, 3H), of 1.17 (t, 3H), 2,53-of 2.64 (m, 4H), 2,76-2,87 (m, 1H), 3,26-to 3.38 (m, 1H), of 4.04 (d, 1H), 6,87-6,97 (m, 1H), 7,11 (DD, 1H), 7,17-7.23 percent (m, 2H), 7,28-7,38 (m, 2H), 7,65 (DD, 1H), becomes 9.97 (s, 1H), 12,12(ush.s, 1H).

[α]D20=+94,0°, C=0,620, chloroform.

Example 44 and Example 45

3-(4-Chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)butane acid (diastereomers 1 and 2)

The above diastereomeric mixture of 3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)butane acid (Example 7) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralpak AS-H, 5 μm, 250 mm×20 m�; injection volume: 0.20 ml; temperature: 30°C; eluent: 90% isohexane/10% (isopropanol + 0.2% of TFA + 1% water); flow rate: 15 ml/min; detection: 220 nm]. Based on 210 mg of a mixture of diastereomers, was obtained 110 mg of diastereoisomer 1 (Example 44) and 99 mg of diastereoisomer 2 (Example 45):

Example 44 (diastereoisomer 1):

(+)-(3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)butane acid

LC-MS (Method 6): Rt=1,26 min; m/z=456 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), of 1.13-to 1.21 (m, 6H), of 2.45 (d, 2H), 2,59 (kV, 2H), is 3.08 (q, 1H), 3,27-to 3.38 (m, 1H), 4,07 (d, 1H), 7,06 (DD, 1H), 7,21 (d, 2H), 7,35 (DD, 3H), of 7.46 (d, 1H), 9,72 (s, 1H), 12,05 (ush.s, 1H).

[α]D20=+Representing 86.8°, C=0,440, chloroform. Example 45 (diastereoisomer 2):

(+)-(3R)-3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)butane acid

LC-MS (Method 6): Rt=1,26 min; m/z=456 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 1,11-1,22 (m, 6H), of 2.45 (d, 2H), 2,55-2,63 (m, 2H), is 3.08 (q, 1H), or 3.28-to 3.38 (m, 1H), 4,08 (d, 1H), 7,06 (DD, 1H), 7,20 (d, 2H), 7,35 (DD, 3H), 7,47 (d, 1H), 9,72 (s, 1H), 12,05 (ush.s, 1H).

[α]D20=+68,0°, C=0,415, chloroform. Example 46 and Example 47

3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-chlorophenyl)butane acid (diastereomers 1 and 2)

The above diastereomeric mixture of 3-(3-{[(2S,3R)-2-(4-chlorphen�l)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-chlorophenyl)butane acid (Example 8) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralpak AS-H, 5 µm, 250 mm×20 mm; injection volume: 0,30 ml; temperature: 30°C; eluent: 90% isohexane/10% isopropanol; flow rate: 15 ml/min; detection: 220 nm]. Based on 250 mg of a mixture of diastereomers, was obtained 116 mg of diastereoisomer 1 (Example 46) and 113 mg of diastereoisomer 2 (Example 47):

Example 46 (diastereoisomer 1):

(+)-(3S)-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-chlorophenyl)butane acid

LC-MS (Method 4): Rt=To 1.36 min; m/z=462 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.16 (d, 3H), of 2.45 (d, 2H), 3,03-3,14 (m, 1H), 3,33-of 3.42 (m, 1H), 4,13 (d, 1H), was 7.08 (DD, 1H), of 7.36 (d, 1H), 7,41 (d, 1H), 7,43-7,51 (m, 4H), to 9.81 (s, 1H), the 12.05 (s, 1H).

[α]D20=+88,6°, C=0,435, chloroform.

Example 47 (diastereoisomer 2):

(+)-(3R)-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-chlorophenyl)butane acid

LC-MS (Method 4): Rt=To 1.36 min; m/z=462 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.16 (d, 3H), of 2.45 (d, 2H), 3,09 (kV, 1H), 3,33-of 3.42 (m, 1H), 4,13 (d, 1H), was 7.08 (DD, 1H), 7,35 (d, 1H), of 7.42 (d, 1H), 7,43-7,51 (m, 4H), to 9.81 (s, 1H), the 12.05 (s, 1H).

[α]D20=+57,9°, C=0,365, chloroform.

Example 48 and Example 49

3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)butane acid (diastereomers 1 and 2)

The above diastereomeric mixture of 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-IU�albuterol]amino}-4-fluorophenyl)butane acid (Example 9) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralpak AS-H, 5 µm, 250 mm×20 mm; injection volume: 0.25 ml; temperature: 30°C; eluent: 85% isohexane/15% isopropanol; flow rate: 15 ml/min; detection: 220 nm]. Proceeding from 295 mg of a mixture of diastereomers, was obtained 121 mg of diastereoisomer 1 (Example 48) and 111 mg of diastereoisomer 2 (Example 49):

Example 48 (diastereoisomer 1):

(+)-(38)-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)butane acid

LC-MS (Method 6): Rt=1,14 min; m/z=446 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), of 1.16 (d, 3H), 2,44 (d, 2H), 3,02-of 3.12 (m, 1H), 3,33-of 3.42 (m, 1H), 4,12 (d, 1H), 7,00-to 7.04 (m, 1H), 7,13 (DD, 1H), 7,43-of 7.48 (m, 4H), 7,68 (DD, 1H), 10,04 (s, 1H), a 12.03 (s, 1H).

[α]D20=+142,0°, C=0,350, chloroform.

Example 49 (diastereoisomer 2):

(+)-(3R)-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)butane acid

LC-MS (Method 6): Rt=1,14 min; m/z=446 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 1,15 (d, 3H), 2,44 (d, 2H), is 3.08 (q, 1H), 3,30-of 3.42 (m, 1H), 4,12 (d, 1H), 6,94-7,06 (m, 1H), 7,13 (DD, 1H), 7,40-of 7.50 (m, 4H), 7,68 (DD, 1H), 10,04 (s, 1H), 12,04 (ush. s, 1H).

[α]D20=+139,8°, C=0,405, chloroform.

General method 4: Acid hydrolysis of complex ethyl esters

The corresponding ethyl ether complex dissolved in a mixture of composition 7:2 from acetic acid and concentrated hydrochloric acid (about 10 ml/mmol substrate) and�rivaetsya until complete conversion at 100°C (typically between 1 h and 8 h). Then the reaction mass is cooled, poured into water and extracted several times with dichloromethane. The combined organic phases washed three times with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. If necessary this residue was purified using flash chromatography or preparative HPLC.

In accordance with the General method 4 the following example connections:

ExampleName/StructureAnalytical data
50The threo-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylbutanoate acidLC-MS (Method 6): Rt=To 1.21 min; m/z=460 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,75-0,95 (m, 3H), 1,00-1,06 (m, 2H), 1,07-1,17 (m, 3H), 1,24 (s, 1H), 1.91 a (s, 1H), 2,93 (t, 1H), 3,35 is-3.45 (m, 1H), 4,06-4,20 (m, 1H), 6,93-to 7.04 (m, 1H), 7,07-of 7.19 (m, 1H), 7,39-7,54 (m, 4H), With 7.66 (dt, 1H), 9,98-of 10.09 (m, 1H), 11,96 (ush. s, 1H).
51Erythro-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-2-methylbutanoate to�slot LC-MS (Method 5): Rt=2,52 min; m/z=460 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,71-of 0.91 (m, 4H), 1,00-1,11 (m, 1H), 1.14 in (d, 3H), 1,23 (ush. s, 2H), 1.91 a (s, 1H), 3,37 is-3.45 (m, 1H), 4,12 (d, 1H), 6,90-7,05 (m, 1H), 7,14 (t, 1H), to 7.33-7,56 (m, 4H), 7,65 (d, 1H), of 10.05 (s, 1H).

ExampleName/StructureAnalytical data
522-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-TRANS-cyclopropanecarbonyl acidLC-MS (Method 5): Rt=2,45 min; m/z=444 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): 8 [M. D.]=0,79 (d, 3H), 1,19-of 1.28 (m, 1H), 1,38 (dt, 1H), 1,65-1,75 (m, 1H), 2,30-2,40 (m, 1H), 4,12 (d, 1H), to 6.88-6,97 (m, 1H), 7,13 (DD, 1H), value of 7, 37-7,52 (m, 4H), 7.62 mm (DD, 1H), to 10.06 (s, 1H), 12,30 (ush. s, 1H).

Example 53 and Example 54

2-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-TRANS-cyclopropanecarbonyl acid (diastereomers 1 and 2)

71 mg of the mixture of diastereoisomers of 2-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutane�l]amino}-4-fluorophenyl)-TRANS-cyclopropanecarboxylic acid (Example 52) was dissolved in 2 ml of ethanol and 2 ml of isohexane and further separated using preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 µm, 250 mm×200 mm; injection volume: 0.25 ml; temperature: 30°C; eluent: 15% isopropanol/85% isohexane; flow rate: 15 ml/min; detection: 220 nm]. There was obtained 36 mg of diastereoisomer 1 (Example 53) and 37 mg of diastereoisomer 2 [Example 54):

Example 53 (diastereoisomer 1):

LC-MS (Method 6): Rt=1,15 min; m/z=444 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 1,24 (DDD, 1H), 1,38 (dt, 1H), 1,64-of 1.80 (m, 1H), of 2.35 (DDD, 1H), 4,12 (d, 1H), of 6.85-7,01 (m, 1H), 7,13 (DD, 1H), value of 7, 37-7,56 (m, 4H), 7.62 mm (DD, 1H), to 10.06 (s, 1H).

[α]D20=+291,4°, C=0,48, chloroform.

Example 54 (diastereoisomer 2):

LC-MS (Method 6): Rt=1,15 min; m/z=444 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 1,24 (DDD, 1H), 1,38 (dt, 1H), 1,64-of 1.76 (m, 1H), 2,29-to 2.40 (m, 2H), 4,12 (d, 1H), at 6.92 (DDD, 1H), 7,13 (DD, 1H), 7,39-7,52 (m, 4H), 7.62 mm (DD, 1H), to 10.06 (s, 1H).

[α]D20=+44,3°, C=0,40, chloroform.

Example 55

3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-cyanophenyl)propane acid

16.5 mg (33 μmol) tert-butyl-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-cyanophenyl)propanoate was dissolved in 1.1 ml of dichloromethane and added 275 μl of trifluoroacetic acid. This reaction mixture was stirred 1.5 h at Tbr, then diluted with 20 ml of dichloromethane and evaporated in vacuo. The remainder of the overnight dried in a high vacuum. Got 14,8 mg (97% of theory.) the target compound./p>

LC-MS (Method 6): Rt=1,10 min; m/z=439 (M+NH4)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,81 (d, 3H), 2,80-to 2.94 (m, 2H), 4,01 (d, 1H), 7,22 (DD, 1H), 7,32 (s, 1H), 7,40-7,52 (m, 4H), 7,69 (d, 1H), 10,48 (s, 1H).

Example 56

(+/-)-3-(3-{[2-(4-Chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-fluorophenyl)propane acid (diastereoisomer 1)

270 mg (0,553 mmol) of complex mpem-butyl ether(+/-)-3-(3-{[2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-fluorophenyl)-propane acid (diastereoisomer 1 Example 102A) was dissolved in 0.2 ml of dichloromethane and at Tbradded to 0.85 ml of trifluoroacetic acid. The reaction mixture was stirred for 4 h at Tbrand then was evaporated in vacuum. The residue was purified using preparative reverse phase HPLC (mixture of acetonitrile/water). Received 188 mg (78,7% of Theor.) target connection.

LC-MS (Method 6): Rt=1,16 min; m/z=432 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 2,48-2,53 (m, 2H), 2,82 (t, 2H), 3,35-3,48 (m, 1H), 4,13 (d, 1H), to 6.88-7,13 (m, 2H), value of 7, 37-7,51 (m, 4H), 7,54-7,76 (m, 1H), 10,04 (s, 1H), 12,19 (ush. s, 1H).

Similarly, it was obtained the following compound:

Example 57

(+/-)-3-(3-{[2-(4-Chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-fluorophenyl)propane acid {diastereoisomer 2)

LC-MS (Method 6): Rt=1,15 min; m/z=432 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=1,22 (d, 3H), 2,52-,56 (m, 2H), 2,83 (m, 2H), up 3.22 (DD, 1H), 4,15 (d, 1H), 6,98-7,10 (m, 2H), of 7.36-the 7.43 (m, 2H), 7,45-7,53 (m, 2H), 7.62 mm (TD, 1H), 10,13 (s, 1H), 12,19 (s, 1H).

The following examples were obtained in accordance with the General method 2 (the breakdown of complex tert-butyl esters to the corresponding carboxylic acids using trifluoroacetic acid):

ExampleName/Structure/Initial connectionAnalytical data
58(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propane acidLC-MS (Method 6): Rt=1,17 min; m/z=466 (M+H)*.
1H-NMR (400 MHz, DMSO-de): δ [M. D.]=0,83 (d, 3H), 2.49 USD (m, 2H), to 2.76 (t, 2H), 3,34-of 3.46 (m, 1H), 4,14 (d, 1H), 7,06 (DD, 1H), 7,28-7,41 (m, 3H), 7,49 (DD, 1H), a 7.62 (t, 1H), 9,87 (s, 1H), 12,13 (s, 1H).
[α]D20=+79,9°, C=0,520, chloroform.
(from (+)-tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propanoate)

ExampleName/Structure/Source connect�tion Analytical data
59(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chloro-3-methylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propane acidLC-MS (Method 6): Rt=1,20 min; m/z=462 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 2,33 (s, 3H), 2,48 (m, 2H), to 2.76 (t, 2H), 3,27-of 3.42 (m, 1H), 4,04 of 4.09 (m, 1H), to 7.04 (DD, 1H), 7,29 (DD, 1H), 7,32-of 7.36 (m, 1H), 7,38 was 7.45 (m, 3H), 9,81 (s, 1H), 12,16 (ush. S. 1H).
[α]D20=+86,0°, C=0.250 kg, chloroform.
(from tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propanoate)
60(+)-3-(4-Chloro-3-{[(2S,3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propane acidLC-MS (Method 6): Rt=1,23 min; m/z=480/482 (M-H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,83 (d, 3H), 2,47 (t, 2H), 2,72-of 2.81 (m, 2H), 3,35-3,47 (m, 1H), of 4.09-4,17 (m, 1H), 7,06 (DD, 1H), 7,31-7,41 (m, 2H), 7,45 (DD, 1 H), 7,67 (d, 1H), 7,72 (d, 1H), for 9.88 (s, 1H).
[α]D =+98,8°, C=0,325, methanol.
(from tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propanoate)

Example 61Name/Structure/Initial connectionAnalytical data
3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)-2-methylpropanoate acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,20 min; m/z=476 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,80 (d, 3H), of 1.03 (ush. C. 3H), 1,51/1,57 (2 ush. with, joint., 2H), 2,15 (ush. s, about 2H), 2,86 (ush. s, about 1H), 3,37 is-3.45 (m, about 1H), 3,90-4,00 (m, 1H), 6,99-7,12 (m, 1H), made 7.16 interest (ush. s, 1H),7,25 (ush. s, 1H), 7,35-7,54 (m, 5H), for 9.88 (ush. s, 1H), 12,18 (ush. s, 1 H) [Sounds strongly broadened due to the presence of rotamers}.
(from tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)-2-methylpropanoate (mixture of diastereoisomers))
62(+)-(2R)-3-{4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)-2-methyl�Romanova acid LC-MS (Method 6): Rt=1,26 min; m/z=476 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.03 (ush. s, 3H), 2,42-2,62 (ush. from about 2H, partially overlapped), 3,30-3,44 (m, 1H), 3,94 (d, 1H), 7,05 (d, 1H), 7.23 percent (ush. s, 1H), 7,45 (s, 4H), 12,15 (ush. s, 1H) [Sounds strongly broadened due to the presence of rotamers}.
(from (+)-tert-butyl-(2R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)-2-methylpropanoate)[α]D20=+108,9°, C=0,510, methanol.

ExampleName/Structure/Initial connectionAnalytical data
63(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)-2-methylpropanoate acidLC-MS (Method 6): Rt=1,26 min; m/z=476 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.03 (ush. s, 3H), 3,17 (d, 1H), 3,34-of 3.43 (m, 1H), 3,94 (d, 1H), 7,05 (d, 1H), 7,45 (ush. s, 4H), 9,86 (ush. s, 1H), 12,15 (ush. s, 1H) [Sounds strongly broadened La�the effect of the presence of rotamers].
[α]D20=+143,7°, C=0,505, methanol.
(from (+)-tert-butyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)-2-methylpropanoate)
642-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-2-methylbutanoate acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,28 min; m/z=490 (M+H)+.
1H-NMR (400 MHz, DMSO-d6both of the diastereoisomer δ [M. D.]=to 0.73-0.87 (m, 6H), of 0.92 (d, 3H), of 1.31-1.42 (m, 1H), 1,52-1,72 (m, 1H),2,60 (d, 1H), 2,85/2,87 (2D, joint., 1H), 3,32-3,36 (m, 1H), 3,94-4,18 (m, 1H),6,95 (DD, 1H), 7,27-value of 7, 37 (m, 2H), 7,39-7,53 (m, 4H), 9,84 (s, 1H).
(from tert-butyl-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-2-methylbutanoate (mixture of diastereoisomers))

ExampleName/Structure/Initial connectionAnalytical data
65(+)-2-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-2-methylbutanoate keys�OTA (diastereoisomer B) LC-MS (Method 6): Rt=1,26 min; m/z=490 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,73-of 0.85 (m, 6H), 0,92 (s, 3H), 1,32-of 1.41 (m, 1H), 1,57-of 1.66 (m, 1H), 2,60 (d, 1H), 2,85 (d, 1H), 3,35-of 3.43 (m, 1H),4,11 (d, 1H), 6,94 (d, 1H), 7,34 (d, 2H), 7,41-7,53 (m, 4H), 9,82 (s, 1H), 12,27 (ush. s, 1H).
[α]D20=+80,6°, C=0,350, chloroform.
(istrat-butyl-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-2-methylbutanoate (diastereoisomer B))
663-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-triptoreline acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,18 min; m/z=561 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,80 (d, 3H), 2,84 (DD, 1H), 2,95 (DD, 1H), 3,35-3,44 (m, 1H), 4,01-of 4.09 (m, 1H), 4,14 (d, 1H), 7,26 (DD, 1H), 7,39-7,52 (m, 5H), 7,61 (DD, 1H), 9,95 (s, 1H), of 12.55 (ush. s, 1H).
(from tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-tricorporate (mixture of diastereoisomers))

ExampleName/Structure/Initial connectionAnalytical data
673-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclobutylamine acid (mixture of diastereomers)LC-MS (Method 6): Rt=To 1.29 min; m/z=502 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,80 (d, 3H), 1,67-of 1.83 (m, 4H), 1,88-of 1.99 (m, 2H), 2,30-of 2.42 (m, 1H), 2,43-2,48 (m, 1H), 2,57-2,83 (m, 2H), 3,38-of 3.42 (m, 1H),4,12 (d, 1H), 8,98 (d, 1H), 7,29-7,38 (m, 2H), 7,41-7,50 (m, 4H), 9,82 (s, 1H), 12,07 (s, 1H).
(from tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclobutylamine (mixture of diastereoisomers))
68(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclobutylamine acid (diastereoisomer A)LC-MS (Method 8): Rt=To 1.32 min; m/z=502 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 1.85 to of 1.83 (m,4H), 1,88-of 1.98 (m, 2H), 2,29-2,43 (m, 1H), 2,43-2,48 (m, 1H), 2,58-2,83 (m, 2H), 3,37-to 3.41 (m, 1H), 4,12 (d, 1H), ,98 (DD, 1H), 7,28-7,38 (m, 2H), of 7.42 and 7.55 (m,4H), 9,82 (s, 1H), to 12.08 (ush. s, 1H).
[α]D20=+50,3°, C=0,520, chloroform.
(istrat-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclobutylamine (diastereoisomer A))

ExampleName/Structure/Initial connectionAnalytical data
69(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclobutylamine acid (diastereoisomer B)LC-MS (Method 6): Rt=To 1.29 min; m/z=502 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 1,62-of 1.83 (m, 4H), 1,86-2,00 (m, 2H), 2,28-2,43 (m, 1H), 2,45-2,49 (m, 1H), 2,60 (d, 2H), 3,36-3,44 (m, 1H), 4,12 (d, 1H), 6,99 (DD, 1H), 7,24-value of 7, 37 (m, 2H), 7,41-7,53 (m, 4H), 9,82 (s, 1H), 12,07 (s, 1H).
[α]D20=+97,8°, C=0,445, chloroform.
(from tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cycle�of butylperbenzoate (diastereoisomer B))
703-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclopropylamino acid (mixture of diastereomers)LC-MS (Method 4): Rt=1,48 min; m/z=488 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,05-0,13(m, 1H), 0.20 to 0.25 (m, 1H), 0,42 (d, 2H), 0.79 in (d, 3H), 0,82-0,92 (m, 1H), 1,78 (TD, 1H), 2,74-2,90 (m, 2H), 3,30 is 3.40 (m, 1H), 4,11 (d, 1H), 7,01 (d, 1H), to 7.33 (d, 1H), Value of 7, 37 (d, 1H), of 7.42-7,50 (m, 4H), 9,82 (s, 1H).
(from tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-cyclopropylethanol (mixture of diastereoisomers))

Example 71

(+)-2-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-2-methylbutanoate acid {diastereoisomer A)

302 mg (0,553 mmol) of (+)-tert-butyl-2-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}benzyl)-2-methylbutanoate {diastereoisomer A) was dissolved in 2.3 ml of dichloromethane and at Tbrwas added 2 ml TFA. After 30 min the reaction mixture was evaporated in vacuo, and the residue was dried in high vacuum. Then the residue was purified using preparative reverse phase HPLC (eluent: acetonitrile/water). Got 110,8 mg target p�of keep this product (40,9% of Theor.).

LC-MS (Method 4): Rt=1,50 min; m/z=490 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,71-0,86 (m, 6H), 0,92 (s, 3H), of 1.30-of 1.43 (m, 1H), 1,54-to 1.69 (m, 1H), 2,60 (d, 1H), 2,86 (d, 1H), 3,34-3,45 (m, 1H), 4,11 (d, 1H), 6,86-7,00 (m, 1H), 7,25-of 7.36 (m, 2H), 7,39-7,52 (m, 4H), Case 9.83 (s, 1H), to 12.28 (s, 1H).

[α]D20=+74,0°, C=0,280, chloroform.

The following examples were obtained in accordance with the General method 3 (the breakdown of complex methyl or ethyl esters to the corresponding carboxylic acids in mixtures of hydrochloric acid or sulfuric acid with acetic acid):

ExampleName/Structure/Initial connectionAnalytical data
72(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate acidLC-MS (Method 6): Rt=1,22 min; m/z=480 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,86 (d, 3H), of 1.03 (d, 3H), 2,55-2,63 (m, 2H), 2,79-2,90 (m, 1H), 3,36-3,44 (m, 1H), 4,36 (d, 1H), to 7.04 (DD, 1H), 7,26-7,39 (m, 3H), 7,52 (DD, 1H), a 7.62 (t, 1H), 10,02 (s, 1H), 12,18 (ush. s, 1H).
[α]D20=+92,1°, C=0,365, chloroform.
(from (+)-ethyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate)

ExampleName/Structure/Initial connectionAnalytical data
73(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-2-methylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate acidLC-MS (Method 6): Rt=1,26 min; m/z=476 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,77 (d, 3H), of 1.02 (d, 3H), 2,54-2,63 (m, 2H), 2,79-of 2.91 (m, 1H),3,38 (ush. s, 1H), 4,15 (d, 1H), 7,03 (DD, 1H), 7,22-7,38 (m, 4H), 7,52 (d, 1H), of 9.89 (s, 1H), 12,18 (ush. s, 1H).
[α]D20=+124,3°, C=0,390, chloroform.
(from (+)-ethyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-2-methylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate)
74(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate acidLC-MS (Method 6): Rt=1,20 min; m/z=480 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,83 (d, 3H), of 1.02 (d, 3H), 2,55-2,62 (m, 2H), 2,77-2,88 (m, 1H), 3,36-3,48 (m, 1H), 4,05-is 4.21 (m, 1H), 7,02 (DD, 1H), 7,25-7,41 (m, 3H), 7,49 (DD, 1H), a 7.62 (t, 1H), 9,87 (s, 1H), 12,16 (ush. s, 1H).
[α]D20=+95,7°, C=0,470, chloroform.
(from (+)-ethyl-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate)

ExampleName/Structure/Initial connectionAnalytical data
75(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate acidLC-MS (Method 4): Rt=To 1.44 min; m/z=476 (M+PS.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,78-0,85 (m, 3H), of 1.02 (d, 3H), 2,33 (s, 3H), 2,55-2,61 (m, 2H), 2,77-2,89 (m, 1H), 3,34-to 3.41 (m, about 1H, overlapped), 4,04-4,10 (m, 1H), 7,00 (DD, 1H), 7,26-7,45 (m, 5H), to 9.81 (s, 1H), 12,17 (ush. s, 1H).
[α]D20=+397,5°, C=0,340, chloroform.
(from ethyl(2S)--(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methylphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate)
76(+)-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate kislotaLC-MS (Method 6): Rt=1,24 min; m/z=496/498 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,83 (d, 3H), of 1.02 (d, 3H), 2,54-2,62 (m, 2H), 2,77-2,91 (m, 1H), 3,35-3,48 (m, 1H), 4,08-4,17 (m, 1H), 7,02 (DD, 1H), 7,31-7,39 (m ,2H), 7,45 (DD, 1H), 7,67 (d, 1H), 7,72 (d, 1H), 9,87 (C, 1H), 12,16 (ush. s, 1H).
[α]D20=+109,5°, C=0,305, methanol.
(from ethyl(2S)-3-(4-chloro-3-{[(2S,3R)-2-(3,4-dichlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate)

ExampleName/Structure/Initial connectionAnalytical data
773-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)propane acidLC-MS (Method 6): Rt=1,12 min; m/z=462 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): � [M. D.]=0,80 (l, 3H), 1.91 a/2,14 (2 ush. with, joint., 3H), 2,42 (ush. s, 2H), 2,73 (d, 2H), 3,34-of 3.43 (m, 1H), 3,96 (d, 1H), 7,04-7,14 (m, 1H), 7,14-7,35 (m, 1H), 7,45 (s, 4H), to 9.91 (ush. s, 1H), 12,13 (ush. s, 1H) [Sounds strongly broadened due to the presence of rotamers].
(from methyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)propanoate)
783-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-4,4,4-triptoreline acid (mixture of diastereomers)LC-MS (Method 6): Rt=1,14 min; m/z=500 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,79 (d, 3H), 2,83 (DD, 1H), 2,95 (DD, 1H), 3,25-of 3.46 (m, 2H), 3,96-4,07 (m, 1H), 4,13 (d, 1H), of 7.19-7,29 (m, 2H), 7,41-of 7.50 (m, 4H), of 7.88 (d, 1H), 10,17(s, 1H).
(Isatel-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-4,4,4-tricorporate)

Example 79 Example 80

(+)-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-4,4,4-triptoreline acid (diastereomers 1 and 2)

The above diastereomeric mixture of 3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)-4,4,4-tripterocalyx acids (�reamer 78) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 µm, 250 mm×20 mm; flow rate: 15 ml/min; detection: 230 nm; injection volume: 0,80 ml; temperature: 45°C; eluent: 92% of isohexane/8% isopropanol]. On the basis of 1.95 g of a mixture of diastereomers, received 556 mg of diastereoisomer 1 (Example 79) and 730 mg of diastereoisomer 2 (Example 80):

Example 79 (diastereoisomer 1):

The diastereoisomer of 1 was further purified using preparative reverse phase HPLC (eluent: methanol/water). Received 418 mg.

LC-MS (Method 4): Rt=1,49 min; m/z=500 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 2,82 (DD, 1H), to 2.94 (DD, 1H), 3,37-3,44 (m, 1H), was 4.02 (dt, 1H), 4,13 (d, 1H), 7,17-7,30 (m, 2H), 7,40-of 7.50 (m, 4H), a 7.87 (d, 1H), 10,18 (s, 1H), of 12.53 (ush. s, 1H).

[α]D20=+130°, C=0,29, chloroform.

Example 80 (diastereoisomer 2):

The diastereoisomer 2 was further purified using preparative reverse phase HPLC (eluent: methanol/water). Received 352 mg.

LC-MS (Method 6): Rt=1,18 min; m/z=500 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 2,82 (DD, 1H), to 2.94 (DD, 1H), 3,94-4,08 (m, 1H), 4,13 (d, 1H), 7,17-of 7.33 (m, 2H), 7,40-7,52 (m, 4H), of 7.88 (d, 1H), 10,18 (s, 1H).

[α]D20=+104°, C=is 0.260, chloroform.

Example 81

3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)hexanoic acid (mixture of diastereomers)

1,50 g (of 2.97 mmol) of methyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)hexanoate (a mixture of diastereomer�) was dissolved in 5 ml of acetic acid, was added 5 ml of 30% sulfuric acid and heated to reflux (temperature of the bath to about 140°C). After 1.5 h, to this was added 2.5 ml of acetic acid, and the reaction mixture was stirred for another 2.5 h at reflux. After cooling, the mixture was allowed to stand over night at Tbr, then was poured into water and three times were extracted with diethyl ether. The combined organic phases were washed with 5% sodium bicarbonate solution and us. a solution of sodium chloride, dried over magnesium sulfate, was evaporated in vacuum, and the residue was dried in high vacuum. Was obtained 1.44 g of the desired product (98,8% of Theor.).

LC-MS (Method 6): Rt=To 1.29 min; m/z=490 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,74-0,83 (m, 6H), 0,99-to 1.14 (m, 2H), 1,37-1,60 (m, 2H), 2,39 (DD, 1H), 2,85-to 2.99 (m, 1H), 3,36-3,44 (m, 1H), 4,13 (d, 1H), 6,97-7,10 (m, 1H), 7,32-7,40 (m, 2H), of 7.42-7,53 (m, 4H), case 9.83 (s, 1H), 12,02 (ush. s, 1H).

Example 82 Example 83

(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)hexanoic acid {diastereoisomers 1 and 2)

The above diastereomeric mixture of 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)hexanoic acid (Example 81) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm,250 mm×20 mm; flow rate: 20 ml/min; detection: 230 nm; injection volume: 0,60 ml; temperature: 25°C; eluent: 95% of isohexane/5% isopropanol]. Based on of 59.2 mg of a mixture of diastereomers, was obtained 19 mg of diastereoisomer 1 (Example 82) and 17 mg of diastereoisomer 2 (Example 83):

Example 82 (diastereoisomer 1):

(+)-(3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)hexanoic acid

LC-MS (Method 6): Rt=1,27 min; m/z=490 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,72-0,86 (m, 6H), 0.98 m-1,19 (m, 2H), 1,37-to 1.61 (m, 2H), 2,34-of 2.44 (m, 1H), 2,88-of 2.97 (m, 1H), 3,34-of 3.43 (m, 1H), 4,13 (d, 1H), 7,05 (DD, 1H), 7,26-7,40 (m, 2H), 7,41-7,63 (m, 4H), 9,82 (s, 1H), 12,02 (s, 1H).

[α]D20=+52°, C=0,30, chloroform.

According to the same preparative HPLC method was also divided more (1.40 g) of the diastereomeric 3-(4-xnop-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)hexanoic acid (Example 81). The obtained diastereoisomer 1 in this case, which was further purified by reverse phase HPLC [column: Sunfire 250 mm×20 mm; eluent: 80% acetonitrile/5% water. TFA (1%)/15% water]. Thus was obtained 337 mg of pure diastereoisomer of 1.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,74-0,86 (m, 6H), 0,97-of 1.16 (m, 2H), 1,40-1,60 (m, 2H), 2,35-of 2.44 (m, 1H), 2,89-of 2.97 (m, 1H), 3,35-of 3.43 (m, 1H), 4,13 (d, 1H), 7,05 (DD, 1H), 7,30-7,40 (m, 2H), 7,41-7,54 (m, 4H), case 9.83 (s, 1H), 12,02 (ush. s, 1H).

[α]D20=+86°, C=0,480, chloroform.

Approx�R 83 (diastereoisomer 2):

(+)-(3R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)hexanoic acid

LC-MS (Method 6); Rt=1,27 min; m/z=490 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,77-0,83 (m, 6H), 1,00-1,12 (m, 2H), 1.41 to to 1.60 (m, 2H), 2,35-of 2.44 (m, 1H), 2,88-2,98 (m, 1H), 3,35 is-3.45 (m, 1H), 4,13 (d, 1H), 7,05 (DD, 1H), 7,32-7,40 (m, 2H), 7,43-of 7.64 (m, 4H), 9,82 (s, 1H), 12,04 (ush. s, 1H).

[α]D20=+22,1°, C=0,40, chloroform.

Example 84 Example 85

(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-triptoreline acid (diastereomers 1 and 2)

The above diastereomeric mixture of 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-tripterocalyx acid (Example 66) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; flow rate: 15 ml/min; detection: 220 nm; injection volume: 0.25 ml; temperature: 30°C; eluent: 93% of isohexane/7% isopropanol]. Proceeding from 150 mg of a mixture of diastereomers, received 70 mg of diastereoisomer 1 (Example 84) and 79 mg of diastereoisomer 2 (Example 85):

Example 84 (diastereoisomer 1):

(+)-(3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-triptoreline acid

LC-MS (Method 6): Rt=1,18 min; m/z=516 (M+H)+.

1H-NMR (400 MHz, DMSO-d 6): δ [M. D.]=0,80 (d, 3H), 2,84 (DD, 1H), 2,95 (DD, 1H), 3,36-of 3.43 (m, 1H), 4,06 (TD, 1H), 4,14 (d, 1H), 7,26 (DD, 1H), 7,40-7,52 (m, 5H), 7,60 (d, 1H), 9,95 (s, 1H), 12,54 (ush. s, 1H).

[α]D20=+78°, C=0,52, chloroform.

Alternatively, (+)- (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-triptoreline acid also could be obtained in the following way:

Of 1.76 g (is 3.08 mmol) of (+)-tert-butyl-(3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-tricorporate (Example A) was dissolved in 4.9 ml of dichloromethane and at Tbradded to 4.7 ml of TFA. The reaction mixture was stirred 2 h at Tbrand then was evaporated in vacuum. The residue is transferred into ethyl acetate and washed with us. the sodium bicarbonate solution and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified using preparative reverse phase HPLC (eluent: methanol/water). Got 1,30 g of the target product (81,9% of Theor.).

LC-MS (Method 4): Rt=1,46 min; m/z=515 (M)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 2,83 (DD, 1H), 2,95 (DD, 1H), 3,37 is-3.45 (m, 1H), 4,06 (TD, 1H), 4,14 (d, 1H), 7,26 (DD, 1H), 7,43-7,52 (m, 5H), 7,60 (d, 1H), 9,95 (s, 1H), 12,56 (ush. s, 1H).

[α]D20=+79,9°, C=0,475, chloroform.

Example 85 (diastereoisomer 2):

(+)-(3R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-triptoreline acid

LC-MS (Method 6): Rt=1,19 min; m/z=516 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 2,84 (DD, 1H), 2,95 (DD, 1H), or 3.28-3,44 (m, 1H), 3,95-4,11 (m, 1H), 4,15 (d, 1H), 7,22-7,30 (m, 1H), 7,41-7,53 (m, 5H), EUR 7.57-of 7.70 (m, 1H), 9,95 (s, 1H), of 12.55 (ush. s, 1H).

[α]D20=+40,2°, C=0,52, chloroform.

Alternatively, (+)- (3R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-triptoreline acid also could be obtained in the following way:

1.17 g (2.04 mmol) of (+)-tert-butyl-(3R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-4,4,4-tricorporate (Example A) was dissolved in 4.9 ml of dichloromethane and at Tbradded 3.2 ml of TPA. The reaction mixture was stirred 2 h at Tbrand then was evaporated in vacuum. The residue is transferred into ethyl acetate and washed with us. the sodium bicarbonate solution and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The crude product was purified using preparative reverse phase HPLC (eluent: methanol/water). Received of 0.76 g of the desired product (72% of theory.).

LC-MS (Method 6): Rt=1,19 min; m/z=516 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 2,83 (DD, 1H), to 2.94 (DD, 1H), 3,37-3,47 (m, 1H), 3,93-4,10 (m, 1H), 4,15 (d, 1H), 7,26 (DD, 1H), 7,43-7,52 (m, 5H), 7,58-7,66 (m, 1H), 9,95 (s, 1H), 12,57 (ush. s, 1H).

[α]D20=+44,8°, C=0,47, chloroform. Example 86

3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trif�or-3-methylbutanoyl]amino}phenyl)pentanoic acid (mixture of diastereomers)

650 mg (1.33 mmol) of methyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methyl-butanoyl]amino}phenyl)pentanoate (mixture of diastereomers) was dissolved in 2 ml acetic acid was added 1 ml of 30% sulfuric acid and heated to reflux (temperature of the bath to about 140°C). After 1.5 h, the reaction mixture was cooled and poured into water. Three times were extracted with ethyl acetate. The combined organic phases were washed with us. the sodium bicarbonate solution and us. a solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. After drying in a high vacuum, the residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 50:1). Received 600 mg of the desired product (95% of theory.).

LC-MS (Method 6): Rt=1,24 min; m/z=476 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): both diastereoisomer δ [M. D.]=0,69 (TD, 3H), of 0.80 (d, 3H), 1,40-of 1.52 (m, 1H), 1,55-1,68 (m, 1H), is 2.40 (DD, 1H), 2,55-2,59 (m, 1H), 2,78-2,89 (m, 1H), 3,36-of 3.43 (m, 1H), 4,13 (d, 1H), to 7.04 (DD, 1H), 7,31-7,41 (m, 2H), Of 7.42-EUR 7.57 (m, 4H), 9,84 (s, 1H), 12,04 (ush. s, 1H).

Example 87 Example 88

(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)pentanoic acid (diastereomers 1 and 2)

The above diastereomeric mixture of 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)pentanoic acid (Example 86) additional�Uo were separated by using preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 µm, 250 mm×20 mm; flow rate: 18 ml/min; detection: 230 nm; injection volume: 0.25 ml; temperature: 25°C; eluent: 95% of isohexane/5% isopropanol]. On the basis of 545 mg of a mixture of diastereomers, was obtained 140 mg of diastereoisomer 1 (Example 87) and 156 mg of diastereoisomer 2 (Example 88):

Example 87 (diastereoisomer 1):

(+)-(3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)pentanoic acid

LC-MS (Method 4): Rt=1,47 min; m/z=476 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,69 (t, 3H), of 0.80 (d, 3H), 1,37-is 1.51 (m, 1H), 1,54-1,68 (m, 1H), 2,35-of 2.44 (m, 1H), 2,55-2,59 (m, 1H), 2,80-2,87 (m, 1H), 3,36 is 3.40 (m, 1H), 4,13 (d, 1H), to 7.04 (DD, 1H), 7,32-7,40 (m, 2H), Of 7.42-7,50 (m, 4H), case 9.83 (s, 1H), a 12.03 (ush. s, 1H).

[α]D20=+87,0, C=0,47, chloroform.

Example 88 (diastereoisomer 2):

(+)-(3R)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)pentanoic acid

LC-MS (Method 4): Rt=1,47 min; m/z=476 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,69 (t, 3H), of 0.80 (d, 3H), of 1.39-1,50 (m, 1H), 1.56 to of 1.65 (m, 1H), 2,35-2,45 (m, 1H), 2,52-of 2.58 (m, 1H), 2,80-2,87 (m, 1H), 3,35-to 3.41 (m, 1H), 4,13 (d, 1H), to 7.04 (DD, 1H), 7,31-7,41 (m, 2H), Of 7.42-7,52 (m, 4H), case 9.83 (s, 1H), 12,04 (ush. s, 1H).

[α]D20=+71,4, C=0,48, chloroform.

The following examples were obtained in accordance with the General method 2 (the breakdown of complex tert-butyl esters to the corresponding carboxylic acids using triflorus�Noah acid):

ExampleName/Structure/Initial connectionAnalytical data
893-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2,2-dimethylpropanoate acidLC-MS (Method 6): Rt=1,24 min; m/z=476/478 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 1,046 (s, 3H), 1,051 (s, 3H), 2,74 (s, 2H), 3,29 is-3.45 (m, 1H, partially overlapped with a signal of H2O), 4,11 (d, 1H), 6,95 (DD, 1H), 7,31-value of 7, 37 (m, 2H), of 7.42-7,50 (m, 4H), 9,84 (s, 1H), 12,17-12,44 (ush. s, 1H).
(from tert-butyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2,2-dimethylpropanoate)

ExampleName/Structure/Initial connectionAnalytical data
90[1-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-cyclobutyl]acetic acidMS: m/z=488 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), 1,67-of 1.81 (m, 1H), 1,96-of 2.08 (m, 1H), 2,17-of 2.35 (m,4H), 2,69 (s, 2H), 3,27-of 3.42 (m, 1H, partially overlapped with a signal of H2O), 4,14 (d, 1H), 6,99 (DD, 1H), 7,35 (d, 1H), 7,41 (d, 1H), 7,43-of 7.50 (m, 4H), to 9.81 (s, 1H), 11,88 (s, 1H).
[α]D20=+88°, C=0,290, methanol.
(from tert-butyl-[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)cyclobutyl]-acetate)
913-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)propane acidLC-MS (Method 4): Rt=1,27 min; m/z=428 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.92 (s, 3H), 2,43 (t, 2H), 2,79 (t, 2H), or 3.28-3,44 (m, 1H, partially overlapped with a signal of H2O), 3,94 (d, 1H), 6,93-to 7.09 (m, 3H), 7,39-7,52 (m, 4H), 9,69 (s, 1H), 12,14 (s, 1H).
(istrat-butyl-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-2-methylphenyl)propanoate)

ExampleName/Structure/Initial connectionAnalytically� data
923-[4-Chloro-3-({(2S,3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoyl}amino)phenyl]propane acidLC-MS (Method 6): Rt=1,20 min; m/z=502/504 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,79 (d, 3H), 2,48 (m, 2H, overlapped with DMSO signal), 2,60-2,73 (m, 2H), to 2.76 (t, 2H), 2,92-3,06 (m, 2H), 3,29-of 3.46 (m, 2H, partially overlapped with a signal of H2O), 4,10 (d, 1H), 7,03 (DD, 1H), 7,32 (t, 3H), 7,41 (d, 3H), 9,76 (s, 1H), 12,02-12,26 (ush. s, 1H).
(istrat-butyl-3-[4-chloro-3-({(2S,3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoyl}amino)phenyl]-propanoate)
933-(4-Chloro-3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propane acidLC-MS (Method 6): Rt=1,10 min; m/z=476/478 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,83 (d, 3H), 2,48 (m, 2H, overlapped with DMSO signal), 2,77 (t, 2H), 3,33-3,48 (m, 1H),3,87(s,ZN), of 4.09 (d,1H), 7,00-was 7.08 (m, 2H), 7.23 percent (d, 1H), 7,35 (d, 1H), 7,40 (d, 1H), of 7.42 (d, 1H), 9,81 (C, 1H), 11,50-12,57 (ush. s, 1H).
(istrat-bootie�-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)propanoate)

ExampleName/Structure/Initial connectionAnalytical data
943-(3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)propane acidLC-MS (Method 6): Rf=about 1.06 min; m/z=460/462 (M-H)-.
^-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,81 (d, 3H), 2,48 (m, 2H, overlapped with DMSO signal), 2,75 (t, 2H), 3,32-3,47 (m, 1H, partially overlapped with a signal of H2O), a 3.87 (s, 3H), 4,07 (d, 1 H), 6,94-7,06 (m,2H), 7,13 (t,1H), 7,20 (s, 1H), of 7.42 (d, 1H), of 7.64 (d, 1H), 10,01 (s, 1H), 11,77-12,45 (ush. s, 1H).
(from tert-butyl-3-(3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-fluorophenyl)propanoate)
953-[4-Chloro-3-({(2S,3R)-2-[4-(2,2-diversicolor)phenyl]-4,4,4-Cryptor-3-methylbutanoyl}amino)phenyl]propane acidLC-MS (Method 7): Rt=2,52 min; m/z=488/490 (M-H)-.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,77 (d, 3H), 1,87-2,04 (m, 2H), 2,48 (m, 2H, cha�partially overlapped by DMSO signal), To 2.76 (t, 2H), 2,92-3,05 (m, 1H), 3,27-to 3.41 (m, 1H), of 4.09 (d, 1H), to 7.04 (DD, 1H), 7,28 (d, 2H), 7,34 (d, 1H), 7,38-7,44 (m, 3H), 9,78 (s, 1H), 11,60-of 12.59 (ush. s, 1H).
(from tert-butyl-3-[4-chloro-3-({(2S,3R)-2-[4-(2,2-diversicolor)phenyl]-4,4,4-Cryptor-3-methylbutanoyl}amino)phenyl]-propanoate)

ExampleName/Structure/Initial connectionAnalytical data
96[1-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-cyclopropyl]acetic acidLC-MS (Method 6): Rt=To 1.21 min; m/z=474/476 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,75-of 0.82 (m, 5H), 0,85-of 0.91 (m, 2H), 2,52 (s, 2H, partially overlapped by DMSO signal), 3,29-of 3.43 (m, 1H, partially overlapped with a signal of H2O), of 4.13 (d, 1H),7,07 (DD, 1H), 7,32 (d, 1H), of 7.42-7,50 (m, 5H), 9,82 (s, 1H), 11,89-12,10 (ush. s, 1H).
(istrat-butyl-[1-(4-chloro-3-{[(25,3/?)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]-amino}phenyl)cyclopropyl]acetate)
973-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-cyanophenyl)-2-methylpropanol� acid LC-MS (Method 6): Rt=1,07 min; m/z=453/455 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,81 (d, 3H), of 1.03 (d, 3H), 2,57-2,73 (m, 2H), 2,85-2,95 (m, 1H), 3,27-3,44 (m, 1H, partially overlapped with a signal of H2O), was 4.02 (d, 1H), 7,18 (d, 1H), 7,30 (s, 1H), 7,40-7,52 (m, 4H), of 7.70 (d ,1H), 10,50 (s, 1H), 12,23 (ush. s, 1H).
(from tert-butyl-3-(3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}-4-cyanophenyl)-2-methylpropanoate)

The following examples were obtained in accordance with the General method 3 (the breakdown of complex methyl or ethyl esters to the corresponding carboxylic acids in mixtures of hydrochloric acid or sulfuric acid with acetic acid):

ExampleName/Structure/Initial connectionAnalytical data
98(2S)-3-[4-chloro-3-({(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butanoyl}amino)phenyl]-2-methylpropanoate acidLC-MS (Method 4): Rt=1,49 min; m/z=536/538 (M-N)-.
16): δ [M. D.]=0,69 (d, 3H), of 1.02 (d, 3H), 1,54 (s, 6H), 2,51-2,62 (m, 2H, overlapped with DMSO signal), 2,78-2,89 (m, 1H), 3,29-3,45 (m, 1H, partially overlapped with a signal of H2O), 4,14 (d, 1H), 7,00 (DD, 1H), 7,35 (d, 1H), 7,45 (d, 1H), of 7.48 (d, 2H), 7,54 (d, 2H), 9,80 (s, 1H), 12,14 (s, 1H).
(from ethyl(2S)-3-[4-chloro-3-({(2S,3R)-4,4,4-Cryptor-3-methyl-2-[4-(1,1,1-Cryptor-2-methylpropan-2-yl)phenyl]butanoyl}-amino)phenyl]-2-methylpropanoate)

ExampleName/Structure/Initial connectionAnalytical data
99(2S)-3-[4-chloro-3-({4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoyl}amino)-phenyl]-2-methylpropanoate acidLC-MS (Method 4): Rt=To 1.39 min; m/z=508/510 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): 5 [M. D.]=0,70 (d, 3H), 1,01 (d, 3H), 2,50-2,61 (m, 2H, overlapped with DMSO signal), 2,78-2,90 (m, 1H), 3,29-3,45 (m, 1H, partially overlapped with a signal of H2O), 3,63 (kV, 2H), 4,11 (d, 1H), 7,00 (DD, 1H), 7,35 (d, 2H), 7,39 (d, 2H), of 7.46 (d, 2H), 9,80 (s, 1H), 12,15 (s, 1H).
(from ethyl(2S)-3-[4-chloro-3-({4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoyl}amino)phenyl]-2-m�of dipropanoat)
100(2S)-3-[4-chloro-3-({(2S,3R)-2-[4-(3,3-diversicolor)phenyl]-4,4,4-Cryptor-3-methylbutanoyl}amino)phenyl]-2-methylpropanoate acidLC-MS (Method 6): Rt=1,24 min; m/z=516/518 (M-N)-.
1H-NMR (400 MHz, DMSO-d6): 5 [M. D.]=0,79 (d, 3H), 1,01 (d, 3H), 2,46-2,60 (m, 2H, overlapped with DMSO signal), 2,60 is 2.76 (m, 2H), 2,77-2,87 (m, 1H), 2,91-3,06 (m, 2H), 3,26-of 3.46 (m, 2H, partially overlapped with a signal of H2O), 4,10 (d, 1H), 6,99 (DD, 1H), to 7.33 (t, 3H), of 7.42 (d, 3H), 9,76 (s, 1H), 11,86-of 12.37 (ush. s, 1H).
(from ethyl(2S)-3-[4-chloro-3-({(2S,3R)-2-[4-(3,3-diversilobum)phenyl]-4,4,4-Cryptor-3-methylbutanoyl}amino)phenyl]-2-methylpropanoate)

ExampleName/Structure/Initial connectionAnalytical data
101(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate acidLC-MS (Method 6): Rt=1,15 min; m/z=492/494 (M+H)+.
1 H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,83 (d, 3H), of 1.02 (d, 3H), 2,46-2,61 (m, 2H, overlapped with DMSO signal), 2,77-2,88 (m, 1H), 3,36-3,47 (m, 1H), a 3.87 (s, 3H), of 4.09 (d, 1H), 6,98-7,06 (m, 2H), 7.23 percent (d, 1H), of 7.36 (d, 1H), 7,38 (d, 1H), The 7.43 (d, 1H), 9,81 (s, 1H), 12,04-12,26 (ush. s, 1H).
(Isatel-(2S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-2-methylpropanoate)
102[1-(4-Chloro-3-{[(23,3^)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-3,3-diversilobum]acetic acidLC-MS (Method 6): Rt=1,22 min; m/z=524/526 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), to 2.76 (s, 2H), 2,81-to 2.94 (m, 2H), 2,95-3,09 (m, 2H), 3,29-3,44 (m, 1H, partially overlapped with a signal of H2O), 4,15 (d, 1H), 7,12 (DD, 1H), 7,41 (d, 1H), of 7.42-7,49 (m, 4H), 7,50 (d, 1H), for 9.88 (s, 1H), 12,09-12,24 (ush. s, 1H).
(from ethyl-[1-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-3,3-diversilobum]acetate)

Example 103 Example 104

(2S)-3-[4-chloro-3-({4,4,4-Cryptor-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoyl}amino)phenyl]-2-methylpropanoate acid (diastereomers 1 and 2)

74 mg (0.15 mmol) of a mixture of isomers (2S)-3-[4-chloro-3-({4,4,4-Cryptor-3-methyl-2-[4-(2,2,-trifluoroethyl)phenyl]butanoyl}amino)phenyl]-2-methylpropanoic acid (Example 99) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralpak AY-H, 5 µm, 250 mm×20 mm; eluent: isohexane/ethanol 1:1 (V/V); flow rate: 15 ml/min; UV detection: 220 nm; temperature: 45°C]:

Example 103 (diastereoisomer 1):

Yield:39 mg

Rt=3,72 min; chemical purity > 98%; > 99% de

[column: Daicel Chiralpak AY-H, 5 μm, 250 mm×4 mm; eluent: isohexane/(isopropanol + 0.2% of TFA + 1% water) 70:30 (V/V); flow rate: 1 ml/min; temperature: 45°C; UV detection: 220 nm].

LC-MS (Method 6): Rt=1,16 min; m/z=508/510 (M-N)-.

Example 104 (diastereoisomer 2):

Yield:39 mg Rt=6,09 min; chemical purity > 98%; > 99% de

[column: Daicel Chiralpak AY-H, 5 μm, 250 mm×4 mm; eluent: isohexane/(isopropanol + 0.2% of TFA + 1% water) 70:30 (V/V); flow rate: 1 ml/min; temperature: 45°C; UV detection: 220 nm].

LC-MS (Method 6): Rt=1,16 min; m/z=508/510 (M-N)-.

Examples 105-108

(2S)-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}-phenyl)-2-methylpropanoate acid (isomers 1-4)

205 mg (0,44 mmol) of a mixture of diastereoisomers (2S)-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}phenyl)-2-methylpropanoic acid (Example 20) was further separated using preparative HPLC on a chiral phase [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm×20 mm; eluent: isohexane/ethanol 70:30 (V/V); flow rate: 25 ml/min; UV detection: 230 nm; temperature: 25°C]. Received two different factions, which respectively consisted of a mixture of d�wow isomers. Both these fractions were separated into individual isomers by another preparative HPLC on a chiral phase [Fraction 1: column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; eluent: isohexane/isopropanol 80:20 (V/V); flow rate: 20 ml/min; UV detection: 230 nm; temperature: 25°C. Fraction 2: column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; eluent: isohexane/ethanol 90:10 (V/V); flow rate: 20 ml/min; UV detection: 230 nm; temperature: 25°C]:

Example 105 (isomer 1):

Yield:30 mg Rt=15,70 min; chemical purity > 89,8%

[column: Daicel Chiralpak AD-H, 5 μm, 250 mm×4 mm; eluent: isohexane/isopropanol 70:30 (V/V); flow rate: 1 ml/min; UV detection: 230 nm; temperature: 25°C].

LC-MS (Method 6): Rt=1,22 min; m/z=470/472 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 1.02 (d, 3H), 1,21-of 1.35 (m, 1H), 1,45-1,58 (m, 1H), 1,84-of 2.20 (m, 3H), 2,28-2,43 (m, 1H), 2,53-2,62 (m, 2H, overlapped with DMSO signal), 2,76-2,90 (m, 2H), of 3.75 (d, 1H), 7,03 (DD, 1H), 7,32-7,49 (m, 6H), To 9.74 (s, 1H), 12,04-12,35 (ush. s, 1H).

Example 106 (isomer 2):

Yield: 35 mg Rt=20,07 min; chemical purity > 98,9%

[column: Daicel Chiralpak AD-H, 5 μm, 250 mm×4 mm; eluent: isohexane/isopropanol 70:30 (V/V); flow rate: 1 ml/min; UV detection: 230 nm; temperature: 25°C].

LC-MS (Method 5): Rt=2,58 min; m/z=470/472 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=to 1.02 (d, 3H), 1,52-to 1.69 (m, 2H), 1,81-of 1.96 (m, 1H), 1,98-to 2.29 (m, 3H), 2,52-2,62 (m, 2H, overlapped with DMSO signal), 2,78-of 2.92 (m, 2�), 3,78 (d, 1H), 7,03 (DD, 1H), to 7.33-of 7.48 (m, 6H), 9,78 (s, 1H), 12,04-12,26 (ush. s, 1H).

Example 107 (isomer 3):

Yield: 37 mg

Rt=14,17 min; chemical purity > 95,7%

[column: Daicel Chiralpak AD-H, 5 μm, 250 mm×4 mm; eluent: isohexane/ethanol 90:10 (V/V); flow rate: 1 ml/min; UV detection: 230 nm; temperature: 25°C].

LC-MS (Method 5): Rt=2,57 min; m/z=470/472 (M+H)+.

1H-NMR: see Example 106 (isomer 2).

Example 108 (isomer 4Y

Yield:29 mg

Rt=17,77 min; chemical purity > 99,5%

[column: Daicel Chiralpak AD-H, 5 microns, 250 mm x 4 mm; eluent: isohexane/ethanol 90:10 (V/V); flow rate: 1 ml/min; UV detection: 230 nm; temperature: 25°C].

LC-MS (Method 5): Rt=2,58 min; m/z=470/472 (M+H)+.

1H-NMR: see example 105 (isomer 1). Examples 109-112

(2R)-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}-phenyl)-2-methylpropanoate acid (isomers 1-4)

160 mg (0,32 mmol) of a mixture of diastereoisomers (2R)-3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-diverticulitis)acetyl]amino}phenyl)-2-methylpropanoic acid (Example 21) were divided into 4 isomers by using preparative HPLC on a chiral phase [column: Daicel Chiralcel OJ-H, 5 μm, 250 mm×20 mm; eluent: isohexane/ethanol/methanol 90:5:5 (V/V); flow rate: 20 ml/min; UV detection: 230 nm; temperature: 25°C]:

Example 109 (isomer 1):

Yield: 16.7 mg Rt=10,49 min; chemical purity > 92,8%

[column: Daicel Chiralpak OJ-H,5 microns, 250 mm×4 mm; eluent: isohexane/ethanol/methanol 90:5:5 (V/V); flow rate: 1 ml/min; UV detection: 230 nm; temperature: 25°C].

LC-MS (Method 4): Rt=To 1.39 min; m/z=470/472 (M+H)+.

Example 110 (isomer 2):

Output: 24,4 mg Rt=12,26 min; chemical purity > 94.7% of

[column: Daicel Chiralpak OJ-H, 5 μm, 250 mm×4 mm; eluent: isohexane/ethanol/methanol 90:5:5 (V/V); flow rate: 1 ml/min; UV detection: 230 nm; temperature: 25°C].

LC-MS (Method 4): Rt=To 1.39 min; m/z=470/472 (M+H)+.

398 Example 111 (isomer 3):

Yield: 22 mg Rt=18,89 min; chemical purity > 97,8%

[column: Daicel Chiralpak OJ-H, 5 μm, 250 mm×4 mm; eluent: isohexane/ethanol/methanol 90:5:5 (V/V); flow rate: 1 ml/min; UV detection: 230 nm; temperature: 25°C].

LC-MS (Method 4): Rt=To 1.39 min; m/z=470/472 (M+H)+.

Example 112 (isomer 4):

Yield: 25 mg Rt=28,37 min; chemical purity > 97,8%

[column: Daicel Chiralpak OJ-H, 5 μm, 250 mm×4 mm; eluent: isohexane/ethanol/methanol 90:5:5 (V/V); flow rate: 1 ml/min; UV detection: 230 nm; temperature: 25°C].

LC-MS (Method 4): Rt=To 1.39 min; m/z=470/472 (M+H)+

The following example was obtained in accordance with the General method 3:

3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-3-methylbutanoate acid
ExampleName/Structure/Initial connectionAnalytical data
113LC-MS (Method 6): Rt=1,23 min; m/z=476/478 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [M. D.]=0,80 (d, 3H), of 1.31 (s, 6H), 2,53 (s, 2H, partially overlapped by DMSO signal), 3,30-3,44 (m, 1H, signal partially overlaps W), 4,14 (d, 1H), 7,20 (DD, 1H), 7,35 (d, 1H), of 7.42-7,50 (m, 4H), 7,56 (d, 1H), case 9.83 (s, 1H), 11,85-11,97 (ush. s, 1H).
(from ethyl-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-Cryptor-3-methylbutanoyl]amino}phenyl)-3-methylbutanoate)

B. assessment of the pharmacological efficiency

Pharmacological efficacy of the compounds according to the invention can be illustrated by the following biological tests:

In-1. Stimulation of recombinant soluble guanylyl cyclases (NTF in vitro (outside the body)

Study of the stimulation of recombinant soluble guanylyl cyclases (RGC) using the compounds according to the invention in the presence or in the absence of sodium nitroprusside, and in the presence or in the absence gimzauskas inhibitor RHC 1H-1,2,4-oxadiazole[4,3-a]quinoxaline-1-one (ODQ) are carried out in accordance with the method described in detail in the following literature reference: M. Hoenicka, E. M. Becker, H. Apeler, T. Sirichoke, H. Schroeder, R. Gerzer und J. P. Stasch, "Purified soluble guanylyl adenylate expressed in a baculovirus/Sf9 system: Stimulation by YC-1, nitric oxide, and carbon oxide", J. Mol. Med. 77 (1999), 14-23. He contains heme guanilatziklazu obtained by adding tween 20 to the buffer for sample (0.5% final concentration).

Activation of the TWG with the help of a test substance given as x-fold stimulation of basal activity. This result of example 15 shown in table 1A, and for example 17 table 1B:

Table 1A:
Stimulation (x-fold) of recombinant soluble guanylyl cyclases (RGC) in vitro using example 15
The concentration of example 15 [μm]Hem-comprising RHCNot containing heme RHC
The basal level(n=8)+0,01 µm DEA/NO+10 μm ODQThe basal level (n=8)
01,0±0,06,5±0,84,4±0,81,0±0,0
0,011,1±0,15,9±0,74,6±0,8 1,7±0,3
0,11,0±0,17,4±0,84,5±0,61,8±0,2
1,00,9±0,18,5±0,74,8±0,83,0±0,5
103,1±0,311,5±0,916,3±1,317,9±3,1
10031,6±2,645,9±3,197,3±7,740,3±6,6

Table 1B:
Stimulation (x-fold) of recombinant soluble guanylyl cyclases (RGC) in vitro using Example 17
The concentration of example 17 [µm]Hem-comprising RHCNot containing heme RHC
The basal level (n=6)+0,01 µm DEA/NO+10 μm ODQThe basal level (n=6)
0 1,0±0,07,9±0,72,8±0,61,0±0,0
0,010,7±0,29,6±0,84,9±1,21,7±0,2
0,10,6±0,18,8±1,25,3±1,32,0±0,3
1,00,6±0,19,8±1,24,5±1,14,1±0,3
101,8±0,310,7±1,08,3±1,422,9±1,8
1004,9±0,711,4±1,215,0±2,033,5±3,3
[DEA/NO=2-(N,N-diethylamino)diastolic-2-oxide; ODQ=1H-1,2,4-oxadiazole[4,3-a]quinoxaline-1-he].

From tables 1A and 1B it is obvious that stimulation is achieved as hem-comprising, and containing heme of the enzyme. Furthermore, combination of example 15 or example 17 2-(N,N-diethylamino)diastolic-2-oxide (DEA/NO), donor N0, shows a synergistic e�reaction, that is, the effectiveness of DEA/NO is not potentiated by, as would be expected in the case of the activator RHC acting on wasawesome mechanism. In addition, the efficiency of the activator RHC according to the invention is not blocked 1H-1,2,4-oxadiazole[4,3-a]quinoxaline-1-one (ODQ), gimzewski inhibitor of soluble guanylyl cyclases, and even enhanced. Therefore, the results in tables 1A and 1B confirm the mechanism of action of the compounds according to the invention as activators of soluble guanylyl cyclases.

In-2. Efficiency of reporter cell lines recombinant guanylyl cyclases

Cellular efficacy of the compounds according to the invention is determined on a reporter cell line recombinant guanylyl cyclases, as described in the publication F. Wunderc et al., Anal. Biochem. 339.104-112 (2005).

Representative results for the compounds according to the invention are shown in table 2:

Table 2:
RHC-activating effect in reporter cells SSS in vitro
Example No.IEC [nm]
20,3
53,0
70,2
105,2
1510
174,8
1810
281,0
300,3
3710
5030
53300
7110
810,3
820,23
841
871
893
901
961
9910
1003
1021
10530
(MEC = minimum effective concentration).

In-3. Stimulation of enzyme activity RHC

Soluble guanilatziklazu (RHC) when stimulation turns GTP into cGMP and pyrophosphate (PPi). PPi is detected by the following test. Signal that occurs in the test increases as progressive interaction and serves as a criterion for the activity of the enzyme at the indicated stimulation.

To conduct this test, 29 μl of enzyme solution [0-10 nm soluble guanylyl cyclases (obtained according Honicka et al., J. Mol. M(3d. 77, 14-23 (1999)) in 50 mm tea, 2 mm MgCl2, 0,1% BSA (fraction V), of 0.005% Brij®, pH 7,5] placed in a microplate and thereto was added 1 μl of the substance that you want to investigate (in the form of a serially diluted solution in DMSO). Loaded mass was incubated for 10 min at room temperature. Then add 20 ál of the mixture diagnostic [1,2 nm Firefly luciferase (Photinus pyralis-Luciferase, firm Promega), 29 μm digitalisieren (prepared according to Bitler & McElroy, Arch. Biochem. Biophys. 72, 358 (1957)), 122 microns lucife-Rina (firm Promega), 153 µm ATP (Sigma) and 0.4 mm RTI (firm Sigma) in 50 mM tea, 2 mm MgCb, 0.1% of BSA (fraction V), 0.005% of Brij®phi 7,5]. The enzymatic reaction is started by adding 20 μl of the substrate solution [1.25 mm guanosine-5-triphosphate (firm Sigma) in 5C mm tea, 2 mm MgCl2, 0,1% BSA (fraction V), 0.005% of Brij®, pH 7,5] and continuously measured luminosities. The degree of stimulation under the action pending investigation of the matter may be determined relative to the signal of unstimulated response.

In esultate adding 25 µm 1H-1,2,4-oxadiazole[4,3-a]quinoxaline-1-one (ODQ) to the enzyme solution, followed by 30-minute incubation investigated activation not containing heme guanylyl cyclases and is compared with the stimulation of native enzyme.

Representative results relating to the compounds according to the invention, are shown in table 3:

Table 3:
The activating effect on the enzyme in vitro
Example No.IEC [nm]EC50[nm]
1510290
177130
(MEC = minimum effective concentration; EC50= concentration at 50% maximum efficiency).

In-{4. Radiotelemetric measurement of blood pressure and heart rate with�of radeni in awake rats with spontaneous hypertension (SH-rats)

For measurements described later in waking SG-rats used a commercially available telemetry system from Data Sciences International DSI, USA.

This system consists of 3 main components: (1) implantable transmitters, (2) the receivers are using a hub connected to (3) a computer to collect data. Telemetry equipment makes it possible to continuously record blood pressure and heart rate in awake animals in their usual habitat.

The study carried out on adult female specimens of rats with spontaneous hypertension (SH-rats) with a body weight of > 200 g. Experimental animals after implantation of the transmitter are contained individually in cages made of Makrolon type 3. They have free access to standard feed and water. The rhythm of day/night in the experimental laboratory varies with the lighting at 6:00 o'clock in the morning and at 19:00 o'clock in the evening.

Used telemetry transmitters (PA-C40, DSI) experimental animals implanted surgically under aseptic conditions at least 14 days before the first test. Animals, tool thus prepared can be used again after healing of the wound and the healing of the implant.

For implantation the animals subjected to anesthesia on an empty stomach with photoshoptutorial (Nembutal, company Sanofi, 50 mg/kg intraperitoneally) and shaved and disinfected vast area on the belly. After opening the abdominal cavity along the linea of the liquid-filled measuring catheter of the system introduced above branching in the cranial direction in the descending aorta and fixed with glue for fabrics (VetBonD™, 3M). The transmitter housing is fixed intraperitoneally on the muscles of the abdominal wall and the incision is closed in layers. For the prevention of postoperative infection antibiotic is introduced (Tardomyocel COMP, Bayer AG, 1 ml/kg n/a).

Test process:

Substances to be tested in each case the injected group of animals (n=6) orally using a stomach probe. In accordance with the application rate of 5 ml/kg of body weight, the test substances are dissolved in suitable mixtures of solvents or are suspended in 0.5% tylose. The group of animals subjected to introduction of the solvent, is used as a control.

Measuring telemetry equipment is configured for 24 animals. Each experiment is recorded under the same number of the experiment.

For those living in installing instrumented rat stipulate its own receiving antenna (Receiver 1010, the firm DSI). Implanted transmitters can be activated from the outside using vstroennoj� electromagnetic relay and test switch on the transmission. Radiated signals using the computer for data collection (Dataquest™ A. R. T. for Windows, DSI) may be logged in real time and be handled accordingly. The data is stored respectively in the open for the purpose of the directory, which has the number of the experiment.

In a standard process throughout each 10-second period are measured: (1) systolic blood pressure (SCP), (2) diastolic blood pressure (DCD), (3) mean arterial pressure (SBP) and (4) heart rate (HR).

Registration of the measured values is repeated under computer control with 5-minute intervals. The baseline data collected in the form of absolute values, are adjusted on the chart with the measured current barometric pressure and stored in separate files. Other technical details are given in the documentation of the manufacturer (DSI).

The introduction of the tested compounds on the day of the experiment at 9:00. By the end of the reception within 24 hours of the measured parameters described above. After the experiment, the collected data are sorted using the analysis software (Dataquest™ A. R. T. Analysis). As an initial value of the accepted time, 2 hours before ingestion of the substance, so �edeleny the data set covers the time period from 7:00 PM on the day of the experiment to 9:00 am the next day.

These data using a pre-set time averaged by determining the average value (15-minute average, 30 minute average) and transferred to an information carrier in the form of text data. Pre-sorted and thus compressed measured values are transferred to Excel and presented in tables.

C. application Examples for pharmaceutical compositions

Compounds according to the invention may be converted into pharmaceutical compositions as follows:

Tablets:

Composition:

100 mg of the compounds according to the invention, 50 mg of lactose (monohydrate), 50mg of corn starch (natural), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Weight pills 212 mg, Diameter 8 mm, radius of curvature 12 mm.

Manufacturer:

A mixture of compounds according to the invention, lactose and starch is granulated with a 5% solution (wt./mass.) PVP in water. This granulate after drying 5 minutes, mixed with magnesium stearate. This mixture is compressed using a conventional tablet press (tablet size see above). As an indicative value is used for pressing the pressing force of 15 kN.

Suspension for oral administration:

Composition:

1000 mg of the compounds according to the invent�NIJ, 1000 mg of ethanol (96%), 400 mg Rhodigel®(xanthan gum firm FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compounds according to the invention correspond to the 10 ml suspension for oral use.

Manufacturer:

Component Rhodigel suspended in ethanol, the compound according to the invention are added to this suspension. When mixing is carried out the addition of water. Until the completion of the swelling of the Rhodigel is stirred for approximately 6 hours.

The solution for oral administration:

Composition:

500 mg of the compounds according to the invention, 2.5 g of Polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compounds according to the invention correspond to 20 g of solution for oral use.

Manufacturer:

The connection according to the invention suspended with stirring in a mixture of polyethylene glycol and Polysorbate. The mixing process was continued until complete dissolution of the compounds according to the invention.

Solution for intravenous use (in/in):

The connection according to the invention with a concentration below the solubility at saturation is dissolved in a physiologically acceptable solvent (for example isotonic sodium chloride, 5% glucose solution and/or 30% solution of PEG 400). This solution is filtered under sterile conditions and filled into sterile and non-pyrogenic capacity�and for injection.

1. The compound of formula (I)

in which
R1Arepresents hydrogen, methyl, ethyl, cyclopropyl or cyclobutyl,
R1Bis hydrogen or bromide
R2Arepresents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl,
R2Bis hydrogen or bromide or
R1Aand R2Aare linked together and together with the carbon atoms to which they are connected, form a cyclopropyl ring of the formula

in which
R1Band R2Bhave the meanings given above, or
R2Aand R2Bare linked together and together with the carbon atom to which they are connected, form a cyclic group of the formula
or
in which
n denotes the number 1 or 2,
R3is hydrogen fluoride or bromide
R4represents hydrogen, fluorine, chlorine or cyano group,
R5Ais methyl,
R5Bis a trifluoromethyl sulfide or
R5Aand R5Bare linked together and together with the carbon atom to which they are connected, form diversamente cycloalkyl ring formula

R6represents chlorine, alkyl with 1-4 carbon atoms, alkenyl with 2-4 carbon atoms, cyclopropyl or cyclobutyl, preach�m alkyl with 1-4 carbon atoms and the alkenyl with 2-4 carbon atoms can contain up to three fluorine atoms, and the cyclopropyl and cyclobutyl up to two fluorine atoms as substituents, and
R7represents hydrogen, fluorine, chlorine, methyl or methoxy group, as well as its physiologically acceptable salt.

2. The compound of formula (I) according to claim 1, in which
R1Arepresents hydrogen, methyl, ethyl, cyclopropyl or cyclobutyl,
R1Bis hydrogen or bromide
R2Arepresents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl,
R2Bis hydrogen or bromide or
R2Aand R2Bare linked together and together with the carbon atom to which they are connected, form a cyclic group of the formula
or
in which
n denotes the number 1 or 2,
R3is hydrogen fluoride or bromide
R4represents hydrogen, fluorine, chlorine or cyano group,
R5Ais methyl,
R5Bis a trifluoromethyl sulfide or
R5Aand R5Bare linked together and together with the carbon atom to which they are connected, form diversamente cycloalkyl ring formula
or
R6represents chlorine, alkyl with 1-4 carbon atoms, alkenyl of 2-3 carbon atoms, cyclopropyl or cyclobutyl, and alkyl with 1-4 carbon atoms and alkenyl of from 23 carbon atoms can contain up to three fluorine atoms, and the cyclopropyl and cyclobutyl up to two fluorine atoms as substituents, and
R7represents hydrogen, fluorine, chlorine, methyl or methoxy group, as well as its physiologically acceptable salt.

3. The compound of formula (I) according to claims.1 or 2, in which
R1Arepresents hydrogen, methyl or ethyl,
R1Bis hydrogen,
R2Arepresents hydrogen, methyl, trifluoromethyl, ethyl or n-propyl,
R2Bis hydrogen or bromide or
R2Aand R2Bare linked together and together with the carbon atom to which they are connected, form a cyclic group of the formula
or
in which
n denotes the number 1 or 2,
R3is hydrogen,
R4represents fluorine or chlorine,
R5Ais methyl,
R5Bis a trifluoromethyl sulfide or
R5Aand R5Bare linked together and together with the carbon atom to which they are connected, form diversamente cyclopentenone ring formula
or
R6represents chlorine, methyl, trifluoromethyl, ethyl, 1,1-deflorati, 2,2,2-trifluoroethyl, isopropyl, tert-butyl, 1,1,1-Cryptor-2-methylpropan-2-yl, vinyl, 1-forfinal, cyclopropyl, 2,2-divorcecare, cyclobutyl or 3.3-diversilobum and
R 7represents hydrogen, fluorine, chlorine or methyl,
as well as its physiologically acceptable salt.

4. The compound as defined in one of claims.1-3, for use in the method of treatment and/or prophylaxis of heart failure, angina, hypertension, pulmonary hypertension, ischemia, vascular disease, microcirculation disorders, thromboembolic disease and arteriosclerosis.

5. A drug that activates a form of soluble guanylyl cyclases that do not contain heme containing the compound as defined in one of claims.1-3, in combination with one or more inert, nontoxic, pharmaceutically suitable auxiliary substances.

6. The method of obtaining compounds of formula (I), as defined in the claims.1-3, characterized in that the carboxylic acid of formula (II)

in which
R5A, R5B, R6and R7have the meanings given in claims.1-3,
in an inert solvent using a condensing agent or via the intermediate stage of the corresponding acid chloride of the carboxylic acid, in the presence of base is subjected to the combination with the amine of formula (III)

in which
R1A, R1B, R2A, R2B, R3and R4have the meanings given in claims.1-3 and
T1represents alkyl with 1-4 carbon atoms�a or benzyl,
with the formation of carboxylic acid amide of the formula (IV)

in which R1A, R1B, R2A, R2B, R3, R4, R5A, R5B, R6, R7and T1have the meanings given above,
and then Hatshepsut the ester residue of the T1using basic or acidic solvolysis or if T1represents benzyl, also using the experimental data showed, with obtaining carboxylic acids of the formula (I), and optionally a compound of formula (I) using methods known to the expert, separated into their enantiomers and/or diastereomers and/or converted to their physiologically acceptable salts with the corresponding (i) solvents and/or (ii) bases.



 

Same patents:

FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (I): or its pharmaceutically acceptable salt, ether, ester, amide, hydrate or solvate wherein each R1, R2 and R3 is chosen independently from group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C3-C6)-cycloalkyl, halogen atom, cyano, -CF3, difluoromethoxy, trifluoromethoxy, -O-(C1-C6)-alkyl, -O-(C3-C6)-cycloalkyl and -NR12R13; wherein R4 represents -(CR5R6)mH or -(CR7R8)n (4-10-membered) aromatic or nonaromatic heterocycle comprising one or more heteroatoms each of them is chosen from oxygen (O), sulfurs (S) and nitrogen (N) atoms, and wherein m represents a whole number in the range from 1 to 5, and wherein n represents a whole number in the range from 0 to 5, wherein indicated 4-10-membered aromatic heterocycle is substituted possibly with 1-3 substitutes R9, and wherein indicated 4-10-membered nonaromatic heterocycle is substituted possibly with 1-3 substitutes R10 by any position and substituted possibly with 1-3 substitutes R11 by any position but not adjacent or directly bound to heteroatom; wherein Each R5, R6, R7 and R8 is chosen independently from group consisting of H and (C1-C6)-alkyl; wherein each R9 is chosen independently from H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, cyano, -CF3, difluoromethoxy, trifluoromethoxy, -O-(C1-C6)-alkyl, -O-(C3-C6)-cycloalkyl and -NR14R15; wherein each R10 is chosen independently from H, (C1-C6)-alkyl and (C3-C6)-cycloalkyl; wherein each R11 is chosen from halogen atom, cyano, -CF3, difluoromethoxy, trifluoromethoxy, -O-(C1-C6)-alkyl, -O-(C3-C6)-cycloalkyl and -NR16R17; wherein R12, R13, R14, R15, R16 and R17 are chosen independently from group consisting of H, (C1-C6)-alkyl and (C3-C6)-cycloalkyl wherein each abovementioned (C1-C6)-alkyl, (C3-C6)-cycloalkyl, -O-(C1-C6)-alkyl and -O-(C3-C6)-cycloalkyl substitutes wherein they present can be substituted independently with substitutes in the amount from 1 to 3 and chosen independently from group consisting of halogen atom, cyano, amino, (C1-C6)-alkylamino, [(C1-C6)-alkyl]-amino, perhalogen-(C1-C6)-alkyl, perhalogen-(C1-C6)-alkoxy, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, hydroxy and (C1-C6)-alkoxy. Method of synthesis involves interaction of compound of the formula (II): wherein BOC represents tert.-butoxycarbonyl, and R1, R2, R3 and R4 are given above for compound of the formula (I) with metal alkoxide in the presence of water to obtain compounds of the formula (I). Invention provides a novel method for synthesis of compounds of the formula (I) that are useful in treatment of cells anomalous growth, such as cancer, in mammals.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

12 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: present group of inventions relates to a method of producing an amide derivative of formula (3), which is efficient in pest control, by reacting a compound of formula (1) with a compound of formula (2); intermediate compounds of formula (8) and formula (12), where values of all substitutes are given in the claim.

EFFECT: obtaining an amide derivative.

11 cl, 27 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula representing (2S)-3-(4-cyano-3-fluorphenoxy)-N-(4-cyano-3-methylpheniyl)-2-hydroxy-2-methylpropionamide which exhibits action modulating androgen receptor activity.

EFFECT: production of a pharmaceutical composition and a method of treating or preventing the conditions caused by androgen receptors.

3 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to amide of δ-amino-γ-hydroxy-ω-arylalcane acid of formula and its pharmaceutically acceptable salts. Also described are pharmaceutical compositions, which include said compounds, and application of said compounds for preparation of medication, intended for treatment of pathological states, associated with renin activity, in particular for treatment of hypertension.

EFFECT: obtaining pharmaceutically acceptable salts, which possess rennin-inhibiting ability.

21 cl, 161 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to 2, 3', 4'-tricyanodiphenyl derivatives of general formula I: , where R = NO2 (la), NH2 (Ib), NHCOCH3 (Ic).

EFFECT: obtaining novel compounds which can be used in synthesis of corresponding substituted phthalocyanines.

1 cl, 1 dwg, 5 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of general formula I and salt thereof, wherein F is non-aromatic ring system containing five carbon atoms and at least one double bond wherein one ring carbon atom is optionally substituted with X group, such as S, O, or SO2, and one or more ring carbon atoms are optionally substituted with R1; D represents S, O, SO2, NR4, or CH2; Z1 and Z2 are independently O; Y is steryl, mono- or polycyclic non-substituted ring system, containing one or more X group such as S, O, SO2, N; m, n, p, r and q = 0 or 1; meanings of the rest substituents are as defined in specification. Also invention relates to compounds of general formula I , wherein m, n, and q = 0; r = 1. Disclosed is pharmaceutical composition having inhibitory activity in relates to dihydroorotate dehydrogenase (DHODH) containing effective amount of said compound in free form or in form of pharmaceutically acceptable salts together with pharmaceutically acceptable diluents or carriers. Compounds of formula I are useful as drug inhibiting DHODH for treatment of disease or therapeutic condition in which inhibition of DHODH is beneficial.

EFFECT: new compounds as anti-inflammatory, immunomodulating, and anti-proliferative agents.

13 cl, 1 tbl, 1 dwg, 76 ex

-(3-n-methylpyridin s)-alanine as-(l)- rarn-Сhg-Рal iu(3)-nh2" target="_blank">

The invention relates to a new method of obtaining N-acetyl-(L)-4-cyanopyrrolidine separation of the racemate ethyl ester of N-acetyl-(D,L)-4-cyanopyrrolidine and to a new method of obtaining stereoisomer Ac-(L)-pAph-Chg-Me Pal(3)-NH2using as an intermediate compound N-acetyl-(L)-4-cyanopyrrolidine

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining polyquinone by oxidative dehydration of initial monomer: hydroquinone, and/or benzoquinone, and/or quinhydrone, and/or pyrocatechol, and/or their mixtures in presence of mild dehydrating agent, spatially substituted diphenoquinone of general formula (1) with obtaining final product: polyquinone and equimolar quantity of spatially substituted bisphenol of general formula (2). Reaction can take place in presence of water in neutral medium, and/or acidic medium, and/or alkaline medium in mixture with hydrocarbon solvent, in which dehydrating agent and initial monomer are dissolved, in interval of temperatures from 50 to 200°C and reaction duration not more than 3 hours. Claimed method makes it possible to obtain polyquinone with output to 95% with conversion on initial spatially substituted diphenoquinone to 100%. (1), (2). In formulae (1) and (2) R1-4 stand for alkyl radical, and/or halogen, and/or cyano group.

EFFECT: increase of output.

3 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of industrial synthesis of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide of formula (I)

method is realised by interaction of allyl cyanide of formula (II) with compound of formula (III) in presence of free-radical initiator, where Xa represents group -S-C(S)-OR, in which R represents linear or branched (C1-C6)alkyl group, to obtain compound of formula (IV) in which Xa is such as determined above. Compound of formula (IV) optionally can be separated before it is subjected to cyclisation reaction in presence of free-radical initiator to obtain compound of formula (V) Compound of formula (V), also optionally, can be separated before it is subjected to reaction of reduction/dehydration to obtain compound of formula (VI) which is after that subjected to aromatisation reaction to obtain compound of formula (VII) which is subjected to reduction with hydrogen in presence of Raney nickel in polar protic medium and reaction with acetic anhydride to obtain compound of formula (I), which is separated in form of solid substance. Also claimed are novel intermediate compounds, namely (7-methoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)acetonitryl of formula (V) and (7-methoxy-1,2-dihydro-1-naphthalenyl)acetonitryl of formula (VI).

EFFECT: obtaining agomelatine from simple initial substances, which are easily available in great amounts at low cost.

20 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: synthesis of tetracyanoethylene is carried out via oxidative dimerisation of malonic acid dinitrile with selenium (IV) oxide in a nonpolar aprotic anhydrous organic solvent at a temperature not lower than the boiling point of the latter. The preferred nonpolar aprotic anhydrous organic solvent is benzene, toluene or chlorobenzene.

EFFECT: method increases output of the end product while reducing labour input and cost of the process.

4 cl, 1 tbl, 3 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a compound of formula

,

wherein R represents one or more groups optionally specified in halogen atoms, and n makes 1 or 2; or its pharmaceutically acceptable salts. The method involves the following stages: (1) reacting a compound of formula

,

wherein X' is specified in chlorine, bromine, iodine and triflate group (CF3SO3), with 1,2-dibromethane to form a compound of formula

,

(2) binding in the presence of a palladium catalyst representing mixture of Pd(OAc)2 and triphenylphosphine, a compound of formula (V) to a compound of formula ,

wherein R is such as specified above to form a compound of formula ;

(3) hydrolysing the compound of formula (VII) to form a compound of formula (IA). The invention also refers to a method for preparing a pharmaceutical composition involving the above stages (1)-(3) and the additional stage involving mixing to one or more pharmaceutically acceptable excipients.

EFFECT: method enables preparing the high-yield products.

9 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), which can be applied as an aromatic compound or a smell-masking agent. In formula (I) R stands for a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl or =CH2; Z stands for CN or CHO; and there is not more than one dashed bond. The following conditions must be observed: if Z stands for CHO and there is one of the dashed bonds, R does not stand for a hydrogen atom, and if there is a dashed bond between carbons Ca and Cb, R does not stand for a group = CH2. The invention also relates to a method of obtaining a formula (I) compound, its application as the aromatic compound or the smell-masking agent, and a perfumery composition.

EFFECT: increased activity of the composition application.

10 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 4-[2-chloro-1-formyl-2-R-vinyl]-5-nitrophthalonitriles of said general formula where R denotes C6H5, or 4-OCH3C6H4, or 4-CH3C6H4, or 2-thienyl, which can be used as precursors in synthesis of biologically active substances, phthalocyanines and hexazocyclanes. The disclosed method includes use of substituted 4-nitro-5-(2-oxoethyl)phthalonitriles and phosphorus oxychloride POCl3 as starting reagents. Reaction of said reagents takes place at 90-110°C and molar ratio 1:2-3, respectively, for 2.5-5 hours in dimethylformamide solution. The reaction mass is then cooled and poured into cold 5-20% sodium bicarbonate solution. The crystalline precipitate is filtered, recrystallised from an alcohol and dried on air.

EFFECT: high degree of purity of the compound.

1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a method of obtaining 2-cyano-3-arylacrylic acids of general formula given below, which can be applied as a regulator of plant growth, synthesis of medications, fungicides and pesticides. The method consists in boiling respective 2-arylidenemalononitriles in a medium of diluted nitric acid with a ratio nitric acid (65%): water as 5:3 (by volume) in the presence of catalytic amounts of potassium permanganate for 4-6 hours. The obtained sediment is washed with water, the target product is separated by re-crystallisation from water. In the said general formula Ar represents C6H5 (a), 2-ClC6H4 (b) and 3-ClC6H4 (c).

EFFECT: claimed method makes it possible to obtain 2-cyano-3-arylacrylic acids with good output, with the simultaneous reduction of harmful wastes and elimination of organic solvents from the process.

3 ex

FIELD: chemistry.

SUBSTANCE: method of producing di(4-cyanophenyl)bromomethane can be used as an intermediate product in synthesis of medicinal agents, particularly anticancer drug letrozole. The disclosed method of producing di(4-cyanophenyl)bromomethane includes bromation of di(4-cyanophenyl)methane with bromosuccinimide in an inert solvent in the presence of benzoyl peroxide while heating. The reaction is carried out with an excess of 0.2-0.3 mol bromosuccinimide at 105-115°C.

EFFECT: method increases output and purity of the product.

2 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: method consists in an interaction of α-aminonitrile with amines with heating. As α-aminonitrile, 2-amino-2-cyanoadamantane is used, and as amines - cyclohexylamine, 3-aminopropanol and morpholine. The process is carried out in the presence of potassium carbonate at 80-100°C.

EFFECT: method makes it possible to increase the output of 2-amino-2-cyanoadamantane derivatives.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of obtaining 2-amino-2-cyanoadamantane derivatives of the given general formula , which can be applied as semi-products in a synthesis of biologically active amino acids, diamines and heterocyclic compounds. The claimed method consists in a reaction of adamantanone-2 with amines and a cyanogroup carrier in heating in the presence of potassium carbonate. As amines used are cyclohexylamine, 2-aminoethanol, aniline, piperidine, morpholine or piperazine, and as the cyanogroup carrier used is acetone cyanohydrin or 2-amino isobutyronitrile. The process is carried out in one stage for 1.5-2 h at 80-100°C. In the given general formula R=H, , -CH2CH2OH, C6H5, R-R1=-(CH2)5-, -CH2CH2OCH2CH2-, -CH2CH2NHCH2CH2-.

EFFECT: method makes it possible to obtain derivatives of 2-amino-2-cyanoadamantane of the said general formula with the high output.

8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel anthranilic acid derivatives having inhibitory effect on production of matrix metalloprotease 13 of formula 1 , where R1 is a hydrogen atom or carboxy protective group selected from C1-3alkyl; R2 is phenyl, C3-6cycloalkyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl, which can be optionally substituted with C1-6alkyl, C1-6alkoxy, acetyl, acetoxy, halogen, halogenC1-6alkyl, nitro group, hydroxyl group, CN, amino group, phenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-4 heteroatoms selected from N, O, S, which can be disubstituted with C1-6alkyl; R3 is phenyl, C3-6cycloalkyl, C5cycloalkenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl (except benzoxazole), which can be optionally substituted with C1-6alkyl, C1-6alkoxy, phenyl, acetyl, halogen, halogenC1-6alkyl, halogenC1-6alkoxy, nitro group, hydroxyl group, hydroxyC1-6alkyl, CN, acetylamino, ketone, phenoxy, benzoyl, benzyl, amino group, which can be disubstituted with C1-6alkyl, carboxy group, C1-6alkylsufonyl group or pyrrolyl; X1 is a carbonyl group or sulfonyl group; X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl, or a bond; provided that when X1 is a sulfonyl group and X4 is a bond, X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl; X3 is an oxygen atom or a bond; and X4 is a group with general formula -X5-X6- or -X6-X5-, where the bond on the left side of each formula is bonded to R3; and X5 is an oxygen atom, a sulphur atom, an imino group which can be optionally protected or a bond; X6 is a C1-4alkylene, C2-3alkenylene or C2-3alkynylene group or a bond, as well as to their pharmaceutically acceptable salts. The invention also relates to a matrix metalloprotease 13 production inhibitor and a therapeutic agent for making a medicinal agent for treating rheumatoid arthritis.

EFFECT: possibility of making a medicinal agent for treating rheumatoid arthritis.

8 cl, 7 tbl, 633 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of industrial synthesis of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide of formula (I)

method is realised by interaction of allyl cyanide of formula (II) with compound of formula (III) in presence of free-radical initiator, where Xa represents group -S-C(S)-OR, in which R represents linear or branched (C1-C6)alkyl group, to obtain compound of formula (IV) in which Xa is such as determined above. Compound of formula (IV) optionally can be separated before it is subjected to cyclisation reaction in presence of free-radical initiator to obtain compound of formula (V) Compound of formula (V), also optionally, can be separated before it is subjected to reaction of reduction/dehydration to obtain compound of formula (VI) which is after that subjected to aromatisation reaction to obtain compound of formula (VII) which is subjected to reduction with hydrogen in presence of Raney nickel in polar protic medium and reaction with acetic anhydride to obtain compound of formula (I), which is separated in form of solid substance. Also claimed are novel intermediate compounds, namely (7-methoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)acetonitryl of formula (V) and (7-methoxy-1,2-dihydro-1-naphthalenyl)acetonitryl of formula (VI).

EFFECT: obtaining agomelatine from simple initial substances, which are easily available in great amounts at low cost.

20 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: group of inventions relates to methods of opening a ring of a compound, containing a lactone and/or lactam cycle. The methods includes the reaction of the cycle-containing compound, including at least one lactone cycle and/or at least one lactam cycle with at least one amine in the presence of at least one catalyst - monocarboxylic acid in an amount from 0.5 equ to 1.5 equ counted per the quantity of moles of the used cycle-containing compound, with the absence of a catalyst based on a metal salt. The invention also relates to methods of obtaining an amide of δ-amino-γ-hydroxy-ω-arylalkanoic acid of the general formula (where values of substituents are such as given in the invention formula). The methods of obtaining amides of formula (I) also include a reaction of a cycle-containing compound with at least one amine in the presence of at least one catalyst of the ring opening. One of the methods includes the application of monocarboxylic acid as the catalyst in an amount from 0.5 equ to 1.5 equ counted per the quantity of moles of the used cycle-containing compound, with the absence of the catalyst based on the metal salt. Other method additionally includes the removal of at least one protective group of an amino group or one protective group of a hydroxygroup from an intermediate compound and/or reaction product.

EFFECT: opening rings of the compounds, containing the lactone and/or lactam cycle, with higher reaction rate and with the application of a less expensive catalyst.

15 cl, 9 dwg, 8 tbl, 190 ex

Up!