WO2023200364A1 - Methods 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 - Google Patents

Abstract

The group of inventions relates to the field of medicine, pharmacology and the chemical and pharmaceutical industry, and more particularly to novel improvements to methods for producing (1R,2S,5S)-N-[(3S)-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)), as well as to methods for producing intermediate products for use in the method for producing the compound of formula (I).

Description

METHODS FOR PREPARATION (lR,2S,5S)-N-[(lS)-l-IXHAHO-2-[(3S)-2-OXOPYRROLIDIN-3-YL]ETHYL]-3-[(28)-3,3- DIMETHYL-2-[(2,2,2-TRIFLUROACETYL)AMINO]BUTANOYL]-6,6-DIMETHYL-3-AZABICYCLO[3.1.0]HEXANE-2-CARBOXAMIDE

DESCRIPTION

The invention relates to the field of medicine, pharmacology and the pharmaceutical chemical industry, namely, to new improved methods for producing (1K,28,58)-M-[(18)-1-cyano-2-[(38)-2-oxopyrrolidine-3 -yl]ethyl]-3-[(28)-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 methods for preparing intermediates for use in methods for producing compounds of formula (I).

Prerequisites for creating the invention. Field of technology.

One of the most pressing 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 approximately 40 new infectious diseases discovered since the 1970s. Some of the most dangerous among new emerging viruses are RNA viruses, notable examples of which over the past 20 years are: severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002-2003, influenza (swine flu) A/H1N1 in 2009 ., the Middle East respiratory syndrome (MERS) coronavirus in 2012, the Ebola virus disease epidemic in 2013-2015, the Zika virus pandemic in 2016-2017, 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 as new epidemics emerge (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 the picornavirus-like supercluster, which includes viruses belonging to the families Picomaviridae, Caliciviridae and Coronaviridae. A common feature of the viruses of the picornavirus-like supercluster is that they use 3S or 3S-like protease (3Crgo or 3Crgo, respectively) in their metabolism. Conserved sites 3Crgo or 3Spro may serve as attractive targets for the development of broad-spectrum antiviral drugs for viruses in the picornavirus-like supercluster. (Yunjeong Kim et al. Broad-Spectrum Antivirals against 3C or ZS-Like Proteases of Picomaviruses, 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 recorded every day. As of October 11, 2021, the number of cases totaled 251 million people, and deaths crossed the line of 5 million people. Since the onset of the global pandemic, the toll has taken a heavy toll on both global human health and the global economy. The pandemic has posed 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 requires the creation of new drugs. In addition to existing therapies, specific drugs are needed that have a direct effect on the virus, leading to alleviation of the symptoms of the disease, accelerated resolution of the disease, blocking the transmission of infection and reducing the risk of developing clinical complications.

One promising way to block the SARS-CoV2 virus is to inhibit the SARS-CoV2 protease, also called 3CL-like protease (3CL or 3CLrgo). Inhibition of 3CL protease results in the prevention of viral replication. (^,28.58)- -[(18)-1-cyano-2-[(38)-2-oxopyrrolidin-3-yl]ethyl]-3-[(28)-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), suppresses the activity of the cysteine residue in the protease stages of proteolysis. 3clrgo is responsible for the process of cleavage of viral lipoproteins containing 3clrgo itself, PLrgo (papain-like protease) and 14 other proteins. The molecule showed high antiviral activity in preclinical studies using a mouse model adapted to SARS-CoV-2. In addition, it is known from the prior art that (lR,2S,5S)-N-[(lS)-l-4HaHO-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(28 )-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 inhibitory properties There is no 3S-like protease SARS-CoV-2 only, highlighting the possibility of use for other human viruses.

Compound of formula (I)

When developing drugs, 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 control the quality of the active agent is to develop a unique synthetic protocol. The synthesis of the active agent makes it possible to regulate 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 during chemical transformations; stereoisomeric purity; etc.

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 effectiveness in both human and veterinary medicine. Increasing the chemical purity of a substance improves its original biological properties and reduces possible side effects associated with the presence of impurities.

The development of new approaches to the synthesis of the active agent opens up the possibility of improving the profile of the physicochemical and technological characteristics of the pharmaceutical product. This expands the range of active agents that a 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 allows the introduction of environmental, resource-efficient, atom-efficient innovative technologies into production that contribute to economic development and minimization of environmental damage.

Thus, there is currently a constant 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 national goals and strategic objectives of the development of the Russian Federation for the period until 2024” within the framework program for import substitution "Pharma-2030" the authors of the present invention made efforts to create an innovative method for producing the antiviral compound (^,28,58)-M-[(18)-1-cyano-2-[(38)-2-oxopyrrolidine -3-yl]ethyl]-3-[(28)-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)).

Important intermediates in the synthesis of a compound of formula (I) are compounds of formula (IV), formula (IV') and formula (II):

Compound of formula (IV'),

Compound of formula (II).

Prior art.

Several methods are known from the prior art for the synthesis of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(38)-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.

In the state of the art (Owen DR 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 the solvated methyl tert-butyl ether form of the compound of formula (I) followed by conversion to the free form by the action of heptane with isopropyl acetate. In this case, the previous stage is the preparation of an intermediate product through the reaction of (1K,28,58)-6,6-dimethyl-3-[3-methyl-1 -(trifluoroacetyl)-valyl]-3-azabicyclo[3.1.0] hexane-2-carboxylic acid with 3-[(38)-2-oxopyrrolidin-3-yl]-b-alaninamide 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 the Burgess reagent;

IP A - isopropanol;

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

DIEA-M,1-diisopropylethylamine;

DMF-dimethylformamide; THF-tetrahydrofuran;

Dioxane- dioxane;

DCM-dichloromethane;

EDC1-1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

HOPO-2-hydroxypyridine-M-oxide;

MEK - methyl ethyl ketone;

MTBE-methyl tert-butyl ether;

IP AC - 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 scale production. Moreover, such reagents form by-products during the synthesis process: the use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is accompanied by the formation of the following by-products (products of the addition of the carbodiimide group to the amine and internal acylation products (acylureas): Application WO2021250648 describes the synthesis of a compound of formula (I), which is the reaction of methyl (1K,28.58)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride salt with O-(7- azabenzotriazol-1-yl)-M,M,Ni,Ni-tetramethyluronium hexafluorophosphate and M-(tert-butoxycarbonyl)-3-methyl-b-valine in the presence of N,N-dimethylformamide, followed by the addition of lithium hydroxide to the resulting product in the presence a mixture of tetrahydrofuran and methanol, followed by mixing the resulting product with (28)-2-amino-3-[(38)-2-oxopyrrolidin-3-yl]propanenitrile methanesulfonate salt in acetonitrile with the sequential addition of O-(7-azabenzotriazol-1 -nn)-N,N,N',N'-tetramethyluronium hexafluorophosphate, solution of 4-methylmorpholine in acetonitrile. The last stage of the synthesis involves the addition of methanesulfonic acid to the product obtained in the previous stage, in 1,1,1,3,3,3-hexafluoropropan-2-ol, with further concentration in a mixture of solvents acetonitrile/ethyl acetate and ethyl acetate/heptane, followed by dissolution in dichloromethane and treatment with 4-methylmopholine and trifluoroacetic anhydride.

, where HATU- O-(7-azabenzotriazol-1-yl)-M,M,K’,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 the 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)-M,LH,L1',LH-tetramethyluronium hexafluorophosphate and diisopropylethylamine.

The authors of the invention would also like to note that when the intermediate product in the said synthesis reacts with sodium hydroxide, trifluoroacetyl is eliminated, which contradicts what is indicated in the synthesis (Albert Isidro-Llobet et al. Amino Acid-Protecting Groups // Chem. Rev. - 2009.- 109, 6.- p. 2455-2504). , where HATU is O-(7-azabenzotriazol-1-yl)-M,M,N',K'-tetramethyluronium hexafluorophosphate;

DIPEA-ID -diisopropylethylamine;

DMF-dimethylformamide.

At the same time, the main disadvantages of the syntheses of the compound of formula (I) indicated in the prior art is the use of expensive toxic reagents, including 2-hydroxypyridine-1-oxide, O-(7-azabenzotriazol-1-yl)-M,H,LG, 1'-tetramethyluronium hexafluorophosphate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, which are used only for synthesis in laboratory conditions, which does not allow scaling up the synthesis into industrial production. Moreover, such reagents form by-products during the synthesis process: the use of O-(7-azabenzotriazol-1-yl)-M, ,N,M'-tetramethyluronium hexafluorophosphate is accompanied by the formation of the by-product tetramethylurea, which has a hazard class of teratogenicity and cannot be further treated recycling, which has an extremely negative impact on the environment. When methyl (lR,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (C AS 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 at all stages of the synthesis, which is impractical for industrial production.

Disclosure of the Invention

The objective of the present invention is to develop new, improved, environmentally friendly, safe methods for obtaining a compound of formula (I) with 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 new, improved syntheses of intermediates in the synthesis of the compound of formula (I).

As a result of research, the authors of the present invention have developed new ones adapted for industrial production, improved compared to methods for producing compounds of formula (I) known in the prior art, including, in particular cases of the present invention, new stages of obtaining intermediate products, namely, compounds of formula (IV), formula (IV') and formula (II), suitable for industrial production. At the same time, the inventors unexpectedly discovered that the methods for preparing the compound of formula (I) of the present invention make it possible to obtain the target product (compound of formula (I)) with a total yield of all stages exceeding the yield in the methods described in the prior art for producing the compound of formula ( I). Also, in the course of research, the inventors were able to develop new methods for the preparation of intermediates (compounds of formula (IV), formula (IV') and formula (II)), as a result of which they obtained stereoisomerically pure intermediates (compounds of formula (IV), formula (IV') and formula (II)) 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 compound of formula (I);

- adaptation of methods for obtaining compounds of formula (I) for industrial production;

- reduction of time and economic costs for carrying out syntheses;

- ensuring environmentally friendly production;

- reducing the formation of undesirable impurities during syntheses.

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

Unless otherwise specified, all technical and technical terms used in this context have their common meaning in the art.

The term “comprising”, “contains”, “including” in the context of the present invention means that the specified pharmaceutical formulations, products, compositions and drugs include the listed components, but do not exclude the inclusion of other components, and also the specified methods for obtaining the compounds include the listed synthesis steps , but do not exclude the inclusion of others.

The term "effective amount" in the context of the present invention means an amount of a substance (as well as a combination of substances) that, 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 produce the effect of such treatment and/or prevention for 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 receiving such treatment (prevention) is necessary.

As used herein, the terms "about" or "about" mean approximately plus or minus ten percent of the stated value.

The term "impurities" in the context of the present invention is any component in the synthesis product that 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 reagents used in the synthesis of starting substances, by-products, decomposition or polymerization products, reagents, ligands, structural or spatial isomers, catalysts, technological equipment, filter material residues, insufficiently purified starting materials 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 relative to the total amount of the sample. Chemically pure in the present invention is a substance whose chemical purity is 97.0% or more, more preferably 98.0% or more, and especially 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 different spatial arrangements of atoms or groups of atoms relative to the bonds, while isomeric compounds are not are interchangeable. Unless otherwise specified, the chemical designation of a compound includes a 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. Except where otherwise indicated, all stereoisomeric forms of the compounds used herein are intended to be invention, both in pure (individual) form and in mixture with each other, are included within the scope of the present invention.

The term "diastereomers" refers to stereoisomers whose structure contains two or more asymmetric carbon atoms, 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 at one stereocenter, then such stereoisomers are diastereomers.

The term "enantiomers" refers to stereoisomers whose structure contains one or more asymmetric carbon atoms, namely carbon atoms attached to four different substituents, provided that the pair of these stereoisomers are mirror images of each other, not superimposed in space. If two stereoisomers have opposite configurations of all corresponding 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 the other. A stereoisomeric pure substance of 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% or greater 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 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 stereoisomeric 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 suitable starting materials, provided that the reaction proceeds stereoselectively. If a specific stereoisomer is desired, said compound will preferably be synthesized by stereoselective preparation methods. These methods will advantageously use stereoisomerically pure starting materials.

One of the main methods for monitoring the stereoisomeric purity of the chemical compounds of the present invention is the high performance liquid chromatography (HPLC) method, which is based on the 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 reduced particle size (eg, less than 2 microns) 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 intermolecular interactions that occur. Each of these types can be highly efficient if the chromatography is performed using high pressure column chromatography.

Another way to separate isomers can be recrystallization. Recrystallization is a method of purifying compounds from various impurities (for example, related, technological), based on the difference in solubility of substances in various solvents or their mixtures at different temperatures. One option for performing recrystallization is to add an antisolvent (solvent in which the substance has low solubility) to the solution of a substance, as a result of which the dissolving ability of the medium deteriorates and the dissolved substance passes from solution to solid form. The advantages of the recrystallization method are a high degree of purification, but in some cases the disadvantage may be a high loss of substance.

Within the framework of the present invention, the problem is solved, and the stated technical results are achieved through new methods for obtaining the compound of formula (I).

One embodiment of the present invention is a method for preparing a compound of formula (I), which includes dehydrating a compound of formula (II) to form a compound of formula (I) using 2,4,6-trichloro-1,3,5-triazine in a solvent environment , carried out according to the following scheme: The stated problem is solved, and the stated technical results are achieved by means of a new method for producing a compound of formula (I), which includes dehydration of a compound of formula (II) obtained by any of the methods of the present invention, with the formation of a compound of formula (I) using 2, 4, 6-trichloro-1, 3,5-triazine in a solvent environment, according to the following scheme:

One embodiment of the invention is a method for preparing a compound of formula (I), which includes dehydrating the amide group of a compound of formula (II) to form a compound of formula (I) using 2, 4, 6-trichloro-1, 3,5-triazine in a medium solvent.

One embodiment of the invention is a method for producing a compound of formula (I), in which N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone is used as a solvent.

One embodiment of the invention is a method for preparing a compound of formula (I), in which the dehydration of a compound of formula (II) is carried out at a temperature in the range from 0°C to 100°C, more preferably from 15°C to 25°C.

One embodiment of the invention is a method for producing a compound of formula (I), in which the step of dehydration of a compound of formula (II) additionally includes the following stages: a) isolation of the product; b) washing the isolated product; c) drying the product.

One embodiment of the invention is a method for preparing a compound of formula (I), wherein the step of dehydrating the compound of formula (II) additionally includes the following steps: a) isolating the product and/or b) washing the isolated product; and/or c) drying the product.

One embodiment of the invention is a method for producing a compound of formula (I), in which the step of dehydration of a compound of formula (II) additionally includes the following steps: a) isolating the target product and/or b) washing the isolated target product; and/or c) drying the target product.

More preferably, the additional step a) of isolating the product is carried out by precipitation or extraction.

More preferably, the additional step a) of isolating the product is carried out by filtration.

More preferably, the additional step a) of isolating the product is carried out by precipitation followed by filtration.

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

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

One embodiment of the invention is a method for producing a compound of formula (I), in which the step of dehydrating the compound of formula (II) additionally includes the following steps: a) isolating the product and/or b) washing the isolated product and/or; c) drying the product, where the step of washing the isolated product further includes the step of recrystallizing the product from an organic solvent.

More preferably, the step of recrystallizing 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.

More preferably, cooling occurs naturally at room temperature.

One embodiment of the invention is a method for producing a compound of formula (I) (target product), in which the stage of dehydration of a compound of formula (II) additionally includes the following stages: a) isolating the target product and/or b) washing the isolated target product and/or; c) drying the target product, where the step of washing the isolated target product further includes a step of recrystallizing the target product by suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained and then cooling naturally at room temperature.

One embodiment of the invention is a method for producing a compound of formula (I), in which the step of dehydrating the compound of formula (II) additionally includes the following steps: a) isolating the product and/or b) washing the isolated product and/or; c) drying the product, where the step of washing the product further includes a step of purifying the product by chromatography.

Within the framework of the present invention, the stated problem is solved, and the stated technical results are achieved by means of a new method for obtaining a compound of formula (IV), which involves the interaction of a compound of formula (II'), obtained by any method according to the present invention or commercially available, with a compound of formula (III) in 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, according to the following synthesis scheme:

One embodiment of the present invention is a method for preparing a compound of formula (IV), in which the reaction of a compound of formula (1D) with a compound of formula (III) takes place in an organic solvent.

More preferably, to obtain the compound of formula (IV), water-immiscible solvents are used as said organic solvent.

More preferably, to prepare the compound of formula (IV), the organic solvent in said reaction is, but is not limited to, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or mixtures thereof.

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

One embodiment of the present invention is a method for producing a compound of formula (IV), in which the reaction of a compound of formula (1D) with a compound of formula (III) takes place in the presence of an aqueous solution of an alkaline earth metal bicarbonate, where magnesium bicarbonate or calcium bicarbonate is used as the alkaline earth metal bicarbonate .

One embodiment of the invention is a method for preparing a compound of formula (IV), which is carried out at a temperature in the range from -10°C to 50°C, more preferably from -5°C to 40°C, more preferably from -5°C to 30°C, more preferably -5°C to 20°C, more preferably -5°C to 10°C, more preferably -5°C to 5°C, more preferably 0°C to 10°C .

при условии, что когда Rf представляет собой водород, R2’ представляет собой третбутил, реакцию проводят в присутствии соединения формулы RiO-CO-Cl, где Ri представляет собой С1-С5 алкил; С1-С5 алкил, замещенный галогеном; фенил; фенил, замещенный галогеном, нитро группой, С1-С5 алкилом или бензил, замещенный галогеном, нитро группой, С1-С5 алкилом. Более предпочтительно соединение формулы RiO-CO-Cl по настоящему изобретению характеризуется формулой RiO-CO-Cl, где Ri представляет собой С1-С5 алкил; С1-С5 алкил, замещенный галогеном, таким как, не ограничиваясь указанным, хлор, бром, фтор; фенил; фенил, замещенный галогеном, таким как, не ограничиваясь указанным, хлор, бром, фтор, нитро группой или С1-С5 алкилом; бензил, замещенный галогеном, таким как, не ограничиваясь указанным, хлор, бром, фтор, нитро группой или С1-С5 алкилом. Within the framework of the present invention, the stated problem is solved, and the stated technical results are also achieved through a new method for obtaining a compound of formula (IV), which includes the interaction of a compound of formula (I”), obtained by any method according to the present invention or commercially available, with a compound of formula (PG) or salts thereof in an organic solvent in the presence of a base, provided that R]' is selected from the group: pentafluorophenyl, succinimidyl, R2' represents hydrogen; when Rf is hydrogen, R2' is tert-butyl, according to the following synthesis scheme:

with the proviso that when Rf is hydrogen, R2' is tert-butyl, the reaction is carried out in the presence of a compound of the formula RiO-CO-Cl, wherein Ri is C1-C5 alkyl; C1-C5 alkyl substituted with halogen; phenyl; phenyl substituted with halogen, nitro group, C1-C5 alkyl or benzyl substituted with halogen, nitro group, C1-C5 alkyl. More preferably, the compound of formula RiO-CO-Cl of the present invention is characterized by the formula RiO-CO-Cl, where Ri represents C1-C5 alkyl; C1-C5 alkyl substituted with halogen, such as, but not limited to, chlorine, bromine, fluorine; phenyl; phenyl substituted with a halogen such as, but not limited to, chlorine, bromo, fluorine, nitro or C1-C5 alkyl; benzyl substituted with a halogen such as, but not limited to, chlorine, bromo, fluorine, nitro or C1-C5 alkyl.

More preferably, the compound of formula RiO-CO-Cl of the present invention is selected from the group consisting of, but not limited to, methyl chloroformate, ethyl chloroformate, propyl chloroformate, butyl chloroformate, isobutyl chloroformate, or tert-butyl chloroformate.

More preferably, an aprotic solvent is used as an organic solvent in the reaction to produce a compound of formula (IV) by reacting a compound of formula (P”) with a compound of formula (PG).

More preferably, the organic solvent in the reaction to produce a compound of formula (IV) by reacting a compound of formula (II”) with a compound of formula (PG) is, but is not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, ethyl acetate or mixtures thereof .

More preferably, an organic base, such as, but not limited to, pyridine, is used as a base in the reaction to produce a compound of formula (IV) by reacting a compound of formula (P”) with a compound of formula (PG) of the present invention; pyridine substituted with C1-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl; tertiary amine

More preferably, the tertiary amine of the present invention is, but is not limited to, a compound of the formula R2R3R4N, wherein R2, R3, R4 independently represent a C-C5 alkyl group or, when R2 and R3 together with a nitrogen atom form a C4-C8 cycloalkyl group or a C -Cya heterocyclic group, where the heteroatom is oxygen and R4 is C1-C5 alkyl.

More preferably, the tertiary amine of the present invention is, but is not limited to, a compound of the formula R2R3R4N, wherein R2, R3, R4 independently represent a C1-C5 alkyl group or, when R2 and R3 together with a nitrogen atom form a C4-C8 cycloalkyl group or a C4-C8 heterocyclic group, wherein the heteroatom is oxygen, R4 is C1-C5 alkyl, and R4 is bonded to a nitrogen atom. More preferably, the tertiary amine of the present invention is, but is not limited to, a compound of the formula R2R3R4N, wherein R2, R3, R4 are independently selected from the group consisting of methyl, ethyl, propyl or isopropyl.

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

One embodiment of the invention is a method for producing a compound of formula (IV), in which the reaction of a compound of formula (P”) with a compound of formula (PG) or a salt thereof is carried out at a temperature in the range from -50°C to 50°C, more preferably -40°C to 40°C, more preferably -30°C to 30°C, more preferably -20°C to 25°C, more preferably 0°C to 25°C, more preferably -5 °C to 5°C, more preferably 0°C to 20°C.

One embodiment of the present invention is a method for producing a compound of formula (IV), in which a hydrochloride or a calcium salt is used as salts of the compound of formula (PG).

One embodiment of the invention is a method for preparing a compound of formula (IV), wherein, provided that when Rf is hydrogen, R2' is tert-butyl, the compound of formula (PG) is used in the form of a hydrochloride salt.

One embodiment of the invention is a method for preparing a compound of formula (IV), in which, provided that Rf is succinimidyl, R2' is hydrogen, the compound (PG) is used in the form of a calcium salt.

One embodiment of the invention is a method for preparing a compound of formula (IV), wherein the step of reacting a compound of formula (P") with a compound of formula (PG) or a salt thereof further includes the subsequent step of removing the protecting group by adding an anhydrous strong acid, provided that Ri' represents hydrogen, R2' represents tert-butyl.

One embodiment of the invention is a method for preparing a compound of formula (IV), in which the additional step of deprotection is carried out at a temperature from -10°C to 50°C, more preferably from -5°C to 40°C, more preferably from - 5°C to 30°C, more preferably -5°C to 20°C, more preferably -5°C to 10°C, more preferably 0°C to 10°C.

One embodiment of the invention is a method for preparing a compound of formula (IV) by reacting a compound of formula (P”) with a compound of formula (IG) or a salt thereof, wherein, provided that R is hydrogen and R2' is tert-butyl, the reaction is carried out in the presence of a compound of formula RiO-CO-Cl as defined above and an anhydrous strong acid, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid or phosphoric acid.

The stated problem is solved, and the stated technical results are achieved through a new method for obtaining a compound of formula (I), which includes the following stages: a) the interaction of a compound of formula (V) or its salt, including, but not limited to, the hydrochloride, with a compound of formula (IV) prepared by any method of the present invention using a compound of formula RiO-CO-Cl as defined above in the presence of a base to obtain a compound of formula (II)

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

One embodiment of the invention is a method for preparing a compound of formula (I), in which steps a)' and b)' are carried out in an organic solvent.

More preferably, the organic solvent in said reaction steps a)' and b)' is an aprotic organic solvent.

More preferably, said organic solvent in said reaction steps a)' and b)' is selected from the group consisting of, but not limited to as indicated, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, ethyl acetate or mixtures thereof.

More preferably, in the reaction to produce a compound of formula (II) by a compound of formula (V) or a salt thereof with a compound of formula (IV), an organic base, such as, but not limited to, pyridine, is used as the base of the present invention; pyridine substituted with C1-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl; a tertiary amine, for example, but not limited to, a compound of the formula R2R3R4N as defined above.

One embodiment of the invention is a method for preparing a compound of formula (I), in which step a)' is carried out at a temperature in the range from -50°C to 50°C, more preferably from -40°C to 40°C, more preferably from - 30°C to 30°C, more preferably -20°C to 20°C, more preferably -10°C to 10°C, more preferably -5°C to 5°C.

One embodiment of the invention is a method for preparing a compound of formula (I), in which step b)' is carried out at a temperature in the range from 0°C to 100°C, more preferably from 15°C to 25°C.

One embodiment of the invention is a method for preparing a compound of formula (I), in which, in step a)', a compound of the formula RiO-CO-Cl, 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°C and kept, then a compound of formula (V) or its salt, for example, hydrochloride, and a base are added to the reaction mass at a temperature from -50°C to 10°C, and then the resulting reaction mass is kept at a temperature from -10°C to 50°C until reaction completes.

One embodiment of the invention is a method for preparing a compound of formula (I), in which, in step a)', compounds of the formula RiO-CO-Cl, described above, are added to a solution of a compound of formula (IV) in the presence of a base, at a temperature of -30 °C to -15°C and kept, then a compound of formula (V) or its salt, including hydrochloride, and a base are added to the reaction mass at a temperature from -25°C to -15°C, and then the resulting reaction mass is kept at a temperature from -5°C to 5°C until the end of the reaction.

One embodiment of the present invention is a method for preparing a compound of formula (I), in which steps a)' and/or b)' additionally include the following stages: c)' isolation of the product; d)' washing the isolated product; e) drying of the product.

One embodiment of the present invention is a method for producing a compound of formula (I), in which steps a)' and/or b)' additionally include the following steps: c)' isolating the product and/or d)' washing the isolated product and/or; f)’ drying the product.

More preferably, the additional product isolation step c)' is carried out by precipitation or extraction.

More preferably, the additional product isolation step c)' is carried out by filtration.

More preferably, the additional product isolation step c)' is carried out by precipitation followed by filtration.

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

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

One embodiment of the invention is a method for producing a compound of formula (I), in which stages a)' and/or b)' additionally include the following stages: c)' isolating the product and/or d)' washing the isolated product and/or; e)' drying the product, where the step d)' of washing the isolated product further includes the step of recrystallizing the product from an organic solvent.

More preferably, said step of recrystallizing 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.

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

One embodiment of the invention is a method for producing a compound of formula (I), in which steps a)' and/or b)' additionally include 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. Within the framework of the present invention, the stated problem is solved, and the stated technical results are achieved through a new method for obtaining a compound of formula (II), which involves the interaction of a compound of formula (V) or its salt, for example, a hydrochloride, with a compound of formula (IV), obtained by any method according to the present invention, using a compound of the formula RjO-CO-C1, described above, in the presence of a base, according to the following synthesis scheme:

One embodiment of the present invention is a method for preparing a compound of formula (II), in which the reaction of a compound of formula (V) or a salt thereof, for example, a hydrochloride, with a compound of formula (IV) takes place in an organic solvent, for example, an aprotic organic solvent selected from the group including, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, ethyl acetate, or mixtures thereof, in the presence of a base, for example, an organic base selected from the group, but not limited to, pyridine; pyridine substituted with C1-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl; a tertiary amine, for example, a compound of the formula R2R3R4N, as described above.

One embodiment of the invention is a method for producing a compound of formula (II), in which the step of reacting a compound of formula (V) or a salt thereof, for example, a hydrochloride, with a compound of formula (IV) additionally includes the following steps: recrystallization of the product from an organic solvent and/or purification of the product by chromatography.

More preferably, the step of recrystallizing 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.

More preferably, cooling occurs naturally at room temperature. Within the framework of the present invention, the stated problem is solved, and the stated technical results are achieved through a new method for obtaining a compound of formula (IV'), which involves the interaction of a compound of formula (II'”) with a compound of formula (III”) using a compound of formula RjO-CO-Cl , described above in the text, in the presence of a base, in accordance with the following synthesis scheme:

One embodiment of the present invention is a method for preparing a compound of formula (IV'), which involves reacting a compound of formula (ID") with a compound of formula (III") using a compound of formula RiO-CO-Cl, as defined above, in the presence of a base .

One embodiment of the present invention is a method for preparing a compound of formula (IV'), in which the reaction of a compound of formula (1D") with a compound of formula (III") takes place in an organic solvent.

More preferably, the organic solvent in said reaction for producing the compound of formula (IV') is an aprotic organic solvent.

More preferably, the organic solvent in said reaction to produce the compound of formula (IV') is selected from the group consisting of, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dichloromethane, ethyl acetate, or mixtures thereof.

More preferably, the compound of the formula RiO-CO-Cl of the present invention is an alkyl chloroformate, wherein Ri is a C1-C5 alkyl.

More preferably, an organic base is used as the base in the reaction for producing the compound of formula (IV') of the present invention.

More preferably, the base in the reaction for preparing the compound of formula (IV') of the present invention is, but is not limited to, pyridine; pyridine substituted with C1-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl. More preferably, the organic base in the reaction to produce the compound of formula (IV') of the present invention is a tertiary amine.

More preferably, the tertiary amine in the reaction to produce the compound of formula (IV') of the present invention is a compound of formula R2R3R4N as defined above.

One embodiment of the invention is a method for preparing a compound of formula (IV') is carried out at a temperature in the range from -50°C to 50°C, more preferably from -40°C to 40°C, more preferably from -30°C to 30 °C, more preferably -20°C to 20°C, more preferably -10°C to 10°C, more preferably -5°C to 5°C.

One embodiment of the present invention is a method for preparing a compound of formula (IV'), in which a compound of the formula RiO-CO-Cl, described above, is added to a solution of a compound of formula (III") in the presence of a base, at a temperature of -50°C to 10°C and kept, then a compound of formula (II'”) and a base are added to the reaction mass at a temperature from -50°C to 10°C, and then the resulting reaction mass is kept at a temperature from -10°C to 50°C until the end of the reaction.

One embodiment of the present invention is a method for preparing a compound of formula (IV'), in which a compound of the formula RiO-CO-Cl, described above, is added to a solution of a compound of formula (III") in the presence of a base, at a temperature of -30° C to -15°C and kept, then a compound of formula (1G") and a base are added to the reaction mass at a temperature from -25°C to -15°C, and then the resulting reaction mass is kept at a temperature from -5°C to 5 °C until the reaction is completed.

Ь)” реакцию удаление защитной группы соединения формулы (V’) с образованием соединения формулы (VI)

где Y представляет собой остаток кислоты; с)” обработка соединения формулы (VI) реагентом формулы CF3COOR’ в присутствии основания с образованием соединения формулы (VII”),

при условии, что когда R’ представляет собой Ci-Cs-алкил; С1-С5-алкил, замещенный галогеном, выбранным из группы, не ограничиваясь указанным, хлор, бром, фтор, или трифторацетил; Ri” представляет собой водород; когда R’ представляет собой пентафторфенил; Ri” представляет собой пентафторфенил; d)” взаимодействие соединения формулы (VII”) с соединением формулы (V) или его солью, например, не ограничиваясь указанным, гидрохлоридом, с использованием соединения формулы RiO-CO-Cl, охарактеризованного выше по тексту, в присутствии основания с получением соединения формулы (II):

е)” дегидратация соединения формулы (II) с использованием 2, 4, 6-трихлор- 1,3,5- триазина с образованием соединения формулы (I): Одним из вариантов воплощения изобретения является способ получения соединения формулы (I), в котором стадию а)” проводят при температуре в интервале от -20°С до 40°С, более предпочтительно от 0 до 5°С. The stated problem is solved, and the stated technical results are achieved through a new method for obtaining a compound of formula (I), which includes the following stages: a)” reaction of alkaline hydrolysis of the ester group of a compound of formula (IV'), obtained by any method according to the present invention, with the formation compounds of formula (V')

b)" reaction deprotecting a compound of formula (V') to form a compound of formula (VI)

where Y represents an acid residue; c)" treatment of a compound of formula (VI) with a reagent of formula CF3COOR' in the presence of a base to form a compound of formula (VII"),

with the proviso that when R' represents Ci-Cs-alkyl; C1-C5 alkyl substituted with a halogen selected from the group, but not limited to, chlorine, bromo, fluorine, or trifluoroacetyl; Ri” represents hydrogen; when R' represents pentafluorophenyl; Ri" is pentafluorophenyl; d)" reacting a compound of formula (VII") with a compound of formula (V) or a salt thereof, such as, but not limited to, a hydrochloride, using a compound of formula RiO-CO-Cl as defined above, in the presence of a base, to obtain a compound of formula (II):

e)" dehydration of a compound of formula (II) using 2, 4, 6-trichloro-1,3,5-triazine to form a compound of formula (I): One embodiment of the invention is a method for preparing a compound of formula (I), in which step a) is carried out at a temperature in the range from -20°C to 40°C, more preferably from 0 to 5°C.

One embodiment of the invention is a method for preparing a compound of formula (I), in which step b) is carried out at a temperature in the range of -10°C to 50°C, more preferably from 20°C to 25°C.

One embodiment of the invention is a method for preparing a compound of formula (I), in which step c) is carried out at a temperature in the range from 0°C to 100°C, more preferably from 20°C to 25°C.

One embodiment of the invention is a process for preparing a compound of formula (I), wherein step d) is carried out at a temperature in the range of -50°C to 50°C, more preferably -5°C to 5°C.

One embodiment of the invention is a method for preparing a compound of formula (I), in which step e) is carried out at a temperature in the range from 0°C to 100°C, more preferably from 15°C to 25°C.

One embodiment of the invention is a method for preparing a compound of formula (I), in which step a) is carried out using an alkali or alkaline earth metal hydroxide.

More preferably, the alkali hydroxide that is used in step a) of the present invention is sodium hydroxide, potassium hydroxide or lithium hydroxide.

One embodiment of the invention is a method for preparing a compound of formula (I), in which step b) is carried out using an acid.

More preferably, step b) of the present invention is carried out using anhydrous strong acid.

More preferably, step b) of the present invention is carried out using an organic acid.

More preferably, step b) of the present invention is carried out using an inorganic acid. More preferably, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid is used as the organic acid in step b) of the present invention.

More preferably, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid is used as the inorganic acid in step b) of the present invention.

One embodiment of the invention is a method for preparing a compound of formula (I), in which steps c)" and/or d)" are carried out in the presence of a base.

More preferably, in step c)" and/or d)" of the present invention, an organic base is used as the base.

More preferably, in step c)" and/or d)" of the present invention, pyridine is used as a base; pyridine substituted with C1-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl.

More preferably, in step c)" and/or d)" of the present invention, the organic base is a tertiary amine.

More preferably, in step c)" and/or d)" of the present invention, the tertiary amine is a compound of formula R2R3R4N as defined above.

One embodiment of the present invention is a method for producing a compound of formula (I), in which steps a)”, b)”, c)”, d)” and/or e)” further comprise the following steps: f) isolating the product; j) washing the isolated product; h) drying of the product.

One embodiment of the present invention is a method for producing a compound of formula (I), in which steps a)”, b)”, c)”, d)” and/or e)” additionally include the following stages: f) isolation of the product and/ or j) washing the isolated product and/or; h) drying of the product.

One embodiment of the present invention is a method for producing a compound of formula (I), in which steps a)” and/or b)”, and/or c)”, and/or d)”, and/or e)” further include the following steps: f) isolating the product and/or ]) washing the isolated product and/or; h) drying of the product.

More preferably, the additional step f) of isolating the product is carried out by precipitation or extraction.

More preferably, the additional step f) of isolating the product is carried out by filtration. More preferably, the additional product isolation step f) is carried out by precipitation followed by filtration.

More preferably, the additional step of washing j) of the isolated product is carried out using water, citric acid solution or aqueous sodium hydrogen carbonate solution.

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

One embodiment of the invention is a method for producing a compound of formula (I), in which steps a)”, b)”, c)”, d)” and/or e)” additionally include the following stages: f) isolation of the product; j) washing the isolated product; h) drying the product, where step j) washing the isolated product further includes the step of recrystallizing the product from an organic solvent.

More preferably, said step of recrystallizing 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.

More preferably, cooling occurs naturally at room temperature.

One embodiment of the invention is a method for producing a compound of formula (I) (target product), in which stages a)”, b)”, c)”, d)” and/or e)” additionally include the following stages: f) isolation product and/or j) washing the isolated product and/or; h) drying the product, where the step of washing the isolated product further includes the step of recrystallizing the product by suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained and then cooling naturally at room temperature.

One embodiment of the invention is a method for producing a compound of formula (I), in which steps a)”, b)”, c)”, d)” and/or e)” additionally include the following steps: f) isolation of the product and/or j) washing the isolated product and/or; h) drying the product, where step j) washing the product further includes the step of purifying the product by chromatography.

The stated problem is solved, and the stated technical results are also achieved through the use of a method for producing a compound of formula (I) according to the present invention for batch chemical industrial production, semi-continuous industrial production or continuous industrial production of a compound of formula (I).

The stated problem is solved, and the stated technical results are achieved by applying the method for producing a 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 stated problem is solved, and the stated technical results are achieved through the use of a method for producing a compound of formula (I), which includes dehydration of a compound of formula (II) to form a compound of formula (I) using 2, 4, 6-trichloro-1,3, 5 -triazine in a solvent environment, for batch chemical industrial production, semi-continuous industrial production or continuous industrial production of the compound of formula (I).

The stated problem is solved, and the stated technical results are achieved through the use of a method for producing a compound of formula (I) according to the present invention to obtain a product containing a compound of formula (I).

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

A 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, plant, animal, microbial and other) origin, intended for the production of medicines, which during the production of the medicine (of the 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 embodiment 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% % by weight of the pharmaceutical product.

One embodiment 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% by weight. %, but more than 0.001 wt.% by weight of the pharmaceutical product.

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, but is 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 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 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, which exhibits prophylactic and/or therapeutic antiviral activity against the SARS-CoV-2 virus.

The stated problem is solved, and the stated technical results are 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 stated problem is solved, and the stated technical results are 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 embodiment 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 groups, but not limited to, picornavirus, norovirus, foot-and-mouth disease virus, hepatitis A virus, polyvirus, rhinovirus, enterovirus, calicivirus or coronavirus.

The stated problem is solved, and the stated technical results are 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 embodiment 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% by weight. % by weight of the pharmaceutical composition.

One embodiment 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% by weight. %, 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 is 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, where 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 stated problem is solved, and the stated technical results are 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 embodiment 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 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 SARS-CoV, MERS-CoV or SARS-CoV-2.

One embodiment of the invention is a method for preparing a compound of formula (I), in which the stereochemistry of the reactants and the target product is controlled, allowing the synthesis of a specific stereoisomer of the compound of formula (I).

One embodiment of the invention is a method for producing a compound of formula (I), which allows one to obtain the target product in a yield exceeding that of the methods described in the prior art.

One embodiment of the invention is a method for producing a compound of formula (I), which allows one 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 80%.

One embodiment of the invention is a method for producing a compound of formula (I), which allows the target product to be obtained 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 method for producing a compound of formula (I), which allows one 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 90%.

One embodiment of the invention is a method for producing a compound of formula (I), which allows one 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 embodiment of the invention is a method for producing a compound of formula (I), which allows one 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 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, esters 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, di ethyl 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, tetraline, 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, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone, dimethylolethylenurea, dimethylolpropylene urea, dimethyl sulfoxide, sulfolane, nitromethane, bifunctional solvents such as methoxyethanol, ethoxyethanol, 1-methoxypropan-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, and supercritical fluids such as carbon dioxide, water, methane, ethane, propane, ethylene, propylene , methanol, ethanol, acetone, nitrogen oxides, sulfur oxide, and/or mixtures thereof.

Monitoring 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 a compound of formula (I) according to one of the embodiments of the present invention involves obtaining a compound of formula (I) according to the following synthesis scheme:

The compound of formula (I) is prepared by reacting a commercially available compound of formula (II), which can also be synthesized by methods known in the art or by methods of the present invention, and 2,4,6-trichloro-1,3,5-triazine in a suitable solvent , for example, protic, selected from the group including, but not limited to: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, at a temperature from 0°C to 100°C for 1.5-3.0 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 that is immiscible with water. The resulting extract is washed, if necessary, with water, solutions of citric acid, sodium bicarbonate or sodium chloride solution, dried with water-removing agents, such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated under vacuum on a rotary evaporator at bath temperature not higher than 50°C and a residual pressure of 20-50 mbar, the residue is recrystallized from a suitable organic solvent and/or purified by liquid chromatography, followed by drying if necessary. In this case, 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). The target product compound of formula (I) of the present invention can also be isolated by precipitation by filtration.

The proposed method for obtaining a compound of formula (I) according to one of the embodiments of the present invention involves obtaining a compound of formula (I) according to the following synthesis scheme: The compounds of formula (P') of the present invention can be prepared by the following methods, without limitation:

1) provided that R represents chlorine or bromine:

- reacting a compound of formula (VII) with commercially available sulfurous acid halides (provided 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 temperatures from -50°C to 50°C. The resulting solution of the compound of formula (1D) 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 R2R3R4N, characterized above in the text, at temperatures from -50°C to 50°C. Next, 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 prepared by reacting a compound of formula (III) and a compound of formula (P') 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 alkali or alkaline earth metal bicarbonate such as, but not limited to, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, etc., at a temperature of -10°C to 50°C. After completion of the reaction, the reaction mass is evaporated or diluted with water, acidified with inorganic or organic acid to a pH from 0 to 6.9.

A compound of formula (II) is prepared 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, not limited to: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), dichloromethane, ethyl acetate, etc., as well as mixtures thereof, in the presence a compound of the formula RiO-CO-Cl described above, and a base, including, but not limited to, pyridine, pyridine substituted with a C1-C5 alkyl, quinoline or quinoline substituted with a C1-C5 alkyl, tertiary amine, including , a tertiary amine of the formula R2R3R4N, as described above, at a temperature of -50°C to 50°C.

Both one-stage and two-stage carrying out of this process are 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 the hydrochloride, a compound of formula (IV) and said base, for example a tertiary amine in a suitable solvent, for example an aprotic solvent, is added a compound of formula RiO- CO-Cl, described above in the text, at a temperature from -50°C to 10°C, and then maintain the resulting reaction mass at a temperature from 10°C to 50°C until the end of the reaction.

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

Also in a two-step process, reverse addition is possible, when to a solution of a compound of formula (IV) and a compound of formula RiO-CO-Cl, described above, in a suitable solvent, for example, but not limited to aprotic, is added the specified base, for example, tertiary amine, described above, at a temperature from -50°C to 10°C, and then maintain the resulting reaction mass at a temperature from -50°C to 10°C until the end of the reaction of formation of a mixed anhydride. Then a compound of formula (V) or its salt, for example a hydrochloride, and the specified base, for example a tertiary amine, are added to the reaction mass at a temperature from -50°C to 10°C and then the resulting reaction mass is maintained at a temperature 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 (II) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (I) is prepared by reacting the compound of formula (II) obtained in the previous step and 2, 4, 6-trichloro-1, 3,5-triazine in a suitable solvent, for example, but not limited to, protic, selected from the group , including, but not limited to: dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone, at a temperature from 0°C to 100°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 that is immiscible with water.

The resulting extracts at each stage of the synthesis are, if necessary, washed with water, solutions of citric acid, sodium bicarbonate and/or sodium chloride solution, dried with water-removing agents, such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated and the residue recrystallize from a suitable organic solvent, or purify by liquid chromatography, or use in the next step without further purification. In this case, 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). The intermediate products of the synthesis as well as the final product compound of formula (I) of the present invention can also be isolated by precipitation by filtration.

Соединения формулы (П”) по настоящему изобретению могут быть получены следующими способами, не ограничиваясь указанным:

путем введение защитной группы R посредством взаимодействия соединения формулы (VII’) с реагентами, выбранными из группы: The proposed method for obtaining a compound of formula (I) according to one of the embodiments of the present invention involves obtaining a compound of formula (I) according to the following synthesis scheme:

The compounds of formula (P”) of the present invention can be prepared by the following methods, without limitation:

by introducing a protecting group R by reacting a compound of formula (VII') with reagents selected from the group:

- a reagent of the formula CF3COOR1', provided that Ri' represents pentafluorophenyl, R< represents hydrogen.

Compound (P”) is prepared by reacting compound (VII') with a reagent of formula CF3COOR1', provided that Ri' is pentafluorophenyl, in a suitable aprotic solvent selected from the group, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), dichloromethane, ethyl acetate, etc., and bases such as, but not limited to, pyridine, C1-C5 alkyl substituted pyridine, quinoline or C1-C5 alkyl substituted quinoline, tertiary amine, including , a tertiary amine of the formula R2R3R4N, described above in the text, at a temperature of -50°C to 50°C. After completion of the reaction, the reaction mass is evaporated or diluted with water, the compound formula (P”) is extracted with a suitable organic solvent that is immiscible with water.

The resulting extract is washed, if necessary, with water, solutions of citric acid, sodium bicarbonate 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, either purified by liquid chromatography or used in the next step without further purification. In this case, 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). The compound of formula (II”) of the present invention can also be isolated by precipitation by filtration.

- with the reagent pentafluorophenol, provided that Ri' represents pentafluorophenyl, R$ represents trifluoroacetate.

Compound (P”) is prepared by reacting a compound of formula (VII') with pentafluorophenol in a suitable aprotic solvent selected from the group, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), dichloromethane, ethyl acetate, etc. , and a base such as, but not limited to, pyridine, C1-C5 alkyl-substituted pyridine, quinoline or C1-C5 alkyl-substituted quinoline, a tertiary amine, including the tertiary amine of the formula R2R3R4N described above, at a temperature from -50°С to 50°С. After completion of the reaction, the reaction mass is evaporated or diluted with water, the compound of formula (P”) is extracted with a suitable organic solvent that is immiscible with water.

The resulting extract is washed, if necessary, with water, solutions of citric acid, sodium bicarbonate or sodium chloride solution, dried with water-removing agents such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated and the residue recrystallized from a suitable organic solvent, either purified by liquid chromatography or used in the next step without further purification. In this case, 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 natural room temperature). The compound of formula (P”) of the present invention can also be isolated by precipitation by filtration.

- with the reagent N-hydroxysuccinimide, provided that Ri' represents succinimidyl, R(, represents trifluoroacetate.

A compound of formula (P") is prepared by reacting a compound of formula (VII') with N-hydroxysuccinimide in a suitable aprotic solvent selected from the group, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, THF, dichloromethane, ethyl acetate, etc. ., as well as their mixtures, in the presence of carbodiimide R7N=C=NRs (as a dehydrating agent), where R7 and Rs independently of each other represent methyl, ethyl, cyclohexyl, isopropyl, etc., at a temperature of -50 °C to 50°C. Next, the reaction mass is filtered from the precipitated urea, evaporated or diluted with water, the compound of formula (P”) is extracted with a suitable organic solvent that is immiscible with water.

The resulting extract is washed, if necessary, with water, solutions of citric acid, sodium bicarbonate 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, either purified by liquid chromatography or used in the next step without further purification. In this case, 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). The compound of formula (P”) of the present invention can also be isolated by precipitation by filtration.

The compound of formula (I) within the scope of the present invention, according to the synthesis presented above, can also be obtained:

- provided that RT is hydrogen, R2' is tert-butyl.

The compound of formula (IV) can be prepared according to the present invention by reacting commercially available compounds of formula (P") (or prepared in accordance with the method of the present invention) and formula (PG) or a salt thereof in a suitable organic solvent, including an aprotic solvent selected from the group, without limitation, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), dichloromethane, ethyl acetate, etc., as well as mixtures thereof, in the presence of a compound of the formula RiO-CO-Cl as a dehydrating agent, as defined above, and a base such as, but not limited to, pyridine, C1-C5 alkyl substituted pyridine, quinoline or C1-C5 alkyl substituted quinoline, a tertiary amine, including the tertiary amine of the formula R2R3R4N, as defined above by text, at temperatures from -50°C to 50°C.

Both one-stage and two-stage processes are possible. In the case of a one-step process, to a solution or suspension of compounds of formulas (II"), formulas (III') or a salt thereof and the specified base, including, but not limited to, the tertiary amine described above, in a suitable specified organic solvent, add a compound of the formula RiO-CO-Cl, described above, at a temperature from -50°C to 10°C, and then maintain the resulting reaction mass at a temperature from 10°C to 50°C until the end of the reaction.

In the case of a two-step process, to a solution of the compound of formula (P") and said base, in particular, but not limited to, the tertiary amine specified above, in a suitable specified organic solvent, add the compound of formula RiO-CO-Cl, described above, at a temperature from -50°C to 10°C, and then the resulting reaction mass is kept at a temperature from -50°C to 10°C until the reaction of mixed anhydride formation is completed. Then, a compound of formula (III') or a salt thereof and the specified base, in particular, but not limited to, the tertiary amine described above, are added to the reaction mass at a temperature of -50°C to 10°C and then the resulting reaction mass is maintained at a temperature from 10°C to 50°C until the end of the reaction.

Also in a two-stage process, reverse addition is possible, when the specified base, in particular, but not limited to, is added to a solution of the compound of formula (II”) and the compound of formula RiO-CO-Cl, described above, in the specified suitable organic solvent , described above, at a temperature from -50°C to 10°C, and then the resulting reaction mass is kept at a temperature from -50°C to 10°C until the end of the reaction of formation of a mixed anhydride. Then a compound of formula (PG) or its salt and the specified base are added to the reaction mass at a temperature from -50°C to 10°C and then the resulting reaction mass is maintained at a temperature from 10°C to 50°C until the end of the reaction.

Next, a suitable solvent is added to the reaction mass, including, but not limited to, ethyl alcohol, methyl alcohol, isopropyl alcohol, THF, dioxane, ethyl acetate, etc., as well as an anhydrous strong acid selected from group, including, but not limited to: hydrochloric, hydrobromic, hydroiodic, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, phosphoric acid, etc. at temperatures from -10°C to 50°C.

One of the special cases of implementing the method for obtaining an intermediate compound of formula (IV) according to the present invention is the preparation of a compound of formula (IV) in two stages. At the first stage, the reaction of compounds of formula (P") and formula (PG) or its salt is carried out in a suitable organic solvent, described above, in the presence of a compound of the formula RiO-CO-Cl and the base described above, at a temperature of -50° From up to 50°C. The second step is to add a suitable solvent to the resulting reaction mass, as well as an anhydrous strong acid selected from the group including, but not limited to: hydrochloric, hydrobromic, hydroiodic, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, phosphoric acid, etc. at temperatures from -10°C to 50°C.

After completion of the reaction, the reaction mass is evaporated or diluted with water, the compound of formula (IV) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (II) is prepared by reacting the compound of formula (IV) obtained in the previous step and a commercially available compound of formula (V) or a salt thereof, including a hydrochloride, in a suitable solvent, including, but not limited to, aprotic, selected from the group, not limited to: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, THF, dichloromethane, ethyl acetate, etc., as well as mixtures thereof, in the presence as a dehydrating agent of a compound of the formula RiO-CO-Cl, described above by text, and bases, including those selected from the group, but not limited to, pyridine; pyridine substituted with C1-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl; a tertiary amine, including a tertiary amine of the formula R2R3R4N, as described above, at a temperature of -50°C to 50°C.

Both one-stage and two-stage carrying out of this process are possible. In the case of a one-step process, a solution or suspension containing a compound of formula (V) or a salt thereof, including the hydrochloride, a compound of formula (IV) and said base, for example a tertiary amine as defined above, in a suitable solvent, e.g. limited to the above, aprotic, add a compound of the formula RiO-CO-Cl, described above in the text, at temperature from -50°C to 10°C, and then the resulting reaction mass is kept at a temperature from 10°C to 50°C until the end of the reaction.

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

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

The compound of formula (I) is prepared by reacting the compound of formula (II) obtained in the previous step and 2, 4, 6-trichloro-1, 3,5-triazine in a suitable solvent, for example, but not limited to, protic, selected from the group , including, but not limited to: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, at temperatures from 0°C to 100°C. 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 that is immiscible with water.

The resulting extracts at each stage of synthesis are, if necessary, washed with water, solutions of citric acid, sodium bicarbonate and/or sodium chloride solution, dried with water-removing agents, such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., are evaporated and the residue is recrystallized from a suitable organic solvent, or purified by liquid chromatography, or used in the next step without further purification. In this case, 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). The intermediate products of the synthesis as well as the final product compound of formula (I) of the present invention can also be isolated by precipitation by filtration.

- Provided that R is pentafluorophenyl, R2' is hydrogen.

The compound of formula (IV) can be obtained according to the present invention by reacting a compound of formula (P”) obtained by a known synthesis in the prior art or a new synthesis according to the present invention and a commercially available compound of formula (PG) or a salt thereof in a suitable organic solvent, including an aprotic one , selected from the group containing, but not limited to: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran (THF), dichloromethane, ethyl acetate, etc., as well as mixtures thereof; water and base, including those selected from the group, but not limited to, pyridine; pyridine substituted with Ci-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl; a tertiary amine, including a tertiary amine of the formula R2R3R4N, as described above, at a temperature of from 0 C to 80 ° C. After completion of the reaction, the reaction mass is evaporated or diluted with water, acidified with inorganic or organic acid to pH from 0 to 6.9, the compound of formula (IV) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (II) is prepared by reacting the compound of formula (IV) obtained in the previous step and a commercially available compound of formula (V) or a salt thereof in a suitable solvent, including an aprotic solvent selected from the group, but not limited to: dimethylformamide, dimethylacetamide , N-methylpyrrolidone, THF, dichloromethane, ethyl acetate, etc., as well as mixtures thereof, in the presence as a dehydrating agent of a compound of the formula RiO-CO-C1, described above in the text, and a base, including one selected from groups, but not limited to, pyridine; pyridine substituted with C1-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl; tertiary amine, including a tertiary amine of the formula R2R3R4N, as described above, at a temperature of -50°C to 50°C.

Both one-stage and two-stage carrying out of this process are possible. In the case of a one-step process, to a solution or suspension containing a compound of formula (V) or a salt thereof, a compound of formula (IV) and said base, for example a tertiary amine as defined above, in a suitable solvent, for example an aprotic solvent, is added a compound of formula RiO- CO-Cl, described above in the text, at a temperature from -50°C to 10°C, and then maintain the resulting reaction mass at a temperature from 10°C to 50°C until the end of the reaction.

In the case of a two-step process, to a solution of the compound of formula (IV) and the specified base, for example, the tertiary amine described above, in a suitable solvent, for example, aprotic, is added the compound of the formula RiO-CO-C1, described above, at a temperature of -50 °C to 10°C, and then the resulting reaction mass is kept at a temperature from -50°C to 10°C until the reaction of mixed anhydride formation is completed. Then a compound of formula (V) or a salt thereof and the specified base, for example a tertiary amine as described above, are added to the reaction mass at a temperature from -50°C to 10°C and then the resulting reaction mass is maintained at a temperature from 10°C to 50 °C until the reaction is completed.

Also in a two-stage process, reverse addition is possible, when the specified base, for example, a tertiary amine, is added to a solution of a compound of formula (IV) and a compound of the formula RiO-CO-Cl, described above, in a suitable solvent, for example, aprotic, at a temperature from -50°C to 10°C, and then the resulting reaction mass is kept at a temperature from -50°C to 10°C until the reaction of mixed anhydride formation is completed. Then, a compound of formula (V) or a salt thereof and the specified base, for example, a tertiary amine as described above, are added to the reaction mass at a temperature from -50°C to 10°C and then the resulting reaction mass is maintained at a temperature from 10°C to 50 °C until the reaction is completed. After completion of the reaction, the reaction mass is evaporated or diluted with water, the compound of formula (II) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (I) is prepared by reacting the compound of formula (II) obtained in the previous step and 2, 4, 6-trichloro-1,3, 5-triazine in a suitable solvent, for example protic, selected from the group consisting of limited to the following: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, at temperatures from 0°C to 100°C. 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 that is immiscible with water.

The resulting extracts at each stage of the synthesis are, if necessary, washed with water, solutions of citric acid, sodium bicarbonate or sodium chloride solution, dried with water-removing agents, such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated and the residue recrystallized from a suitable organic solvent, either purified by liquid chromatography, or used in the next step without further purification. In this case, 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). The intermediate products of the synthesis as well as the final product compound of formula (I) of the present invention can also be isolated by precipitation by filtration.

- Provided that Rf is succinimidyl, R > is hydrogen.

The compound of formula (IV) can be prepared according to the present invention by reacting a compound of formula (II) obtained by a known synthesis or a new synthesis according to the present invention and a commercially available compound of formula (PG) or a salt thereof, in particular an alkali or alkaline earth metal salt of the compound formula (PG), in a solvent selected from the group consisting of, but not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetonitrile or a mixture thereof, at a temperature from 0°C to 100°C. If necessary, a base is added to the reaction mixture, in particular selected from the group, but not limited to, pyridine; pyridine substituted with C1-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl; a tertiary amine, including a tertiary amine of the formula R2R3R4N, as described above. After completion of the reaction, the reaction mass is evaporated or diluted with water, acidified, if necessary, with inorganic or organic acid to pH from 0 to 6.9, the compound of formula (IV) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (II) is prepared by reacting the compound of formula (IV) obtained in the previous step and a commercially available compound formula (V) or its salt in a suitable solvent, including an aprotic one, selected from the group, but not limited to: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, THF, dichloromethane, ethyl acetate, etc., as well as mixtures thereof, in the presence as a dehydrating agent of a compound of the formula RiO-CO-C1, described above in the text, and a base, including, but not limited to, pyridine; pyridine substituted with C1-C5 alkyl; quinoline or quinoline substituted with C1-C5 alkyl; a tertiary amine, including a tertiary amine of the formula R2R3R4N, as described above, at a temperature of -50°C to 50°C.

Both one-stage and two-stage carrying out of this process are possible. In the case of a one-step process, a solution or suspension containing a compound of formula (V) or a salt thereof, including the hydrochloride, of a compound of formula (IV) and said base, for example a tertiary amine as defined above, in a suitable solvent, for example an aprotic , add a compound of the formula RiO-CO-Cl, described above, at a temperature from -50°C to 10°C, and then maintain the resulting reaction mass at a temperature from 10°C to 50°C until the end of the reaction.

In the case of a two-step process, to a solution of the compound of formula (IV) and the specified base, for example, the tertiary amine described above, in a suitable solvent, for example, aprotic, is added the compound of the formula RiO-CO-C1, described above, at a temperature of -50 °C to 10°C, and then the resulting reaction mass is kept at a temperature from -50°C to 10°C until the reaction of mixed anhydride formation is completed. Then a compound of formula (V) or its salt, including the hydrochloride, and the specified base, for example, a tertiary amine described above, are added to the reaction mass at a temperature from -50°C to 10°C and then the resulting reaction mass is kept at temperature from 10°C to 50°C until the end of the reaction.

Also in a two-stage process, reverse addition is possible, when the specified base, for example, the tertiary amine described above, is added to a solution of the compound of formula (IV) and the compound of the formula RiO-CO-Cl, described above, in a suitable solvent, for example, aprotic , at a temperature from -50°C to 10°C, and then maintain the resulting reaction mass at a temperature from -50°C to 10°C until the end of the reaction of formation of a mixed anhydride. Then a compound of formula (V) or its salt, including the hydrochloride, and the specified base, for example, a tertiary amine, are added to the reaction mass, described above, at a temperature from -50°C to 10°C and then maintain the resulting reaction mass at a temperature from 10°C 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 (II) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (I) is prepared by reacting the compound of formula (II) obtained in the previous step and 2,4,6-trichloro-1,3,5-triazine in a suitable solvent, for example protic, selected from the group consisting of limited to the following: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, at a temperature from 0°C to 100°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 that is immiscible with water.

The resulting extracts at each stage of the synthesis are washed, if necessary, with water, solutions of citric acid, sodium bicarbonate or sodium chloride solution, dried with water-removing agents, such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated and the residue recrystallized from a suitable organic solvent, either purified by liquid chromatography, or used in the next step without further purification. In this case, 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). The intermediate products of the synthesis as well as the final product compound of formula (I) of the present invention can also be isolated by precipitation by filtration.

The proposed method for obtaining a compound of formula (I) according to one of the embodiments of the present invention involves obtaining a compound of formula (I) according to the following synthesis scheme The compound of formula (IV') is prepared according to the present invention by reacting commercially available compounds of formulas (1D") and (III") in a suitable organic solvent, including an aprotic one, selected from the group, but not limited to: dimethylformamide, dimethylacetamide, N-methylpyrrolidone , tetrahydrofuran (THF), dichloromethane, ethyl acetate, etc., as well as mixtures thereof, in the presence of a compound of the formula RiO-CO-Cl as defined above and a base such as, but not limited to, pyridine, pyridine, substituted Ci-C5 alkyl, quinoline or quinoline substituted with C1-C5 alkyl, tertiary amine, including the tertiary amine of the formula R2R3R4N, described above, at a temperature of -50°C to 50°C. Both one-stage and two-stage processes are possible. In the case of a one-step process, to a solution or suspension of compounds of formulas (II'"), (III") and the specified base, including, but not limited to, a tertiary amine, in a suitable specified organic solvent, add a compound of the formula RiO-CO-Cl, described above in the text, at a temperature from -50°C to 10°C, and then maintain the resulting reaction mass at a temperature from -10°C to 50°C until the end of the reaction.

In the case of a two-step process, to a solution of a compound of formula (III”) and said base, in particular, but not limited to, a tertiary amine, in a suitable specified organic solvent, add a compound of formula RiO-CO-C1, described above, at a temperature of -50 °C to 10°C, and then the resulting reaction mass is kept at a temperature from -50°C to 10°C until the reaction of mixed anhydride formation is completed. Then a compound of formula (1D”) and the specified base, in particular a tertiary amine, are added to the reaction mass at a temperature from -50°C to 10°C and then the resulting reaction mass is maintained at a temperature from -10°C to 50°C to end of the reaction.

Also in a two-stage process, reverse addition is possible, when the specified base, in particular a tertiary amine, is added to a solution of a compound of formula (III”) and a compound of formula RyO-CO-Cl, described above, in the specified suitable organic solvent, at a temperature from -50°C to 10°C, and then the resulting reaction mass is kept at a temperature from -50°C to 10°C until the reaction of mixed anhydride formation is completed. Then a compound of formula (1D”) and the specified base are added to the reaction mass at a temperature from -50°C to 10°C and then the resulting reaction mass is kept at a temperature from -10°C 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 (IV’) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (V') is prepared by reacting the compound of formula (IV') obtained in the previous step in a suitable water-miscible solvent selected from the group consisting of, but not limited to: ethyl alcohol, methyl alcohol, isopropyl alcohol, THF, dioxane etc., as well as water in proportions from 1:100 to 100:1 by weight with an alkali or alkaline earth metal hydroxide, for example, but not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. at temperatures from -20°C to 40°C. After At the end of the reaction, the reaction mass is evaporated or diluted with water, acidified with an inorganic or organic acid, for example, hydrochloric acid, to a pH of 0 to 6.9, the compound of formula (V') is extracted with a suitable organic solvent that is immiscible with water.

A compound of formula (VI) (wherein Y is an acid moiety such as, but not limited to, hydrochloric, hydrobromic, hydroiodic, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, phosphoric acid) is prepared by reacting a compound of formula (V') prepared by the previous stage, in a suitable solvent selected from the group, but not limited to: ethyl alcohol, methyl alcohol, isopropyl alcohol, tetrahydrofuran (THF), dioxane, ethyl acetate, etc. with an anhydrous strong acid selected from the group, but not limited to: hydrochloric, hydrobromic, hydroiodic, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, phosphoric acid, etc. at temperatures from -10°C to 50°C. The resulting product is precipitated by adding a suitable solvent selected from the group: methyl tert-butyl ether, dibutyl ether, diisopropyl ether, ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, etc., filtered and dried to constant weight.

The compound of formula (VII”) (provided that Ri” is hydrogen) is prepared by reacting the compound of formula (VI) obtained in the previous step in a suitable solvent selected from the group, but not limited to: ethyl alcohol, methyl alcohol, alcohol isopropyl, THF, dioxane, ethyl acetate, etc. with a compound of formula CF3COOR' (wherein R' is selected from the group consisting of: trifluoroacetyl, C1-C5 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, etc., C1-C5 alkyl substituted with halogen , selected from the group, but not limited to, chlorine, bromine, fluorine) in the presence of a base selected from the group, but not limited to, pyridine, pyridine substituted with a C1-C5 alkyl, quinoline or quinoline substituted with a C1-C5 alkyl, tertiary amine, including the tertiary amine of the formula R2R3R4N, described above in the text, at a temperature of from 0°C to 100°C. After completion of the reaction, the reaction mass is evaporated or diluted with water, acidified with inorganic or organic acid to pH from 0 to 6.9, the compound of formula (VII”) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (VII”) (provided that Rj” is pentafluorophenyl) is prepared by reacting the compound of formula (VI) obtained in the previous step in a suitable solvent selected from the group not limited to the above: ethyl alcohol, methyl alcohol, isopropyl alcohol, THF, dioxane, ethyl acetate, etc. with an excess (at least 2 moles) of a compound of formula CF COOR' (where R' is pentafluorophenyl) in the presence of a base selected from the group, but not limited to, pyridine, pyridine substituted with Ci-C5 alkyl, quinoline or quinoline substituted with C1- C5 alkyl, tertiary amine, including the tertiary amine of the formula R2R3R4N, described above, at a temperature of from 0°C to 100°C. After completion of the reaction, the reaction mass is evaporated or diluted with water, acidified with inorganic or organic acid to pH from 0 to 6.9, the compound of formula (VII”) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (II) is prepared by reacting the compound of formula (VII”) obtained in the previous step and a commercially available compound of formula (V) or a salt thereof, for example a hydrochloride, in a suitable solvent, including an aprotic solvent selected from the group not limited to the following: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, THF, dichloromethane, ethyl acetate, etc., as well as mixtures thereof, in the presence of a compound of the formula RiO-CO-Cl, described above, and a base, including, without limitation, pyridine, pyridine substituted with a C1-C5 alkyl, quinoline or quinoline substituted with a C1-C5 alkyl, tertiary amine, including the tertiary amine of the formula R2R3R4N, described above, at a temperature of -50°C to 50 °C.

Both one-stage and two-stage carrying out of this process are possible. In the case of a one-step process, to a solution or suspension containing a compound of formula (VII"), a compound of formula (V) or a salt thereof, for example a hydrochloride, and said base, for example a tertiary amine in a suitable solvent, for example an aprotic solvent, add a compound of formula RiO-CO-Cl, described above, at a temperature from -50°C to 10°C, and then maintain the resulting reaction mass at a temperature from 10°C to 50°C until the end of the reaction.

In the case of a two-step process, to a solution of a compound of formula (VII”) and the specified base, for example a tertiary amine, in a suitable solvent, for example an aprotic solvent, is added a compound of the formula RiO-CO-Cl, described above, at a temperature of -50°C up to 10°C, and then maintain the resulting reaction mass at a temperature from -50°C to 10°C until the end of the reaction of formation of a mixed anhydride. Then a compound of formula (V) or a salt thereof, for example a hydrochloride, and said base, for example a tertiary amine, are added to the reaction mixture. at a temperature from -50°C to 10°C and then maintain the resulting reaction mass at a temperature from -10°C to 50°C until the end of the reaction.

Also in a two-stage process, reverse addition is possible, when the specified base, for example, a tertiary amine, is added to a solution of a compound of formula (VII”) and a compound of formula RiO-CO-Cl, described above in a suitable solvent, for example, aprotic, at temperature from -50°C to 10°C, and then the resulting reaction mass is kept at a temperature from -50°C to 10°C until the end of the reaction of formation of mixed anhydride. Then a compound of formula (V) or its salt, for example a hydrochloride, and the specified base, for example a tertiary amine, are added to the reaction mass at a temperature from -50°C to 10°C and then the resulting reaction mass is maintained at a temperature from -10°C From 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 (II) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (I) is prepared by reacting the compound of formula (II) obtained in the previous step and 2, 4, 6-trichloro-1, 3,5-triazine in a suitable solvent, for example protic, selected from the group consisting of limited to the specified: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, at a temperature of 0°C to 100°C for 1.5-3.0 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 that is immiscible with water.

The resulting extracts at each stage of the synthesis are, if necessary, washed with water, solutions of citric acid, sodium bicarbonate or sodium chloride solution, dried with water-removing agents, such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated and the residue recrystallized from a suitable organic solvent and/or purified by liquid chromatography, or used in the next step without further purification. In this case, 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). The intermediate products of the synthesis as well as the final product compound of formula (I) of the present invention can also be isolated by precipitation by filtration. The proposed method for obtaining a compound of formula (I) according to one of the embodiments of the present invention involves obtaining a compound of formula (I) according to the following synthesis scheme:

The compound of formula (II) within the scope of the present invention is prepared by reacting a commercially available compound of formula (V) or a salt thereof, such as, but not limited to, the hydrochloride, and a compound of formula (IV) (these compounds can also be synthesized by methods known in the art) in a suitable solvent, including an aprotic one, selected from the group, but not limited to: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, THF, dichloromethane, ethyl acetate, etc., as well as mixtures thereof, in the presence of a compound of the formula RiO-CO-Cl , described above, and a base, including, but not limited to, pyridine, pyridine substituted with a C1-C5 alkyl, quinoline or quinoline substituted with a C1-C5 alkyl, a tertiary amine, including a tertiary amine of the formula R2R3R4N, characterized above in the text, at temperatures from -50°C to 50°C.

Within the framework of the present invention, both one-stage and two-stage implementation of this 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 the hydrochloride, a compound of formula (IV) and said base, for example a tertiary amine as defined above, in a suitable solvent, for example an aprotic solvent, is added compound of the formula RiO-CO-Cl, described above, at a temperature from -50°C to 10°C, and then maintain the resulting reaction mass at a temperature from 10°C to 50°C until the end of the reaction. In the case of a two-step process, to a solution of the compound of formula (IV) and the specified base, for example, the tertiary amine described above, in a suitable solvent, for example, aprotic, is added the compound of the formula RjO-CO-C1, described above, at a temperature of -50 °C to 10°C, and then the resulting reaction mass is kept at a temperature from -50°C to 10°C until the reaction of mixed anhydride formation is completed. Then a compound of formula (V) or a salt thereof, for example a hydrochloride, and said base, for example a tertiary amine as described above, are added to the reaction mass at a temperature of -50°C to 10°C and then the resulting reaction mass is maintained at a temperature of - 10°C to 50°C until the end of the reaction.

Also in a two-stage process, reverse addition is possible, when the specified base, for example, a tertiary amine, is added to a solution of a compound of formula (IV) and a compound of the formula RiO-CO-Cl, described above, in a suitable solvent, for example, aprotic, at a temperature from -50°C to 10°C, and then the resulting reaction mass is kept at a temperature from -50°C to 10°C until the reaction of mixed anhydride formation is completed. Then a compound of formula (V) or a salt thereof, for example a hydrochloride, and said base, for example a tertiary amine as described above, are added to the reaction mass at a temperature from -50°C to 10°C and then the resulting reaction mass is maintained at a temperature from 10°C to 50°C until reaction completes. After completion of the reaction, the reaction mass is evaporated or diluted with water, the compound of formula (II) is extracted with a suitable organic solvent that is immiscible with water.

The compound of formula (I) is prepared by reacting the compound of formula (II) obtained in the previous step and 2, 4, 6-trichloro-1, 3,5-triazine in a suitable solvent, for example protic, selected from the group consisting of limited to the specified: dimethylformamide, dimethylacetamide, N-methylpyrrolidone, at a temperature of 0°C to 100°C for 1.5-3.0 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 that is immiscible with water.

The resulting extracts at each stage of the synthesis are washed, if necessary, with water, solutions of citric acid, sodium bicarbonate or sodium chloride solution, dried with water-removing agents, such as, but not limited to, calcium chloride, sodium sulfate, magnesium sulfate, etc., evaporated and the residue recrystallized from suitable organic solvent, either purified by liquid chromatography, or used in the next step without additional cleaning. In this case, 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). The intermediate products of the synthesis as well as the final product compound of formula (I) of the present invention can also be isolated by precipitation by filtration.

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

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

Example 1. Method for preparing (lR,2S,5S)-N-[(lS)-l-4HaHO-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(28)-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)).

Particular cases of implementation of the present invention are the following methods for obtaining a compound of formula (I), without being limited to the above.

Method 1.

51.70 g of the compound of formula (II) were mixed with 300.00 ml of N,N-dimethyl acetamide and added with stirring 9.20 g (1.50 equivalents) of 2, 4, 6-trichloro-1, 3,5- triazine at a temperature of 40°C. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar, and the resulting mixture was extracted with dichloromethane. The resulting extract was washed with a solution of sodium bicarbonate, then recrystallized from heptane, followed by vacuum drying at a temperature of 40°C and a residual pressure of 10 mbar. After drying, the target product compound of formula (I) was obtained in the form of a powder with a yield of 97%.

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

'H NMR (600 MHz, DMSO-d6) 5 9.48 (d, J = 8.4 Hz, 1H), 9.00 (d, J = 8.6 Hz, 1H), 7.63 (s, 1H), 4.96 (ddd, J = 10.9 , 8.6, 5.1 Hz, 1H), 4.44 (d, J = 8.4 Hz, 1H), 4.16 (s, 1H), 3.94 (dd, J = 10.4, 5.5 Hz, 1H), 3.64 (d, J = 10.4 Hz , 1H), 3.18 (t, J = 9.1 Hz, 1H), 3.09 (td, J = 9.4, 7.1 Hz, 1H), 2.42 (tdd, J = 10.4, 8.4, 4.4 Hz, 1H), 2.24-2.02 (m, 2H), 1.80 - 1.65 (m, 2H), 1.50 (dd, J = 7.6, 5.4 Hz, 1H), 1.37 (d, J = 7.6 Hz, 1H), 1.06 (s, 3H), 0.99 (s, 9H), 0.85 (s, 3H).

¹³ C NMR (151 MHz, DMSO-d6) 8 178.15, 171.29, 167.91, 158.10, 157.64, 157.16, 156.66, 120.05, 118.21, 116.83, 114.39, 60.50, 58 .66, 48.05, 38.25, 37.16, 35.00, 34.64, 30.74, 27.80, 27.35, 26.70, 26.16, 19.30, 12.89.

Mass spectrum: m/z calculated for C23H33F3N5O4 [M+H] ⁺ 500.2474, found 500.2478.

Method 2

51.70 g of the compound of formula (II) were mixed with 150.00 ml of N-methylpyrrolidone and 9.20 g (1.50 equivalents) of 2, 4, 6-trichloro-1, 3,5-triazine were added with stirring at a temperature of 65 °C. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar, the reaction mixture was extracted with ethyl acetate. The resulting extract was washed first with water, then with a solution of sodium hydrogen carbonate and purified by liquid chromatography, followed by vacuum drying at a temperature of 40°C and a residual pressure of 10 mbar to obtain the target product of the compound of formula (I) in the form of a solid powder with a yield of 96%.

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

*H NMR (600 MHz, DMSO-d6) 8 9.44 (d, J = 8.4 Hz, 1H), 9.02 (d, J = 8.6 Hz, 1H), 7.65 (s, 1H), 4.96 (ddd, J = 10.9 , 8.6, 5.1 Hz, 1H), 4.42 (d, J = 8.4 Hz, 1H), 4.15 (s, 1H), 3.90 (dd, J = 10.4, 5.5 Hz, 1H), 3.66 (d, J = 10.4 Hz , 1H), 3.10 (t, J = 9.1 Hz, 1H), 3.06 (td, J = 9.4, 7.1 Hz, 1H), 2.45 (tdd, J = 10.4, 8.4, 4.4 Hz, 1H), 2.20-2.00 ( m, 2H), 1.81 - 1.65 (m, 2H), 1.59 (dd, J = 7.6, 5.4 Hz, 1H), 1.34 (d, J = 7.6 Hz, 1H), 1.06 (s, 3H), 0.97 (s , 9H), 0.85 (s, 3H).

¹³ C NMR (151 MHz, DMSO-d6) 8 178.16, 171.23, 167.95, 158.15, 157.69, 157.14, 156.61, 120.05, 118.22, 116.86, 114.35, 60.50, 58 .60, 48.00, 38.24, 37.15, 35.00, 34.61, 30.77, 27.80, 27.32, 26.71, 26.17, 19.31, 12.78.

Mass spectrum: m/z calculated for C23H33F3N5O4 [M+H] ⁺ 500.2474, found 500.2476.

Method 3. In a particular case of the present invention, compounds of formula (1D) were prepared as follows: a compound of formula (VII) (170.30 mg, 0.74 mmol) was charged into a 25.00 ml round-bottom flask and 2.00 ml of dichloromethane was added. The reaction mixture was cooled to -15°C and cyanurfluoride (2, , 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 the compound of formula (1D).

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 bicarbonate (2.20 equivalents) and stirred until completely dissolved. The solution of the compound of formula (II') prepared earlier was then added dropwise at a temperature of 0°C to 5°C. After completion of the reaction, 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 a solution of citric acid, dried with calcium chloride, and 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%.

Next, 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 equivalent) of isobutyl chloroformate was added dropwise at a temperature of 0°C. After adding all the isobutyl chloroformate, the resulting reaction mass was kept at a temperature of 25°C for 12-18 hours. After completion of the reaction, the reaction mass was evaporated to constant weight, the resulting compound of formula (II) 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 (II) was used in the next step without purification.

Next, 51.70 g of the compound of formula (II) 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 were added with stirring -triazine at a temperature of 25°C. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar, and was extracted with ethyl acetate.

The resulting extract was washed with a solution of sodium bicarbonate, 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 target 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: 'H NMR, ¹³ C NMR and mass spectral analysis.

*H NMR (600 MHz, DMSO-d6) 5 9.41 (d, J = 8.4 Hz, W), 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) 5 178.15, 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 C23H33F3N5O4 [M+H] ⁺ 500.2474, found 500.2475. In a particular case of the present invention, compounds of formula (IV) were prepared in the following way: 22.70 g of compound of formula (II”), 24.80 g of compound of formula (PG) and 22.20 g of (2 .20 equivalent) of N-methylmorpholine, and stirred until completely dissolved. 15.00 g (1.10 equivalent) of isobutyl chloroformate was then added dropwise at 0°C. After adding all the isobutyl chloroformate, the reaction mass was heated to 25°C and stirred for another 12-18 hours. Next, 100.00 ml of dioxane and 50.00 g of anhydrous hydrochloric acid were added at a temperature of 20°C and kept for 6 hours.

After completion of the reaction, the reaction mass was evaporated, the compound of formula (IV) was extracted with ethyl acetate. The extract was washed with a solution of citric acid and evaporated to constant weight, 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%. Next, 20.80 g of the compound of formula (IV) and 36.40 g of the compound of formula (V) were dissolved in 350.00 ml of ethyl acetate, followed by the addition of 22.20 g (2.20 equivalents) of N-methylmorpholine and stirred until completely dissolved. 15.00 g (1.10 equivalent) isobutyl chloroformate was then added dropwise at 0°C. After adding all the isobutyl chloroformate, the reaction mass was heated to 25°C and stirred for another 12-18 hours. After completion of the reaction, the reaction mass was washed with water and a solution of sodium bicarbonate, and then evaporated. The resulting substance of formula (II) was used in the next step without purification.

Next, 51.70 g of the compound of formula (II) 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 were added with stirring -triazine at a temperature of 25°C. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar, the compound of formula (I) was extracted with ethyl acetate.

The resulting extract was washed with a solution of sodium bicarbonate, evaporated to constant weight and recrystallized from heptane, followed by vacuum drying at a temperature of 40°C and a residual pressure of 10 mbar. After drying, the target product compound of formula (I) was obtained in the form of a powder with a yield of 96%.

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

*H NMR (600 MHz, DMSO-d6) 3 9.40 (d, J = 8.4 Hz, 1H), 9.02 (d, J = 8.6 Hz, 1H), 7.65 (s, 1H), 4.98 (ddd, J = 10.9 , 8.6, 5.1 Hz, 1H), 4.40 (d, J = 8.4 Hz, 1H), 4.15 (s, 1H), 3.98 (dd, J = 10.4, 5.5 Hz, 1H), 3.70 (d, J = 10.4 Hz , 1H), 3.15 (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), 2.22-2.00 ( m, 2H), 1.75 - 1.62 (m, 2H), 1.58 (dd, J = 7.6, 5.4 Hz, 1H), 1.35 (d, J = 7.6 Hz, 1H), 1.03 (s, 3H), 0.98 (s , 9H), 0.89 (s, 3H).

¹³ C NMR (151 MHz, DMSO-d6) 3 178.16, 171.20, 167.95, 158.16, 157.60, 157.18, 156.70, 120.04, 118.22, 116.90, 114.43, 60.55, 58 .69, 48.10, 38.30, 37.19, 35.05, 34.65, 30.79, 27.80, 27.32, 26.77, 26.17, 19.35, 12.78.

Mass spectrum: m/z calculated for C23H33F3N5O4 [M+H] ⁺ 500.2474, found

500.2477.

Method 5. In a particular case of the present invention, compounds of formula (P”) were prepared by the following method.

To 200.00 ml of dichloromethane were added 22.70 g of the compound of formula (VII’) and 13.60 g of isobutyl chloroformate. The reaction mass was cooled to -20°C and 10.10 g (1.00 equivalent) of N-methylmorpholine was added dropwise. Next, the mixture was stirred for 1 hour at a temperature of -20°C and 18.40 g of pentafluorophenol was added. The reaction mass was heated to room temperature, stirred for 8 hours, washed with water, citric acid solution, and sodium chloride solution. Then the reaction mass was evaporated and the residue was recrystallized from heptane. The output was 82% of the compound of formula (P”).

Next, 15.50 g of the compound of formula (P”) obtained in the previous step, 39.30 g of the compound of formula (PG), and 25.80 g (2.00 equivalents) of diisopropylethylamine were added to 300.00 ml of dimethylacetamide at a temperature of 25° C and stirred for 12-18 hours. After completion of the reaction, the reaction mass was evaporated and acidified with hydrochloric acid to pH 5.0. The compound of formula (IV) was extracted with dichloromethane. The extract was washed with water, evaporated to constant weight, and the residue was recrystallized from heptane. The output was 95% of the intermediate product of the compound of formula (IV) with a stereoisomeric purity of more than 98%.

Next, 36.40 g of the compound of formula (IV) obtained in the previous step, 20.80 g of the compound of formula (V) were dissolved in 250.00 ml of dimethylformamide and added 22.20 g (2.20 equivalents) N-methylmorpholine. The reaction mass was stirred until dissolved, then 15.00 g (1.10 equivalent) of isobutyl chloroformate was added dropwise at a temperature of 0°C. After adding all the isobutyl chloroformate, the resulting reaction mass was kept at a temperature of 25°C for 12-18 hours. After completion of the reaction, the reaction mass was evaporated to constant weight, the resulting compound of formula (II) was extracted from dichloromethane, the extract was washed with water and citric acid solution, and then evaporated to constant weight. The resulting intermediate compound of formula (II) was used in the next step without purification.

Next, 51.70 g of the compound of formula (II) obtained in the previous step was mixed with 400.00 ml of dimethylacetamide and 9.22 g (1.50 equivalents) of 2,4,6-trichloro-1,3,5-triazine were added with stirring at a temperature of 25°C. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar and extracted with ethyl acetate.

The resulting extract was washed with a solution of sodium bicarbonate, evaporated to constant weight and recrystallized from heptane, followed by vacuum drying at a temperature of 40°C and a residual pressure of 10 mbar. After drying, the target product compound of formula (I) was obtained in the form of a powder with a yield of 96%.

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

*H NMR (600 MHz, DMSO-d6) 5 9.40 (d, J = 8.4 Hz, 1H), 9.00 (d, J = 8.6 Hz, 1H), 7.70 (s, 1H), 4.98 (ddd, J = 10.9 , 8.6, 5.1 Hz, 1H), 4.40 (d, J = 8.4 Hz, 1H), 4.17 (s, 1H), 3.90 (dd, J = 10.4, 5.5 Hz, 1H), 3.70 (d, J = 10.4 Hz , 1H), 3.15 (t, J = 9.1 Hz, 1H), 3.07 (td, J = 9.4, 7.1 Hz, 1H), 2.40 (tdd, J = 10.4, 8.4, 4.4 Hz, 1H), 2.22-2.00 ( m, 2H), 1.79 - 1.62 (m, 2H), 1.59 (dd, J = 7.6, 5.4 Hz, 1H), 1.30 (d, J = 7.6 Hz, 1H), 1.06 (s, 3H), 0.97 (s , 9H), 0.85 (s, 3H).

¹³ C NMR (151 MHz, DMSO-d6) 5 178.15, 171.25, 167.93, 158.15, 157.68, 157.17, 156.67, 120.07, 118.25, 116.89, 114.40, 60.54, 58 .69, 48.10, 38.29, 37.19, 35.10, 34.60, 30.76, 27.85, 27.36, 26.76, 26.12, 19.34, 12.78. Mass spectrum: m/z calculated for C23H33F3N5O4 [M+H] ⁺ 500.2474, found 500.2475.

Method 6.

In a particular case of the present invention, compounds of formula (P”) were prepared by the following method. To 400.00 ml of tetrahydrofuran, 13.10 g of the compound of formula (VII'), 56.00 g of trifluoroacetic acid pentafluorobenzoate (2.00 equivalents) and 15.60 g of pyridine (2.00 equivalents) were added at a temperature of 25°C.

After completion of the reaction, the reaction mass was diluted with water, the compound of formula (P”) was extracted with ethyl acetate, the resulting extract was washed with water, dried with calcium chloride and evaporated to constant weight, the residue was purified by liquid chromatography. The output was 89% of the compound of formula (P”).

Next, 15.50 g of a compound of formula (P”), 39.30 g of a compound of formula (PG) and 25.80 g (2.00 equivalents) of diisopropylethylamine were added to 300.00 ml of dimethylformamide at a temperature of 25°C and stirred for 12-18 hours. After completion of the reaction, the reaction mass was evaporated to constant weight and acidified with hydrochloric acid to pH 5.0. The compound of formula (IV) was extracted with ethyl acetate. The extract was washed with water, evaporated to constant weight, and the residue was recrystallized from heptane. The yield was 96% of the intermediate product of the compound of formula (IV) with a stereoisomeric purity of more than 98%.

Next, 36.40 g of the compound of formula (IV) obtained in the previous step, 20.80 g of the compound of formula (V) were dissolved in 250.00 ml of dimethylformamide and added 22.20 g (2.20 equivalents) N-methylmorpholine. The reaction mass was stirred until completely dissolved, then 15.00 g (1.10 equivalent) of isobutyl chloroformate was added dropwise at a temperature of 0°C. After adding all the isobutyl chloroformate, the resulting reaction mass was kept at a temperature of 25°C for 12-18 hours. After completion of the reaction, the reaction mass was evaporated to constant weight, the resulting compound of formula (II) was extracted with dichloromethane, the extract was washed with water and sodium chloride solution, and then evaporated to constant weight. The resulting substance of formula (II) was used in the next step without purification.

Next, 51.70 g of the compound of formula (II) obtained in the previous step was mixed with 400.00 ml of dimethylacetamide and 9.22 g (1.50 equivalents) of 2, 4, 6-trichloro-1, 3,5-triazine were added with stirring at a temperature of 25°C. After completion of the reaction, the reaction mass was diluted with water and extracted with ethyl acetate. The resulting extract was washed with a solution of sodium bicarbonate, 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 target product compound of formula (I) was obtained in the form of a powder with a yield of 96%.

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

*H NMR (600 MHz, DMSO-d6) 5 9.44 (d, J = 8.4 Hz, 1H), 9.03 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 4.97 (ddd, J = 10.9 , 8.6, 5.1 Hz, 1H), 4.40 (d, J = 8.4 Hz, 1H), 4.12 (s, 1H), 3.90 (dd, J = 10.4, 5.5 Hz, 1H), 3.69 (d, J = 10.4 Hz , 1H), 3.15 (t, J = 9.1 Hz, 1H), 3.07 (td, J = 9.4, 7.1 Hz, 1H), 2.44 (tdd, J = 10.6, 8.5, 4.4 Hz, 1H), 2.22-2.00 ( m, 2H), 1.75 - 1.60 (m, 2H), 1.58 (dd, J = 7.6, 5.4 Hz, 1H), 1.32 (d, J = 7.6 Hz, 1H), 1.07 (s, 3H), 0.94 (s , 9H), 0.88 (s, 3H).

¹³ C NMR (151 MHz, DMSO-d6) 5 178.10, 171.20, 167.95, 158.10, 157.66, 157.10, 156.68, 120.02, 118.22, 116.90, 114.40, 60.54, 58 .69, 48.09, 38.28, 37.20, 35.05, 34.65, 30.74, 27.88, 27.32, 26.75, 26.15, 19.31, 12.75.

Mass spectrum: m/z calculated for C23H33F3N5O4 [M+H] ⁺ 500.2474, found

500.2473.

Method 7.

In a particular case of the present invention, compounds of formula (P”) were prepared by the following method. To 300.00 ml of ethyl acetate were added 22.70 g of the compound of formula (VIF) and 11.50 g of N-hydroxysuccinimide, in the presence of 20.60 g of dicyclohexylcarbodiimide at a temperature of -10°C. The reaction mixture was heated to room temperature and kept at 25°C for 8 hours. Next, the reaction mass was filtered from the precipitated urea and evaporated to constant weight, the residue was recrystallized from heptane. The output was 98% of the compound of formula (P”).

Next, 32.40 g of the compound of formula (P”) obtained in the previous step and 19.50 g of the calcium salt of the compound of formula (PG) were added to 250.00 ml of dimethylformamide at a temperature of 25°C. After completion of the reaction, the reaction mass was diluted with water and acidified with hydrochloric acid to pH 5.0. The compound of formula (IV) was extracted with ethyl acetate. The extract was washed with water, evaporated and purified by HPLC. The yield was 96% of the intermediate product of the compound of formula (IV) with a stereoisomeric purity of more than 98%.

Next, 36.40 g of the compound of formula (IV) obtained in the previous step, 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, then 15.00 g (1.10 equivalent) of isobutyl chloroformate was added dropwise at a temperature of 0°C. After adding everything isobutylchloroformate, the resulting reaction mass was kept at a temperature of 25°C for 12-18 hours. After completion of the reaction, the reaction mass was evaporated to constant weight, the resulting compound of formula (II) was extracted with ethyl acetate, the extract was washed with water, and then evaporated. The resulting substance of formula (II) was used in the next step without purification.

Next, 51.70 g of the compound of formula (II) 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 were added with stirring -triazine at a temperature of 25°C. After completion of the reaction, the reaction mass was evaporated to constant weight and extracted with ethyl acetate.

The resulting extract was washed with a solution of sodium bicarbonate, 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 target product compound of formula (I) was obtained in the form of a powder with a yield of 97%.

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

'n NMR (600 MHz, DMSO-d6) 5 9.41 (d, J = 8.4 Hz, 1H), 9.02 (d, J - 8.6 Hz, 1H), 7.68 (s, 1H), 4.96 (ddd, J - 10.9 , 8.6, 5.1 Hz, 1H), 4.46 (d, J = 8.4 Hz, 1H), 4.17 (s, 1H), 3.91 (dd, J = 10.4, 5.5 Hz, 1H), 3.68 (d, J = 10.4 Hz , 1H), 3.15 (t, J = 9.1 Hz, 1H), 3.05 (td, J = 9.4, 7.1 Hz, 1H), 2.40 (tdd, J = 10.4, 8.4, 4.4 Hz, 1H), 2.21-2.00 ( m, 2H), 1.78 - 1.61 (m, 2H), 1.55 (dd, J = 7.6, 5.4 Hz, 1H), 1.32 (d, J = 7.6 Hz, 1H), 1.04 (s, 3H), 0.98 (s , 9H), 0.88 (s, 3H).

¹³ C NMR (151 MHz, DMSO-d6) 5 178.11, 171.23, 167.96, 158.13, 157.65, 157.16, 156.66, 120.07, 118.22, 116.89, 114.38, 60.55, 58 .66, 48.04, 38.28, 37.19, 35.07, 34.62, 30.75, 27.80, 27.32, 26.70, 26.19, 19.30, 12.79.

Mass spectrum: m/z calculated for C23H33F3N5O4 [M+H] ⁺ 500.2474, found 500.2479.

Method 8.

A special case of the present invention is also a method for preparing a compound of formula (I) according to the following synthesis scheme: 20.60 g of a compound of formula (1D"), 23.10 g of a compound of formula (III") were dissolved in 210.00 ml of dimethylacetamide 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 equivalent) of isobutyl chloroformate was added dropwise at a temperature of 0 ° C. After adding all the isobutyl chloroformate, the resulting reaction mass was kept at a temperature of 25 ° C for 12-18 hours. 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° C. and a residual pressure of 30 mbar. The resulting compound of formula (IV') was extracted with ethyl acetate, the extract was washed with water and a solution of citric acid, and then evaporated. Next, purification was carried out using liquid chromatography, followed by vacuum drying at a temperature of 40°C and a residual pressure of 10 mbar. After drying, the intermediate product compound of formula (IV') was obtained in the form of a powder in 98% yield with a stereoisomeric purity of more than 97%.

Next, 38.20 g of the compound of formula (IV') was dissolved in 350.00 g of ethyl alcohol, 4.62 g (1.10 equivalent) of lithium hydroxide hydrate was added at a temperature of 10°C and the reaction mass was kept for 10 hours at a temperature of 10 °C. After completion of the reaction, the reaction mass was diluted with water and acidified with hydrochloric acid to pH=6.0. The resulting compound of formula (V') was extracted with ethyl acetate, the extract was washed with citric acid solution, water and sodium chloride solution, and evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar.

To a solution containing 36.80 g of the compound of formula (V') obtained in the previous step and 350.00 ml of isopropyl alcohol was added 7.30 g (2.00 equivalents) of anhydrous hydrochloric acid in 50.00 ml of dioxane at a temperature 25°C, the reaction mass was kept for 12 hours at a temperature of 25°C. After completion of the reaction, the compound of formula (VI) was precipitated by adding dibutyl ether, filtered and dried to constant weight.

Next, 30.50 g of compound (VI) obtained in the previous step was mixed with 200.00 ml of ethanol and 28.40 g (2.00 equivalent) of trifluoroacetic acid ethyl ester was added to the resulting solution in the presence of 20.20 g (2.00 equivalent ) triethylamine at a temperature of 30°C and the reaction mixture was kept at 30°C for 4 hours. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar, and acidified with hydrochloric acid to pH = 5.0. The resulting compound of formula (VII”) was extracted with ethyl acetate, the extract was washed with a solution of citric acid, water and a solution of sodium chloride, and evaporated. The resulting substance was used in the next step without purification.

Next, 36.40 g of the compound of formula (VII”), 20.80 g of the compound of formula (V) were dissolved in 250.00 ml of dimethylformamide 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 equivalent) of isobutyl chloroformate was added dropwise at a temperature of 0°C. After adding all the isobutyl chloroformate, the resulting reaction mass was kept at a temperature of 25°C for 12-18 hours. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at bath temperature of 45°C and a residual pressure of 30 mbar, the resulting compound of formula (II) was extracted with ethyl acetate, the extract was washed with water and a solution of citric acid, and then evaporated to constant weight. The resulting substance of formula (II) was used in the next step without purification.

Next, 51.70 g of the compound of formula (II) obtained in the previous step was mixed with 500.00 ml of N-methylpyrrolidone and 9.22 (1.50 equivalents) g of 2, 4, 6-trichloro-1,3, 5 were added with stirring -triazine at a temperature of 25°C. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar, and was extracted with ethyl acetate. The resulting extract was washed with a solution of sodium bicarbonate, 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 target product compound of formula (I) was obtained in the form of a powder with a yield of 96%.

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

'I NMR (600 MHz, DMSO-d6) 8 9.47 (d, J = 8.4 Hz, 1H), 9.06 (d, J = 8.6 Hz, 1H), 7.60 (s, 1H), 4.99 (ddd, J = 10.9 , 8.6, 5.1 Hz, 1H), 4.41 (d, J = 8.4 Hz, 1H), 4.17 (s, 1H), 3.92 (dd, J = 10.4, 5.5 Hz, 1H), 3.65 (d, J = 10.4 Hz , 1H), 3.13 (t, J = 9.1 Hz, 1H), 3.08 (td, J = 9.4, 7.1 Hz, 1H), 2.41 (tdd, J = 10.4, 8.4, 4.4 Hz, 1H), 2.22-2.02 ( m, 2H), 1.77 - 1.62 (m, 2H), 1.59 (dd, J = 7.6, 5.4 Hz, 1H), 1.36 (d, J = 7.6 Hz, 1H), 1.05 (s, 3H), 0.98 (s , 9H), 0.89 (s, 3H).

¹³ C NMR (151 MHz, DMSO-d6) 8 178.11, 171.23, 167.95, 158.13, 157.66, 157.11, 156.60, 120.00, 118.21, 116.88, 114.35, 60.59, 58 .60, 48.03, 38.28, 37.19, 35.00, 34.60, 30.71, 27.80, 27.30, 26.70, 26.15, 19.30, 12.75.

Mass spectrum: m/z calculated for C23H33F3N5O4 [M+H] ⁺ 500.2474, found 500.2475.

Method 9.

The method for preparing the compound of formula (I) of the present invention can also be carried out by the following synthesis scheme: 20.60 g of the compound of formula (P'") > 23.10 g of the compound of formula (III") were dissolved in 210.00 ml of N-methylpyrrolidone 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 equivalent) of isobutyl chloroformate was added dropwise at a temperature of 0°C. After adding all the isobutyl chloroformate, the resulting reaction mass was kept at a temperature of 25 °C for 12-18 hours. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar, the resulting compound of formula (IV') was extracted with dichloromethane, the extract was washed with water and sodium bicarbonate solution, and then evaporated to constant weight . Next, cleaning was carried out using liquid chromatography followed by vacuum drying at a temperature of 40°C and a residual pressure of 10 mbar. After drying, the intermediate product compound of formula (IV') was obtained in the form of a powder in 97% yield with a stereoisomeric purity of more than 98%.

To a solution containing 38.20 g of a compound of formula (IV') and 350.00 g of methyl alcohol, 4.62 g (1.10 equivalent) of lithium hydroxide hydrate was added at a temperature of 10°C and then the reaction mass was kept for 10 hours at a temperature of 10°C. After completion of the reaction, the reaction mass was diluted with water and acidified with hydrochloric acid to pH=6.0. The resulting compound of formula (V') was extracted with isopropyl acetate, the extract was washed with a solution of citric acid and water, and then evaporated under vacuum to constant weight.

To a solution containing 36.80 g of the compound of formula (V') obtained in the previous step and 350.00 g of tetrahydrofuran, 19.20 g (2.00 equivalents) of anhydrous methanesulfonic acid were added at a temperature of 25 ° C, the reaction mass was kept 12 hours at 25°C. After completion of the reaction, the compound of formula (VI) was precipitated by adding methyl tert-butyl ether, filtered and dried to constant weight.

Next, 36.40 g of compound (VI) obtained in the previous step was mixed with 300.00 ml of pyridine and 56.00 g of trifluoroacetic acid pentafluorophenyl ester was added to the resulting solution at a temperature of 20°C. After completion of the reaction, the reaction mass was evaporated to constant weight and acidified with a 20% solution of citric acid to pH = 5.5. The resulting compound of formula (VII”) was extracted with dichloromethane, the extract was washed with a solution of sodium bicarbonate and water, and then evaporated to constant weight. The residue was recrystallized from a mixture of methyl tert-butyl ether and heptane in a mass ratio of 1:5.

Next, 53.00 g of the compound of formula (VII”), 20.80 g of the compound of formula (V) were dissolved in 500.00 ml of ethyl acetate and 20.20 g (2.00 equivalents) of N-methylmorpholine were added at a temperature of 0°C. Then the resulting reaction mass was kept at a temperature of 25°C for 20 hours. After completion of the reaction, the reaction mass was evaporated, the resulting compound of formula (II) was extracted, washed with water, and then evaporated. The resulting substance of formula (II) was used in the next step without purification.

Next, 51.70 g of the compound of formula (II) obtained in the previous step was mixed with 500.00 ml of dimethylformamide and 9.22 g (1.50 equivalents) of 2, 4, 6-trichloro-1,3, 5-triazine were added with stirring at a temperature of 25°C. After graduation reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar, the compound of formula (I) was extracted with ethyl acetate. The resulting extract was washed with a solution of sodium bicarbonate, 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 target product compound of formula (I) was obtained in the form of a powder with a yield of 97%.

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

*H NMR (600 MHz, DMSO-d6) 5 9.40 (d, J = 8.4 Hz, 1H), 9.05 (d, J = 8.6 Hz, 1H), 7.60 (s, 1H), 4.97 (ddd, J = 10.9 , 8.6, 5.1 Hz, 1H), 4.45 (d, J = 8.4 Hz, 1H), 4.18 (s, 1H), 3.93 (dd, J = 10.4, 5.5 Hz, 1H), 3.69 (d, J = 10.4 Hz , 1H), 3.14 (t, J = 9.1 Hz, 1H), 3.08 (td, J = 9.4, 7.1 Hz, 1H), 2.42 (tdd, J = 10.4, 8.4, 4.4 Hz, 1H), 2.24-2.00 ( m, 2H), 1.79 - 1.65 (m, 2H), 1.55 (dd, J = 7.6, 5.4 Hz, 1H), 1.35 (d, J = 7.6 Hz, 1H), 1.03 (s, 3H), 0.98 (s , 9H), 0.85 (s, 3H).

¹³ C NMR (151 MHz, DMSO-d6) 5 178.10, 171.25, 167.95, 158.12, 157.65, 157.16, 156.61, 120.05, 118.20, 116.86, 114.38, 60.52, 58 .66, 48.08, 38.25, 37.19, 35.00, 34.61, 30.74, 27.80, 27.32, 26.70, 26.17, 19.30, 12.78.

Mass spectrum: m/z calculated for C23H33F3N5O4 [M+H] ⁺ 500.2474, found 500.2477.

Method 10.

The method for preparing the compound of formula (I) of the present invention can also be carried out by the following synthesis scheme:

36.40 g of the compound of formula (IV), 20.80 g of the compound of formula (V) were dissolved in 250.00 ml of dimethylformamide and 22.20 g (2.20 equivalents) of N-methylmorpholine were added. The reaction mixture was stirred until dissolved and then 15.00 g (1.10 equivalent) of isobutyl chloroformate was added dropwise at 0°C. After adding all the isobutyl chloroformate, the resulting reaction mass was kept at a temperature of 25°C for 12-18 hours. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar, the resulting compound of the formula ( II) was extracted with ethyl acetate, the extract was washed with water and sodium bicarbonate solution, and then evaporated and dried. The yield was 94% of the intermediate product of the compound of formula (II) with a stereoisomeric purity of more than 97%.

Next, 51.70 g of the compound of formula (II) 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 were added with stirring -triazine at a temperature of 25°C. After completion of the reaction, the reaction mass was evaporated to constant weight under vacuum on a rotary evaporator at a bath temperature of 45°C and a residual pressure of 30 mbar, and the resulting mixture was extracted with ethyl acetate. Next, the extract was washed with a solution of sodium bicarbonate, 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 target product compound of formula (I) was obtained in the form of a powder with a yield of 96%. Identification of the compound of formula (I) was carried out by analytical methods: *H NMR, ^13C NMR and mass spectral analysis.

*H NMR (600 MHz, DMSO-d6) 5 9.45 (d, J = 8.4 Hz, 1H), 9.00 (d, J = 8.6 Hz, W), 7.69 (s, 1H), 4.97 (ddd, J = 10.9 , 8.6, 5.1 Hz, 1H), 4.45 (d, J = 8.4 Hz, 1H), 4.12 (s, 1H), 3.90 (dd, J = 10.4, 5.5 Hz, 1H), 3.65 (d, J = 10.4 Hz , 1H), 3.13 (t, J = 9.1 Hz, 1H), 3.01 (td, J = 9.4, 7.1 Hz, 1H), 2.43 (tdd, J = 10.4, 8.4, 4.4 Hz, 1H), 2.25-2.00 ( m, 2H), 1.75 - 1.65 (m, 2H), 1.53 (dd, J = 7.6, 5.4 Hz, 1H), 1.34 (d, J = 7.6 Hz, 1H), 1.05 (s, 3H), 0.97 (s , 9H), 0.83 (s, 3H).

¹³ C NMR (151 MHz, DMSO-d6) 8 178.11, 171.20, 167.94, 158.15, 157.65, 157.19, 156.65, 120.05, 118.23, 116.85, 114.37, 60.54, 58 .65, 48.04, 38.25, 37.19, 35.08, 34.65, 30.75, 27.80, 27.32, 26.70, 26.19, 19.30, 12.80.

Mass spectrum: m/z calculated for C23H33F3N5O4 [M+H] ⁺ 500.2474, found 500.2471.

It should also be noted that Burgess' reagent, trifluoroacetic anhydride, phosphorus trichloroxide and 2, 4,6-tripropyl-1,3, 5,2 are also known from the prior art as reagents for dehydration of the amide group of a compound of formula (II) ,4,6-trioxatriphosphinane 2,4,6-trioxide. The authors of the present invention have carried out 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 (II) 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 dehydration of the amide group of the compound of formula (II) under various reaction conditions.

Example 2. Preparation of a product containing (lR,2S,5S)-N-[(lS)-l-unaHO-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(28) -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 powder of the compound of formula (I) obtained according to the methods of the present invention (Example 1) was placed with stirring in a reactor equipped with a stirrer, jacket, reflux condenser, thermometer and pressure gauge, under a nitrogen atmosphere, where a measured amount of isopropyl alcohol was previously charged . At the end of the loading, the resulting suspension was stirred at a temperature of 40°C until the compound of formula (I) was completely dissolved. Next, the resulting solution was filtered using a suction filter. The filtrate was fed into a crystallizer equipped with a jacket, thermometer, stirrer, and 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°C and stirred at a set temperature for 7.0-10.0 hours to completely precipitate the compound 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 mill hopper for grinding. The result was a powder product containing compound (I), with a chemical purity of more than 99% and its stereoisomeric purity of 100%.

Claims

Formula 1. A method for preparing a compound of formula (I), which includes dehydration of a compound of formula (II) using 2, 4, 6-trichloro-1, 3,5-triazine in a solvent:

2. The method according to claim 1, in which N,N-dimethylformamide, M,14-dimethylacetamide or N-methylpyrrolidone is used as a solvent. 3. The method according to claim 1, in which the dehydration of the compound of formula (II) is carried out at a temperature in the range from 0°C to 100°C. 4. The method according to claim 3, in which the dehydration of the compound of formula (II) is carried out at a temperature in the range from 15°C to 25°C. 5. Method according to paragraphs. 1-4, in which the stage of dehydration of the compound of formula (II) further includes the following stages: a) isolating the product and/or b) washing the isolated product and/or; c) drying the product. 6. The method according to claim 5, in which step a) is carried out by precipitation or extraction. 7. The method according to claim 5, in which step a) is carried out by filtration. 8. The method according to claim 5, in which step b) additionally includes the step of recrystallizing the product from an organic solvent. 9. The method according to claim 5, in which step b) is carried out using water, a solution of citric acid or an aqueous solution of sodium bicarbonate. 10. The method according to claim 8, where the step of recrystallizing the resulting product includes suspending the precipitated product in an organic solvent, heating the resulting mixture until a homogeneous solution is obtained, and subsequent cooling. 11. The method according to claim 10, in which cooling is performed naturally at room temperature. 12. The method according to claim 5, in which step b) additionally includes the step of purifying the product by chromatography. 13. The method according to claim 5, in which step c) is a drying step under reduced pressure. 14. Application of the method according to paragraphs. 1-13 for batch chemical industrial production, semi-continuous industrial production or continuous industrial production of the compound of formula (I).