Intermediate compounds for the synthesis of inhibitors of hiv proteases and methods for their production
(57) Abstract:The invention relates to new intermediate compounds and an improved method of producing compounds that inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular L-735524, or their pharmaceutically acceptable salts. The method of obtaining derivatives of heterocyclic carboxylic acids of formula I involves reacting the compounds of formula IV with an amine of the formula V, where stereocenter and has R-configuration or S-configuration, or is racemic; r is an integer from 0 to 5 inclusive; R1and R2taken together with the nitrogen atom that is attached to R1and the carbon atom that is attached to R2form a 6-membered monocyclic saturated ring system consisting of a nitrogen atom that is attached to R1from 4 to carbon atoms and one substituted heteroatom where Rais alkyl; R3is phenyl; R4- C1-C5-alkyl. The proposed method is much shorter, more diastereoselective, leads to higher yields of the target compounds. 4 C. and 16 h.p. f-crystals. This application is a partial continuation of application 08/093225 filed 16 the compounds which inhibit the protease encoded by human immunodeficiency virus (HIV); and, in particular, L-735524, or their pharmaceutically acceptable salts. These compounds are of value to prevent HIV infection, to treat infections caused by HIV, and to treat the arising of acquired immunodeficiency syndrome (AIDS).More specifically, the method involves the reaction of ameerat obtained from amide, such as N-(2(R)-hydroxy-1(S)-indolyl)-3-phenylpropanamide with activated deracemization derived glycidol, such as 2(S)-glycidylether, obtaining epoxy intermediate compound, which is a key intermediate compound required to obtain compounds which are inhibitors of HIV protease, including L-735524. Proposed an improved method of synthesis of specific dialkylamino used to obtain inhibitors of HIV protease.Retrovirus called human immunodeficiency virus (HIV) is the etiological agent of the complex disease that involves progressive destruction of the immune system (acquired immune deficiency syndrome, AIDS) and degeneration of Central and periphery is plicatio is an intense post-translational processing of the precursor polyprotein at the expense of the encoded virus protease with production of Mature viral proteins, required for Assembly and function of viruses. Inhibition of such processing prevents the production usually infectious virus. For example, the authors Kohl, N. E. et al. Proc. Nat' (Acad. Sci., 85, 4686 (1988) demonstrated that genetic inactivation of HIV encoded protease leads to the production of immature, noninfectious viral particles. These results indicate that the inhibition of HIV protease is a valuable method for the treatment of AIDS and prevent or treat HIV infection.The nucleotide sequence demonstrating the presence of HIV pol gene open reading frame (Rather, L. et. al., Nayure, 313, 277 (1985). Gomologichnosti amino acid sequence is evidence that the pol sequence encodes reverse transcriptase, endonuclease and HIV protease (Toh, H. et. al, EMBO J., 4, 1267 (1985); Power, M. D., et al. , Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)). Final products-compounds, including L-735524, which is presented in example 4 hereinafter, which can be obtained from the intermediate compounds according to the invention and by the method of the present invention are inhibitors of HIV protease disclosed in EPO 541168, published may 12, 1993Previously, the synthesis of L-735524 and related is -5(S)-hydroxymethyl-3-(2H)-furanone, which was alkilirovanija, the method included the replacement of alcohol tsepliaeva group on alkilirovannami furanone piperidinium fragment. Then the product of the merger hydrolyzed with disclosure purananooru ring hydroxynicotinic fragment, and the acid finally was connected to 2(R)-hydroxy-1(S)-aminoindan. This process is described in EPO 541168. The extreme complexity of this scheme (12 stages) makes this method time-consuming and laborious, and requires the use of many expensive reagents and expensive raw materials. The method requires fewer steps and reagents would provide economic and time-saving advantages.In EPO 541168 also presents a modified method of obtaining L-735524 and related compounds based on diastereoselective alkylation of enolate obtained from N-(2(R)-hydroxy-1(S)-indan-N,O-isopropylidene-yl)-3-phenylpropanamide, where C3-C5the three carbon fragment is administered in the form of allyl groups, and then oxidize. With this method involve some of the following issues: (a) for the introduction of the three carbon goldlenovo fragment necessary (stage 4), (b) this method uses highly toxic OsO4and (c) at the stage of dihydroxypropane achieved lower classes directly in the desired chiral oxidized form.In addition, the synthesis of chiral pieperazinove intermediate compound was made from 2-pyrazinecarboxamide acid according to the method of the 6 stages and required the use of expensive reagents, such as BOC-ON and EDC (ethylene dichloride). Thus, desirable would also be a shorter way to pieperazinove intermediate derivative, which would not need to use expensive reagents.From the literature there are several examples of condensation stabilized carbanions with glycidol and its derivatives (activated or inactivated); however, none of the known methods gives a new epoxide with a good yield. Cm. for example, Hanson, R. M. Chem. Rev. 1991, 91, 437-475. In the case of activated glycidol derivatives and carbon nucleophiles this is due mainly to the expected and undesirable "double" the addition of the nucleophile to the epoxy product. Further, none of the known examples there amide fragment as a carbanion-stabilizing group (amicalola), and none of the known examples involves attaching containing stabilized carbanion chirality to chiral, deracemization Goldonna derivative (double diastereoselectivity).idorname derivatives, malonty anion was added as deracemization the epichlorohydrin i and deracemization glycidylether ii, to obtain cyclopropyl-lactone iii. See, for example, Pirrung, M. C. , et al., Helvetica Chimica Acta 1989, 72, 1301-1310, and Burgess, K. , et al. J. Org. Chem. 1992, 57, 5931-5936. In this case, the intermediate epoxide undergoes further reaction, giving cyclopropyl ring system. In case i, the initial reaction with malonate anion passes through the epoxy to the end of /C3/, whereas in case ii, the initial reaction proceeds by triflation C1the end.< / BR>A related example is the reaction sulfon-stabilized carbanion derived from V, with goldencasinocom iv with getting hydroxyethylation vi. Cm. Baldwin J. E. et al., J. Chem. Soc., Chem. Commun. 1992, 1249-1251. In this case, though the double connection of a carbanion and is not the main problem required an additional step to convert the intermediate hydroxy-tosilata vi in the target epoxide vii.< / BR>Similarly, the literature largely unknown, and it is assumed that the nitrogen-containing nucleophiles can be selectively attached to the activated derivative of glycidol, removing the problem of double connection.Also known condensation AMI what aminopeptidase viii obtaining target hydroxyethylaminophenol sistemnogo derived ix with a high degree of stereocontrol in respect of C2-(R)-stereocenter. See, for example, Askin, D., et al. J. Org.Chem. 1992, 57, 2771-2773 and U.S. patent 5169952 Askin, D., et al. After hydrolysis get hydroxyethylpiperazine (with remote protection) isostere inhibitors.< / BR>Known division 2-piperazinecarboxamide acid with (+)-CSA. Cm. for example, Felder, E et al., Helvetica Chim. Acta, 1960, 43, 888. However, in the literature there are examples of separation of piperazinone.In the present invention an improved method of obtaining inhibitors of HIV protease in comparison with previously known. In addition, it is much shorter, much more diastereoselective, leads to higher outputs compounds disclosed in EPO 541168, and in particular L-735524, does not require the use of such toxic chemicals as osmium tetroxide or extremely expensive reagents, as (S)-(+)-dihydro-5-(hydroxymethyl)-2(3H)-furanone.Summary of the invention
The present invention includes new methods of synthesis of such intermediate epoxides, as 3, which is used for the synthesis of inhibitors of HIV protease. The invention also includes the reaction of amideast, such as enolate obtained from 1, with activated deracemization derived glycidol, so Qualitat this reaction is unexpected, since it was assumed that the epoxide 3 will continue to react in terms of addition reactions of giving a large number of dimeric product 3-a, and thus giving a low yield of product 3.< / BR>The present invention relates also to an intermediate epoxy compounds, and methods of attaching the intermediate epoxides to the amide of formula V as defined hereinafter, with the formation of HIV protease intermediate and final products.In the description uses the following abbreviations:
Designation - Protective group
BOC /Boc/ tert-butyloxycarbonyl
CBz /Cbz/ - benzyloxycarbonyl/carbobenzoxy/
TBS /TBDMS/ - tert-butyl-dimethylsilane
Designation - activating group
Ts or tosyl or toilet - pair-toluensulfonyl
Ns or noil or nosrat - 3-nitrobenzenesulfonyl
Tf or trifler or triplet - trifloromethyl
Ms or mesyl or mesylate, methanesulfonyl
Designation - Reagent accession
BOP reagent benzotriazol-1-yloxytris(dimethylamino)-fosfodiesterasa
BOP-Cl - bis(2-oxo-3-oxazolidinyl)Gostiniy chloride
EDC - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide - Other
BOC-ON - 2-(tert-UB>4N+F-- tetrabutylammonium
nBuLi (n-Buli) - n-utility
(S)-CSA - (1S)-(+)-10-camphorsulfonic acid
DIEA or DIPEA - diisopropylethylamine
DMAP - dimethylaminopyridine
DME - dimethoxyethan
DMF - dimethylformamide
Et3N - triethylamine
EtOAc - ethyl acetate
h - hour/hours/
IPA - 2-propanol
LDA - sitedisability
L-PGA - (L)-Pyroglutamate acid
TFA - triperoxonane acid
THF - tetrahydrofuran
TLC - Thin layer chromatography /TLC/
Detailed description of the invention
In this invention a new method is proposed to obtain the intermediate compounds of formulas I and IV, which are used in obtaining inhibitors of HIV protease, and in particular compounds disclosed in EPO 541168. The way to obtain the intermediate compounds of the formula I:
< / BR>involves the following stages:
/1/ interaction or
a. glycidol formula II
< / BR>b. the epichlorohydrin of the formula
< / BR>with amidol formula III
< / BR>in the presence of a strong base, at a low temperature, to obtain the adduct IV
< / BR>/2/ interaction IV with an amine of the formula V with the product I
< / BR>where the stereocenter meets or R configuration or S configuration is Livonia, pair-toluensulfonyl, benzosulfimide and 3-nitrobenzenesulfonyl;
r is an integer from 0 to 5 /inclusive/;
R1and R2independently chosen in each case from the group consisting of 1/ hydrogen, 2/ -C1-4the alkyl, unsubstituted or substituted by one or more of the
c/ aryl, unsubstituted or substituted by one or more of the C1-4of alkyl, hydroxy or aryl,
d/ -W-aryl, or-W-benzyl, where W represents-O - or-S-,
e) a 5-7 membered cycloalkyl group, unsubstituted or substituted by one or more of:
i/ hydroxy, ii/ C1-3alkoxy, or (iii/ aryl,
f/ heterocycle, unsubstituted or substituted by one or more of hydroxy, C1-4of alkyl, C1-4of alkyl, substituted hydroxy or Boc,
g/ -NH-COOC1-3of alkyl,
h/ -NH-CO-C1-3the alkyl
i/ -NH-SO2C1-3of alkyl,
j/ -COOR, or
k/ -//CH3/mO/nR, or
3/ aryl, unsubstituted or substituted by one or more of the group:
d/ C1-4of alkyl,
e/ C1-3alkoxy, unsubstituted or substituted by one or more of-OH or C1-3alkoxy,
q) -R5as defined below; or
R1and R2can be joined together with the nitrogen attached to R1and the carbon attached to R2with the formation of a 3-10 membered monocyclic or bicyclic saturated ring system which consists of nitrogen, attached to R1and 2 to 9 carbon atoms, such as:
< / BR>and which is not substituted or substituted by one or more of:
2/ C1-4the alkyl, unsubstituted or substituted by one or more of: a/ halogen, b/ hydroxy, c/ C1-3alkoxy, d/ aryl, e/ 5-7-membered cycloalkyl group, unsubstituted or substituted by one or more of the i/ hydroxy, ii/ C1-3alkoxy, or (iii/ aryl or f/ heterocycle,
4/ -NH-COOC1-3of alkyl,
5/ -NH-CO-C1-3of alkyl,
8/ -W-aryl, or
9/ -W-CO-aryl, where W has the previously indicated meaning; or
R1and R2can be joined together with the nitrogen attached to R1and the carbon attached to R2with the formation of a 3-10 membered monocyclic or billions is Yes and one or more unsubstituted or substituted heteroatom, selected from
where V is absent or represents-CO-Q - or-SO2-Q-,
R1has these values for the case when R1does not depend on and is not attached to R2,
and when Q is absent or is-O-, -N(R)- or heterocycle, optionally substituted C1-4the alkyl,
3/ alkenyl, unsubstituted or substituted aryl,
4/ alkenyl, unsubstituted or substituted aryl,
5/ -S(O)p- where p is 0, 1 or 2, or
such as, for example,
< / BR>< / BR>< / BR>R3selected from the group consisting of
2/ -C1-4of alkyl,
3/ C5-C10cycloalkyl, optionally substituted by a hydroxy-group,
4/ C6-C10aryl, unsubstituted or substituted by one or more of:
d/ C1-4of alkyl,
e/ C1-3alkoxy, unsubstituted or substituted by one or more of-OH or C1-3alkoxy,
m/ aryl C1-3alkoxy,
p/ OP(O) (ORx)2or
is from 1 to 3 heteroatoms, selected from the group consisting of N, O and S, for example, 2-preidel, 3-pyridyl or 4-pyridyl, and which is unsubstituted or substituted R5and optionally one or more of:
a/ halogen, b/ C1-4the alkyl, or c/ C1-3alkoxy; m = 2, 3, 4, or 5; n = 0, 1, 2 or 3; R is hydrogen or C1-4alkyl; Rxrepresents H or aryl; R4represents C1-5alkyl, branched or unbranched; and
R5represents 1/ -W-(CH2)m-NR6R7where W and m have the above significance, and R6and R7independently chosen in each case from:
b/ C1-6the alkyl, unsubstituted or substituted by one or more of the i/ C1-3alkoxy, ii/ -OH, or iii/ -N/R/2,
c/ aromatic heterocycle unsubstituted or substituted by one or more of the i/ C1-4the alkyl, or ii/ -N/R/2d/ or R6and R7joined together with the nitrogen to which they are attached with the formation of a 5 to 7 membered heterocycle, such as morpholino containing up to two additional heteroatoms, selected from N/R/, -O-, -S-, -S(O) or-S(O)2, heterocycle, optionally substituted C1-4the alkyl,
2/ -(CH2)q-NR6R7where q is an integer from 1 dostavlyayut H or unsubstituted C1-6alkyl, or
3/ benzopyrene, indolyl, azacyclonol, azabicyclo C7-11cycloalkyl, or benzoperylene, unsubstituted or substituted C1-4the alkyl.The following figure 1 illustrates this process. However, this method is not limited to any particular substituents used in the scheme, which is used for illustration purposes.< / BR>Intermediate compounds of formula IV is obtained reaction glycidol or its derivative II and amide III in the presence of a strong base. A strong Foundation must be metal-containing base, and the reaction may proceed in an inert anhydrous organic solvent, such as, for example, cyclic or acyclic hydrocarbons, including hexane, pentane, cyclohexane, etc. or without him. Suitable strong bases include: LiN[(CH3)3Si]2, KN[(CH3)3Si]2, NaN[(CH3)3Si]2n-utility (n-BuLi, S-BuLi, tert-BuLi, tert-piperonyl potassium, sitedisability (LDA), litoizobrazitelnoie, lilierrolv, limitationscelebrity, finality, isopropylaniline, isobutylamine and other similar strong base, SUB> and LDA, with the most preferred n-BuLi and LiN[(CH3)3Si]2.It is preferable to use about 1 to 2 molar equivalents of a strong base, 1 molar equivalent III, with the ratio of about 1.15 : 1 molar equivalents of the base III is most preferable. The reaction of II and III can be accomplished by combining II and III in the same reactor, and then adding a strong base, or it can be performed sequentially, i.e. first processing Amin III base, and then adding II. A strong Foundation carries out the replacement of hydrogen by the metal in amide III in the position alpha to the carbonyl group, to obtain the reactive metallidest, which then carries out the ring opening of epoxide II in the limit position, with the receipt of the product IV. The new center of asymmetry is created in the product isostere IV in position 2.The reaction is preferably carried out at a low temperature, for example, in the range of from about -82oC and 0oC. To implement the metallation amide III temperature range support preferably, from -82oC -40oC, and most preferably in the range from -50oC to -45oC. For the interactions between metallizovanogo -10oC, and most preferably from about -30 to -20oC for 4 to 5 hours
Preferably, the reaction of II with III are in the ether solvent. The ether solvent is any solvent suitable for use at this stage of the reaction, including, for example, tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether and methyl tert-butyl ether, or combinations thereof, preferably tetrahydrofuran.The compound of the formula I get in the interaction of the compounds of formula IV with an amine of the formula V. it is Preferable to use from about 1 to about 3 molar equivalents of amine V is the molar equivalent of epoxide IV, and most preferably the ratio of molar equivalents V : IV about equal to 1.05 : 1.This reaction can be conducted in any suitable solvent, for example, selected from hydrocarbons, such as toluene, such ethers like diethyl ether, such alcohol as methanol, ethanol or isopropanol, NITRILES such as acetonitrile, and in such esters as ethyl acetate, or their combinations, preferably alcohols, and most preferred is isopropanol. The reaction temperature can be maintained in the range from room temperature up to the boiling point with a counter example, in the interval from 80oC to 90oC, and most preferably from about 83oC to 85oC.Activated glycidol formula II can be obtained well-known specialists of ways, such as described, for example, J. Klunder et. al, J. Org, Chem., 1989, 54 1295-1304 and there in the links.Amides of formula III can be obtained in accordance with standard procedures known in the art, such as by the procedure of example 1, using appropriate starting materials.If necessary, in the practice of the present invention can use such protective groups, as asutamisega group. For example, nitrogen in 4-position 2-tert-BUTYLCARBAMATE you can protect this group, as BOC, CBZ, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, triptorelin, trialkylsilyl, or other groups known in the art.The final product, the inhibitor of HIV protease, obtained from compounds of the formula I by removal of any remaining protective groups, in accordance with the methods of removal of the protective groups known in the art. For example, Catalunya protective group can be removed by treating compound I with acid in the presence of methanol, or aqueous acid or 1 n HCl in ways, well-known specialists.In one embodiment of the present invention stereocenter a has S configuration; X is para-toluensulfonyl; r = 1; R1and R2joined together with formation of a cyclic structure selected from the group consisting of
< / BR>R3selected from phenyl,
< / BR>R4represents tert-butyl.In this embodiment, a preferred compound of formula II is an intermediate compound of formula IV-a:
< / BR>Also in this embodiment, preferred compounds of formula I, which are intermediate compounds of formula 2-a and 1-b:
< / BR>< / BR>Connection-1-b can be obtained by direct addition of 2(S)-tert-BUTYLCARBAMATE-4N-(methyl-3-pyridyl)-piperazine IV-a. Preferably, the end product of L-735524 obtained by removal of the protection and picolylamine 1-a, as described in examples 3-4.Methods and intermediate compounds of the present invention is suitable to obtain the final products, compounds which are suitable for the inhibition of HIV protease, the prevention or treatment of infection by human immunodeficiency virus (HIV) and treatment related pathological conditions such as AIDS. Treatment of AIDS or p which will be about the range of States of HIV infection: AIDS, ARC (AIDS-related complications), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the final products, compounds that can be obtained according to the method of the present invention, and intermediate compounds of the present invention is suitable for the treatment of HIV infections after suspicions of possible infection, for example, after blood transfusion, organ transplant, the replacement of body fluids, bites, accidental needle sticks with needles or contact with the blood of the patient during operations.The end product inhibitors of HIV protease, can also be used for preparations and analysis of screening for antiviral compounds. For example, the end products can be used to highlight enzyme mutants, which are excellent tools for screening when searching for a stronger antiviral compounds. In addition, such compounds can be used for establishing or determining the binding sites with other anti-HIV protease, for example, if competitive inhibition. Such end connections that are obtained by the method of the present invention, and is for this purpose.Connection-inhibitors of HIV protease, which can be obtained from intermediates and in accordance with the methods of the present invention, disclosed EPO 541164. Inhibitors of HIV protease can be entered in need of such treatment to patients in pharmaceutical compositions containing a pharmaceutical carrier and a therapeutically effective amount of the compound or its pharmaceutically acceptable salt. In EPO 541164 disclosed suitable pharmaceutical compositions, routes of administration, form salts and doses for these compounds.Compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereoisomers or enantiomers, with all isomeric forms are included in the scope of the present invention.If any variable (e.g. aryl, heterocycle, R, R1, R2, n, X and so on ) occurs more than one time in any constituent or in formula I-V, its definition in each case depends on its definition in each of the other cases. In addition, the valid combinations of substituents and/or variables, only if such combinations result in stable compounds.In the sense, as zasidannya aliphatic hydrocarbon group, containing a specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl; tert-Bu); "alkoxy" represents an alkyl group with the specified number of carbon atoms attached through an oxygen bridge; "cycloalkyl" include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl /Cyh/ and cycloheptyl. "Alkenyl" includes hydrocarbon group, branched or non-branched configuration with one or more carbon-carbon double bonds, which can be in any stable point along the chain, such as ethynyl, propenyl, butenyl, pentenyl etc. "Quinil" includes hydrocarbon group, branched or non-branched configuration with one or more carbon-carbon triple bond, which may be in any stable point along the chain, for example, ethinyl, PROPYNYL, butynyl, pentenyl, etc. "Halogen" in the sense used here, represents fluorine, chlorine, bromine and iodine. "Aryl" refers to phenyl /Ph/ or naphthyl.The term heterocycle or heterocyclic, in this context, except in special instructions are stable 5-7 membered mono - or bicyclic or stable 7-10 member of Ishenim, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and in which such heteroatoms as nitrogen and sulfur may be optionally oxidized, and the nitrogen atom may be optionally quaternity, and include any bicyclic group in which any of videopreteen geterotsiklicheskikh ring condensed with the benzene ring. Heterocyclic ring may be attached at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heterocyclic elements include piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxoazetidin, azepine, pyrrole, 4-piperidinyl, pyrrolidinyl, pyrazolyl, pyrazolidine, imidazole, imidazolidine, imidazoline, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidine, morpholine, thiazolyl, diazolidinyl, isothiazolin, hinokitiol, isothiazolinones, indolyl, chinoline, ethenolysis, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothiazyl, thiomorpholine, themorphological, thiomorpholine procedures using the new method described in detail hereinafter. These procedures are only examples, and they should not be construed as limiting the new method of the present invention.Example 1.Getting amide 1:
< / BR>A solution of (-)-CIS-1-aminoindan-2-ol /884 g, to 5.93 mol) 17.8 l of dry THF /KF = 55 mg/ml/ (KF means titration for water Karl Fischer) and triethylamine /868 ml, 6.22 per mol/ 50 ml round bottom flask, equipped with a thermocouple probe, mechanical stirrer, adaptor for input and nitrogen bubbler, cooled to 15oC. Then for 75 minutes add 3-phenylpropionylamino /1000 g, to 5.93 mol/ maintaining the temperature inside the reactor between 14 and 24oC due to obladaushiy baths with a mixture of ice-water. After the addition the mixture is left for 30 minutes at 18-20oC, and according to HPLC analysis followed by the disappearance of the (-)-CIS-1-aminoindan-2-ol.Over the course of the reaction is monitored by HPLC analysis: column 25 cm DuPont C8-PX, 60:40 acetonitrile/10 mm (KH2PO4/K2HPO4), 1.0 ml/min, injected volume = 20 ml, detection = 200 nm, sample preparation = 500 X dilution. The approximate retention periods:
Retention time /min/ - identity
6,3 - CIS-aminoindane
Reacciona the C after diluting 1 ml of the sample an equal volume of water is between 4,3-4,6/. Then add 2-methoxypropan /1,27 l, 13,24 mol, 2.2 equiv) and the reaction mixture is heated to 38-40oC for 2 hours. The reaction mixture is cooled to 20oC and separated between ethyl acetate /12 l/ and 5% aqueous NaHCO3/10 l/, stirring the mixture and separating the salt. An ethyl acetate extract is washed with 5% aqueous NaHCO3/10 l/ and water /4 l/. An ethyl acetate extract is dried by distillation at atmospheric pressure, and the solvent changed to cyclohexane /full volume of about 30 l/. At the end of the distillation and concentration /20% extraction volume ethyl acetate/ hot cyclohexane solution was left to slowly cool to 25oC for crystallization. The resulting suspension is cooled further to 10oC and leave for an hour. The product distinguish by filtration and the wet cake washed with cold /10oC/ cyclohexane /double-899 ml/. Wash the pellet in a vacuum /26 inch = 6,6 mm RT.art./ when 40oC to obtain 1.65kg acetonide 1 (86,4%, 98% area HPLC)
1H NMR (300,13 Mghz, CDCl3the main rotamer) : of 7.36-7,14 /m, 9H/, 5,03 /d, J = 4,4, 1H/, 4,66 /m 1H/, 3,15 /m, 2H/, 3,06 /Shir. C. 2H/, 2,97 /m, 2H/, 1,62 /c, 3H/, 1,37 /3H/;13C (75,5 Mghz, CDCl3the main rotamer)c/168,8, 140,9, 140,8, 140,4, 128,6, 128,5, 128,4, 127,1, 126,3, 125,8, 124,1, 96,5, 78,6, 65,9, 38,4, 36,2, 31,9, 26,5, 24,1.Example 2.Getting epoxide 3:
a. toiletry way
< / BR>A solution of acetonide 1/1000 g, 3,11 mol/ 2(S)-glycidylmethacrylate 2 /853 g, 3,74 mol, 1.2 EQ. / 15.6 l THF /KF = 22 mg/ml/ 50 l chetyrehkolkoy round bottom flask equipped with a thermocouple, mechanical stirrer, a drop funnel and adapter for the input of nitrogen, Tegaserod three times due to the change of vacuum and purging with nitrogen, and then cooled to -56oC. and Then for 2 hours add litigationrelated (LiN[(CH3)3Si] 2) /2.6 liters, 1,38 M, 1.15 EQ. /, keeping the temperature inside the reactor between -50 and -45oC. the Reaction mixture was stirred at -45 to -40oC for 1 hour and then allowed to warm to -25oC for 1 hour. This mixture is stirred at a temperature of from -25 to -22oC for 4 hours and /or until such time as the proportion of the original acetonide will not make up 3% of the area/.Over the course of the reaction is monitored by HPLC: 25 cm by 4.6 nm Bond Silica column, 20% ethyl acetate in hexane, 2.0 ml/min, injected volume: 20 ml, detection at 254 nm, sample diluted 100 times. The approximate retention periods:
holding time - identity
5,5 - amide 1
6,5 - glycidylether 2
13,5 - epoxide 3
The reaction mixture was quenched Deianeira. An ethyl acetate extract is washed with a mixture of 1% NaHCO35 l/ and saturated NaCl /0.5 l/. An ethyl acetate extract /28.3 l/ concentrate by vacuum distillation /28 inches = 711 mm RT.art./ and add additional ethyl acetate, to complete the replacement of the solvent to ethyl acetate /finite volume = 11,7 l/. An ethyl acetate concentrate processed further to replace the solvent in MeOH for crystallization of the product and concentrate to a final volume of 3.2 liters Remaining an ethyl acetate solvent is removed by adding 10 l of methanol and collecting 10 l of distillate. The resulting suspension was stirred at 22oC for 1 hour and then cooled to 5oC and leave for 0.5 hour. The product distinguish by filtration and the wet cake washed with cold methanol /2 250 ml/. The washed cake is dried in vacuum /26 inch = 660 mm RT.art./ at 25oC to obtain 727 g of epoxide 3 /61,2%, 98.7 per cent of the area of the main epoxide according to HPLC/;13With Yarm (300 Mghz, CDCl3) ; 171,1, 140,6, 140,5, 139,6, 129,6, 128,8, 128,2, 137,2, 126,8, 125,6, 124,1, 96,8, 79,2, 65,8, 50,0, 48,0, 44,8, 39,2, 37,4, 36,2, 26,6, 24,1.b. Method using epichlorohydrin
/Get epoxide 3 /epichlorhydrine way/
< / BR>A solution of acetonide 1 /3.00 g, was 9.33 mmole/ 47 ml dried sieves THF Tegaserod nitrogen, and polycentricity the solution is stored at -79oC for 15 minutes, then added dropwise 2(S)-epichlorohydrin /1.2 ml, 15.3 mmole) and the mixture allowed to warm to -25oC for 1 hour, and then leave for 1 hour. Then the reaction mixture was again cooled to -78oC and treated with 3.0 ml litigationrelated solution, and then 1.0 ml /S/-epichlorohydrin. The reaction mixture is allowed to warm to -25oC and leave for 2 hours. The reaction mixture is quenched with 20 ml saturated aqueous sodium bicarbonate and extracted with 120 ml of EtOAc, and conduct a reverse extraction with 60 ml of EtOAc. The combined organic phase washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 3,97 oil, which is purified by chromatography on silica gel /80 g SiO2eluent 4:1 hexane/ethyl acetate to obtain 2.9 g of the mixture of the target epoxide 3 and intermediate chlorhydrin. A portion of the mixture /1.29 g/ dissolved in dried sieves THF /20 ml/ 25oC and treated with 1.73 g of 25% /by weight/ solution of potassium tert-Amiata, and the mixture was incubated at 25oC for 1 hour. The reaction mixture was separated between ethyl acetate and saturated sodium bicarbonate. The organic phase is washed with brine, dried over magnesium sulfate and concentrated under reduced Yes/ to obtain 1.1 g /70% full output/ epoxide 3/.Example 3.Getting connection 6
< / BR>A suspension of 2(S)-tert-butylcarbamoyl-4-N-Boc-piperazine 4 /1950, 6,83 mole, more than 99.5% of her/ /it=enantiomeric surplus/ and epoxide 3 /2456 g of 97.5: 2.5 mixture 4S/R epoxides, 6,51 mol/ isopropanol /2-propanol, 18.6 l/ 72-liter round bottom flask with four inlet holes, equipped with a mechanical stirrer, reflux condenser, steam bath, covered with a Teflon thermocouple and input for nitrogen, heated to boiling under reflux /internal temperature 84-85oC/. After 40 minutes to get a homogeneous solution. The resulting mixture was refluxed for 28 hours.The internal temperature is maintained 84-85oC. the reaction course is monitored by HPLC /column 25 cm DuPont C8-RX, 60:40 acetonitrile/10 mm (KH2PO4/K2HPO4), 1.0 ml/min, detection at 220 nm, the drug sample = 2 μl, the reaction mixture was diluted to 1 ml with acetonitrile/. The approximate retention periods:
Retention time /min/ identification
4,8 - piperazine 4
8,9 - epoxide 3
15,2 - product of accession 5
After 28 hours remaining epoxide 3 and product fitting 5 /according to HPLC analysis is 1.50% of the area and 91 - 93%SUP>oC. After complete addition, the mixture is heated to 22oC. At this time there is gas. The mixture was kept at 20 - 22oC for 6 hours.The reaction course is monitored according to HPLC: conditions are the same as previously specified. The approximate retention periods:
retention time identification
7,0 - CIS-aminoindane
11,9 connection 6
15,1 - product of accession 5
This mixture is cooled to 0oC and slowly add 7.5 l of 50% NaOH to bring the pH of the mixture to 11.6, and the temperature at the same time supporting me 25oC. the Mixture was separated between ethyl acetate /40 l/ and water /3 l/. The organic phase /60 l/ concentrated under reduced pressure /29 inch = 736 mm RT.art./ and the solvent replaced with DMF and concentrated to a final volume of 10.5 l /KF = 1.8 mg/ml/. HPLC analysis of the product 6 in ethyl acetate gives 86,5%. The connection 6, penultimate in DMF directly used in the next stage without additional purification. For the selected product 6:13C NMR (75,4 Mghz, CDCl3) : 175,2, 170,5, 140,8, 140,5, 139,9, 129,1, 128,5, 127,9, 126,8, 126,5, 125,2, 124,2, 73,0, 66,0, 64,8, 62,2, 57,5, 49,5, 47,9, 46,4, 45,3, 39,6, 39,3, 38,2, 28,9.Example 4.< / BR>Obtaining L-735524-monohydrate
A solution of compound 6 in DMF /105,5 l, KF = 10 live on the steam bath under a pressure of 30 inches = 762 mm RT. Art. in order to drive away the main part of the water and/or residues of solvents: isopropanol and ethyl acetate. The final volume of concentrate is 13.5 l /KF = 1.8 mg/ml; and then add tetramin /2,86 l, 20,51 mol/ at a temperature of 25oC, and then to the solution was added 3-pikolinoilhydrazones /96%, 1287 7,84 mol/. The resulting suspension is heated to 68oC.Over the course of the reaction is monitored by HPLC using the conditions specified at the previous stage. The approximate retention times:
Retention time /min/ identification
2,7 - DMF)
4,2 - 3-picolylamine
4,8 - L-735524
9,1 connection 6
< / BR>2-pyrazinecarboxamide acid /8/ - 3.35 kg /27 moles/
Oxalicacid - 3.46 kg /27,2 mol/
tert-butylamine /KF = 460 mcg/ml/ - 9,36 d /89 moles/
EtOAc /KF = 56 ág/ml/ - 9,36 l /89 moles/
DMF - 120 ml
1-propanol - 30 l
Carboxylic acid, 8 suspended in 27 l of EtOAc and 120 ml of DMF in a 72-liter three-neck flask with mechanical stirring under nitrogen atmosphere, and cooled suspension of up to 2oC. Add oxalicacid, keeping the temperature between 5 and 8oC.Adding complete in 5 hours. During the exothermic doba is, areata is a HCl salt of pyrazinamide. Analysis of the formation of the acid chloride is carried out, quenching the anhydrous sample of the reaction mixture of tert-butylamine. At the end of the reaction remains less than 0.7% acid 8.Analysis at the completion of the formation of the acid chloride is important because not conducted until the end of the reaction leads to the formation of bis-tert-butylacetamide impurities.Over the course of the reaction can be monitored using HPLC: column 25 cm DuPont Bond RXC8 at a flow rate of 1 ml/min and detection at 250 nm; linear gradient from 98% of 0.1% aqueous H3PO4and 2% CH3CN to 50% water (H3PO4and 50% of CH3CN for 30 minutes. The retention periods:
acid 8 = 10,7 min; amide 9 = 28,1 minutesThe reaction mixture was kept at 5oC for 1 hour. The resulting suspension is cooled to 0oC, and tert-butylamine add such a rate that the temperature inside the reactor remained below the 20oC.Add requires 6 hours, since the reaction is extremely exothermic. A small part of the resulting tert-butylaminoethyl falls from the reaction mixture in the form of chapeaurouge white solid.The mixture was incubated at 18oC 30 United organic phases are washed with 6 l of 3% NaHCO3and 2 x 2 l of saturated aqueous NaCl. The organic phase is treated with 200 g of Darco G60 carbon and filtered through Solka Flok, and the cake was washed with 4 l of EtOAc.Processing carbon effectively removes slight purple coloration of the product.A solution of 9 in EyOAc concentrate at 10 mbar = 103n/m2up to 25% of the initial volume. Add 30 l of 1-propanol and the distillation continued until a final volume of 20 L.At this point, the amount of EtOAc was below the limits of detection method1H NMR /less than 1%/. The internal temperature when the replacement of the solvent is less than 30oC. a Solution of compound 3 in a mixture of 1-propanol/EtOAc remains stable up to reflux at atmospheric pressure for several days.By evaporation of the aliquot get a solid product is yellow-brown with tons of melting point 87-88oC.13With NMR (75 Mghz, CDCl3MD) 161,8, 146,8, 145,0, 143,8, 142,1, 51,0, 28,5.Example 6
racemic 2-tert-butyl-carboxamides 10
< / BR>Materials:
Pyrazin-2-tert-BUTYLCARBAMATE 9 2,41 kg /13,4 mol/ 1-propanole solution, 12 l, 20% Pd(OH)2C 16 wt.% water 144,The solution pyrazin-2-tert-BUTYLCARBAMATE 9 in 1-propanol was placed in an autoclave with a capacity of 5 gallons = 18,93 l Dobash">After 24 hours the reaction mixture absorbs theoretically calculated amount of hydrogen, and according to gas chromatography, the product 9 is less than 1%. The resulting mixture is cooled, through her blow N2and the catalyst removed by filtration through Solka Flok. The catalyst was washed with 2 liters of hot 1-propanol.It was found that the use of warm 1-propanol when washing filter cakes improves infiltration and reduces product losses in the filter cake.Over the course of the reaction is monitored by gas chromatography: Column: 30 m Megabore, from 100 to 160oC at a speed of 10oC/min, kept 5 min, and then at the speed of 10oC/min to 250oC; retention time : 9 = 7,0 min; 10 = 9,4 minutes Over the course of the reaction can also be monitored according to TLC using the solvent EtOAc/MeOH /50:50/ and ninhydrin as a showing agent.After evaporation of the aliquot is that the output after amidation and hydrogenation is 88%, and the concentration 10 is 133 g/lAfter evaporation of the aliquot receive the product 10 as a white solid with tons of melting point 150 - 151oC;13With NMR (75 Mghz, D2O, ml) 173,5, 59,8, 52,0, 48,7, 45,0, 44,8, 28,7.Prematurely:
racemic 2-tert-BUTYLCARBAMATE 10 - 4,10 kg/22,12 mol/
in the form of a solution in 1-propanol - 25.5 kg dissolved.(S)-(+)-10-camphorsulfonic acid - 10,0 kg /43,2 mol/
1-propanol - 12 l
Acetonitrile - 39 l
Water - 2,4 l
A solution of amine 10 in 1-propanol was placed in a 100 liter flask with joining portions of the hub. The solution is concentrated at a pressure of 10 mbar = 103n/m2and at a temperature of less than 25oC to a volume of approximately 12 litersAt this point, the product precipitates from the solution, but when heated the mixture up to 50oC goes back into solution.The analysis of homogeneous aliquot indicates that the concentration of the product 10 is 341 g/l Concentration determined according to HPLC: column 25 cm DuPont Bond PXC8 at a flow rate of 1.5 ml/min and detection at 210 nm, isocrate /98/3/ CH3CN/0.1% aq. H3PO4. Retention time of product 10 : 2,5 minutesTo obtain a clear, slightly brown solution was added 39 ml of acetonitrile and 2.4 l of water.The water content was determined by KF titration and integration of spectra1H NMR gives the ratio of CH3CN/1-propanol/H2O = 26/8/1,6. Concentration in the solution was 72.2 g/L.
Bis(S)-(+)-CSA salt 11,95% it is 5.54 kg /8,53 mol/
Di-tert-BUTYLCARBAMATE - 1.86 kg /8,53 mol/
Et3N - 5,95 l /42,6 mol/
EtOH strictly 200 fortress - 55 l
EtOAc - 2 l
To (S)-CSA salt II in 100 liter three-neck flask with dropping funnel in a nitrogen atmosphere add EtOH, then triethylamine at 25oC. the Hard part is easily dissolved by adding Et3NBoc2O is dissolved in EtOAc and loaded into the addition funnel. A solution of Boc2O in EtOAc add such a rate that the temperature did not increase 25oC. This addition takes 3 hours. The reaction mixture was incubated for 1 hour after complete addition, a solution of Boc2O.Over the course of the reaction can be monitored according to HPLC : 25 cm DuPont Bond RXC8 column, flow rate 1 ml/min and detection at 228 nm, socrata mixture (50/50) CH3CN/0.1 M KH2PO4bring pH to 6.8 with NaOH. Retention time of product 4 = 7.2 minutes. Chiral analysis is performed using the same TBE solvent 100% EtOAc /Rf= 0,7/.Then the solution is concentrated to approximately 10 l at a temperature within the reactor below the 20oC in the hub portion type at a pressure of 10 mbar = 103n/m2. The replace solvent, slowly adding 20 l of EtOAc, and then concentrating to 10 L. the Reaction mixture was washed with 16 l of 5% aqueous solution of Na2CO3twice in 10 l of deionized water and twice with 6 l of saturated aqueous sodium chloride. United water washing is subjected to back extraction with 20 l of EtOAc, and the organic phase is washed twice with 3 l of water and twice with 4 l of saturated aqueous sodium chloride. The combined EtOAc extracts are concentrated at a pressure of 140 mbar = 103n/m2and the temperature inside the reactor is less than 20oC stolarova concentrate batch type to about 8 HP Replacement solvent cyclohexane reach, slowly Prilepa about 20 l of cyclohexane, and again concentrating to about 8 liters To the resulting suspension add 5 l of cyclohexane and 280 ml of EtOAc, and the resulting mixture is heated to boiling under reflux, when everything goes into solution. This solution is cooled and 58oC enter 10 g of seed. The suspension is cooled to 22oC for 4 hours, and the resulting product is myauth 1.8 l of cyclohexane and dried in the vacuum unit 35oC in nitrogen atmosphere to obtain 1.87 kg (77%, more than 99.8% of sites on the chromatogram HPLC, R-isomer below detection level) of the product 4 in the form of slightly yellowish-brown powder. 2D5= 22,0o(C = 0,20, MeOH), so pl. 107oC.13NMR (75, Mggc, CDCL3, ml)170,1, 154,5, 79,8, 58,7, 50,6, 46,6, 43,6, 43,4, 28,6, 28,3.Example 9.(S)-2-tert-butyl-carboxamidine-bis-(L)pyroglutamyl acid 12
< / BR>Materials
Racemic 2-tert-BUTYLCARBAMATE 10 /of 0.11 mol/ 1-propanole solution - 155 ml, analysis = 21.1 g L
L-pyroglutamyl acid and 28 g /of 0.21 mol/
Water - 5 ml
A solution of racemic-2-tert-butyl-carboxamidine 10 in 1-propanol loaded into a 500 ml round bottom flask with a fridge, a mechanical stirrer and input for nitrogen. Water is added together with L-pyroglutamic acid, and the resulting suspension is refluxed. Homogeneous yellow solution is cooled to 50oC, and enter the seed - bis-(S)-PGA salt R Amin /50 mg/. Immediately formed a solid product. This solution is cooled further to 25oC and incubated for 16 hours. The hard part is filtered off with 22oC, and the filter cake promyvatelem nitrogen, to obtain 23,74 g /48%/ (R)-2-tert-BUTYLCARBAMATE-bis-(L)-pyroglutamic acid. The value of her material is 98% according to HPLC analysis on chirality, as described earlier. Royal solutions yellow contains 22,6 g /46%/ salt (S)-2-tert-BUTYLCARBAMATE bis(L)-pyroglutamic acid 12, and its value is 95% according to HPLC analysis on chirality. The mother solution is evaporated and used directly on the stage of protection.Example 10.(S)-2-tert-butylcarbamoyl-4-tert-butoxycarbonyl-piperazine 4 of salts of (S)-2-tert-BUTYLCARBAMATE-bis(L)-pyroglutamic acid 12
< / BR>Materials
salt (S)-2-tert-BUTYLCARBAMATE-bis(L)-pyroglutamic acid, 95%, and 22.6 g /50,1 mmole/
Di-tert-BUTYLCARBAMATE - 11.1 g /50,1 mmole/
Et3N - of 35.5 ml /0,254 mol/
1-propanol - 226 ml
EtOAc - 24 ml
To salt (S)-2-tert-BUTYLCARBAMATE bis/L/-pyroglutamic acid in a 500 ml three-neck flask with addition funnel, under nitrogen atmosphere was added 1-propanol. Adding Et3N is readily soluble resinous solid. For 2 hours at 22oC add a solution of Boc2O in EtOAc. The reaction mixture was incubated for 1 is b, as for the conversion of 11 to 4.Then the solution is concentrated, and the solvent is replaced by an ethyl acetate /200 ml/. The reaction mixture is washed with 50 ml of a 7% aqueous solution of Na2CO3, 2000 ml of water, dried over sodium sulfate and filtered. EtOAc solution was concentrated, and the solvent is replaced by cyclohexane /60 ml/. Add EtOAc /1 ml, and the resulting mixture is heated to boiling under reflux to dissolve all solids. The mixture is cooled and injected seed /50 mg/ when 52oC. the Suspension is cooled to 22oC for 2 hours, and the product produce by filtration after standing for 1 hour at 22oC. the Filter cake was washed with 8 ml of cyclohexane and dried in the vacuum unit 35oC in nitrogen atmosphere to obtain 10.8 g /74%/ (over 99.9% of the area of the HPLC chromatogram, R-isomer below detection level) of the product 4 as off-white powder.Example 11.Kinetic selection of their product 4 (S/K)-2-tert-butylcarbamoyl-4-tert-butoxycarbonylamino-13.< / BR>Materials
The crude (S/R)-2-tert-butylcarbamoyl-4-tert-butoxycarbonylmethyl 13 - 1.40 g
(S)-2-tert-butylcarbamoyl-4-tert-butoxycarbonylmethyl 4 (>99.5% EE) - 4 x 0,14 the si solvents, heating to 90oC. the Solution is allowed to cool, and 10oC interval, the solution is seeded with 0.14 g of product 4 / > 99.5% EE/. When 55oC fourth portion 0.14 g of the seed is no longer soluble, and further slow cooling to room temperature formed a white crystalline mass. The reaction mixture is filtered, washed with 3 ml of a mixture solvent methylcyclohexane/EtOAc and dried in a vacuum thermostat in a stream of nitrogen to obtain 0.95 g of a white solid. Determination of enantiomeric purity in column Chiracell As gives 93% EE.Example 12.Obtain TRANS-3-(4-pyridyl)acrylic acid
< / BR>To a solution of 4-pyridinecarboxamide/ 36,7 ml, 0,384 mol/ and malonic acid /40 g, 0,384 mol/ 31 ml of pyridine added piperidine /0,12 ml, and the mixture was heated to 100oC. Warning: allocated large amounts of CO2. After half an hour the reaction mixture is cooled to room temperature and the solution solidifies. His triturated with 240 ml of water and filtered, washed twice with 50 ml portions of water. The hard part is dried overnight at 42oC at a pressure of 10 mm RT.article to get to 37.1 g of a white solid substance; so pl. 295-297oC.Example 13.Example 14.Obtaining N-(1,2-N,0-isopropylidene-2(R)-hydroxy-1(S)-indanyl)- TRANS-3-(4-pyridyl)acrylamide
< / BR>To a suspension of N-(2(R)-hydroxy-1(S)-indanyl(TRANS-3-(4-pyridyl)-acrylamide /18,5 g of 0.066 mol/ 700 ml of methylene chloride add dimethoxypropane /49,0 ml, 0,402 mol/ and then the (+)-/camphorsulfonic acid /46,8 g, 0,201 mol/. After 20 minutes the reaction mixture becomes homogeneous. The reaction mixture is stirred for 3 hours, washed with saturated sodium bicarbonate /2 x 150 ml/. The aqueous layer was extracted with methylene chloride /3 x 200 ml) and the combined organic layer is dried with yeperenye (100 x 150 mm column with silica gel; gradient elution 1:30: 69, 2: 30: 68, 3:30:67, 5:30:65 a mixture of MeOH : CHCl3saturated NH3:CH2Cl2leads to obtain 16.0 g of a white foam (Rf= 0,46 5:30:65 MeOH : CHCl3saturated NH3CH2Cl2/
Example 15.Obtaining N-(1,2-N, O-isopropylidene-2(R)hydroxy-1(S)indanyl)- 3-(4-pyridyl)Propylamine
< / BR>To N-(1,2-N, O-isopropylidene-2(R)-hydroxy-1(S)-indanyl)-TRANS-3- (4-pyridyl)acrylamide /16.0 g, 0,0499 mol/ dissolved in 200 ml of ethanol and 200 ml of THF, added 14.0 g of Pd(OH)2coal /20 wt.%/. Then injected into the flask H2and the reaction mixture is stirred for 9 hours. The solution is rinsed with argon, filtered through a layer of celite and washed with ethanol /100 ml. The solvent is removed in vacuum and the resulting product was then purified using pleskrestore (column with silica gel 100 x 150 mm; gradient elution 1:30:69, 2:30: 67, 5: 30: 65 a mixture of MeOH : CHCl3saturated NH3:CH2Cl2), resulting in a gain of 13.8 g of a white foam (Rf= 0.5 V 5:30:65 MeOH : CHCl3saturated NH3: CH2Cl2)
< / BR>Using almost the same way as to obtain N-(2(R)-hydroxy-1(S)-indanyl)-TRANS-3-(4-feast of the physical characteristics: I. pl. 119-120oC.Elemental analysis: Calculated for C17H16N2O20,65 H2O:
C 69,92; H 5,97; N 9,59. Found: C 69,94; H 5,74; N 9,84.Example 17.Obtaining N-(1,2-N,O-isopropylidene-2(R)-hydroxy-1(S)-indanyl)- TRANS-3-/3-pyridyl/acrylamide
< / BR>Using almost the same way as to obtain the N-(1,2-N,0-isopropylidene-2(R)-hydroxy-1(S)indanyl)-TRANS-3-(4-pyridyl) acrylamide, but substituting the appropriate starting materials, get mentioned in the title compound. Physical characteristics: I. pl. 134 - 136. Elemental analysis: Calculated for C20H20N2O20,25 H2O: C 73,94; H 6,36; N 8,62. Found: C 73,95; H 6,18; N 8,70.Example 18.Obtaining N-(1,2-N, O-isopropylidene-2(R)-hydroxy-1(S)-indanyl)-3-(2-pyridyl) Propylamine
< / BR>Using almost the same way as to obtain the N-(1,2-N,O-isopropylidene-2(R)-hydroxy-1(S)-indanyl)-3-(4-pyridyl) propylamide, but substituting the appropriate starting materials, get mentioned in the title compound.Although stated in the description of the principles of the present invention, and examples are offered for purposes of illustration, consider that the practice of the present invention covers all the usual VA is S="ptx2">1. The method of obtaining derivatives of heterocyclic carboxylic acids of the formula I
< / BR>including the interaction of the compounds of formula IV
< / BR>with an amine of the formula V
< / BR>where stereocenter has R-configuration or S-configuration, or is racemic;
r represents an integer from 0 to 5 inclusive;
R1and R2taken together with the nitrogen atom that is attached to R1and the carbon atom that is attached to R2form a 6-membered monocyclic saturated ring system consisting of a nitrogen atom that is attached to R1from 4 to carbon atoms and one substituted heteroatom
< / BR>where Randis unsubstituted C1-4alkyl;
R4represents C1-C5-alkyl straight or branched chain.2. The method according to p. 1, characterized in that the reaction is carried out in a solvent selected from C1-C3-alcohol, and at a temperature of from about 80 to 90oC.3. The method according to p. 2, wherein the solvent is isopropanol and the temperature is from about 83 to 85oC.4. The method according to p. 1, characterized in that it further p or (b) of epichlorohydrin patterns
< / BR>with amidol formula III
< / BR>in the presence of a strong base at low temperature, where X is selected from the group consisting of-H, methanesulfonyl, trifloromethyl, p-toluensulfonyl, benzosulfimide and 3-nitrobenzenesulfonyl.5. The method according to p. 4, characterized in that X is p-toluensulfonyl.6. The method according to p. 1, characterized in that stereocenter has the S-configuration; r = 1; R1and R2joined together with formation of a cyclic structure
< / BR>R3represents phenyl and R4represents tert-butyl.7. The method according to p. 6, wherein R3represents phenyl and R1and R2together represent
< / BR>8. The method of obtaining derivatives of N-(1,2-N,O-isopropylidene-2(R)-hydroxy-1(S)-indanyl)-3-(2-oxiranyl)propylamide formula IV
< / BR>where stereocenter has the R-configuration or S-configuration or is racemic;
r represents an integer from 0 to 5 inclusive;
characterized in that interact the compounds of formula II
< / BR>with amidol formula III
< / BR>where a, r and R3have the meanings defined above;
X is selected from the group consisting of ia,
in the presence of a strong base at low temperature.9. The method according to p. 8, wherein the strong base is selected from the group consisting of LiN[(CH3)3Si]2, KN[(CH3)3Si]2, NaN[(CH3)3Si]2n-utility, sec-utility, tert-utility, of potassium tert-butylate, diisopropylamide lithium, isopropylcyclohexane lithium, pyrrolidide lithium, tetramethylpiperidine lithium finelite, isopropylacrylamide and Isobutyraldehyde.10. The method according to p. 9, characterized in that the process temperature is about -82 0oC.11. The method according to p. 10, characterized in that the reaction is carried out in a solvent selected from the group consisting of tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether and methyl tert-butyl ether, or combinations thereof.12. The method according to p. 11, wherein the strong base is selected from the group consisting of n-utility, sec-utility, LiN[(CH3)3Si]2and diisopropylamide lithium.13. The method according to p. 12, wherein the temperature is in the range of approximately -82 . . . -40oC for metallation of amide III and in the range of about -50 ... -10oC for recitales is tetrahydrofuran.15. The method according to p. 14, wherein the strong base is selected from the group consisting of n-utility and LiN[(CH3)3Si]2.16. The method according to p. 15, wherein the temperature is in the range of about -50 . . . -45oC for metallation of amide III and in the range of approximately -30 -20 ... oC for the reaction metallizovannogo derived compounds III and II.17. The method according to p. 11, characterized in that stereocenter has the S-configuration; r = 1 and R3represents phenyl.18. Derivatives of N-(1,2-N,O-isopropylidene-2(R)-hydroxy-1(S)-indanyl)-3-(2-oxiranyl)propylamide formula IV
< / BR>where stereocenter has the R-configuration or S-configuration or is racemic;
r represents an integer from 0 to 5 inclusive;
R3represents phenyl.19. Connection on p. 18, in which stereocenter has the S-configuration; r = 1 and R3represents phenyl.20. [3aS-[3[S*(R*)] ,3a,8a]]-3,3 a,8,8 a-Tetrahydro-2,2-dimethyl-3-[2-(oxiranylmethyl)-3-phenylpropyl]-1-oxo-2H-indeno[1,2-d]oxazol formula
< / BR>Priority points:
16.07.93 on PP.1 to 3 and 6 to 20;
26.01.94 on PP.4 and 5.
< / BR>where
R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;
R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;
R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;
R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms
< / BR>in particular 1,3-bis(2'-hydroxy-3'-morpholinopropan)-6-methyluracil(a); 1,3-bis(2'-hydroxy-3'-piperidinoethyl)-6-stands-rallu (b); 3-bis(2'-hydroxy-3'-morpholinopropan)-5-hydroxy-6-methyluracil (); 1,3-bis(2'-hydroxy-3'-piperidinoethyl)- 5-hydroxy-6-methyluracil (g); 1,3-bis(2'-hydroxy-3'-morpholinopropan)-5-(2'-hydro - XI-3'-morpholinoethoxy)-6 - methyluracil (d) and 1,3-bis(2'-hydroxy-3'-piperidinoethyl)-5-(2'-hydroxy-3'-piperidino - poxy)- 6-methyluracil (E), showing immunotropic and anti-inflammatory activity
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to a compound of formula (I), its tautomers and pharmaceutically acceptable salts. In formula X is chosen from hydrogen, -NR11 R12, A" is a group chosen from: and R11 and R12 are independently chosen from alkyl with 1-6 carbon atoms; Y represents hydrogen; R is chosen from alkyl containing 1 to 6 carbon atoms which can have optionally independently 1-2 substitutes representing halogen, alkenyl with 2-6 carbon atoms which optionally independently contain 1-2 substitutes chosen from phenyl, optionally substituted by alkoxy with 1 to 6 carbon atoms, halogen, heteroaryl with 5 atoms of a ring containing 1 heteroatom; -CH2NR1R2; aryl with 6 carbon atoms which optionally contains 1-3 substitutes independently chosen from halogen, cyano, hydroxy, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, benzyloxy, di(alkyl with 1-6 carbon atoms)amino, and methylene dioxy; heteroaryl with 5 or 6 ring atoms containing 1-2 heteroatoms which can be identical or different and are independently chosen from nitrogen, oxygen, sulphur, optionally containing 1 substitute representing -CH2OCOCH3; benzofuranyl and benzothienyl; or a group consisting of -SR3; R1 and R2 are independently H or alkyl with 1-6 carbon atoms, or R1 and R2 together with nitrogen atom whereto each of them is bound, form a 5- or 6-members saturated ring containing one heteroatom N; R3 is chosen from -CH2-phenyl optionally substituted by halogen; CH2(CO)OCH2phenyl; provided X is NR11R12, and R11 is hydrogen, then R12 is methyl, ethyl, n-propyl, n-butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl; and provided R11 is methyl or ethyl, then R12 is methyl, ethyl, n-propyl, 1-methylethyl, n-propyl, 1- methylpropyl or 2- methylpropyl.
EFFECT: preparation of a pharmaceutical composition exhibiting antimicrobial activity, containing a compound of the invention, development of a method of treating or controlling a bacterial infections and a method of producing the chemical compound of formula:
28 cl, 8 tbl, 2 dwg, 49 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to compounds of general formula (I) wherein R1 represents (a) C1-6alkyl optionally containing 1-3 substitutes specified in C1-6alkylcarbonyloxy, hydroxy and a halogen atom, (b) C3-6cycloalkyl, (c) phenyl or (d) mono-C1-6alkylamino; R5 represents a hydrogen atom; R6 represents a hydrogen atom; X represents an oxygen atom or a sulphur atom; m is equal to 1; the ring A is an unsaturated 5-member ring optionally containing a substitute specified in (a) C1-6alkyl optionally containing 1-3 substitutes specified in phenyl, hydroxy and a halogen atom, C1-6alkylcarbonyl, benzyloxy and pyridyl, (b) C3-6cycloalkyl, (c) phenyl or (d) C1-6alkoxy, (e) mercapto, (f) C1-6alkylthio or (g) di-C1-3alkylamino; the ring B is an unsubstituted phenyl; the ring C is a saturated or unsaturated 5-member ring optionally containing a substitute specified in C1-6alkyl and hydroxy. Also the invention refers to the intermediate compounds of formula (II) and to the pharmaceutical composition containing the compounds of formula (I) showing melatonin agonist activity.
EFFECT: preparing the compounds of formula (I) as melatonin agonists.
14 cl, 7 dwg, 2 tbl, 98 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to spirocyclic nitriles of formula (1a): wherein the radicals A, B, C, X, Y, R24, R25, R26 and R27 are presented in cl.1 of the patent claim, inhibiting thiol proteases, particularly cathepsins, a method for preparing and using them as a drug for treating the diseases directly or indirectly mediated by cathepsins.
EFFECT: preparing the agent for treating the diseases directly or indirectly mediated by cathepsins.
12 cl, 2 tbl, 105 ex
SUBSTANCE: method includes reacting adamantanone-2 with 2-aminoethanol, o-aminophenol or anthranilic acid in molar ratio 1:1-1.25, respectively, in a toluene medium with azeotropic water distillation.
EFFECT: obtaining adamantyl-containing spiroheterocycles in mild conditions with high output.
FIELD: organic chemistry, medicine.
SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):
wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
13 cl, 1 tbl, 30 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
9 cl, 47 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):
wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.
EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.
8 cl, 94 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula :
or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula :
wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae  or  wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula  that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.
29 cl, 1 tbl, 170 ex
FIELD: organic chemistry, chemical technology, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):
wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).
EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.
9 cl, 1 tbl, 41 ex
FIELD: organic chemistry, medicine.
SUBSTANCE: invention relates to compounds of the general formula (I): wherein Z1 represents -CR1 or nitrogen atom (N); Z2 represents -CR2; Z3 represents -CR3 or N; Z4 represents -CR4; W1 represents oxygen (O), sulfur (S) atom or -NR5; one of W2 and W3 represents N or -CR6 and another among W2 and W3 represents CG; W1 represents NG; W2 represents -CR5 or N; W3 represents -CR6 or N; or W1 and W3 represent N and W2 represents NG; G represents compound of the formula (II): wherein Y represents oxygen atom (O), -C(O)- or absent; p = 1, 2, 3, 4 or 5; Z is absent; each t = 2. Also, invention describes a method for enhancing activity of the muscarinic cholinergic receptor and a method for treatment of morbid states when modification of cholinergic and, especially, muscarinic receptors m1, m4 or both m1 and m4 offers the favorable effect.
EFFECT: valuable medicinal properties of agonists.
14 cl, 2 tbl, 101 ex