Methods and intermediate products for producing macrocyclic hepatitis c virus protease inhibitor

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention relates to methods of synthesis and to intermediate products of compounds of formula (XVII) and salts thereof.

EFFECT: preparing the hepatitis C virus protease inhibitor.

32 cl, 13 ex

 

The technical field to which the invention relates.

The invention relates to the synthesis methods and intermediate products for the synthesis of macrocyclic protease inhibitor of the hepatitis C virus (HCV).

Background of invention

Hepatitis C virus (HCV) is the main reason of the widespread worldwide chronic liver disease. After the initial acute infection, most infected individuals develop chronic hepatitis, as HCV preferably replicates in hepatocytes, but is not directly cytopathic. Chronic hepatitis can progress to liver fibrosis, leading to cirrhosis, end-stage liver disease, and HCC (liver cell cancer), which is the main cause of liver transplantations. This large number of affected patients, making HCV the focus of considerable medical research. Replication of the HCV genome is mediated by a large number of enzymes, including NS3-semipretioase HCV and its associated cofactor, NS4A, which mediates a large number of proteolytic splitting of HCV-polyprotein, resulting in the generation of enzymes replication of HCV. Believe that NS3-semipretioase is necessary for viral replication and is a representing in the EPEC target for finding drugs.

Modern anti-HCV therapy is based on (paglinawan) interferon-alpha (IFN-b) in combination with ribavirin. The result of this therapy is not only limited efficiency because only a portion of patients successfully cured, but also in the case of this therapy are faced with significant side effects and poor tolerability of drugs many patients. Therefore, there is a need for more effective, suitable, and with improved tolerance therapy. There is a need for further inhibitors of HCV, which allow to overcome the deficiencies in the current HCV therapy such as side effects, limited efficacy, the emergence of resistance, and related adverse outcomes.

Describes the various agents that inhibit the NS3-semipretioase HCV and its associated cofactor, NS4A. In the International application WO-05/073195 disclosed linear and macrocyclic inhibitors of the NS3-semipretioase substituted with Central prolinnova balance, and in the case of International applications WO-05/073216 - Central cyclopentenyl balance. Among them interest are macrocyclic derivatives, which show clear activity against HCV and have good pharmacokinetic profile.

Currently, it is found that the specific macrocyclic the is begins with a Central, replaced by hinolinovogo, cyclopentenyl balance is of particular interest from the point of view of effectiveness, and pharmacokinetics. It is a compound of formula (XVII) with the structure presented below:

The compound of formula (XVII) is a very effective inhibitor semipretioase hepatitis C virus (HCV) and is described in International application WO-2007/014926, published on 8 February 2007. Due to its suitable properties, it was selected as a potential "candidate" to obtain drugs against hepatitis C. there is Therefore a need for large amounts of this active ingredient on the basis of methods that provide a product with a high yield and with high purity.

The present invention relates to methods of producing the compounds of formula (XVII) or its pharmaceutically acceptable salts, to obtain intermediate products used in these ways, and some of these intermediate products.

The compound of formula (XVII) can be obtained by the reaction of the currency, based on the intermediate (XIV), which cyclist to obtain the intermediate (XV), which is then hydrolized to the macrocyclic acid (XVI). The latter is associated with sulfonium the house (XVII) through the formation of amide, thereby obtaining the final product (XVII), as shown in the following reaction scheme:

Pharmaceutically acceptable salt forms of the compounds of formula (XVII) can be obtained by introducing into the interaction of the free form of this compound with an acid or a base.

In the case of this and the following reaction schemes or views of the individual compounds, for example, compound (XIV), R means1-4-alkyl, in particular, R is C1-3-alkyl, more specifically, R is C1-2-alkyl, or, in one embodiment, R is ethyl. The reaction conversion of compound (XV) to compound (XVI) is a hydrolysis reaction, which is preferably carried out using a base, in an aqueous environment, such as a mixture of water and water soluble organic solvent, such as tetrahydrofuran (THF) or alcohol, in particular ethanol, from which the ester (XIV), or a mixture of such solvents. The base used can be an alkali metal hydroxide, such as NaOH or KOH, in particular, it can represent a LiOH.

The intermediate product (XIV) cyclist the exchange reaction of the olefin in the presence of a suitable metal catalyst, such as, for example, radenovic the catalyst based on Ru, in particular, not battelino substituted Gilderoy or inteeligence catalyst, such as bis(tricyclohexylphosphine)-3-phenyl-1H-inden-1-eletrochemical (Neolyst M1®) or bis(tricyclohexylphosphine)[(phenylthio)methylene]-butenedioic. Other catalysts that can be used are catalysts of the first and second generation Grubbs, i.e. benzylidene(tricyclohexylphosphine)-dichloroethene and (1,3-bis(2,4,6-trimetilfenil)-2-imidazolidinone)dichloro(phenylmethylene)(tricyclohexylphosphine)-ruthenium, respectively. Of particular interest are the catalysts of the first and second generation Hoveyda-Grubbs, which are dichloro(about-isopropoxyphenyl)-(tricyclohexylphosphine)ruthenium(II) and 1,3-bis(2,4,6-trimetilfenil)-2-imidazolidinone)dichloro(about-isopropoxyphenyl-methylene)ruthenium, respectively. The exchange reaction can be carried out in a suitable solvent, such as, for example, a simple ester, for example, THF, dioxane; halogenated hydrocarbons such as dichloromethane, CHCl3, 1,2-dichloroethane and the like, hydrocarbons, e.g. toluene. In the preferred embodiment, the exchange reaction is carried out in toluene.

The intermediate product (XVI) may be associated with cyclopropylalanine reaction of the formation of amide, such as when using any of the methods of amide bond formation. In particular, the compound (XVI) can be treated with a coupling agent, for example, N,N'-carbonyl is of imidazole (CDI), N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), N-isobutylketone-2-isobutoxy-1,2-dihydroquinoline (IIDQ), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDCI) or benzotriazol-1-electricfireplacesdirectlive.info (commercially available as PyBOP®), in a solvent such as a simple ether, for example THF, or a halogenated hydrocarbon, e.g. dichloromethane, chloroform, dichloroethane, and to enter into interaction with cyclopropylalanine, preferably, after the interaction of the compound (XVI) with a bonding agent. The reaction of compound (XVI) with cyclopropylalanine preferably carried out in the presence of a base, for example, trialkylamine, such as triethylamine or diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The intermediate product (XVI) can also be converted into an activated form, for example, in activated form, such as gelegenheid acid, particularly an acid chloride or bromohydrin acid, or an active ester, for example, in acid, esterified with alloctype, such as phenoxy, p-nitrophenoxy, Pantothenate, trichlorophenoxy, pentachlorophenoxy and the like; or by conversion of macrocyclic acid (XVI) into a mixed anhydride.

Intermediates (XIV) are the starting materials for the production of compounds of formula (XVII) and SL is therefore there is a need to develop methods of obtaining these intermediate products in large-scale production, that is, in tonnage scale, or more. These methods should lead to the final product with high yield and purity. In particular, the presence of various chiral centers in the molecule is of particular problems, as chiral purity is necessary to obtain a product which is suitable for therapeutic applications. Therefore, methods of obtaining compound (XIV) should result in products with suitable chiral purity, without burdening cleanup operations with the loss of significant quantities of unwanted stereoisomeric forms.

One aspect of this invention relates to methods for intermediates (XIV) with high yield and purity, which are suitable for large-scale industrial applications.

This invention also relates to intermediate products, which are suitable for producing compounds of formula (XVII). The number of these intermediate products is:

The compounds listed in the above table, R1is set, determination is Noah lower and R has the meaning as defined above. In one embodiment, R1means methyl. In another embodiment, R is ethyl.

Honda and others, Tetrahedron Letters, vol. 22, No. 28, s-2682, 1981, discloses the synthesis of (±)-brefeldin And using the following starting compounds:

The synthesis according to Honda, etc. effected on the basis ofdl-TRANS-4-oxocyclopent-1,2-dicarboxylic acid (2), which atrificial to obtain the corresponding methyl ester (3and restore when using Raney Nickel to alcohol (4). Partial hydrolysis product4and benzylidene produce predominantly one diastereoisomer of ester5that is , of diastereoisomer, where the hydroxyl and carboxyl groups are in the CIS-position. The last ester5according to Honda, etc. and the compound (V) are both racemates, but diastereoisomer each are other, more accurately, epimerase relative to the carbon atom No. 4 bearing a hydroxyl group. The compound (Va) is one of the two enantiomers, obtained by separation of racemic compounds (V). The other enantiomer is a compound (Vb).

In the International application WO-2005/073195 describes the synthesis enantioselective bicyclic lactone (8b), on the basis of enantiomers of 3,4-bis(methoxycarbonyl)qi is loopantenna. The latter is obtained as described Rosenquist and others in Acta Chemica Scandinavica,46, 1127-1129 (1992). The TRANS-isomer (3R,4R)-3,4-bis(methoxycarbonyl)of Cyclopentanone in turn bicyclic lactone (8b):

In the International application WO-2005/073195, besides, further, describes how to modify a lactone (8b) to complex tert-butyl ether, the opening of the lactone and linking with suitably protected amino acids, for example, ethyl ester, (1R,2S)-1-amino-2-vinylcyclopropanes acid, where, in the latter case, get:

Obtaining compounds of formula (XVII) inevitably involves the introduction thiazolidinediones quinoline residue in cyclopentenone ring through simple essential communication. The Mitsunobu reaction is an "attractive" reaction path for obtaining aromatic simple alkylation, where simple alkilany ether activate and enter into interaction with the aromatic alcohol. In addition, the Mitsunobu reaction, in General, are more efficient than the reaction of O-arilirovaniya that require additional stages of synthesis. In the case of a proceeding under mild conditions this reaction is inverted stereochemistry of alkyl part. The reaction leads to an increase in by-products, such as R OOC-NH-NH-COOR', where R' means1-4-alkyl, in particular ethyl or isopr the saws, other nitrogen-containing compounds and triphenylphosphine that must be separated from the desired end product.

The methods according to the present invention are advantageous because they are suitable for large-scale production. Reduced the number of labor-intensive stages of purification, in particular by chromatography.

In addition, the choice of protective groups are benzyl (Bn) and (C1-4-alkyl, in particular methyl (Me), the compounds (V), (Va) and (Vb) allows for selective manipulation of these compounds. Complex benzyl ether or complex1-4-alkilany ether (and, in particular, methyl ester) can selectively cleave through the use of different reaction conditions for the removal of benzyl group or1-4is an alkyl group, particularly a methyl group. In addition, the balance complex benzyl ether compound (IV), (V) or (Va) introduces the advantage that it allows the efficient separation of compounds (IV), (V) or (Va) using chiral chromatography and facilitates the analysis and detection of these compounds as benzyl residue is UV active.

The description of this invention

In one aspect, the present invention relates to a method for obtaining compounds of formula (XIV)on the basis of intermediate (XI), hydrolyzing docility (XII), which, in turn, is associated with the broadcast cyclopropylamine (XIII)to give the desired end product (XIV), as shown in the following reaction scheme:

In the above scheme, R is set as described above, i.e. With1-4-alkyl, and R1regardless of R, also means1-4-alkyl. In one embodiment, R is ethyl. In another embodiment, R1means methyl. Interest method, as shown above, and intermediate products of the formula (XI), (XIII) and (XIV), where R is ethyl and R1means methyl.

The intermediate product (XI) is the starting material in the above method and it is getting further aspect of the present invention. In accordance with this aspect, the invention relates to a method for producing the intermediate product (XI)on the basis of complex hydroxycyclopent bis-ester of formula (Va), or

(a) by introducing into the complex interaction hydroxycyclopent bis-ester of formula (Va) with thiazolidinediones hyalinella (VIII) by the reaction of formation of simple ether, obtaining, thus, difficult chinainternational bis-ester of formula (IX), where the ester group, which is in the CIS-position relative to the simple ether group in a complex hyalinobatrachium bis-ether of the formula (IX), selectiveness to monocarboxylic acid (X), which, in turn, is associated with alkanolamines by the reaction of formation of amide, and thus, the desired end product of formula (XI); or

(b) by selective transformation of complex hydroxycyclopent bis-ester of formula (Va) in the monocarboxylic acid (VI), which, in turn, is associated with alkanolamines by the reaction of formation of amide to obtain hydroxycyclophosphamide (VII), which, in turn, enter into interaction with thiazolidinediones hyalinella (VIII), and thus, the desired end product of formula (XI);

as shown in the following reaction scheme:

Each R1in the methods presented in the above scheme, and, in particular, in the intermediate products (Va), (VI), (VII), (IX), (X) and (XI), is set as described above, and, preferably, R1means methyl. Bn means benzyl.

The intermediate product (Va) is the starting material in the above method and it is getting further aspect of the present invention. In accordance with this aspect of the invention relates to a method for producing the intermediate product (Va), on the basis of 4-oxocyclopent-1,2-bicarbonate acid (I), by restoring ketogroup to alcohol, and thus, 4-hydroxycyclopent-1,2-bicarbonate acid (II), which, in its PTS who lived, cyclist to the bicyclic lactone (III), where the carboxyl group in the bicyclic lactone (III) etherification using benzyl alcohol, and thus, benzyl ether lactone (IV), where the lactone open and thus obtained carboxyl group etherification using1-4-alkanol, and thus, difficult hydroxycyclopent bis-ester of formula (V), which, in turn, are divided into stereoisomers (Vb) and (Va); as shown in the following reaction scheme:

Each R1in the methods presented in the above scheme, and, in particular, in the intermediate product (V), (Va) and (Vb), is set as described above, and, preferably, R1means methyl.

In one embodiment, the present invention relates to the use of compounds of formula (I), (II), (III), (IV), (V), (Va), (Vb), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIV) as intermediates in obtaining the compounds of formula (XVII) or its salt. Of particular interest are compounds of formula (IX), (XI), (XII) and (XIV) and all intermediate products leading to the formation of the above compounds.

In another embodiment, the present invention relates, essentially, to compounds of formula (II), (III), (IV), (V), (Va), (Vb), (VI), (VII), (IX), (X), (XI), (XII) or (XIV) and salts of compounds of formula (II), (III), (VI), (IX), (X) and (XII). These compounds can be vydelennoi form or in solution. In particular, the compounds of formula (VI), (IX), (X) or (XI) is isolated in solid form.

In one embodiment, the present invention relates to a method for obtaining compounds of formula (IX) or formula (XI), where the compound of formula (Va), respectively, of formula (VII)enter into interaction with the compound of the formula (VIII) by the Mitsunobu reaction. This reaction involves the interaction of the original substances with azodicarboxylate formula R OOC-N=N-COOR', a phosphine of the formula R ' 3P is inert to the reaction solvent; where

R' represents an ethyl or isopropyl or tert-butyl;

R” means each, independently, phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.

Presented in this context Mitsunobu reactions are of interest in that they allow a suitable method of preparing compounds of formulas (XI) and (IX). So obtaining compounds of formula (XI) and (IX)when coming from the compounds (VII) and (Va), respectively, involves the inversion of stereochemistry cyclopentene carbon bearing a hydroxyl group or a group of simple ether.

Compounds of formulas (XI) and (IX) are important intermediate products, as found that both compounds are able to crystallize, especially when they are mixed with the alcohol solvent, more specifically, when they are mixed with1-4-alkanols. Crystallization of the compounds of formulas (XI) and (IX) submitted the interest is what it allows you to control the purity of these compounds, as well as any compounds obtained from them at the subsequent stages of the method. In particular, this allows to obtain compounds of formulas (XI) and (IX) with higher enantiomeric purity.

This crystallization of the compounds of formulas (XI) and (IX) not only gives the option to remove the by-products of the Mitsunobu reaction, which receive these connections, but also allows the subsequent allocation of the compounds of formulas (XI) and (IX) from their respective reaction mixtures by simple. This selection is easily performed by replacement of the solvent, i.e. by simply adding an alcoholic solvent to the reaction mixture, obtained by Mitsunobu reactions, without conducting any further manipulation of the reaction mixture, or any of its component.

Further, as the compounds of formulas (XI) and (IX) insoluble in an alcohol solvent, while by-products are soluble, this allows for direct purification of the compounds of formulas (XI) and (IX)emitted from the reaction mixture.

The methods presented in this context, i.e. the Mitsunobu reaction, followed by the replacement of solvent, offer advantages in the case of large-scale production. Other methods for isolating or purifying the compounds of formulas (XI) and (IX), such chromatography, mountains, the health is less suitable for large-scale synthesis, require more manipulation and are more expensive.

As used above and below the context, use the following definitions, except otherwise specified. The term "halogen" is shared by fluorine, chlorine, bromine and iodine. The term "C1-4-alkyl" means a saturated hydrocarbon radical with a linear or branched chain having 1-4 carbon atoms, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl. Interest1-4-alkyl radicals without 2-methyl-1-propyl. The term "C1-3-alkyl" is shared by methyl, ethyl, 1-propyl and 2-propyl. The term "C1-3-alkyl" is common to methyl and ethyl. The term "C1-4-alkanol" refers to alcohol that is derived from C1-4is an alkyl group.

Pharmaceutically acceptable salts, which may form the compound of formula (XVII)are pharmaceutically acceptable additive salts of acids or additive salts of the bases.

Additive salts of the acids, as such, is obtained by introducing into the interaction of the main forms of the compounds of formula (XVII) with an appropriate acid, such as, for example, inorganic acid, such as halogen acid, e.g. hydrochloric or Hydrobromic acid, sulfuric acid, semiseria acid, nitric acid, phospho what Naya acid and the like acids; or organic acid, such as, for example, acetic acid, aspartic acid, modellerna acid, heptane acid, hexanoic acid, nicotinic acid, propanoic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid, cyclonona acid, salicylic acid, p-aminosalicylic acid, amoeba acid and similar acids. On the contrary, the additive form of the salt of the acid can be converted into the free base by treatment with a suitable base. Additive salts of the bases are formed by treatment with appropriate organic and inorganic bases. The appropriate form of the additive salts of the bases include, for example, ammonium salts, salts of alkali and alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example, salt, benzathine, N-methyl-D-glucamine, geranamine, and salts with amino acids such as, for example, arginine, lysine, etc.

The compound of formula (XVII) has three chiral centre and accurate stereo is MIA in the case of all three centers is an important task for any synthesis methods, designed for obtaining this compound. For a better understanding of the stereochemistry of the intermediate products used in the methods according to the present invention, for reasons of clarity the following definitions are provided, although it is known in the prior art.

Stereoisomeric represents the arrangement of the atoms in the molecules, which in terms of connectivity remain the same but their arrangement in space is different in each isomer. Stereoisomers can be divided into two categories enantiomers (mirroring) and diastereoisomers (non-display). The term "enantiomer" refers to one of a pair of molecules unblended mirroring. The diastereomers are stereoisomers that are not enantiomers or mirror images of each other. The diastereomers can have different physical properties and different reactivity. The term "racemic" or "racemate" refers to a mixture of equal amounts of enantiomers of chiral molecules. The term "epimer" refers to a stereoisomer, which has a different configuration just in case one of several stereogenic centers. Thus, stereoisomers differ only in the configuration in the case of one atom.

Generally accepted in the present Convention for the item sterek the chemical compounds is as follows:

- If the connection is depicted without stereobase, as depicted compound of formula (III), then imply that the compound is racemic or configuration of the stereogenic(s) centre(s) is not defined.

- If the connection is depicted with stereobase and, in addition, specify one of the descriptors "(±)", "rel" or "rac" in relation to chemical structure, then imply that the compound is racemic and the stereochemistry is relative.

- If the connection is depicted with stereobase, but none of the descriptors "(±)", "rel" or "rac" is not specified in the framework, then imply that the compound is an optically pure compound, in other words, the stereochemistry is absolute.

For example, in the link, Honda, etc. designation "(±)", used in the title of the article, implying that describes the racemic synthesis of racemic intermediate products. However, the above-mentioned Convention may not necessarily follow in all publications.

In one embodiment, the present invention relates to the use of compounds selected from compounds (I)to(XIV)listed in the table above, as intermediates for obtaining the compounds of formula (XVII) or its salts.

In another embodiment, the present invention relates to a compound of formula (II), (III), (IV), (V), (Va), (Vb), (VI) (VII), (IX), (X), (XI), (XII) or (XIV) or salts of the compounds of formula (II), (III), (VI), (X) and (XII), as indicated in the above table. The connection may be available in the currently selected form or in solution.

The term "isolated form", "allocated", or any equivalent, refers to solid or liquid state, in which the connection is in a pure form, i.e. essentially free from other components.

In another embodiment, the present invention relates to a compound of formula (VI), (IX), (X) or (XI), where the compound is in solid form. The term "solid form" includes both crystalline and amorphous solid forms, or any mixtures thereof.

The compound of formula (I)

The compound of formula (I) is commercially available or can be obtained in accordance with the procedure described in example 1.

Stage (I) → (II)

This stage refers to the restoration of ketogroup in the compound of formula (I) to the corresponding alcohol compound of the formula (II). The latter is obtained by introducing into the interaction of the compounds of formula (I) with hydrogen in the presence of a catalyst, optionally in the presence of a base. The catalyst can be selected from catalysts based on noble metals such as rhodium-on-charcoal, rhodium-on-alumina, platinum-on-coal-or platinum-on-alumina. The base can be selected from hydroxide selecing the metal, in particular, sodium hydroxide, aluminum oxide or three-From1-4-alkylamine, such as triethylamine. Upon completion of the interaction, you can add acid to convert the resulting salt form back to the free acid. This may be an inorganic acid, such as halogen acid, such as HCl or sulfuric acid.

Stage (II) → (III)

This stage leads to the formation of the lactone. The compound of formula (III) or its salt obtained by introducing into the interaction of the compounds of formula (II) or its salt With1-4-alkylchlorosilanes formula ClCOOR2where R2means1-4-alkyl, in particular methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl, and inorganic base. In one embodiment, it is possible to isolate the compound of formula (III). The organic base may be a tertiary amine, such as tri-C1-4-alkylamine, for example, triethylamine.

Stage (III) → (IV)

This stage leads to the formation of complex benzyl ether. The compound of formula (IV) are obtained by introducing into the interaction of the compounds of formula (III) with benzyl alcohol; starting material (III) and benzyl alcohol can interact in the presence of the agent formation of ester, for example, a bonding agent. Or the acid (III) can be converted into an activated form, such as by introducing into the interaction the interaction with chloroformiate, in particular, with C1-4-alkylchlorosilanes formula ClCOOR2where R2has the meaning indicated above, in the presence of organic bases.

The binding agent can be selected from carbodiimides, such as EDCI, N,N'-dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide, or N,N'-carbonyldiimidazole (CDI), with or without 4-dimethylaminopyridine (DMAP), or ethyl/isopropyl/isobutylphthalate. The organic base may be a tertiary amine, such as tri-C1-4-alkylamine, for example, triethylamine.

Stage (IV) → (V)

Stereoisomeric mixture (V) compounds of the formula (Va) and the compounds of formula (Vb) is obtained by interesterification of lactone in C1-4-alkilany ether. Used solvent is preferably an alcohol, which is formed ester, i.e. if must be obtained methyl ester, the reaction is performed in methanol. This interaction is carried out in the presence of an acid catalyst and an excess of alcohol as a solvent, as if the reaction towards formation of ester. The acid catalyst may be in the form of inorganic acid, for example HCl or organic acids, such as methanesulfonate acid, or you can use an acidic resin such as Amberlyst 15™ (A15), which can easily be removed by filtering.

Study the (V) → (Va) + (Vb)

The compound of formula (Va) is obtained by separation from the compounds of formula (Vb), from a mixture of isomers (Va) and (Vb), in particular, the racemic mixture of compounds (Va) and (Vb). This enantiomeric separation can be performed using chromatography on a column with a chiral phase or by chiral liquid chromatography. This includes the use of chiral stationary phase, for example, a stationary phase based on paliomylos or polycellulose, such as Chiralpak AD™.

Stage (Va) → (VI)

This stage involves the breakdown of complex benzyl ester to the free acid. The compound of formula (VI) are obtained from the compounds of formula (Va) by removing the benzyl group by hydrogenation. This can be done by using hydrogen in the presence of a catalyst. The catalyst can be selected from palladium-on-coal or palladium salt or hydroxide, such as palladium acetate, palladium chloride, palladium hydroxide or palladium hydroxide-on-charcoal grill.

This reaction can be carried out in a suitable solvent, which you can choose from a simple ester, in particular, from simple ether such as methyl tert-butyl ether (MBTE), or cyclic simple ether, such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (Methf); ketone such as acetone, methyl isobutyl ketone; alcohol, such as1-4-alkanol, for example, methanol, e is anal, propanol; dipolar aprotic solvent such as dimethylformamide (DMF), dimethylacetamide (DMA); hydrocarbons such as toluene; or any mixture of such solvents. The reaction mixture containing the compound (Va), the catalyst and the solvent, can be mixed in the atmosphere of hydrogen. The compound of formula (VI) can crystallize the removal by filtration of the catalyst from the reaction mixture, washing and make the necessary replacements of the solvent, for example, by replacing part or all of the solvent by simple ether such as MTBE, then, next, optional introduction of the seed using seed crystals of the compounds of formula (VI)with optional cooling to a temperature in the range of from about -15°to about 5°C. If desired, the compound of formula (VI) can be obtained in solution, free from catalyst, and can then be used in dissolved form in obtaining the compounds of formula VII).

Other possible ways of dibenzylamine, which can alternatively be applied at this stage can be carried out by hydrogenation with transfer using a mixture of formic acid - triethylamine, sodium formate or potassium, or by hydrosilation using, for example, Et3SiH (TES-H), PhSiH3Ph2SiH2, poly(methylhydrosiloxane) (PMHS) or (RO)3SiH.

Stage (VI)→ (VII)

The compound of formula (VII) are obtained from the compounds of formula (VI) and N-metrex-5-enylamine (NMHA, also known as N-methyl-5-HEXEN-1-amine by amide formation reaction. The latter may be any of those usually used in the case of peptide synthesis. Can be used bonding agent or the acid may be activated by converting it into a mixed anhydride or active ester. Binding agents that can be used, you can choose from EEDQ, N,N,N',N'-tetramethyl-O-(7-asobancaria-1-yl)uranylacetate (HATU), IIDQ, benzotriazol-1-electroparadise-hexaphosphate (commercially available as PyBOP®), DCC, EDCI, or 1,3-diisopropylcarbodiimide. You can add a catalyst, for example, 1-hydroxybenzotriazole (HOBt). This interaction is usually carried out in the presence of a base, in particular, amine as a base, such as tertiary amine, e.g. triethylamine, N-methylmorpholine, N,N-diisopropylethylamine (the latter is also listed above as the basis of Chenega, DIPEA or DIEA). When the reaction of formation of amide preferably avoid the use of substances such as O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine (HATU) or O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylpropylenediamine (HBTU), because there is a risk of explosion in case of large-scale production.

Rea is of binding is usually conducted in an inert towards the reaction solvent, you can choose from a simple ester, in particular, cyclic simple ether, such as THF or Methf, dipolar aprotic solvent, such as DMF, hexamethylphosphoramide (NMRT), DMA, acetonitrile; hydrocarbons such as toluene; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; alcohol, such as1-4-alkanol, for example, methanol, ethanol, propanol; water; or any mixture of such solvents.

Binding assays are usually carried out with optional stirring, at a temperature in the range from about -20°C. to the boiling temperature under reflux the reaction mixture.

Stage (VII) + (VIII) → (XI)

This reaction stage involves the formation of simple essential connection between cyclopentadienyl residue in the compound (VII) and hyalinella residue in the compound (VIII). This simple ester bond is preferably formed by means of the Mitsunobu reaction. According to this reaction, the compound of formula (VII) enter into interaction with the compound of the formula (VIII) in the presence of azodicarboxylate formula R OOC-N=N-COOR', phosphine of the formula R ' 3P and organic solvent; where each R' represents, independently, With1-4-alkyl, in particular ethyl, isopropyl or tert-butyl; and each R” is, independently, phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl. Preferred who are diethylazodicarboxylate (DEAD) or diisopropylcarbodiimide (DIAD), in the presence of triphenylphosphine.

The organic solvent can be selected from halogenated hydrocarbons such as dichloromethane, simple ester, in particular, cyclic simple ether, such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (Methf), complex ester, such as ethyl acetate, isopropylacetate, an aromatic hydrocarbon, such as toluene, or any mixture of such solvents.

Optionally, the initial reaction mixture containing the compound of the formula (VII), the compound of formula (VIII), phosphine of the formula R ' 3P and organic solvent can be partially evaporate, in order to remove traces of water and/or alcohols. This initial reaction mixture can be cooled to approximately 0°C. before adding azodicarboxylate formula R OOC-N=N-COOR'. Optionally, water can be added after the introduction of azodicarboxylate, in order to remove an excess of the latter reagent. Any insoluble by-products produced in the interaction, can be removed by filtering.

The selection of the compounds of formula (XI)

The compound of formula (XI) is recovered from the reaction mixture by replacing the organic solvent, fully or partially, the solvent is selected from C1-4-alkanol, as, for example, 1-butanol, heptane, diisopropyl ether, or any mixtures thereof. This replacement of the races is varicella can be accomplished by distillation or removal of solvents, initially present in the reaction mixture, in whole or in part, and by adding after one or more of the above solvents. Changing the temperature of the reaction mixture also contributes to the implementation of crystallization. Replacement solvents can be repeated several times and also when using a variety of solvents, as is desirable.

The selection of the compounds of formula (XI) can be done by filtering and drying. Crystallization of the compounds of formula (XI) can also be improved by priming the filtrate or the reaction mixture with seed crystals of the same connection.

Stage (XI) → (XII)

At this stage, the ester group-COOR1in the compound of formula (XI) decompose to the corresponding acid. You can use the base in the aquatic environment. Bases that can be used include hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide, and, in particular, lithium hydroxide. The aqueous medium may be water or water mixed with a water-soluble organic solvent such as an alcohol, in particular, With1-4-alkanol, for example, methanol or ethanol; a simple ester, in particular, cyclic simple ether, such as THF, Methf, or any mixture of such solvents. Get a free acid of the formula (XII) or its salt is Christmas, metal, for example, its salt of lithium, sodium or potassium.

In one embodiment, lithium hydroxide, sodium hydroxide or potassium hydroxide is first mixed with the solvent before adding the compounds of formula (XI). The mixture containing the compound of the formula (XI), lithium hydroxide, sodium hydroxide or potassium hydroxide and a solvent, can be mixed at room temperature. If desired, the compound of formula (XII), or its salt of lithium, sodium or potassium, are not allocated, and used in solution for subsequent conversion of compounds of formula (XII) to the compound of formula (XIV).

Stage (XII) → (XIV)

At this stage, the compound of formula (XII) or its salt, then, enter into interaction with the compound of the formula (XIII) or its salt according to the reaction of formation of amide, receiving the compound of formula (XIV). You can use the same reaction conditions as described above in relation to stage (VI) → (VII).

In one embodiment, the binding agent amide selected from IIDQ, EDCI, DCC, or 1,3-diisopropylcarbodiimide and, in particular, EEDQ in a simple ether, such as THF, in particular, in aqueous THF. The reaction mixture indicated above, can be mixed at room temperature.

Stage (Va) + (VIII) → (IX)

At this stage, get the connection formula (IX)where the compound of formula (Va) enter into interaction with the compound of the formula (VIII) before the formation of simple essential communication. Can what about the use of the Mitsunobu reaction, as described in the case of stage (VII) + (VIII) → (XI). The compound (IX) can crystallize by adding a1-4-alkanol, as, for example, methanol, ethanol, 1-propanol or 1-butanol. In one embodiment, after the Mitsunobu reaction, water is added and the by-products are removed by filtration. The filtrate and wash any liquid isolates can be concentrated dry or almost dry and then precrystallization from C1-4-alkanol, for example, methanol.

The selection of the compounds of formula (IX)

The compound of formula (IX), hereinafter, can be isolated from the reaction mixture by solvent exchange, fully or partially, the solvent is selected from C1-4-alcohol, heptane, diisopropyl ether, or any mixtures thereof. This replacement of the solvent can be accomplished by distillation or removal of the solvent initially present in the reaction mixture, and then adding a solvent selected from C1-4-alkanol, heptane, diisopropyl ether, or any mixtures thereof. Changing the temperature of the reaction mixture also facilitates replacement of the solvent. This replacement solvents can be repeated several times and also when using a variety of solvents, as is desirable.

Optionally, the selection of the compounds of formula (XI) can be done by filtering and drying. Receipt is the compounds of formula (XI) can also be improved by priming the filtrate or the reaction mixture with seed crystals of the same connection.

Stage (IX) → (X)

This stage involves the breakdown of complex benzyl ester (IX) to obtain the compounds of formula (X). You can apply the same techniques described above in relation to stage (Va) → (VI).

Stage (X) → (XI)

The compound of formula (XI) can be obtained by introducing into the interaction of the compounds of formula (X) with NMHA and agent education amide, using the same methodology as described above in relation to stage (VI) → (VII). The compound (XI) can be cleaned, as described above, or by recrystallization from a hydrocarbon, such as hexane, heptane or octane, as described above. In one embodiment, the compound (X) and NMHA is subjected to binding assays, the reaction mixture is acidified, for example with aqueous HCl, and extracted with a hydrocarbon, for example, using toluene. The hydrocarbon solvent is removed and the remainder will recrystallized from heptane.

Examples

The following examples are provided to illustrate the present invention and do not limit its scope.

Example 1

Obtaining the compounds of formula (I)

To a solution of 1,2,3,4-butanetetracarboxylic acid (0,99 mol, 234,16 g) in ethanol (750 ml) and toluene (500 ml) was added sulfuric acid (of 0.56 mol, 30,05 ml, 55,30 g)in one portion. This mixture is refluxed for 4.5 hours. The solvent in Aleut by distillation until until the internal temperature reaches 110°C. Add toluene (500 ml)in one portion and the mixture is refluxed with removal of water by azeotropic distillation using a trap Dean-stark. After cooling to a temperature of 80°C, add ethanol (500 ml) and the mixture refluxed for 16 hours. The solvent is removed by distillation until then, until the internal temperature reaches 105°C. Add toluene (500 ml)in one portion and the mixture is refluxed for 1 hours with azeotropic removal of water. The mixture is cooled to a temperature of 22°C, add 50 ml of water and the mixture is stirred for several minutes. Two layers are separated and the toluene phase is washed with 50 ml of water. The combined toluene layers are washed with aqueous sodium carbonate (15 %wt./mass.) (375,00 ml). Toluene phase is evaporated to dryness, obtaining a yellow oil, which is also dried in vacuum at 50°C, during the night, getting 315,7 g (91% separate out) the compounds of formula (Ia), in the form of a yellow coloured oil.

H-NMR (CDCl3- 400 MHz), δ ppm 1,23 of 1.28 (m, N), 2,38 is 2.43 (m, 2H), 2,74-of 2.81 (m, 2H), 3,28-of 3.31 (m, 2H), 4,11-4,17 (m, 2H).

IR spectrum (film): 2970, 2940, 2900, 1730, 1525, 1500, 1375, 1340.

To a solution of tetraethyl ester of 1,2,3,4-butanetetracarboxylic sour is you (1.00 mol, 346,38 g) in methanol (320,00 ml)at a temperature of 22°C, add a solution of sodium methoxide (30%solution in methanol) (2,90 mol, 522,23 g). The mixture is stirred at room temperature for 16 hours. Dropwise, over 15 minutes, add a solution of concentrated hydrochloric acid (3,49 mol, 300,00 ml, 348,90 g) and water (16,65 mol, 300,00 ml, 300 g). After adding the second portion of hydrochloric acid (1,86 mol, 160,00 ml, 186,08 g), the mixture is heated at boiling temperature under reflux and the solvent is distilled until then, until the internal temperature reaches 100°C. the Mixture is refluxed for 16 hours. The mixture is then cooled to a temperature of 90°C. Add 1 g of activated charcoal and the mixture is left for further cooling, with stirring, to a temperature of 50°C. the Reaction mixture is filtered through celite. The filtrate (900 ml) was introduced into the flask with a capacity of 2000 ml 400 ml of Solvent is distilled at atmospheric pressure. Under stirring, the mixture is allowed to cool to room temperature. The solids are filtered and washed with 100 ml of water. The product is dried in vacuum at 50°C, receiving of 156.6 g (yield 91% after discharge) the compounds of formula (I) in a solid white color.

H-NMR (DMSO-d6- 400 MHz), δ ppm 2,23-of 2.38 (m, 2H), 2,48-of 2.54 (m, 2H), 3,20-of 3.27 (m, 2H), 12,60 (USS, 2H).

C-NMR (DMSO-d6- 100 MHz), d is d: 40,70, 43,17, 174,27, 213,45.

IR spectrum (film), cm-1: 3450, 3050, 2900, 1750, 1720, 1480, 1280, 1250, 1220, 1180, 1150.

Example 2

Obtaining the compounds of formula (II)

To the suspension was 32.7 g (to 0.19 mol) of the compound of formula (I) in 237,5 ml of water, under nitrogen atmosphere, add 1.0 ml (0.019 mol) of an aqueous solution of NaOH (50 wt%./mass.). The mixture is heated to a temperature of 60°C and add 2.5 g of Rh/C (5 %wt./mass.). The reaction flask is rinsed with hydrogen and stirred under hydrogen atmosphere until then, until they reach full conversion. Then, the heated reaction mixture is filtered through celite. Filter the precipitate washed twice with 10 ml of water and the filtrate contribute to the reaction flask with a capacity of 500 ml and Then add 60 ml of 4-methyl-2-pentanone and water is removed by azeotropic distillation until then, until the internal temperature reaches 110°C. the Mixture is cooled to a temperature of 50°C. Add 88 ml of acetone and 0.51 ml of sulfuric acid (95%). The mixture is stirred at a temperature of 22°C for 16 hours. The solids are filtered and washed twice with 10 ml acetone. These substances are then dried in vacuum at 50°C receives 21,84 g (yield 66% after discharge) the compounds of formula (II) in a solid white color.

H-NMR (D2O-d6- 400 MHz), δ ppm, 1,80 is 1.86 (m, 1H), 1,94-2,04 (m, 2H), 2,33-to 2.40 (m, 1H), 3,13 (kV, J=8.5 Hz, 1H), 3,30 (kV, J=8.5 Hz, 1H), 429-4,40 (m, 1H).

C-NMR (D2O - 100 MHz)d ppm: 37,61, 38,09, 44,92, 45,30, 71,67, 178,64, 178,92.

Example 3

Obtaining the compounds of formula (III)

To a suspension of compounds of formula (II) (50 g, 0.29 mol) in 860 ml of THF added triethylamine (42,02 ml, 0.30 mol). The mixture is stirred at room temperature until complete dissolution of all solids. Then the reaction mixture is cooled to a temperature of 0-5°C. added dropwise ethylchloride (32,72 g, 0.30 mol) and the mixture is stirred for another hour at a temperature of 0-5°C. the Reaction mixture is heated to a temperature of 22°C and stirred for 5 hours. Then the reaction mixture is filtered through celite and the solids washed with 25 ml of THF. The filtrate is evaporated to dryness. To the residue are added 50 ml of ethyl acetate and the mixture is stirred at a temperature of 22°C for 15 minutes. The solids are filtered and washed with 10 ml of cold ethyl acetate, getting 21,67 g (yield 48% after discharge) the compounds of formula (III) in the form of a solid white color.

H-NMR (CDCl3- 400 MHz), δ ppm, a 1.96 (d, J=10,8 Hz, 1H), 2,27-to 2.29 (m, 3H), 3,05 (t, J=6,8 Hz, 1H), 3,23 (s, 1H), to 5.03 (s, 1H).

C-NMR (CDCl3- 100 MHz): 32,91, 37,87, 39,90, 45,24, 80,25, 167,33, 175,54.

Example 4

Obtaining the compounds of formula (IV)

600 mg (3,84 mmol) of the Compound of formula (III) (racemic the case), 0,418 ml (a 4.03 mmol) of benzyl alcohol, 23,5 mg (0,19 mmol) DMAP and 810 mg (to 4.23 mmol) EDCI suspended in 38 ml of ethyl acetate. The suspension is stirred over night at room temperature. Then add 38 ml of water, the obtained two-phase mixture is stirred at room temperature for several minutes, then leave to decanted and the aqueous layer was removed. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo, getting 993 mg of a crude compound of formula (IV) in the form of almost colorless oil.

993 mg of a Crude compound of formula (IV) is purified using flash chromatography on silica gel using a mixture of diisopropyl ether - hexane (3:1) as eluent. Receive 834 mg (yield 88% after extraction) purified the compounds of formula (IV) as a colourless oil.

Physical data: GC-MS (gas chromatography - mass spectrometry): m/z = 246 (M+).

H-NMR (600 MHz, CDCl3), δ ppm, was 1.94 (d, J=10,95 Hz, 1H), 2,18 (d, J=10,95 Hz, 1H), 2,22-of 2.27 (m, 2H), 2.95 and 3.00 for (m, 1H), 3,17 (s, 1H), equal to 4.97 (s, 1H), 5,18 (s, 2H), 7,33-the 7.43 (m, 5H).

C-NMR (CDCl3- 125 MHz)d ppm: 33,31, 38,01, 39,77, 45,81, 67,31, 80,43, 128,27, 128,58, 128,72, 135,33, 172,37, 176,27.

350 g (1,79 mol) of the Compound of formula (II) (racemic) and 262,1 ml (1.88 mol) of triethylamine are suspended in lower than the 5.37 l THF. The mixture is cooled to a temperature of 0-5°C and add 179,8 ml (1.88 mol) of ethylchloride within 1-2 hours. The mixture was stirred at the rate which the temperature 0-5°C for 2 hours, then over night at room temperature. Then the reaction mixture is filtered and the solids washed twice with 179 ml of THF. The solvent is distilled off from the filtrate and add 4,48 l of ethyl acetate is added to the distillation residue. To the obtained mixture is added to 194.6 ml (1.88 mol) of benzyl alcohol, 377,6 g (1.97 mol) of EDCI and 10.9 g (89,5 mol) of DMAP. The resulting suspension is stirred over night at room temperature. Then add 1,79 l of water and the two layers separated. The organic layer is dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. Get 435 g (yield 99%) of crude compound of formula (IV) in the form of a yellow oil.

Example 5

Obtaining the compounds of formula (V)

600 g (2,44 mol) of the Compound of formula (IV) (racemic) was dissolved in 10 l of methanol. Add 122 g of resin Amberlyst 15 and the reaction mixture was stirred over night at room temperature. Resin Amberlyst 15 is filtered off and the filtrate was concentrated in vacuo, getting 638 g (yield 94%) of crude compound of formula (V).

300 g (1,22 mol) of the Compound of formula (IV) (racemic) was dissolved in 6 l of methanol, add 5 ml (0.08 mol) methanesulfonic acid and the reaction mixture was stirred at room temperature until, until there is no longer the original substance (approximately 2-3 hours). Then add 90 g of carbonate on the matter, pre-dissolved in 0.9 l of water, and the mixture was concentrated in vacuo. The residue is partitioned between 1.2 l of ethyl acetate and 0.6 l of water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. Get 300 grams (89% yield) of the crude compound of formula (V) in the form of oil.

of 1.75 g of Crude compound of formula (V), purified by HPLC on silica gel, receiving 0.55 g of a purified compound of the formula (V).

GC-MS: m/z = 278 (M+). H-NMR (400 MHz, CDCl3), δ ppm,1,90-2,02 (m, 2H), 2,07-2,17 (m, 1H), 2,24 (DDD, 1H), 3,14 (s, 1H), 3,17-3,26 (m, 1H), 3,47 (kV, 1H), the 3.65 (s, 3H), 4,32-4,39 (m, 1H), 5,13 (USS, 2H), 7,26-7,39 (m, 5H).

C-NMR (CDCl3- 100 MHz)d ppm: 38,50, 39,63, 45,21, 45,33, 52,23, 66,60, 72,56, 127,95, 128,20, 128,53, 135,85, 174,53, 175,72.

Example 6

The formation of compounds of the formulas (Va) and (Vb)

749 g of Crude compound of formula (V) (racemic) elute through Chiralpak AD using a mixture of heptane/methanol/ethanol (70:15:15) as eluent, getting 369 g of compound of formula (Va) and 57 g of compound of formula (Vb).

Analyses GC, GC-MS and NMR are identical to those in the purified compounds of the formula (V) (racemic).

Example 7

Obtaining the compounds of formula (VI)

13,92 g (50 mmol) of the Compound of formula (Va) and 2.66 g (2.5 mmol) of dry, 10 %wt./mass., Pd/C is suspended in 250 ml of THF and the suspension is stirred in a hydrogen atmosphere. The catalyst is filtered off and washed with OSU few ml of THF. The filtrate was concentrated in vacuo, getting 10,80 g (114%, crude yield) of the crude compound of formula (VI), in the form of oil, which solidifies upon standing.

LC-MS: m/z = 189,1 (M+N+).

H-NMR (400 MHz, DMSO-d6), δ ppm, 1,65-of 1.73 (m, 1H), 1,74-of 1.81 (m, 1H), 1,83-of 1.92 (m, 1H), 2,19 (DDD, J=13,28, 10,01, 5,41 Hz, 1H), 2,93-of 3.06 (m, 1H), 3,13-of 3.25 (m, 1H), 3,60 (s, 3H), 4,08-4,22 (m, 1H), and 4.68 (s, 1H), 12,27 (s, 1H).

C-NMR (100 MHz, DMSO-d6), d ppm: 38,38, 39,11, 44,31, 44,45, 51,60, 70,50, 174,43, 175,69.

123,9 g (445 mmol) of the Compound of formula (Va) and 4,74 g (of 4.45 mmol) of dry, 10 %wt./mass., Pd/C is suspended in 668 ml of THF. The suspension is stirred in a hydrogen atmosphere. The catalyst is filtered off and washed with 228 ml of THF. The filtrate was concentrated in vacuo and the residue re-suspended in 445 ml of hot heptane. The suspension is allowed to cool to room temperature and was isolated after filtration and drying, an 81.25 g (yield 97%) of the compounds of formula (VI) in the form of a crystalline substance of white color.

11,13 g (40 mmol) of the Compound of formula (Va) and 0.85 grams (0.8 mmol) of dry, 10 %wt./mass., Pd/C is suspended in 60 ml of THF. The suspension is stirred in a hydrogen atmosphere. The catalyst is filtered off and washed 3 times with 15 ml of THF. The filtrate was concentrated in vacuo and the residue re-suspended in 445 ml of hot ethyl acetate. The suspension is allowed to cool to room temperature and was isolated after filtration and drying, 5,12 g (in the course 68%) of the compounds of formula (VI) in the form of a crystalline substance of white color.

20,87 g (75 mmol) of the Compound of formula (Va) and 3.19 g (0.75 mmol) moist, 5 %wt./mass., Pd/C is suspended in 113 ml of THF. The suspension is intensively stirred overnight in a hydrogen atmosphere. The catalyst is filtered off and washed with 19 ml of THF and the filtrate is distilled off 75 ml of THF. Then add 38 ml of toluene and distilled 63 ml of solvent. Finally, add 101 ml of MTBE. In the almost clear solution make the seed crystal compounds of formula (VI). The suspension is cooled to a temperature of -5°C and stirred overnight at a temperature of -5°C. Allocate, after filtration and drying, 9,29 g (yield 66%) of the compounds of formula (VI) in the form of a crystalline substance of white color.

6,47 g (23,3 mmol) of the Compound of formula (Va) and 1.24 g (1,16 mmol) of dry, 10 %wt./mass., Pd/C is suspended in 23 ml of DMF. The suspension is intensively stirred overnight in a hydrogen atmosphere. The catalyst is filtered off and washed with a few ml of DMF. The filtrate is brought to a volume of 50 ml with DMF and the resulting solution was used in the next stage (amide associated with NMHA, to obtain the compound of formula (VII)).

Example 8

Obtaining the compounds of formula (VII)

303 mg (or 2.67 mmol) NMHA, 1,22 ml (6,99 mmol) of the Foundation of Chenega and 1.06 g (2,79 mmol) HATU are added to a solution of the compounds of formula (VI) in DMF (2,33 mmol in 5 ml). The mixture is stirred in ECENA 2 hours at room temperature, then DMF and other volatiles removed in vacuum. The residue re-dissolved in a mixture of Methf-water (5 ml each). Add 1.5 ml of concentrated HCl, the layers separated and the aqueous layer was extracted with 5 ml of Methf. The organic layers are combined, dried over potassium carbonate and magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue is purified using flash chromatography on silica gel using ethyl acetate as eluent. Receive 373 mg (yield 44%) of the compounds of formula (VII) in the form of oil is light yellow in color. Analyses by NMR and GC-MS show the following compound in the form of impurities:

GC-MS: m/z = 283 (M+).

H-NMR (600 MHz, DMSO-d6), δ ppm, of 1.23 to 1.31 (m, 1H), 1,33-of 1.40 (m, 1H), of 1.40 to 1.48 (m, 1H), 1,51-to 1.63 (m, 2H), from 1.66 to 1.76 (m, 1H), 1,80 is 1.91 (m, 1H), 2,02 (kV, J=7.18 in Hz, 1H), 2,07 (kV, J=7.18 in Hz, 1H), 2,15-of 2.24 (m, 1H), 2,80 and 2,99 (2C - rotamer, 3H), 3,13-up 3.22 (m, 1H), 3.25 to to 3.33 and 3.33-3,41 (2m - rotamer, 2H), 3,49 (kV, J=8,43 Hz, 1H), only 3.57 (s, 3H), 4.16 the (s, 1H), 4,71 (t, 1H), 4,91-5,09 (m, 2H), 5,73-by 5.87 (m, 1H).

C-NMR (150 MHz, DMSO-d6), d ppm (mixture of rotamers): 25,23 and 25,28, 26.00 and 27,61, 32,83 and 32,87, 33,20 and 34,62, 28,24 and 38,25, 39,33 and 40,13, 41,27 and 41,69, 44,92 and 45,11, 46,62, 48,67, 51,49, 70,77 and 70,81, 114,74 and 114,98, 138,38 and 138,60, 172,99 and 173,05, 174,65 and 174,68.

9,41 g (50 mmol) of the Compound of formula (VI), 5,94 g (52,5 mmol) NMHA and 10,54 g (55 mmol) of EDCI suspended in 89 ml of THF. The reaction mixture was stirred over night at room temperature. Add 100 ml of Methf and with the ect sequentially washed with 50 ml of water, 50 ml of 0.5 M aqueous HCl solution, 50 ml of 0.5 M aqueous NaOH solution and 50 ml of water, dried over magnesium sulfate, filtered and concentrated in vacuo. Receive rate of 7.54 g (yield 53%) of the crude compound of formula (VII) in the form of a yellow oil.

3.94 g of Crude compound of formula (VII) purified using flash chromatography on silica gel using ethyl acetate as eluent, getting 1.92 g of a purified compound of the formula (VII). The analysis shows the GC purity > 95%.

14,11 g (75 mmol) of the Compound of formula (VI), 8,91 g (78,8 mmol) NMHA 20,40 and g (82,3 mmol) EEDQ dissolved in 75 ml of THF. The reaction mixture was stirred over night while boiling under reflux. Added 1.27 g (11.3 mmol) NMHA and 2,78 g (11.3 mmol) of EEDQ and refluxed in throughout the night. 63 ml of Solvent is distilled off and add 75 ml of xylene, 75 ml of water and 13.5 ml of concentrated HCl. The layers are separated and the organic layer is washed with a 37.5 ml of water and concentrated in vacuo, getting 22,47 g (106% crude yield) of the crude compound of formula (VII) in the form of oil light orange color and this oil is used in the next stage, after it has been received. The LC analysis shows that the main impurity is some amount of residual xylene.

1.0 g (5.3 mmol) of the Compound of formula (VI) and 1.2 g (5.8 mmol) of EDCI suspended in 10 ml of dichloromethane. The suspension is stirred at room Tempe is the atur up to obtain the solution (approximately 15 minutes). Then add to 0.63 g (5.6 mmol) NMHA and 6 mg (0.05 mmol) of DMAP and the reaction mixture was stirred over night at room temperature. Then add 10 ml of ethyl acetate and the mixture washed with 2 M aqueous HCl, then with saturated salt solution. The organic layer was concentrated in vacuo, getting to 0.94 g (yield 63%) of the crude compound of formula (VII) in the form of a yellow oil. The NMR analysis shows the net product.

300 mg (1.6 mmol) of the Compound of formula (VI) and 180 mg (1.6 mmol) NMHA dissolved in 5 ml of acetonitrile. Then add 0.6 g (1.6 mmol) of HBTU and 0.8 ml (4.8 mmol) DIPEA and the mixture is stirred for 2 hours at room temperature. Then add 20 ml of ethyl acetate and the mixture washed with 2 M aqueous HCl, then with saturated salt solution. The organic layer was concentrated in vacuo. Obtain 1.07 g (yield 51%) of the crude compound of formula (VII) in the form of a brown oil.

40,0 g (0.21 mol) of the Compound of formula (VI), 28 g (0.24 mol) NMHA and 63 g (0.26 mol) of EEDQ dissolved in 400 ml of THF. The mixture is stirred at the boiling point under reflux until the reaction is completed, then diluted with 400 ml of MTBE and sequentially washed with 2 times 100 ml of 1 M aqueous HCl, 100 ml of 1 M aqueous NaOH solution and 50 ml of saturated salt solution. The organic layer was concentrated in vacuo, receiving 80 g of crude compound f is rmula (VII), used in the next stage, after it has been received.

Example 9

Obtaining the compounds of formula (IX)

1.7 g (5.6 mmol) of the Compound of formula (Va) is dissolved in 25 ml of toluene. This solution was concentrated in vacuo to dryness in order to remove trace amounts of water or residual alcohol solvent. To the residue add of 1.57 g (5 mmol) of the compound of formula (VIII), 1.77 g (of 6.75 mmol) of triphenylphosphine and 25 ml THF. The mixture is cooled to a temperature of 0°C and added dropwise to 1.24 ml (of 6.75 mmol) of diisopropylcarbodiimide (DIAD). The reaction mixture is stirred for 4 hours at a temperature of 0°C, then overnight at room temperature. To destroy excess reagent Mitsunobu add 0.5 ml (0.5 mmol) of 1 M aqueous NaOH solution. Then the mixture was concentrated in vacuo to dryness and the residue elute using silica gel using ethyl acetate as eluent. Pre-purified product is suspended in 10 ml of boiling methanol and the suspension is cooled to room temperature, stirred overnight at room temperature, then for 1 hour at 0°C. After filtering the suspension and drying, get 2,05 g (71%yield) of a purified compound of the formula (IX) in the form of white powder.

Physical data: melting point: 125,1°C; [b]D: -9,1 is; LC-MS: m/z = 575 ([M+H+]);

H-NMR (400 MHz, DMSO-d6), δ ppm, of 1.33 (d, J=6,80 Hz, 6N), 2.21 are of 2.34 (m, 2H), 2,41 (DD, 1H), 2,58 (s, 3H), 2,59-of 2.66 (m, 1H), 3,14 (hept, 1H), 3,38 (DDD, 1H), 3,55 (dt, J=of 10.58, to 7.93 Hz, 1H), to 3.64 (s, 3H), of 3.95 (s, 3H), 4,98 and 5,06 (AB, J=12,34 Hz, 2H), lower than the 5.37 (s, 1H), 7,14-7,19 (m, 2H), 7,22-7,28 (m, 3H), 7,38 (d, J=to 9.32 Hz, 1H), 7,45 (d, J=3,78 Hz, 2H), 7,88 (d, J=to 9.32 Hz, 1H).

C-NMR (100 MHz, DMSO-d6), d ppm: 9,77, 22,30, 30,40, 35,10, 35,93, 44,66, 45,02, 51,90, 56,08, 66,00, 78,70, 95,35, 112,83, 115,50, 116,07, 120,07, 120,25, 127,60, 127,91, 128,25, 135,80, 147,86, 151,17, 157,96, 160,31, 164,27, 168,64, 173,12, 173,86.

20,75 g (74,5 mmol) of the Compound of formula (Va), 26,25 g (71 mmol) of the compound of formula (VIII) and 28 g (110 mmol) of triphenylphosphine dissolved in 391 ml of toluene. Distilled 50 ml of toluene in order to remove any trace amounts of water or residual alcohol solvent. The mixture is cooled to a temperature of 0°C and added dropwise 21,58 g (110 mmol) of DIAD. The reaction mixture is stirred for 2 hours at a temperature of 0°C. To destroy excess reagent Mitsunobu type of 7.1 ml of water. The mixture is stirred at room temperature for 10 minutes, then the reaction by-products Mitsunobu filtered off and washed with 25 ml of toluene. The filtrate and wash layers concentrated in vacuo and hot oily residue is diluted with 355 ml of methanol. The mixture is cooled to a temperature of 0°C., then stirred overnight at 0°C. Receive, after filtration of the suspension and vissian what I 30,6 g (75%yield) of the compound of formula (IX) in the form of white powder.

Example 10

Obtaining the compounds of formula (X)

1.50 g (2,61 mmol) of the Compound of formula (IX) and 1.25 ml (7,83 mmol) of triethylsilane dissolved in 2.6 ml of THF. Add to 29.3 mg (0.13 mmol) of palladium acetate and the mixture is stirred over night while boiling under reflux. The mixture is cooled to room temperature. Then add 150 mg of Norit A Supra, 150 mg dicalite and 0.2 ml of 1 N. aqueous HCl and the mixture is refluxed for 2-3 hours. The mixture is filtered while hot and the filtrate was concentrated in vacuo to dryness. The residue is suspended in 2 ml of boiling methanol. The suspension is cooled to a temperature of 0°C and then stirred for 1-2 hours. Receive, after filtration and drying, 800 mg (yield 63%) of the compounds of formula (X) in the form of white powder.

Physical data: melting point: 161,3°C.; LC-MS: m/z = 483 ([M-H]-);

H-NMR (400 MHz, DMSO-d6), δ ppm, of 1.34 (d, J=7,05 Hz, 6N), 2,19-of 2.30 (m, 2H), of 2.38 (DD, J=13,85, 7,81 Hz, 1H), 2,58 (s, 3H), 2,60 (DDD, J=9,88, 4,85, of 4.66 Hz, 1H), 3.15 in (hept, 1H), 3,23 (DDD, 1H), 3,49 (DDD, J=10,70, to 7.93, 7,81 Hz, 1H), to 3.67 (s, 3H), of 3.96 (s, 3H), of 5.34 (s, 1H), 7,40 (d, J=to 9.32 Hz, 1H), 7,44 (d, J=0,76 Hz, 1H), 7,46 (s, 1H), of 7.96 (d, J=9,06 Hz, 1H), 12,47 (s, 1H).

C-NMR (100 MHz, DMSO-d6), d ppm: 9,77, 22,30, 30,40, 35,35, 36,06, 44,57, 45,09, 51,84, 56,05, 78,72, 95,30, 112,77, 115,44, 116,12, 120,07, 120,36, 147,83, 151,18, 157,94, 160,42 164,25, 168,65, 174,11, 174,74.

4,48 g (7,79 mmol) of the Compound of formula (IX), 3,74 ml (23,37 mmol) of triethylsilane and 87 mg (0,39 mmol) of palladium acetate are dissolved in 8 ml of Methf. The mixture is stirred over night while boiling under reflux. The mixture is cooled to a temperature of 60°C. Add 220 mg Norit A Supra, 220 mg dicalite, of 0.52 ml of water and 0.6 ml of concentrated HCl and the mixture is refluxed for 1-2 hours. The mixture is cooled to a temperature of 50-55°C, filtered and the solids washed with 8 ml of Methf. The filtrate and washing liquid are combined and the resulting solution of 15.4 g of the solution - 25 %wt./mass. the compounds of formula (X)) is used in the next stage.

Example 11

Obtaining the compounds of formula (XI)

11,49 g (34,58 mmol) of the Compound of formula (VIII) and 9,52 g (36,30 mmol) of triphenylphosphine are added to a solution of the compounds of formula (VII) in toluene (34,58 mmol of compounds of formula (VII) 184,86 g solution). 64 ml of Solvent is distilled in order to remove trace amounts of water and/or alcohols, the mixture is then cooled to a temperature of 0°C. Added to 7.2 ml (36,30 mmol) DIAD. The mixture is stirred for 2 hours at 0°C. After analysis, introduce additional number of triphenylphosphine (0.9 g, 3.46 mmol) and DIAD (0.68 ml, 3.46 mmol) at 0°C and the mixture is stirred further at 0°C for 1 hour, ZAT is left to warm to room temperature for 15 hours, under stirring. The mixture was then cooled and stirred for 1-2 hours at a temperature of 0°C, after which the precipitated precipitated solid is filtered off and washed with 17 ml of toluene (solid substance composed mainly of triphenylphosphine, 18 g, wet weight). From the filtrate distilled to 140 ml of solvent and distil add 103,7 ml of n-butanol. The distillation still and distilled 88 ml of solvent, the mixture is then cooled to a temperature of 80°C and add 103,7 ml isopropanol and 1.73 g dicalite. The mixture is filtered while hot. The filtrate is cooled to a temperature of 30°C, making the seed when using the compounds of formula (XI), cooled and stirred at 0°C for 56 hours. The mixture is filtered, the filter residue is washed with 10.4 ml of cold isopropanol and the product is dried at 70°C in vacuum. Output: 15,00 g (71%).

Physical data: melting point: 130,7°C; [b]D: -12,6°C; LC-MS: m/z = 580 ([M+H]+).

H-NMR (400 MHz, DMSO-d6, mixture of rotamers), δ ppm, 1,19 (m, 2H is one of rotamer), of 1.34 (d, J=6,80 Hz, 6N), 1,36 was 1.43 (m, 4H is one of rotamer), 1,46-to 1.61 (m, 2H is one of rotamer), 1,76-to 1.87 (m, 1H), 1,92 (kV, J=6,80 Hz, 2H is one of rotamer) and 2.07 (q, J=6,88 Hz, 2H is one of rotamer), 2,20-2,40 (m, 2H), 2,58 (s, 3H), 2.71 to 2,78 (m, 1H), and 2.79 (s, 3H) - one rotamer) and 2,98 (s, 3H) - one rotamer), 3,14 (hept, J=6.75 Hz, 1H), 3,21-to 3.52 (m, 4H), 3,62 (s, 3H), 362-3,70 (m, 1H), 3.96 points (s, 3H), a 4.86 (DD, J=10,20, to 0.88 Hz, 1H is one of rotamer), to 4.92 (DD, J=18,13 and 1.51 Hz, 1H is one of rotamer), 4,96 (DD, J=11,08, 1,00 Hz, 1H is one of rotamer), to 5.03 (DD, J=17,12 and 1.51 Hz, 1H is one of rotamer), 5,33 (s, 1H), of 5.68 (DDT, J=17,12, 10,32, 6,74 Hz, 1H - one of rotamer) and of 5.81 (DDT, J=17,00, 10,20, of 6.68 Hz, 1H is one of rotamer), 7,40-of 7.48 (m, 3H), 8,03 (d, J=8,81 Hz, 1H is one of rotamer) and of 8.04 (d, J=9,06 Hz, 1H is one of rotamer).

C-NMR (100 MHz, DMSO-d6, mixture of rotamers)d ppm: 9,77, 22,26, 22,80, 25,14, 25,23, 25,90, 27,56, 30,40, 32,75, 32,86, 33,12, 34,61, 35,68, 35,73, 36,21, 36,76, 42,20, 42,61, 44,92, 45,19, 46,67, 48,58, 51,62, 51,65, 56,06, 78,23, 78,30, 95,35, 95,39, 112,77, 112,86, 114,61, 114,89, 115,47, 116,13, 116,17, 119,99, 120,03, 120,50, 120,56, 138,41, 138,49, 147,83, 147,85, 151,19, 151,20, 157,98, 158,00, 160,55, 160,58, 164,22, 168,64, 168,67, 171,93, 173,95, 174,10.

730 mg (1,51 mmol) of the Compound of formula (X) and 213 mg (1.88 mmol) NMHA dissolved in a mixture of THF-Methf (3 ml + 3 ml). The mixture is heated to a temperature of 50°C. Then add 465 mg (1.88 mmol) of EEDQ and the mixture is stirred over night at 50°C. Added 43 mg (0.38 mmol) NMHA and 93 mg (0.38 mmol) of EEDQ and the mixture is stirred for 2 days at 50°C. the Mixture was concentrated in vacuo, then dissolved in 3 ml of Methf and sequentially washed with 6 ml of 1 N. aqueous HCl, 3 ml of water and 1.5 ml of a saturated salt solution. The organic layer is dried over magnesium sulfate. The solid is filtered off and the filtrate is concentrated to dryness in vacuo. Obtain 0.95 g of the crude compound of formula (XI) in the form of not-quite-white solid which CSOs substances.

The crude solid is re-suspended in 6 ml of boiling heptane. The suspension is cooled to room temperature and then stirred overnight at room temperature. Receive, after filtration and drying, 710 mg (81% yield) of a purified compound of the formula (XI) in the form of white powder.

of 1.23 g (10.9 mmol) NMHA and 2,69 g (10.9 mmol) of EEDQ add to 15.4 g of 25 %wt./mass. the compounds of formula (X), dissolved in Methf (7.8 mmol of compounds of formula (X)). This mixture is stirred over night at 50°C, then cooled to room temperature. After that add 28 ml of water, 3.1 ml of concentrated HCl and 10 ml of toluene, the resulting layers are separated and the organic layer is washed with 16 ml of water. The organic layer is treated with the help of 2.38 g of basic aluminum oxide, 1,94 g dicalite and 1.01 g Norit A Supra and filtered. The filtrate was concentrated in vacuo and the residue suspended in 51 ml of heptane. The suspension is stirred over night at room temperature, then for 2 hours at 0°C. Receive, after filtration and drying, 2.25 g (yield 50%) of the compounds of formula (XI).

Example 12

Obtaining the compounds of formula (XII)

600 mg (1,03 mmol) of the Compound of formula (XI) is dissolved in 4.1 ml of THF, then add to 45.6 mg (1.1 mmol) LiOH·H2Oh, pre-dissolved in 1 ml of water. Received the th mixture is stirred for 2-3 hours at room temperature. Analyses by LC and LC-MS shows almost complete conversion of the compounds of formula (XI) in the compound of formula (XII). This solution, after receiving it, use at the next stage.

Physical data: LC-MS: m/z = 564 ([M-H]-).

Example 13

Obtaining the compounds of formula (XIV)

to 1.14 mmol of Compounds of formula (XIII) and 294 mg (1,19 mmol) EEDQ add to 1,03 mmol lithium salts of the compounds of formula (XII) in the form of a solution in a mixture of THF-water (4,1 ml + 1 ml). The mixture is stirred over night at room temperature. Then add 2.1 ml of toluene and 1.55 ml of 1 N. aqueous HCl. Two layers are separated and the organic layer washed sequentially with the help of 0.52 ml of water, of 1.55 ml of 1 N. aqueous NaOH solution of 0.52 ml of water and 0.52 ml of a saturated salt solution. The organic layer is then dried over sodium sulfate. The solid substance is filtered off and the filtrate is concentrated to dryness in vacuo. Receive 698 mg (yield 96%) of crude compound of formula (XIV) in the form of a glassy compound. Analyses by NMR and LC show > 90% purity.

Physical data: LC-MS: m/z = 703 ([M+H]+).

H-NMR (400 MHz, DMSO-d6the mixture of rotamers), δ ppm of 0.87 (t, J=7,30 Hz, 1H), 1.06 a-1,19 (m, 3H), between 1.19 to 1.31 (m, 2H), 1,33 (d, J=6,80 Hz, 6N), 1,35-1,45 (m, 2H), 1,46-of 1.66 (m, 2H), 1,84 is 2.00 (m, 2H), 2.00 in to 2.18 (m, 3H), 2,25-of 2.36 (m, 1H), 2,58 (s, 3H), 2,64-2,77 (m, 1H), 2,80 (s, 3H) - one rotamer), of 3.00 (s, 3H) - one rotamer), is 3.08 - 3,30 (m, 2H), 3,34 - 352 (m, 3H), of 3.97 (s, 3H), 3,98-4,12 (m, 2H), 4,82-5,13 (m, 3H), 5,18 lower than the 5.37 (m, 2H), 5,55 and 5.86 (m, 2H), 7,39-to 7.50 (m, 3H), of 8.06 (t, J=8,94 Hz, 1H), 8,59 (s, 1H is one of rotamer), 8,73 (s, 1H is one of rotamer).

C-NMR (100 MHz, DMSO-d6, mixture of rotamers)d ppm: 9,79, 13,80, 13,96, 13,99, 14,12, 14,53, 18,59, 22,21, 22,30, 25,25, 25,32, 26,02, 27,64, 30,40, 32,07, 32,14, 32,81, 33,19, 34,64, 34,68, 36,31, 36,76, 36,95, 36,98, 42,28, 46,01, 46,43, 46,74, 48,74, 56,10, 60,33, 60,51, 60,59, 78,73, 78,80, 95,34, 95,38, 112,67, 112,76, 114,67, 114,88, 115,47, 116,20, 116,23, 117,34, 120,03, 120,05, 120,59, 120,62, 134,13, 134,18, 138,41, 138,49, 147,85, 151,22, 157,98, 158,0, 160,75, 164,25, 168,66, 168,69, 169,82, 169,85, 172,48, 172,51, 173,66, 173,83.

1. The method of obtaining the compounds of formula (XIV)on the basis of intermediate (XI), which is hydrolized to the acid (XII), which, in turn, is associated with the broadcast cyclopropylamine (XIII)to give the desired end product (XIV), as shown in the following reaction scheme:

where R is C1-4-alkyl and R1regardless of R, also means1-4-alkyl.

2. The method according to claim 1, where the compound of formula (XI) enter into interaction with the hydroxide of an alkali metal, receiving compound of formula (XII) or its salt of the alkali metal.

3. The method according to claim 1, where the compound of formula (XII) or its salt, then, enter into interaction with the compound of the formula (XIII) or its salt and amide linking agent, receiving the compound of formula (XIV).

4. The method of obtaining the compounds of formula (XI) or its salt, based on complex hydroxic kilometrovogo bis-ester of formula (Va), or:
(a) by introducing into the complex interaction hydroxycyclopent bis-ester of formula (Va) with thiazolidinediones hyalinella (VIII) by the reaction of formation of simple ether, obtaining, thus, difficult chinainternational bis-ester of formula (IX), where the ester group, which is in the CIS-position relative to the simple ether group in a complex hyalinobatrachium bis-ether of the formula (IX), selectively split up monocarboxylic acid (X), which, in turn, is associated with alkanolamines by the reaction of formation of amide, and thus, the desired end the product of formula (XI); or
(b) by selective transformation of complex hydroxycyclopent bis-ester of formula (Va) in the monocarboxylic acid (VI), which, in turn, is associated with alkanolamines by the reaction of formation of amide, getting hydroxycyclophosphamide (VII), which, in turn, enter into interaction with thiazolidinediones hyalinella (VIII), and thus, the desired end product of formula (XI);
as shown in the following reaction scheme,
where R1means1-4-alkyl:

5. The method of obtaining the intermediate product (Va), on the basis of 4-oxocyclopent-1,2-bicarbonate acid (I), by restoring ketogroup to alcohol, receiving, thus the om, 4-hydroxycyclopent-1,2-bicarbonate acid (II), which, in turn, cyclist to the bicyclic lactone (III), where the carboxylic acid group in the bicyclic lactone (III) etherification using benzyl alcohol, and thus, benzyl ether lactone (IV), where the lactone open and thus the resulting carboxylic acid group etherification using1-4-alkanol, and thus, difficult hydroxycyclopent bis-ester of formula (V), which, in turn, are divided into stereoisomers (Vb) and (Va); as shown in the following reaction scheme, where R1means1-4-alkyl:

6. The method according to claim 1, where the compound (XI) are obtained in accordance with the method according to claim 4.

7. The method according to claim 4 or 6, where the compound (Va) receive, in accordance with the method according to claim 5.

8. The method of obtaining the compounds of formula (XIV) or formula (XI) according to any one of claims 4 or 6, where the compound of formula (IX) or formula (XI) are obtained by introducing into the interaction of the compounds of formula (Va), respectively, of formula (VII)with the compound of the formula (VIII)in the presence of azodicarboxylate formula R OOC-N=N-COOR', phosphine of the formula R ' 3P and organic solvent; where
R' represents an ethyl or isopropyl or tert-butyl;
R" means each, independently, phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.

9. Way to obtain is soedineniya formula (XIV) or formula (XI) according to any one of claims 4 or 6, where the compound of formula (VII) or formula (XI) are obtained by introducing into the interaction of the compounds of formula (VI), respectively, the compounds of formula (X), with N-metrex-5-enylamine (NMHA) and the agent linking amide, in an inert towards the reaction solvent.

10. The method according to claim 9, where the amide linking agent selected from EEDQ, IIDQ, EDCI, DCC, or 1,3-diisopropylcarbodiimide.

11. The method of obtaining the compounds of formula (XIV) or formula (XI) according to any one of claims 4 or 6, where the compound of formula (VI) or the compound of formula (X) are obtained by introducing into the interaction of the compounds of formula (Va), respectively, the compounds of formula (IX)with a reducing agent, in an inert towards the reaction solvent.

12. The method according to claim 11, where the reducing agent is hydrogen in the presence of a metal catalyst, or where the reducing agent is formic acid or its salt, a mixture of formic acid and its salts, triethylsilyl, tert-butyldimethylsilyl, phenylsilane or poly(methylhydrosiloxane), optionally in the presence of a base.

13. The method according to item 12, where the reducing agent is hydrogen in the presence of a metal catalyst.

14. The method according to item 13, where the catalyst is selected from palladium-on-charcoal, palladium hydroxide-on-charcoal, palladium acetate or palladium chloride.

15. The method according to any of PP-14, where the basis is three - From1-4-alkylamine.

16. The method according to any of § § 11-14, where the organic solvent is selected from THF, Methf, acetic acid, toluene, or any mixture thereof.

17. The method according to claim 5, where the compound of formula (Va) is obtained by separation of the mixture (V) using a chiral separation.

18. The method according to 17, where chiral separation represents a chiral column chromatography.

19. The method according to any of subparagraph 5 or 6, where the compound of formula (V) are obtained by introducing into the interaction of the compounds of formula (IV) with C1-4-alkanol and acid catalyst.

20. The method according to any of subparagraph 5 or 6, where the compound of formula (IV) are obtained by introducing into the interaction of the compounds of formula (III) with benzyl alcohol in the presence of a binding agent or in the presence of a1-4-alkylphosphonate formula ClCOOR", where R" means1-4-alkyl, such as methyl, ethyl, 1-propyl, 1-butyl, 2-butyl, and organic bases.

21. The method according to claim 20, where the binding agent is selected from EDCI, DCC and diisopropylcarbodiimide.

22. The method according to any of subparagraph 5 or 6, where the compound of formula (III) or its salt obtained by introducing into the interaction of the compounds of formula (II) or its salt With1-4-alkylchlorosilanes formula ClCOOR", where R" has the meaning as described in claim 20, in the presence of organic bases.

23. The method according to any of subparagraph 5 or 6, where the compound of formula (II) is produced by the EOI is to interact the compounds of formula (I) hydrogen, in the presence of a metal catalyst, optionally in the presence of a base.

24. The method according to item 23, where the catalyst is selected from a rhodium-on-charcoal, rhodium-on-alumina, platinum-on-coal-or platinum-on-alumina.

25. The method according to item 22, where the base is selected from sodium hydroxide, aluminum oxide, and three With1-4-alkylamine.

26. The method according to any one of claims 1 to, 2, 3, 4, 5, 6, 10, 12, 13, 14, 17, 18, 21, 24 or 25, where R1means methyl.

27. The method according to any one of claims 1 to, 2, 3, 4, 5, 6, 10, 12, 13, 14, 17, 18, 21, 24 or 25, where R is ethyl.

28. The use of the compounds chosen from:



where R and R1each, independently, means1-4-alkyl,
as an intermediate product in obtaining the compounds of formula (XVII):

or its pharmaceutically acceptable salt.

29. Use p, where R is ethyl and R1means methyl.

30. The compound of formula (VI)

or

where R1 means1-4-alkyl.

31. Connection item 30, where R1means methyl.

32. The method of obtaining the compounds of formula (XVII), including the reaction of intermediate (XIV), which cyclist to obtain the product (XV), which is then hydrolized to the macrocyclic acid XVI);
macrocyclic acid (XVI) associated with sulfanilamide through the formation of amide, thereby obtaining the final product (XVII), as shown in the following reaction scheme:

and where the compound (XIV) are obtained by the method according to any one of claims 1 to 3 and 6-27.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , wherein R2 means methyl, Y means carbon or nitrogen, and R1, R3 and R4 have the value specified in the patent claim. Also, the invention refers to a pharmaceutical composition for the use as a pharmaceutical drug having activity of a phosphatidylinositol-3-kinase inhibitor, to the use of the compounds of formula I for preparing the pharmaceutical drug for treating a disease mediated by phosphatidylinositol 3-kinase and to a method for preparing the compounds of formula I .

EFFECT: preparing the compounds of formula I possessing activity of the phosphatidylinositol-3-kinase inhibitor.

10 cl, 5 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new indole compounds of formula:

wherein A means 5-member heteroaryl or heterocyclyl each of which has 1 to 3 heteroatoms specified in N, O and S, R1 means R5 -X-B-X'-, R2 means -(CR8 R9 )p-Y-R7, R3 means hydrogen, C1-C6-alkyl or -(CH2)q-C3-C6-cycloalkyl, R4 means C3-C6-cycloalkyl (the other radical values are presented in cl.1 of the patent claim), their pharmaceutically acceptable salts or isomers which may be used for preventing or treating cell necrosis and necrosis-related diseases.

EFFECT: preparing the compounds to be used for preventing or treating cell necrosis and necrosis-related diseases.

34 cl, 2 tbl, 263 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented nitrogen-containing heterocyclic compounds presented by the following formula wherein the radical values are specified in the description. These compounds or their pharmaceutically acceptable salts possess strong EP1 activity if introduced in a human or an animal; they are used as an effective component of a pharmaceutical agent, e.g. for preventing and/or treating overactive bladder.

EFFECT: compounds are used as an effective component of the pharmaceutical agent for preventing and/or treating the symptoms including frequent urination, heavy urination demand accompanied by fear of involuntary urination, and urinary incontinence.

24 cl, 145 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 7-substituted indoles of formula I:

or their pharmaceutically acceptable salts wherein the values A1, B1, C1, D1, E1, F1, G1, L are presented in cl. 1 of the patent claim.

EFFECT: compounds inhibit activity of anti-apoptotic protein Mc1-1 that enables using them in pharmaceutical compositions.

5 cl, 7 dwg, 2 tbl, 609 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or pharmaceutically acceptable salts thereof: where: each of R1, R2, R3, R4 is independently selected from a group consisting of a hydrogen atom, a halogen atom, an aryl, a C5-6 heteroaryl having 1-3 heteroatoms in the ring which are selected from O, S and N, -OR5, -NR5R6, and -NR5COR6, where said aryl or C5-6 heteroaryl, having 1-3 heteroatoms in the ring selected from O, S and N, is unsubstituted or additionally substituted with one or more groups selected from a group consisting of alkyl, alkoxyl and halogen, each of R5 and R6 is independently selected from a group consisting of a hydrogen atom or an alkyl, where said alkyl is unsubstituted or additionally substituted with one or more groups selected from a group consisting of an aryl, haloaryl, hydroxyl and alkoxyl. The invention also relates to a pharmaceutical composition which inhibits protein kinase and contains a compound of formula I, a method of producing the compound of formula I, use of said compounds to produce a medicinal agent for treating disorders associated with protein kinase, and a method of modulating catalytic activity of protein kinase.

EFFECT: improved method.

10 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treating diabetes, obesity or metabolic syndrome, which includes therapeutically efficient amount of (5-hydroxyadamantan-2-yl)amide of trans-2'-tret-butyl-2'H-[1,3']bipyrazolyl-4'-carboxylic acid or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

EFFECT: invention also relates to application of said compound for preparation of medication, intended for treatment of said diseases.

2 cl, 1 tbl, 99 ex

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present patent claim discloses sulphonyl-substituted compounds of formula QUIN which are used for the purpose of a method for producing a macrocyclic compound of formula (I)

EFFECT: compounds of formula (I) are effective active agents for treating Hepatitis C viral (HCV) infection.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a stereoselective method of producing norbornadiene-based stressed skeleton carbocyclic compounds. The method is characterised by that it involves codimerisation of norbornadiene with acrylic esters. The catalyst used is a bis(allyl)nickel-based single-component system.

EFFECT: use of the present method increases stereoselectivity of the codimerisation reaction and increases product output.

1 cl, 5 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of bicyclo[3.1.0]hexane derivatives, used as mGIuR agonists having formulae ,

, where R1 and R2 represent hydrogen, X is a halogen, R3 is -O-Ra , Ra is C1-10alkyl, and R4 is (1) hydrogen or (2) Si-(R9)(R10)(R11), where each of R9, R10 and R11 is C1-10alkyl, as well as intermediate compounds obtained when realising the said methods.

EFFECT: design of an efficient method for synthesis of bicyclo[3,1,0]hexane derivatives.

26 cl, 17 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to the field of organic chemistry, in particular, to method for production of methyl ethers of 2-thiophen carbonic acid intended for use in synthesis of optical whiteners, dyes for cotton, wool, artificial fibers, medical preparations, and also as additive to oils or hydraulic liquids. Substance of the method consists in thiophen interaction with methanol in presence of carbon tetrachloride under action of catalysts - oxo-bis-(2,4-pentanodionato)vanadium VO(acac)2 or tris (2,4-pentanodionato)iron Fe(acac)3, or molybdenum hexacarbonyl Mo(CO)6 at the temperature of 130-170°C for 3-6 hours at the following mole ratio - catalyst:thiophen:CCl4:methanol equal to 1:100:200-300:200-300.

EFFECT: suggested method makes it possible to produce target product with yield of 63-85%, using simplified technology.

1 tbl, 14 ex

The invention relates to new derivatives of esters of carboxylic acids of General formula I, where R1represents an alkyl group branched or non-branched chain having 1-4 carbon atoms; R2represents a group of formula IV, in which R4represents a hydrogen atom or etinilnoy group; R5and R6are the same or different selected from the group consisting of a hydrogen atom or a methyl group; R7represents a hydrogen atom; R8selected from propargyl, methoxymethyl or methylthio

The invention relates to a new process for the preparation of esters cyclopropanecarbonyl acid of the formula I

< / BR>
where R is the ester residue, split in neutral or acid medium and which WITH1-18the alkyl possibly substituted with halogen or benzyl radical, possibly substituted on the tops of the aromatic ring by one or more halogen atoms, or a radical of formula (a) -(g),

< / BR>
where R2Is h or methyl;

R3- aryl;

R4- CN, N.;

R5- fluorine, chlorine, bromine or hydrogen;

R6, R7, R8, R9is hydrogen or methyl;

S/1 symbolizes tetrahedrite

The invention relates to a new method of obtaining some of esters of cyclopropane used in the synthesis of important pesticides

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of bicyclo[3.1.0]hexane derivatives, used as mGIuR agonists having formulae ,

, where R1 and R2 represent hydrogen, X is a halogen, R3 is -O-Ra , Ra is C1-10alkyl, and R4 is (1) hydrogen or (2) Si-(R9)(R10)(R11), where each of R9, R10 and R11 is C1-10alkyl, as well as intermediate compounds obtained when realising the said methods.

EFFECT: design of an efficient method for synthesis of bicyclo[3,1,0]hexane derivatives.

26 cl, 17 ex, 1 tbl

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