RU2794754C1 - Method for producing (1r,2s,5s)-n-[(1s)-1-cyano-2-[(3s)-2-oxopyrrrolidin-3-yl]ethyl]-3-[(2s)-3,3- dimethyl-2-[(2,2,2-trifluoracetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-carboxamide - Google Patents

Abstract

FIELD: medicine; pharmacology; pharmaceutical industry.

SUBSTANCE: group of inventions includes a method for producing (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (compound of formula (I)) and its use for batch chemical industrial production, semi-continuous industrial production or continuous industrial production, as well as a method for preparing an intermediate compound of formula (IV) intended for use in a method for producing a compound of formula (I). The process for preparing a compound of formula (I) includes the following steps: a) reaction of a compound of formula (V) or a salt thereof with a compound of formula (IV) using a compound of formula R₁O-CO-Cl, where R₁ is C₁-C₅ alkyl; C₁-C₅ alkyl substituted with halogen; phenyl; phenyl substituted with halogen, nitro or C₁-C₅ alkyl; benzyl substituted with halogen, nitro or C₁-C₅ alkyl in the presence of a base to give a compound of formula (VI); b) dehydration of the compound of formula (VI) using 2,4,6-trichloro-1,3,5-triazine to form a compound of formula (I). The process for preparing an intermediate compound of formula (IV) involves reaction of a compound of formula (II) with a compound of formula (III) in the presence of an aqueous solution of an alkali or alkaline earth metal hydrogen carbonate, where R is chlorine, bromine or fluorine.

EFFECT: improved method of obtaining, leading to an increase in the yield and chemical purity of the compound of formula (I).

39 cl, 1 tbl, 2 ex

Description

The invention relates to the field of medicine, pharmacology and pharmaceutical industry, namely, to a new improved method for obtaining (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine -3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1. 0]hexane-2-carboxamide (compound of formula (I)), as well as a process for preparing intermediates for use in a process for preparing a compound of formula (I).

One of the most urgent problems of modern medicine is the fight against viral infections. According to the World Health Organization (WHO), new infectious diseases are emerging at an alarming rate, with about 40 new infectious diseases discovered since the 1970s. Some of the most dangerous new emerging viruses are: severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002-2003, influenza (swine flu) A/H1N1 in 2009, Middle East respiratory syndrome (MERS) coronavirus in 2012 , the 2013-2015 Ebola virus disease epidemic, the 2016-2017 Zika virus pandemic, and now the COVID-19 pandemic. In addition to these newly identified pathogens, previously recognized viral infections, including pandemic influenza, yellow fever, measles, and others, continue to pose a threat due to the emergence of new epidemics (David A. Schwartz. Prioritizing the Continuing Global Challenges to Emerging and Reemerging Viral Infections // Front.Virol.- 2021).

Phylogenetic analysis has shown that some single-stranded (+)RNA viruses can be assigned to a picornavirus-like supercluster that includes viruses belonging to the Picornaviridae, Caliciviridae, and Coronaviridae families. A common feature of picornavirus-like supercluster viruses is that they use a 3C or 3C-like protease (3Cpro or 3CLpro respectively) in their metabolism. The conserved 3Cpro or 3CLpro sites may serve as attractive targets for the development of broad-spectrum antivirals for viruses in the picornavirus-like supercluster. (Yunjeong Kim et al. Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses // J Virol.- 2012.- 86(21), p. 11754–11762).

The SARS-CoV2 virus is a severe acute respiratory infection. The coronavirus pandemic started on a global scale in December 2019. According to statistics, hundreds of thousands of cases and thousands of deaths are registered daily. As of October 11, 2021, the number of cases is 251 million people, and deaths have crossed the line of 5 million people. Since the onset of the global pandemic, both global human health and the global economy have been severely damaged. The pandemic has served as a challenge to modern medicine, creating an urgent need to develop effective strategies for the prevention and treatment of viral diseases. The lack of specific therapy against the new virus and its high variability require the creation of new drugs. In addition to existing therapies, specific drugs are needed that have a direct effect on the virus, leading to symptomatic relief, accelerated resolution of the disease, blocking transmission and reducing the risk of clinical complications.

One promising way to block the SARS-CoV2 virus is to inhibit the SARS-CoV2 protease, also called the 3C-like protease (3CL or 3CLpro). Inhibition of the 3CL protease results in the prevention of viral replication. (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl- 2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, which is characterized by formula (I), inhibits the activity of a cysteine residue in the protease at the stage of proteolysis. 3CLpro is responsible for the process of splitting the lipoproteins of the virus, containing 3CLpro itself, PLpro (papain-like protease) and 14 other proteins. The molecule has shown high antiviral activity in preclinical studies in a mouse-adapted model of SARS-CoV-2. In addition, it is known from the prior art that (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S )-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide may exhibit broad spectrum inhibition ability The 3C-like protease is not exclusive to SARS-CoV-2, highlighting the possibility of being used for other human viruses.

Compound of formula (I)

When developing medicines, it is important that the substance that is the active agent is available and meets quality requirements. The most optimal way to increase the availability and quality control of the active agent is to develop a unique synthetic protocol. Synthesis of the active agent allows you to control such properties of the substance as the form of the active agent, for example, crystalline, amorphous, or their ratio; chemical purity, in particular, the amount of related impurities or reagents used in the course of chemical transformations, the stereoisomeric purity of the active agent.

Chemical purity is of great importance in the production of substances. It is known that the degree of purity of substances potentially affects their safety and efficacy, both in medicine and in veterinary medicine. Increasing the chemical purity of a substance improves its initial biological properties and reduces possible side effects associated with the presence of impurities.

The development of new approaches to the synthesis of an active agent opens up opportunities for improving the profile of the physicochemical and technological characteristics of a pharmaceutical product. This expands the range of active agents that the drug developer has at his disposal when developing a new drug with an improved safety profile. Also, the sustainable development of modern approaches to the synthesis of active agents makes it possible to introduce into production environmental, resource-efficient, nuclear-saving innovative technologies that contribute to economic development and minimize environmental damage.

Thus, there is currently a continuing need to develop new, improved methods for the synthesis of antiviral agents.

In connection with the decree of the President of the Russian Federation of May 7, 2018 No. 204 "On the national goals and strategic objectives of the development of the Russian Federation for the period up to 2024", within the framework of the import substitution program "Pharma-2030", the authors of the present invention made efforts to create an innovative method compound (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound of formula (I)).

An important intermediate in the synthesis of a compound of formula (I) is a compound of formula (IV):

Compound of formula (IV)

In the prior art (Owen D. R. et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19 //Science. - 2021. - T. 374. - No. 6575. - P. 1586-1593 and WO2021250648) disclose methods for preparing a solvated methyl tert-butyl ether form of a compound of formula (I), followed by free form conversion with heptane with isopropyl acetate. In this case, the previous stage is the preparation of an intermediate product through the interaction of (1R,2S,5S)-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid with 3-[(3S)-2-oxopyrrolidin-3-yl]-L-alanineamide in the form of hydrochloride in the presence of 2-hydroxypyridin-1-oxide in butan-2-one with further addition of 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide.

, where Burgess Reagent is Burgess's reagent;

IPA - isopropanol;

HATU-O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

DIEA-N,N-diisopropylethylamine;

DMF-dimethylformamide;

THF-tetrahydrofuran;

Dioxane - dioxane;

DCM-dichloromethane;

EDCl-1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

HOPO-2-hydroxypyridine-N-oxide;

MEK - methyl ethyl ketone;

MTBE-methyl tert-butyl ether;

IPAC- isopropyl acetate;

Heptane- heptane.

The disadvantage of this synthesis of the compound of formula (I) is, among other things, the use of expensive toxic reagents, for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, which is used only for synthesis in laboratory conditions, which does not allow scaling the synthesis into industrial production. At the same time, such reagents form by-products during the synthesis: the use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is accompanied by the formation of the following by-products (products of addition of the carbodiimide group to the amine and internal acylation products (acylureas):

.

.

Also, WO2021250648 describes the synthesis of a compound of formula (I), which is the reaction of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride salt with O-(7 -azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N-(tert-butoxycarbonyl)-3-methyl-L-valine in the presence of N,N-dimethylformamide, followed by the addition of hydroxide to the resulting product lithium in the presence of a mixture of tetrahydrofuran and methanol, followed by mixing the resulting product with (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile methanesulfonate salt in acetonitrile with successive addition of O-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 4-methylmorpholine solution in acetonitrile. The last stage of the synthesis includes the addition of methanesulfonic acid to the product obtained in the previous stage in 1,1,1,3,3,3-hexafluoropropan-2-ol, followed by concentration in a mixture of solvents acetonitrile/ethyl acetate and ethyl acetate/heptane, followed by dissolution in dichloromethane and treatment with 4-methylmofoline and trifluoroacetic anhydride.

, where HATU is O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

The article (Zhao Y. et al. Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332 //Protein & cell. - 2021. - P. 1-5) describes the synthesis of a compound of formula (I) . The final stage of the synthesis involves the interaction of two intermediates under the action of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and diisopropylethylamine.

Also, the inventors would like to note that the interaction of the intermediate product in the specified synthesis with sodium hydroxide results in the elimination of trifluoroacetyl, which contradicts that indicated in the synthesis (Albert Isidro-Llobet et al. Amino Acid-Protecting Groups // Chem. Rev.- 2009 .- 109, 6.- pp. 2455-2504).

, where HATU is O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIPEA-N,N-diisopropylethylamine;

DMF is dimethylformamide.

At the same time, the main disadvantages of the syntheses of the compound of formula (I) indicated in the prior art are the use of expensive toxic reagents, including 2-hydroxypyridine-1-oxide, O-(7-azabenzotriazol-1-yl)-N,N,N' ,N'-tetramethyluronium hexafluorophosphate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, which are used only for synthesis in laboratory conditions, which does not allow scaling the synthesis into industrial production. Such reagents form by-products during the synthesis: the use of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate is accompanied by the formation of a by-product of tetramethylurea, which has 1 hazard class in terms of teratogenicity and is not amenable to further recycling, which has a negative impact on the environment. When methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylate hydrochloride (CAS 565456-77-1) is used, diketopiperazine is formed as a by-product.

In addition to the above, the described syntheses have a low overall yield of the target product for all stages of the synthesis, which is impractical for industrial production.

The objective of the present invention is to develop a new improved, environmentally friendly, safe method for obtaining the compound of formula (I) with a high yield of the target product, which uses readily available reagents, starting compounds and reaction conditions with which the synthesis can be reproduced on an industrial scale. It is also an object of the present invention to provide a novel, improved synthesis of intermediates in the synthesis of a compound of formula (I).

As a result of research, the authors of the present invention have developed a new improved method for obtaining the compound of formula (I) compared to the prior art, which includes a new stage for obtaining an intermediate product of the compound of formula (IV), suitable for industrial production. At the same time, the authors of the invention unexpectedly found that the method for obtaining the compound of formula (I) according to the present invention makes it possible to obtain the target product (compound of formula (I)) with a total yield over all stages exceeding the yield in the methods described in the prior art for obtaining the compound of formula ( I). Also, the inventors during the research were able to develop a new method for obtaining an intermediate product (compound of formula (IV)), as a result of which a stereoisomerically pure substance (compound of formula (IV)) was obtained in high yield without the formation of undesirable by-products.

Thus, the technical results of the present invention are:

- high yield and chemical purity (including stereoisomeric) of the target product (compound of formula (I)) and intermediate products in the synthesis of the compound of formula (I);

- adaptation of the method for obtaining the compound of formula (I) for industrial production;

- reduction of synthesis steps;

- reduction of time and economic costs for the implementation of the synthesis;

- ensuring environmentally safe production;

- reducing the formation of unwanted by-products during the synthesis.

The following are definitions of terms that are used in the description of the present invention.

Unless otherwise indicated, all technical and technical terms used in this context have the meaning generally accepted in the art.

The term "comprising", "comprising", "comprising" in the context of the present invention means that the specified pharmaceutical compositions, products, compositions and medicinal products include the listed components, but do not exclude the inclusion of other components, and also the specified methods for obtaining compounds include the listed synthetic steps but do not exclude the inclusion of others.

The term "effective amount" in the context of the present invention means the amount of a substance (as well as a combination of substances) which, when administered to a subject for the treatment or prevention of a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to effect such treatment and/or prevention. to a disease, disorder, or symptom. An "effective amount" is determined depending on the disease, disorder and/or symptoms of the disease or disorder, the severity of the disease, disorder and/or symptoms of the disease or disorder, the clinical presentation and general health of the patient, and the age and/or weight of the subject to whom such treatment (prevention) is necessary.

As used in the text, the terms "about", "about" means approximately plus or minus ten percent of the specified value.

The term "impurities" in the context of the present invention is any component in the synthesis product, which is not the target substance. Impurities in the synthesis product include: inorganic impurities, organic impurities (including residual solvents used in the synthesis of compounds). The listed groups also include related and technological impurities. The source of impurities can be the reagents used in the synthesis of starting materials, by-products, decomposition or polymerization products, reagents, ligands, structural or spatial isomers, catalysts, technological equipment, filter material residues, insufficiently purified feedstock used for the synthesis of the active agent.

The term "chemical purity" in the context of the present invention characterizes the content (in%) of the target substance in the sample in relation to the total amount of the sample. The chemical purity of the present invention is a substance whose chemical purity is 97.0% or more, more preferably 98.0% or more, and particularly preferably 99.0% or more.

The term "stereoisomers", in the context of the present invention, defines all possible isomers that the compounds of the present invention may have, formed from identical sets of atoms connected by the same sequence of bonds, but having a different spatial arrangement of atoms or groups of atoms relative to bonds, while the isomeric compounds are not are interchangeable. Unless otherwise indicated, the chemical designation of a compound includes the mixture of all possible stereochemically isomeric forms that the specified compound may have. Said mixture may contain all diastereomers and/or enantiomers of the molecular structure of said compound. It is assumed that, except where otherwise indicated, all stereoisomeric forms of the compounds used in the present invention, both in pure (individual) form and in admixture with each other, are included in the scope of the present invention.

The term "diastereomers" refers to stereoisomers that have two or more asymmetric carbon atoms in their structure, namely carbon atoms bonded to four different substituents, provided that the stereoisomers are not mirror images of each other. However, if the configuration differs at least one stereocenter, then such stereoisomers are diastereomers.

The term "enantiomers" refers to stereoisomers that contain one or more asymmetric carbon atoms in the structure, namely carbon atoms associated with four different substituents, provided that a pair of these stereoisomers are mirror images of each other, not superimposed in space. If two stereoisomers have opposite configurations of all their respective stereocenters, then they are enantiomers.

The term "stereoisomerically pure" in the context of the present invention is defined as the relative excess of one stereoisomer in a sample over another. Stereoisomerically pure according to the present invention is a substance (sample) having a stereoisomeric excess of at least 80% up to a stereoisomeric excess of 100% (i.e. 100% of one stereoisomer and no other), more preferably a substance having a stereoisomeric excess of 90% up to 100%, more preferably having a stereoisomeric excess of 95% to 100%, more preferably having a stereoisomeric excess of 97% to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in the same way, but referring to the enantiomeric excess and diastereomeric excess of the mixture in question, respectively.

Stereoisomerically pure forms of the compounds of the present invention can be obtained by using techniques known in the art. For example, the stereoisomers of the present invention can be separated from each other by selective recrystallization of their diastereomeric salts with optically active acids; the stereoisomers of the present invention can be separated by chromatographic methods using chiral stationary phases. Pure stereochemically isomeric forms of the compounds of the present invention can also be obtained from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction is stereoselective. If a specific stereoisomer is desired, said compound will preferably be synthesized by stereoselective preparation methods. These methods will advantageously employ stereoisomerically pure starting materials.

One of the main methods for controlling the stereoisomeric purity of the chemical compounds of the present invention is the high performance liquid chromatography (HPLC) method, which is based on a different distribution of substances between two immiscible phases. The liquid, which is the mobile phase, passes through the stationary phase, placed in a column with high hydraulic resistance. Liquid chromatography that uses columns with a reduced particle size (eg, less than 2 µm) is called ultra high performance liquid chromatography (UHPLC). Liquid chromatography, depending on the mechanism of separation of substances, can be adsorption, distribution, ion-exchange, exclusion, chiral, etc., in accordance with the nature of the main manifested intermolecular interactions. Each of these types can be highly efficient if high column pressure mode is used for chromatography.

Another way to separate isomers can be recrystallization. Recrystallization is a method of purification of compounds from various impurities (for example, related, technological), based on the difference in the solubility of substances in various solvents or their mixtures at different temperatures. One embodiment of recrystallization is to add an anti-solvent (a solvent in which the substance has low solubility) to the solution, whereby the solvent power of the medium deteriorates and the solute passes from solution to solid form. The advantages of the recrystallization method are a high degree of purification, however, in some cases, a high loss of substance can be a disadvantage.

In the framework of the present invention, the task is solved, and the claimed technical result is achieved by a new method for obtaining a compound of formula (IV), which includes the interaction of a compound of formula (II) with a compound of formula (III) in the presence of an aqueous solution of an alkali or alkaline earth metal hydrogen carbonate, provided that that R is a halogen selected from chlorine, bromine or fluorine according to the following synthesis scheme:

One embodiment of the present invention is a process for preparing a compound of formula (IV) wherein the reaction of a compound of formula (II) with a compound of formula (III) takes place in an organic solvent medium.

More preferably, water-immiscible solvents are used as said organic solvent.

More preferably, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, or mixtures thereof are used as the organic solvent in said reaction, without limitation.

One embodiment of the present invention is a process for the preparation of a compound of formula (IV) wherein the reaction of a compound of formula (II) with a compound of formula (III) takes place in the presence of an aqueous solution of an alkali metal hydrogen carbonate, wherein sodium hydrogen carbonate or potassium hydrogen carbonate is used as the alkali metal hydrogen carbonate. .

One embodiment of the present invention is a process for preparing a compound of formula (IV) wherein the reaction of a compound of formula (II) with a compound of formula (III) is carried out in the presence of an aqueous solution of an alkaline earth metal hydrogen carbonate, wherein magnesium hydrogen carbonate or calcium hydrogen carbonate is used as the alkaline earth metal hydrogen carbonate. .

One embodiment of the invention is a process for the preparation of a compound of formula (IV) which is carried out at a temperature in the range from -10 ^° C to 50 ^° C.

More preferably, the reaction to obtain the compound of formula (IV) of the present invention is carried out at a temperature in the range from -5 ^° C to 40 ^° C.

More preferably, the reaction to obtain the compound of formula (IV) of the present invention is carried out at a temperature in the range from -5 ^° C to 30 ^° C.

More preferably, the reaction to obtain the compound of formula (IV) of the present invention is carried out at a temperature in the range from -5 ^° C to 20 ^° C.

More preferably, the reaction to obtain the compound of formula (IV) of the present invention is carried out at a temperature in the range of -5 ^° C to 10 ^° C.

More preferably, the reaction to obtain the compound of formula (IV) of the present invention is carried out at a temperature in the range from -5 ^° C to 5 ^° C.

More preferably, the reaction to obtain the compound of formula (IV) of the present invention is carried out at a temperature in the range of 0 ^° C to 10 ^° C.

The problem is solved, and the claimed technical result is achieved by a new method for obtaining a compound of formula (I), which includes the following steps: a) interaction of a compound of formula (V) or its salt, including, but not limited to, hydrochloride, with formula (IV) obtained by the method of the present invention, using a compound of formula R ₁ O-CO-Cl, where R ₁ represents C ₁ -C ₅ alkyl; C ₁ -C ₅ alkyl substituted with halogen; phenyl; phenyl substituted with halogen, nitro or C ₁ -C ₅ alkyl; benzyl substituted with halogen, nitro or C ₁ -C ₅ alkyl in the presence of a base to give a compound of formula (VI)

b) dehydration of the compound of formula (VI) using 2,4,6-trichloro-1,3,5-triazine to form a compound of formula (I):

One embodiment of the invention is a process for the preparation of a compound of formula (I) wherein steps a) and b) are carried out in an organic solvent.

More preferably, the organic solvent in said reaction steps is an aprotic organic solvent.

More preferably, said organic solvent in said reaction steps is selected from, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, ethyl acetate, or mixtures thereof.

More preferably, the compound of formula R ₁ O-CO-Cl of the present invention is characterized by the formula R ₁ O-CO-Cl, where R ₁ is C ₁ -C ₅ alkyl; C ₁ -C ₅ alkyl substituted with halogen such as, but not limited to, chlorine, bromine, fluorine; phenyl; phenyl substituted with halogen, such as, but not limited to, chlorine, bromine, fluorine, nitro, or C ₁ -C ₅ alkyl; benzyl substituted with a halogen such as, but not limited to, chlorine, bromine, fluorine, nitro, or C ₁ -C ₅ alkyl.

More preferably, the compound of formula R ₁ O-CO-Cl of the present invention is selected from, but not limited to, methyl chloroformate, ethyl chloroformate, propyl chloroformate, isobutyl chloroformate, butyl chloroformate, or t-butyl chloroformate.

More preferably, an organic base is used as the base of the present invention.

More preferably, the base of the present invention is, but is not limited to, pyridine; pyridine substituted with C ₁ -C ₅ alkyl; quinoline or quinoline substituted with C ₁ -C ₅ alkyl.

More preferably, the organic base of the present invention is a tertiary amine.

More preferably, the tertiary amine of the present invention is, but not limited to, a compound of the formula R ₂ R ₃ R ₄ N, where R ₂ , R ₃ , R ₄ are independently C ₁ -C ₅ alkyl or when R ₂ with R ₃ together with a nitrogen atom form a C ₄ -C ₈ cycloalkyl group or a C ₄ -C ₈ heterocyclic group, where the heteroatom is oxygen, R ₄ is C ₁ -C ₅ alkyl.

More preferably, the tertiary amine of the present invention is, but not limited to, a compound of the formula R ₂ R ₃ R ₄ N, where R ₂ , R ₃ , R ₄ are independently C ₁ -C ₅ alkyl or when R ₂ with R ₃ together with a nitrogen atom form a C ₄ -C ₈ cycloalkyl group or a C ₄ -C ₈ heterocyclic group, where the heteroatom is oxygen, R ₄ is C ₁ -C ₅ alkyl, while R ₄ is connected to the nitrogen atom.

More preferably, the tertiary amine of the present invention is, but not limited to, a compound of the formula R ₂ R ₃ R ₄ N, where R ₂ , R ₃ , R ₄ are independently selected from the group consisting of methyl, ethyl, propyl, or isopropyl .

More preferably, the tertiary amine of the present invention is, but not limited to, N-methylformalin or triethylamine.

One embodiment of the invention is a process for the preparation of a compound of formula (I), wherein step a) is carried out at a temperature in the range from -50 ^° C to 50 ^° C.

More preferably, step a) of the present invention is carried out at a temperature in the range from -40 ^° C to 40 ^° C.

More preferably, step a) of the present invention is carried out at a temperature in the range from -30 ^° C to 30 ^° C.

More preferably, step a) of the present invention is carried out at a temperature in the range from -20 ^° C to 20 ^° C.

More preferably, step a) of the present invention is carried out at a temperature in the range from -10 ^° C to 10 ^° C.

More preferably, step a) of the present invention is carried out at a temperature in the range of -5 ^° C to 5 ^° C.

One embodiment of the invention is a process for the preparation of a compound of formula (I), wherein step b) is carried out at a temperature in the range from 0 ^° C to 100 ^° C.

More preferably, step b) of the present invention is carried out at a temperature in the range of 15 ^° C to 25 ^° C.

One embodiment of the invention is a process for the preparation of a compound of formula (I), wherein in step a) a compound of formula R ₁ O-CO-Cl, as described above, is added to a solution of a compound of formula (IV) in the presence of a base, at a temperature of -50 ^° C to 10 ^o C and incubated, then a compound of formula (V) or its salt, for example, hydrochloride, and a base are added to the reaction mass at a temperature of from -50 ^o C to 10 ^o C, and then the resulting reaction mass is kept at a temperature of - 10 ^o C to 50 ^o C until the end of the reaction.

One embodiment of the invention is a process for the preparation of a compound of formula (I), wherein in step a) to a solution of a compound of formula (IV) in the presence of a base, a compound of formula R ₁ O-CO-Cl, as described above, is added at a temperature of -30 ^° C to -15 ^o C and maintained, then a compound of formula (V) or its salt, for example, hydrochloride, and a base are added to the reaction mass at a temperature of -25 ^o C to -15 ^o C, and then the resulting reaction mass is kept at a temperature from -5 ^o C to 5 ^o C until the end of the reaction.

One embodiment of the present invention is a process for the preparation of a compound of formula (I), wherein steps a) and/or b) further comprise the following steps: c) isolating the product; d) washing the isolated product; e) drying the product.

One embodiment of the present invention is a process for the preparation of a compound of formula (I), wherein steps a) and/or b) further comprise the following steps: c) isolating the product and/or d) washing the isolated product and/or; e) drying the product.

More preferably, the additional step c) isolate the product by precipitation or extraction.

More preferably, the additional step c) isolate the product by filtration.

More preferably, the additional step c) isolate the product by precipitation followed by filtration.

More preferably, the additional washing step d) of the recovered product is carried out with water, citric acid solution or aqueous sodium hydrogen carbonate solution.

More preferably, the additional drying step e) is a drying step under reduced pressure.

One embodiment of the invention is a process for the preparation of a compound of formula (I), wherein steps a) and/or b) further comprise the following steps: c) isolating the product and/or d) washing the isolated product and/or; e) drying the product, where step d) washing the isolated product further comprises the step of recrystallizing the product from an organic solvent.

More preferably, said step of recrystallizing the resulting product comprises suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained, and then cooling.

More preferably, the cooling is carried out naturally at room temperature.

One embodiment of the invention is a process for the preparation of a compound of formula (I), wherein steps a) and/or b) further comprise the following steps: c) isolating the product and/or d) washing the isolated product and/or; e) drying the product, where step d) washing the isolated product further includes the step of purifying the product by chromatography.

The problem is solved, and the claimed technical result is achieved by applying the method for obtaining the compound of formula (I) according to the present invention for periodic chemical industrial production, semi-continuous industrial production or continuous industrial production of the compound of formula (I).

The problem is solved, and the claimed technical result is achieved by applying the method for obtaining the compound of formula (I) according to the present invention for batch chemical industrial production, semi-continuous industrial production or continuous industrial production of a product containing a compound of formula (I).

The problem is solved, and the claimed technical result is achieved by using the method for obtaining the compound of formula (I) according to the present invention to obtain a product containing a compound of formula (I).

The problem is solved, and the claimed technical result is achieved by using the method for obtaining the compound of formula (I) according to the present invention to obtain a pharmaceutical product containing a compound of formula (I).

The problem is solved, and the claimed technical result is achieved by using the method for obtaining the compound of formula (I) according to the present invention to obtain a composition containing a compound of formula (I).

The problem is solved, and the claimed technical result is achieved through the use of a method for obtaining a compound of formula (I) according to the present invention to obtain a pharmaceutical composition containing a compound of formula (I).

The problem is solved, and the claimed technical result is achieved by means of a product containing a compound of formula (I) obtained by the method of the present invention.

The product in the context of the present invention may be a substance containing a compound of formula (I) obtained by any method according to the present invention. The term "substance" in the context of the present invention means a synthesis product containing any substance or mixture of substances of synthetic or other (biological, biochemical, mineral, vegetable, animal, microbial and other) origin, intended for the production of medicines, which in the process of manufacturing a medicine (drug) becomes the active ingredient of that drug and determines its effectiveness.

One embodiment of the invention is a pharmaceutical product containing a compound of formula (I) obtained by the method of the present invention.

One of the embodiments of the invention is a pharmaceutical product containing a compound of formula (I) obtained by the method of the present invention, characterized in that the total content of impurities in its composition does not exceed 1.5 wt. % by weight of the pharmaceutical product.

One of the embodiments of the invention is a pharmaceutical product containing a compound of formula (I) obtained by the method of the present invention, characterized in that the total content of impurities in its composition is less than 1.5 wt. %, but more than 0.001 wt.% by weight of the pharmaceutical product.

One of the embodiments of the present invention is a pharmaceutical product containing a compound of formula (I), obtained by the method of the present invention, for the treatment and/or prevention of viral diseases, where the virus is, but not limited to, picornavirus, norovirus, foot-and-mouth disease virus, hepatitis virus A, polyvirus, rhinovirus, enterovirus, calicivirus, or coronavirus.

One embodiment of the present invention is an antiviral pharmaceutical product containing a compound of formula (I) obtained by the method of the present invention.

One embodiment of the present invention is a pharmaceutical product containing a compound of formula (I), obtained by the method of the present invention, for the treatment and/or prevention of viral diseases, where the virus is SARS-CoV, MERS-CoV or SARS-CoV-2.

One embodiment of the present invention is a pharmaceutical product containing a compound of formula (I) obtained by the method of the present invention, which exhibits prophylactic and/or therapeutic antiviral activity against the SARS-CoV-2 virus.

The problem is solved, and the claimed technical result is achieved through the use of a product containing a compound of formula (I), obtained by the method of the present invention, for the treatment and/or prevention of viral diseases.

The problem is solved, and the claimed technical result is achieved through the use of a pharmaceutical product containing a compound of formula (I), obtained by the method of the present invention, for the treatment and/or prevention of viral diseases.

One of the embodiments of the present invention is the use of a product containing a compound of formula (I), obtained by the method of the present invention, for the treatment and/or prevention of viral diseases selected from the group, but not limited to, picornavirus, norovirus, foot-and-mouth disease virus, hepatitis A virus , polyvirus, rhinovirus, enterovirus, calicivirus or coronavirus.

The problem is solved, and the claimed technical result is achieved by means of a composition containing a compound of formula (I) obtained by the method of the present invention.

One embodiment of the invention is a pharmaceutical composition containing a compound of formula (I) obtained by the method of the present invention.

One of the embodiments of the invention is a pharmaceutical composition containing a compound of formula (I) obtained by the method of the present invention, characterized in that the total content of impurities in its composition does not exceed 1.5 wt. % by weight of the pharmaceutical composition.

One of the embodiments of the invention is a pharmaceutical composition containing a compound of formula (I) obtained by the method of the present invention, characterized in that the total content of impurities in its composition is less than 1.5 wt. %, but more than 0.001 wt.% by weight of the pharmaceutical composition.

One embodiment of the present invention is a pharmaceutical composition for the treatment and/or prevention of viral diseases, where the virus is, but not limited to, picornavirus, norovirus, foot-and-mouth disease virus, hepatitis A virus, polyvirus, rhinovirus, enterovirus, calicivirus, or coronavirus.

One embodiment of the present invention is a pharmaceutical composition for the treatment and/or prevention of viral diseases, wherein the virus is SARS-CoV, MERS-CoV or SARS-CoV-2.

One embodiment of the present invention is a pharmaceutical composition that exhibits prophylactic and/or therapeutic antiviral activity against the SARS-CoV-2 virus.

The problem is solved, and the claimed technical result is achieved through the use of a pharmaceutical composition containing a compound of formula (I), obtained by the method of the present invention, for the treatment and/or prevention of viral diseases.

One of the embodiments of the present invention is the use of a composition containing a compound of formula (I) obtained by the method of the present invention for the treatment and/or prevention of viral diseases selected from the group, but not limited to, picornavirus, norovirus, foot-and-mouth disease virus, hepatitis A virus , polyvirus, rhinovirus, enterovirus, calicivirus or coronavirus.

One embodiment of the present invention is the use of a pharmaceutical composition containing a compound of formula (I) obtained by the method of the present invention, which exhibits prophylactic and/or therapeutic antiviral activity against the SARS-CoV-2 virus.

One embodiment of the invention is a process for the preparation of a compound of formula (I) in which the stereochemistry of the reactants, intermediates, and desired product is controlled to allow the synthesis of specific stereoisomers of a compound of formula (I) and a compound of formula (IV).

One of the embodiments of the invention is a process for the preparation of a compound of formula (I) which makes it possible to obtain the target product in a yield that is higher than that of the methods described in the prior art.

One embodiment of the invention is a process for the preparation of a compound of formula (IV) which makes it possible to obtain an intermediate in the synthesis of a compound of formula (I) in a yield greater than that of the methods described in the prior art.

One embodiment of the invention is a process for the preparation of a compound of formula (IV) which makes it possible to obtain a product in a yield exceeding that of the methods described in the prior art and with a stereoisomeric excess of the compound of formula (IV) greater than 80%.

One embodiment of the invention is a process for the preparation of a compound of formula (IV) which makes it possible to obtain a product in a yield exceeding that of the methods described in the prior art and with a stereoisomeric excess of the compound of formula (IV) greater than 85%.

One embodiment of the invention is a process for the preparation of a compound of formula (IV) which makes it possible to obtain a product in a yield exceeding that of the methods described in the prior art and with a stereoisomeric excess of the compound of formula (IV) greater than 90%.

One embodiment of the invention is a process for the preparation of a compound of formula (IV) which makes it possible to obtain a product in a yield exceeding that of the methods described in the prior art and with a stereoisomeric excess of the compound of formula (IV) greater than 95%.

One embodiment of the invention is a process for the preparation of a compound of formula (IV) which makes it possible to obtain a product in a yield exceeding that of the methods described in the prior art and with a stereoisomeric excess of the compound of formula (IV) greater than 98%.

One of the embodiments of the invention is a process for the preparation of a compound of formula (I) which makes it possible to obtain the target product in a yield exceeding that of the methods described in the prior art and with a stereoisomeric excess of the compound of formula (I) of more than 80%.

One of the embodiments of the invention is a process for the preparation of a compound of formula (I) which makes it possible to obtain the target product in a yield exceeding that of the methods described in the prior art and with a stereoisomeric excess of the compound of formula (I) of more than 85%.

One embodiment of the invention is a process for the preparation of a compound of formula (I) which makes it possible to obtain the target product in a yield exceeding that of the methods described in the prior art and with a stereoisomeric excess of the compound of formula (I) of more than 90%.

One of the embodiments of the invention is a process for the preparation of a compound of formula (I) which makes it possible to obtain the desired product in a yield exceeding that of the methods described in the prior art and with a stereoisomeric excess of the compound of formula (I) of more than 95%.

One of the embodiments of the invention is a process for the preparation of a compound of formula (I) which makes it possible to obtain the target product in a yield exceeding that of the methods described in the prior art and with a stereoisomeric excess of the compound of formula (I) of more than 98%.

The stereoisomeric purity of the compounds of the present invention can be controlled by recrystallization of intermediates and target products in the synthesis. The following solvents, their deuterium derivatives or mixtures thereof can be used for recrystallization: alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, 2-butanol, iso-butanol, tert-butanol, amyl alcohol and its isomers, cyclohexanol, benzyl alcohol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, ketones such as acetone, butanone, methyl isobutyl ketone, 2-hexanone, cyclopentanone, cyclohexonone, ethers such as ethyl formate, methyl acetate, ethyl acetate, n -propyl acetate, iso-propyl acetate, n-butyl acetate, iso-butyl acetate, ethylene glycol diacetate, propylene glycol diacetate, glycerol triacetate, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, anisole, methyl tert-butyl ether, ethyl tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethoxymethane, diglyme, lactones such as butyrolactone, valerolactone, hydrocarbons such as n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane, benzene, toluene, xylenes, cumene, tetralin, limonene, turpentine, halocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, cis-dichloroethylene, trans-dichloroethylene, 1,1,2-trichloroethylene, 1,1,1-trichloroethane, 1 -chlorobutane, chlorobenzene, dichlorobenzene, aprotic polar solvents such as acetonitrile, propionitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylolethyleneurea, dimethylolpropyleneurea, dimethylsulfoxide, sulfolane, nitromethane, difunctional solvents such as methoxyethanol, ethoxyethanol, 1-methoxypropane-2- ol, furfuryl alcohol, tetrahydrofurfuryl alcohol, ethyl lactate, protic solvents such as water, acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, anhydrides such as acetic anhydride, ammonia, amines, such as pyridine, thiethylamine, as well as supercritical fluids such as carbon dioxide, water, methane, ethane, propane, ethylene, propylene, methanol, ethanol, acetone, nitrogen oxides, sulfur oxide, and/or mixtures thereof.

The control of the stereoisomeric purity of the compounds of the present invention can be carried out, including, but not limited to, using analytical HPLC.

Detailed description of the invention

The proposed method for obtaining (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3 -dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide according to one embodiment of the present invention provides for the preparation of a compound of the formula (I) according to the following synthesis scheme:

Compounds of formula (II) according to the present invention can be obtained by the following methods, but not limited to:

1) provided that R is chlorine or bromine:

- reacting a compound of formula (VII) with commercially available sulphurous acid halides (provided that the halogen is chlorine or bromine) in a suitable solvent, including, but not limited to, aprotic, in the presence of dimethylformamide, dimethylacetamide or N-methylpyrrolidone at a temperature -50 ^° C. to 50 ^° C. The resulting solution of the compound of formula (II) can be used in the next step without isolation and purification.

2) provided that R is fluorine:

- reacting a compound of formula (VII) with commercially available cyanuric acid fluoride (2,4,6-trifluoro-1,3,5-triazine) or TFFH (tetramethylfluoroformamidinium hexafluorophosphate) in a suitable solvent, including but not limited to an aprotic solvent , such as, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, ethyl acetate, or mixtures thereof, in the presence of tertiary amines, including, but not limited to, pyridine or quinoline, as well as tertiary amines of the formula R ₂ R ₃ R ₄ N, where R ₂ , R ₃ , R ₄ independently of each other represent C ₁ -C ₅ alkyl, in particular methyl, ethyl, propyl, isopropyl, etc., or when R ₂ with R ₃ together with a nitrogen atom form a C ₄ -C ₈ cycloalkyl group or a C ₄ -C ₈ heterocyclic group, where the heteroatom is oxygen, R ₄ is C ₁ -C ₅ alkyl, while R ₄ is connected to the nitrogen atom, at a temperature of -50 ^about C to 50 ^about C. Then, without heating, the reaction mixture is poured onto ice and extracted with a suitable solvent, the extract is washed with water, dried and evaporated.

A compound of formula (IV) is obtained by reacting a compound of formula (III) and a compound of formula (II) in a suitable organic solvent selected from the group, but not limited to, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, in the presence of an aqueous solution of an alkali or alkaline earth metal hydrogen carbonate, such as, but not limited to, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, etc., at a temperature from -10 ^° C to 50 ^° C. After the reaction is completed, the reaction mass is evaporated or diluted with water, acidified with an inorganic or organic acid to pH 0 to 6.9.

A compound of formula (VI) is obtained by reacting a commercially available compound of formula (V) or a salt thereof, including, but not limited to, the hydrochloride, and a compound of formula (IV) obtained in the previous step, in a suitable solvent, including an aprotic one, selected from the group, without being limited to the following: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), dichloromethane, ethyl acetate, etc., as well as mixtures thereof, in the presence of a compound of formula R ₁ O-CO-Cl, where R ₁ is C ₁ -C ₅ alkyl, in particular, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc., C ₁ -C ₅ alkyl substituted with halogen, such as, but not limited to, chlorine, bromine, fluorine, phenyl; phenyl substituted with halogen such as, but not limited to, chlorine, bromine, fluorine, nitro, C ₁ -C ₅ alkyl; benzyl substituted with halogen such as, but not limited to, chlorine, bromine, fluorine, nitro, C ₁ -C ₅ alkyl, and bases, including but not limited to pyridine, pyridine substituted with C ₁ -C ₅ alkyl , quinoline or quinoline substituted with C ₁ -C ₅ alkyl, a tertiary amine, including a tertiary amine of the formula R ₂ R ₃ R ₄ N, where R ₂ , R ₃ , R ₄ independently of each other represent C ₁ -C ₅ alkyl, in particular methyl, ethyl, propyl, isopropyl, etc., or when R ₂ with R ₃ together with a nitrogen atom form a C ₄ -C ₈ cycloalkyl group or a C ₄ -C ₈ heterocyclic group, where the heteroatom is is oxygen, R ₄ is C ₁ -C ₅ alkyl, with R ₄ bonded to a nitrogen atom, at -50 ^° C. to 50 ^° C.

Both one-stage and two-stage carrying out of the specified process is possible. In the case of a one-step process, to a solution or suspension containing a compound of formula (V) or a salt thereof, for example, a hydrochloride compound of formula (IV) and the specified base, for example, a tertiary amine in a suitable solvent, for example, aprotic, add the compound of formula R ₁ O-CO-Cl, described above, at a temperature of from -50 ^about C to 10 ^about C, and then maintain the resulting reaction mass at a temperature of from 10 ^about C to 50 ^about C until the end of the reaction.

In the case of a two-step process, to a solution of a compound of formula (IV) and a specified base, such as a tertiary amine, as defined above, in a suitable solvent, such as, but not limited to, an aprotic, is added a compound of formula R ₁ O-CO-Cl, as defined above, at temperature from -50 ^about C to 10 ^about C, and then maintain the resulting reaction mass at a temperature from -50 ^about C to 10 ^about C until the end of the reaction of formation of mixed anhydride. Then, a compound of formula (V) or a salt thereof, for example, hydrochloride, and the indicated base, for example, a tertiary amine, as described above, are added to the reaction mass at a temperature of from -50 ^° C. to 10 ^° C., and then the resulting reaction mass is kept at a temperature of from -10 ^o C to 50 ^o C until the end of the reaction.

Also in a two-step process, the reverse addition is possible, when to a solution of a compound of formula (IV) and a compound of formula R ₁ O-CO-Cl, as described above, in a suitable solvent, for example, but not limited to aprotic, add the specified base, for example, tertiary the amine described above at -50 ^° C. to 10 ^° C., and then holding the resulting reaction mass at a temperature of -50 ^° C. to 10 ^° C. until the mixed anhydride formation reaction is complete. Then, a compound of formula (V) or a salt thereof, for example, hydrochloride, and the specified base, for example, a tertiary amine, are added to the reaction mass at a temperature of from -50 ^° C to 10 ^° C, and then the resulting reaction mass is kept at a temperature of from 10 ^° C up to 50 ^° C until the end of the reaction. After completion of the reaction, the reaction mass is evaporated or diluted with water, the compound of formula (VI) is extracted with a suitable organic solvent immiscible with water.

The compound of formula (I) is obtained by reacting the compound of formula (VI) obtained in the previous stage, and 2,4,6-trichloro-1,3,5-triazine in a suitable solvent, for example, but not limited to, proton, selected from the group , including, but not limited to: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, at a temperature of 0 ^o C to 100 ^o C for 1.5-3.5 hours. After completion of the reaction, the reaction mass is evaporated or diluted with water, the compound of formula (I) is extracted with a suitable organic solvent immiscible with water.

The extracts obtained at each stage of the synthesis, if necessary, are washed with water, solutions of citric acid, sodium bicarbonate and/or sodium chloride solution, dried with dewatering agents such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated and the residue recrystallized from a suitable organic solvent, or purified by liquid chromatography, or used in the next step without further purification. At the same time, recrystallization of the product may include suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained, and subsequent cooling (including naturally at room temperature). Synthesis intermediates as well as the final compound of formula (I) of the present invention can also be isolated by precipitation by filtration.

The following are examples of the invention, which illustrate the invention, but do not cover all possible options for its implementation and do not limit the invention.

The person skilled in the art will understand that other particular embodiments of the invention are possible.

Example 1 Process for the preparation of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3 ,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compounds of formula (I)).

In a particular embodiment of the present invention, compounds of formula (II) were prepared as follows: a 25.00 ml round bottom flask was charged with a compound of formula (VII) (170.30 mg, 0.74 mmol) and 2.00 ml of dichloromethane was added. The reaction mixture was cooled to -15° C. and cyanuric fluoride (2,4,6-trifluoro-1,3,5-triazine) (335.00 μl, 3.7 mmol) was added. The reaction mixture was stirred at -15°C for 15 minutes, then anhydrous pyridine (60 μl, 0.74 mmol) was added. Stirring was maintained at -15 ^° C. for 60 minutes. Without heating, the crude reaction mixture was poured onto ice and immediately extracted twice with dichloromethane. The combined extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give compound (II).

Next, 15.50 g of the compound of formula (III) was added to 100.00 ml of dichloromethane in the presence of 370.00 ml of a 5% aqueous solution of sodium hydrogen carbonate (2.20 equivalents), stirred until complete dissolution. Then, a solution of the compound of formula (II), obtained earlier, was added dropwise at a temperature from 0 ^° C. to 5 ^° C. After the reaction was completed, the reaction mass was diluted with water and acidified with hydrochloric acid to pH 5.0. After acidification, the dichloromethane layer was separated and the compound of formula (IV) was further extracted with dichloromethane from the aqueous layer. The extract was washed with water and citric acid solution, dried over calcium chloride, evaporated to constant weight, and the residue was recrystallized from heptane. The output was 96% of the intermediate product of the compound of formula (IV) with a stereoisomeric purity of more than 97%.

Further, 36.40 g of the compound of formula (IV) obtained in the previous step and 20.80 g of the compound of formula (V) were dissolved in 250.00 ml of ethyl acetate and 22.20 g (2.20 equivalents) of N-methylmorpholine were added. The reaction mass was stirred until ^dissolved , and then 15.00 g (1.10 equivalents) of isobutyl chloroformate were added dropwise at 0 ^° C. After completion of the reaction, the reaction mass was evaporated to constant weight, the resulting compound of formula (VI) was extracted with ethyl acetate, the extract was washed with water and solutions of citric acid, sodium chloride, and then evaporated to constant weight. The resulting compound of formula (VI) was used in the next step without purification.

Next, 51.70 g of the compound of formula (VI) obtained in the previous step was mixed with 500.00 ml of N-methylpyrrolidone and 9.22 g (1.50 equivalents) of 2,4,6-trichloro-1,3,5 was added with stirring -triazine at a temperature of 25 ^about C. After the end of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45 ^about C and a residual pressure of 30 mbar, and was extracted with ethyl acetate.

The extract obtained was washed with a sodium bicarbonate solution, evaporated and recrystallized from heptane, followed by vacuum drying at a temperature of 40 ^° C and a residual pressure of 10 mbar. After drying, the expected product compound of formula (I) was obtained in the form of a powder with a yield of 95%.

Identification of the compound of formula (I) was carried out by analytical methods: ¹ H NMR, ¹³ C NMR and mass spectral analysis.

¹ H NMR (600 MHz, DMSO-d6) δ 9.41 (d, J = 8.4 Hz, 1H), 9.05 (d, J = 8.6 Hz, 1H), 7.60 (s, 1H), 4.91 (ddd, J = 10.9 , 8.6, 5.1 Hz, 1H), 4.40 (d, J = 8.4 Hz, 1H), 4.15 (s, 1H), 3.90 (dd, J = 10.4, 5.5 Hz, 1H), 3.75 (d, J = 10.4 Hz , 1H), 3.11 (t, J = 9.1 Hz, 1H), 3.09 (td, J = 9.4, 7.1 Hz, 1H), 2.41 (tdd, J = 10.4, 8.4, 4.4 Hz, 1H), 2.28–2.02 ( m, 2H), 1.75 – 1.65 (m, 2H), 1.56 (dd, J = 7.6, 5.4 Hz, 1H), 1.30 (d, J = 7.6 Hz, 1H), 1.08 (s, 3H), 0.99 (s , 9H), 0.85 (s, 3H).

¹³ C NMR (151 MHz, DMSO-d6) δ 178.15, 171.27, 167.95, 158.13, 157.66, 157.22, 156.66, 120.00, 118.25, 116.92, 114.42, 60.57, 58 .69, 48.15, 38.35, 37.17, 35.08, 34.66, 30.79, 27.81, 27.38, 26.75, 26.17, 19.31, 12.80.

Mass spectrum: m/z calculated for C ₂₃ H ₃₃ F ₃ N ₅ O ₄ [M+H] ⁺ 500.2474, found 500.2475.

It should also be noted that Burgess reagent, trifluoroacetic anhydride, phosphorus trichloroxide and 2,4,6-tripropyl-1,3,5,2 ,4,6-trioxatrifosfinan 2,4,6-trioxide. The authors of the present invention have made a number of experiments to study this reaction using various reagents. It was found that the yield of the desired product of the compound of formula (I) by dehydration of the amide group of the compound of formula (VI) by methods known in the art did not exceed 50%, in contrast to the yield of the compound of formula (I) obtained by the method of the present invention. Some experimental results are presented in Table 1.

Table 1. Study of the dehydration of the amide group of the compound of formula (VI) under various reaction conditions.

Comparative Example Reagent Conditions Exit 1 phosphorus trichloride/imidazole in pyridine -30 ^o C / 3.0 h, followed by heating to 0 ^o C 43% 2 Burgess reagent / dichloromethane 20-25 ^about C / 3.0 h 41% 3 trifluoroacetic anhydride / methylmorpholine / dichloromethane 0 ^° C, followed by heating to 20-25 ^° C / 2.0 h 42% 4 phosphorus trichloride / 4-methylmorpholine -25 ^o C / 2.0 h, followed by heating to 0 ^o C 35% 5 N,N-diisopropylethylamine / tetrahydrofuran / 2,4,6-tripropyl-1,3,5,2,4,6-trioxatrifosfinan 2,4,6-trioxide 45-50 ^o C / 3.5 h 23% 6 (according to the present invention) 2,4,6-trichloro-1,3,5-triazine/ N-methylpyrrolidone 25 ^o C over 95%

Example 2 Preparation of a product containing (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S) -3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (compound of formula (I)) .

A measured amount of the powder of the compound of formula (I) obtained in example 1 was placed with stirring into a reactor equipped with a stirrer, a jacket, a reflux condenser, a thermometer and a pressure gauge, in a nitrogen atmosphere, where a measured amount of isopropyl alcohol was previously loaded. At the end of the download, the resulting suspension was stirred at a temperature of 40 ^about With until complete dissolution of the compounds of formula (I). The resulting solution was then filtered on a suction filter. The filtrate was fed into a crystallizer equipped with a jacket, a thermometer, a stirrer, and a reflux condenser. With continuous stirring, a measured amount of heptane was fed into the crystallizer under a nitrogen atmosphere. Stirring was continued at room temperature. The suspension was cooled to a temperature of 20 ^about C and stirred at the set temperature for 7-10 hours to completely precipitate the compounds of formula (I), after which the resulting suspension was transferred to the centrifugation stage. The resulting precipitate of the compound of formula (I) was washed with water, followed by drying in a cone vacuum dryer at a temperature of 40 ^° C. and a residual pressure of 7 mbar for 5 hours. Next, the resulting powder was loaded into the hopper of the mill for grinding. As a result, a product was obtained in the form of a powder containing compound (I) with a chemical purity of more than 99% and its stereoisomeric purity of 100%.

Claims (47)

1. A process for the preparation of a compound of formula (IV) which comprises reacting a compound of formula (II) with a compound of formula (III) in the presence of an aqueous solution of an alkali or alkaline earth metal hydrogen carbonate, provided that R is a halogen selected from chlorine, bromine or fluorine

2. The method according to p. 1, in which the reaction takes place in an organic solvent medium. 3. The method according to claim 2, wherein water-immiscible solvents are used as the organic solvent. 4. The method according to claim 2, in which dichloromethane, ethyl acetate, acetonitrile or tetrahydrofuran is used as the organic solvent. 5. The method according to claim 1, wherein sodium hydrogen carbonate or potassium hydrogen carbonate is used as the alkali metal hydrogen carbonate. 6. The method of claim 1 wherein the alkaline earth metal hydrogen carbonate is magnesium hydrogen carbonate or calcium hydrogen carbonate. 7. The method according to p. 1, in which the reaction is carried out at a temperature in the range from -10 to 50°C. 8. The method according to p. 7, in which the reaction is carried out at a temperature in the range from 0 to 10°C. 9. A process for the preparation of a compound of formula (I), which includes the following steps: a) interaction of a compound of formula (V) or a salt thereof with a compound of formula (IV) obtained by the method according to paragraphs. 1-8 using a compound of formula R ₁ O-CO-Cl, where R ₁ is C ₁ -C ₅ alkyl; C ₁ -C ₅ alkyl substituted with halogen; phenyl; phenyl substituted with halogen, nitro or C ₁ -C ₅ alkyl; benzyl substituted with halogen, nitro or C ₁ -C ₅ alkyl in the presence of a base to give a compound of formula (VI)

b) dehydration of the compound of formula (VI) using 2,4,6-trichloro-1,3,5-triazine to form a compound of formula (I)

10. The method of claim 9, wherein steps a) and b) are carried out in an organic solvent. 11. The method of claim 10 wherein the solvent is an aprotic organic solvent. 12. The method of claim 11 wherein the organic solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, ethyl acetate, or mixtures thereof. 13. The method of claim 9, wherein the compound of formula R ₁ O-CO-Cl is selected from the group consisting of methyl chloroformate, ethyl chloroformate, propyl chloroformate, butyl chloroformate, isobutyl chloroformate, or t-butyl chloroformate. 14. The method of claim 9, wherein an organic base is used as the base. 15. The method according to p. 14, in which pyridine is used as the base; pyridine substituted with C ₁ -C ₅ alkyl; quinoline or quinoline substituted with C ₁ -C ₅ alkyl. 16. The method of claim 15 wherein the organic base is a tertiary amine. 17. The method according to p. 16, in which the tertiary amine is a compound of formula R ₂ R ₃ R ₄ N, where R ₂ , R ₃ , R ₄ independently of each other represent C ₁ -C ₅ alkyl or when R ₂ with R ₃ together with the nitrogen atom form a C ₄ -C ₈ cycloalkyl group or C ₄ -C ₈ heterocyclic group, where the heteroatom is oxygen, R ₄ is C ₁ -C ₅ alkyl. 18. The method of claim 16, wherein the tertiary amine is a compound of the formula R ₂ R ₃ R ₄ N, where R ₂ , R ₃ , R ₄ are independently selected from the group consisting of methyl, ethyl, propyl, or isopropyl. 19. The method of claim 16 wherein the tertiary amine is N-methylformalin or triethylamine. 20. The method according to p. 9, in which stage a) is carried out at a temperature in the range from -50 to 50°C. 21. The method according to p. 20, in which stage a) is carried out at a temperature in the range from -40 to 40°C. 22. The method according to p. 21, in which stage a) is carried out at a temperature in the range from -30 to 30°C. 23. The method according to p. 22, in which stage a) is carried out at a temperature in the range from -20 to 20°C. 24. The method according to p. 23, in which stage a) is carried out at a temperature in the range from -10 to 10°C. 25. The method according to p. 24, in which stage a) is carried out at a temperature in the range from -5 to 5°C. 26. The method according to p. 9, in which a compound of formula R ₁ O-CO-Cl is added to a solution of a compound of formula (IV) in the presence of a base, where R ₁ is C ₁ -C ₅ alkyl, C ₁ -C ₅ alkyl, substituted with halogen; phenyl; phenyl substituted with halogen, nitro or C ₁ -C ₅ alkyl; benzyl substituted with halogen, nitro group or C ₁ -C ₅ alkyl at a temperature of from -50 to 10°C and maintained, then a compound of formula (V) or its salt and base are added to the reaction mass at a temperature of from -50 to 10°C , and then maintain the resulting reaction mass at a temperature of from -10 to 50°C until the end of the reaction. 27. The method according to p. 26, in which to a solution of the compounds of formula (IV) in the presence of a base add compounds of the formula R ₁ O-CO-Cl, where R ₁ represents C ₁ -C ₅ alkyl; C ₁ -C ₅ alkyl substituted with halogen; phenyl; phenyl substituted with halogen, nitro or C ₁ -C ₅ alkyl; benzyl, substituted by halogen, nitro group or C ₁ -C ₅ alkyl, at a temperature of -30 to -15 ° C and maintained, then a compound of formula (V) or its salt and base are added to the reaction mass at a temperature of -25 ° to - 15°C, and then maintain the resulting reaction mass at a temperature of from -5 to 5°C until the end of the reaction. 28. The method according to p. 9, in which stage b) is carried out at a temperature in the range from 0 to 100°C. 29. The method according to p. 28, in which stage b) is carried out at a temperature in the range from 15 to 25°C. 30. The method according to paragraphs. 9-29, wherein step a) and/or b) further comprises the following steps: c) isolating the product, and/or d) washing the recovered product, and/or e) drying the product. 31. The method according to p. 30, in which stage c) is carried out by precipitation or extraction. 32. The method of claim 30 wherein step c) is carried out by filtration. 33. The method of claim 30, wherein step d) further comprises the step of recrystallizing the product from an organic solvent. 34. The method according to claim 30, wherein step d) is carried out with water, citric acid solution or aqueous sodium hydrogen carbonate solution. 35. The method according to claim 33, where the step of recrystallization of the resulting product includes suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained, and then cooling. 36. The method of claim 35 wherein the cooling is performed naturally at room temperature. 37. The method of claim 30, wherein step d) further comprises the step of purifying the product by chromatography. 38. The method of claim 30 wherein step e) is a drying step under reduced pressure. 39. Application of the method according to paragraphs. 9-38 for batch chemical industrial production, semi-continuous industrial production or continuous industrial production of the compound of formula (I).