A process for production of alpha-structural isomer of (±)-CIS-3-(2'-benzimidazolyl)-1,2,2-trimethylcyclopentanecarbonic acid and its salts

Abstract

This disclosure relates to the chemical and pharmaceutical field, namely processes for production of alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1,2,2- trimethylcyclopentanecarboxylic acid and its salts. The process according to the disclosure comprises the steps such as reacting o- phenylenediamine and (±)-camphoric anhydride compounds, isolating and purifying the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1,2,2- trimethylcyclopentanecarboxylic acid and, if applicable, the step of producing and purifying the salt. The technical contribution resides in the improvement of the process for production of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1,2,2- trimethylcyclopentanecarboxylic acid and its salts, that comprises fewer steps, lower use of the organic solvents, and production of the final product with high purity.

Description

[0001] DESCRIPTION

[0002] A PROCESS FOR PRODUCTION OF ALPHA-STRUCTURAL ISOMER OF (±)-CIS-3- (2'-BENZIMIDAZOLYL)-1,2,2-TRIMETHYLCYCLOPENTANECARBONIC ACID AND ITS SALTS

[0003] FIELD OF INVENTION

[0004] This disclosure relates to the chemical and pharmaceutical field, such as processes for production of chemical compounds, namely alpha-structural isomer of (±)- cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid and its salts.

[0005] BACKGROUND OF INVENTION

[0006] Alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid is a benzimidazole derivative and has the following structural formula:

[0007] Studies of the pharmacological activity of the alpha-structural isomer of (±)-cis-3- (2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid have shown that the compound can be used to treat type 2 diabetes mellitus and manifestations of metabolic syndrome due to its ability to restore the functioning of pancreatic [3-cells, increase tissue sensitivity to insulin (reduce insulin resistance) and reduce glucose production by the liver.

[0008] In addition, in the last 5 years, the cerebroprotective effect of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid has been discovered and actively studied.

[0009] There is a known process for production of the alpha-structural isomer of (±)-cis- 3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid (see the Claims of the patent of Ukraine for invention No. UA 118627 C2, publ. 11 .02.2019) comprising the steps of:

[0010] (a) reacting o-phenylenediamine compound and (±)-camphoric anhydride compound in the medium of an organic solvent selected from benzene, toluene, xylene or dioxane at a temperature of 60-100 °C to obtain the intermediate (±)-a-2'- aminophenylamide-1 ,3-dicarboxylic acid,

[0011] (b) reacting in a reaction medium comprising (±)-a-2'-aminophenylamide-1 ,3- dicarboxylic acid compound and an organic solvent selected from benzene, toluene, xylene, dioxane, N,N-dimethylformamide or their mixtures (wherein one of the mixtures is a mixture of toluene and N,N-dimethylformamide with a ratio of 3:0.3-0.5) at a temperature of 101 -120 °C under conditions suitable for removing intramolecular water i in the form of a azeotropic mixture of water and toluene from the reaction medium solution to obtain the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid, c) purifying the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid by washing it with 20-50% ethanol, homogenizing the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid in boiling 96% ethanol in the presence of activated carbon, filtering the resulting solution, cooling the solution and isolating the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid in a crystallized form.

[0012] The disadvantage of this known process is that the synthesis of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is performed in two steps due to the formation of an intermediate product, namely two chemical reactions are performed sequentially. The use of organic solvents during the first chemical reaction and during the second chemical reaction leads to the need for a significant amount of organic solvents when implementing this process. Furthermore, carrying out two sequential chemical reactions involves loss of time. In addition, the implemented purification process does not allow obtaining the final product with the required level of purity. Another disadvantage of the known process is that the authors did not disclose the methods for removing the so-called intramolecular water from the reaction medium during the reaction occurring in step (b). This aspect is referenced in the Claims but is not described in detail in the Description of the invention.

[0013] There is a known process for production of a mixture of structural isomers of (±)- cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid (see the Claims of the declarative patent of Ukraine for invention No. UA 65046 A, publ. 15.03.2004) comprising the steps of:

[0014] (a) reacting o-phenylenediamine compound and (±)-camphoric acid anhydride compound in a medium being a mixture of toluene and N,N-dimethylformamide solvents with a ratio of 3:1 at a temperature of 70-100 °C for 3-5 hours,

[0015] (b) isolating the product and purifying the product by washing the obtained product with 70% ethanol and crystallization in a 96% ethanol medium.

[0016] The disadvantage of the said known process is that attempts to reproduce the process described in the Claims in laboratory conditions showed that the product produced by this process is the intermediate compound (±)-a-2'-aminophenylamide-1 ,3- dicarboxylic acid.

[0017] To determine the structure of the chemical compound produced by the known process, a13C-NMR spectrum and its analysis were performed. For the analysis, the chemical compound produced by the known process was sampled and dissolved in a deuterated solvent, d6-DMSO. The resulting solution was placed in an ampoule with a volume of 5 mL and a diameter of 5 mm. The ampoule containing the dissolved sample was positioned in a BrukerAvance DRX 400 MHz device, and the device was started to obtain a13C-NMR spectrum. The results of the13C-NMR study are shown in Figure 1. The formula of the chemical compound according to the results of the analysis of the obtained13C-NMR spectrum is as follows:

[0018] That is, this known process does not produce a mixture of structural isomers of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid. It was also recorded that implementation of this known process at temperatures of about 100 °C or slightly higher (95-105 °C) led to Testification of the reaction medium.

[0019] Therefore, currently there is an unmet need for a process for production of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid chemical compound comprising a fewer number of chemical steps, lower use of organic solvents and production of the high purity chemical compound. The alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid, similar to many other chemical compounds, is used in pharmaceutical field in the form of a salt, therefore there is an unmet need for a process for production of a salt of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid, comprising a fewer number of chemical steps, lower use of organic solvents and production of high purity salt.

[0020] SUMMARY OF INVENTION

[0021] The first objective of the present disclosure is to improve the process for production of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid that would comprise a fewer number of steps, lower use of organic solvents and production of the high purity final product.

[0022] The second objective of the present disclosure is to improve the process for production of the salt of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid that would comprise a fewer number of steps, lower use of organic solvents and production of the high purity final product.

[0023] The first objective is achieved by the first disclosure being a process for production of alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid comprising the steps of:

[0024] (a) reacting o-phenylenediamine compound and (±)-camphoric anhydride compound in a medium being a mixture of toluene and N,N-dimethylformamide solvents at an elevated temperature, (b) isolating the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained in step (a), and purifying the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid, wherein step (a) is performed at a temperature of 100-120 °C under conditions suitable for removing water formed during the reaction and the ratio of toluene and N,N- dimethylformamide at the beginning of step (a) ranging from 11 :1 to 13:1 .

[0025] According to one of the embodiments of the first disclosure, step (a) is performed for at least 5 hours.

[0026] According to one of the embodiments of the first disclosure, the conditions suitable for removing water formed during the reaction in step (a) are formed by using a device for withdrawing vapors of an azeotropic mixture of water and toluene from the reaction vessel where the reaction in step (a) is performed.

[0027] According to one of the embodiments of the first disclosure, the isolation of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained in step (a) is performed by cooling the said solution to a temperature of 20-30 °C to obtain a precipitate in the cooled solution and filtering off the precipitate from the cooled solution.

[0028] According to one of the embodiments of the first disclosure, the purification of the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid is performed by washing the precipitate filtered off from the cooled solution with 70% ethanol at a temperature of 15-25 °C, then drying the washed precipitate to obtain crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, then recrystallizing the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid at least once from an ethanol-water mixture with an ethanol to water ratio of 2: 1 .

[0029] According to one of the embodiments of the first disclosure, the recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the ethanol-water mixture is performed by homogenizing the crystals of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid in ethanol under heating, then slowly adding water under heating until the ethanol to water ratio reaches 2:1 , bringing the solution to a boil, then slowly cooling the solution until crystals form and filtering off the resulting crystals.

[0030] According to one of the embodiments of the first disclosure, the recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the ethanol-water mixture is performed twice.

[0031] The second objective is achieved by the second disclosure being a process for production of a salt of alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid comprising the steps of:

[0032] (a) reacting o-phenylenediamine compound and (±)-camphoric anhydride compound in a medium being a mixture of toluene and N,N-dimethylformamide solvents at an elevated temperature,

[0033] (b) isolating the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained in step (a), and purifying the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid,

[0034] (c) reacting the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid compound and an aqueous solution of hydrochloric acid by homogenizing the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid in ethanol and adding an aqueous solution of hydrochloric acid to the resulting solution at an elevated temperature,

[0035] (d) evaporating the solution obtained in step (c) with isolating the salt of the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, wherein step (a) is performed at a temperature of 100-120 °C under conditions suitable for removing water formed during the reaction and the ratio of toluene and N,N- dimethylformamide at the beginning of step (a) ranging from 11 :1 to 13:1 , and step (c) is performed at a temperature of 30-40 °C for 0.5-1 .5 hours.

[0036] According to one of the embodiments of the second disclosure, step (a) is performed for at least 5 hours.

[0037] According to one of the embodiments of the second disclosure, the conditions suitable for removing water formed during the reaction in step (a) are formed by using a device for withdrawing vapors of an azeotropic mixture of water and toluene from the reaction vessel where the reaction in step (a) is performed.

[0038] According to one of the embodiments of the second disclosure, the isolation of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained in step (a) is performed by cooling the said solution to a temperature of 20-30 °C to obtain a precipitate in the cooled solution and filtering off the precipitate from the cooled solution.

[0039] According to one of the embodiments of the second disclosure, the purification of the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid is performed by washing the precipitate filtered off from the cooled solution with 70% ethanol at a temperature of 15-25 °C, then drying the washed precipitate to obtain crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, then recrystallizing the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid at least once from an ethanol-water mixture with an ethanol to water ratio of 2: 1 .

[0040] According to one of the embodiments of the second disclosure, the recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the ethanol-water mixture is performed by homogenizing the crystals of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid in ethanol under heating, then slowly adding water under heating until the ethanol to water ratio reaches 2:1 , bringing the solution to a boil, then slowly cooling the solution until crystals form and filtering off the resulting crystals.

[0041] According to one of the embodiments of the second disclosure, the recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the ethanol-water mixture is performed twice. According to one of the embodiments of the second disclosure, the salt of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid isolated in step (d) is the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate or the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride.

[0042] According to one of the embodiments of the second disclosure, in step (c) the aqueous hydrochloric acid solution is 1 M aqueous hydrochloric acid solution.

[0043] According to one of the embodiments of the second disclosure, the isolation of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride hydrate from the solution obtained in stage (c) is performed by evaporating ethanol and water to obtain crystals of the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate.

[0044] According to one of the embodiments of the second disclosure, the isolation of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride from the solution obtained in step (c) is performed by evaporating ethanol and water to obtain crystals, and drying the crystals to a constant weight of the crystals to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride.

[0045] The process according to the disclosure is characterized by features that enable production of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid or its salts only.

[0046] In the text of this application, the concentration of ethanol in the solution is expressed in percent. By default, percentage in this case should be understood as volume percentage, unless specified otherwise.

[0047] DESCRIPTION OF DRAWINGS

[0048] Fig. 1 shows13C-NMR spectrum of a sample of the chemical compound produced using the known process claimed in the declarative patent of Ukraine for invention No. UA 65046 A.

[0049] Fig. 2 shows PMR spectrum of a sample of the alpha-structural isomer of (±)-cis- 3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid produced using the first disclosure.

[0050] Fig. 3 shows the analysis of the PMR spectrum of Fig. 2.

[0051] Fig. 4 shows13C-NMR spectrum of a sample of the alpha-structural isomer of (±)- cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid produced using the first disclosure.

[0052] Fig. 5 shows the analysis of the13C-NMR spectrum of Fig. 4.

[0053] Fig. 6 shows a chromatogram of a sample of the alpha-structural isomer of (±)-cis- 3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate after step (d).

[0054] DETAILED DESCRIPTION OF INVENTION

[0055] Examples of the implementation of the first disclosure and the second disclosure are provided herein below. Example 1

[0056] Process for production of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0057] Step (a)

[0058] A 250 mL three-necked flask is equipped with a device for removing vapors of the azeotropic mixture of water and toluene from the three-necked flask, such as a Dean- Stark nozzle. Flask is also equipped with a reflux condenser and an overhead stirrer. 18.22 g (0.1 mol) of (±)-camphoric anhydride, 10.81 g (0.1 mol) of o-phenylenediamine, 95.72 mL of toluene and 8.00 mL of N,N-dimethylformamide were added into the threenecked flask. The three-necked flask containing the reaction mixture solution is placed in an oil bath, the stirrer is turned on, and the reaction mixture is stirred under heating at a temperature of 110° C for 5.5 hours. During the reaction, vapor from the azeotropic mixture of water and toluene forms above the reaction mixture and is directed into the Dean-Stark nozzle, where it condenses.

[0059] Step (b)

[0060] Isolation of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained in step (a) is implemented as follows.

[0061] The three-necked flask containing the reaction mixture solution after step (a) is cooled to a reaction mixture solution temperature of 25°C. In the reaction mixture solution, a precipitate forms, which is then filtered off using a filter.

[0062] Purification of the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0063] The filtered precipitate is washed with 70% ethanol at a temperature of 20 °C, then dried in a rotary evaporator flask to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid. Then the first recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from the ethanol-water mixture with a ratio of ethanol to water of 2:1 is performed.

[0064] The recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0065] 10 g of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid is dissolved in 250 mL of ethanol under heating, then 125 mL of water was slowly added (i.e. , at the end of the addition, the ratio of ethanol to water in the solution would reach 2:1 ), then the solution was brought to a boil. Then the heated solution is slowly cooled down until the crystals are formed and the resulting crystals were filtered off. Any other quantity of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid can be recrystallized in a similar way. Accordingly, the amount of ethanol and water required for the recrystallization can be increased or decreased.

[0066] After the first recrystallization of the crystals of the alpha-structural isomer of (±)- cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, a second recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is performed in the same way as the first recrystallization. The yield of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid after the first recrystallization and the second recrystallization is 45%.

[0067] The study of a sample of the chemical compound produced in Example 1 to determine its structure

[0068] To determine the structure of the chemical compound, a PMR spectroscopy and its analysis and a13C-NMR spectroscopy and its analysis were performed.

[0069] The proton magnetic resonance (PMR) spectroscopy of a sample of the chemical compound produced according to Example 1 was performed using a two-channel device for PMR such as BrukerAvance DRX with the following characteristics:

[0070] - magnetic field - 9.39 T;

[0071] - operating frequency for 1 H nuclei - 400 MHz;

[0072] - two independent radio frequency channels - 10-430 MHz (6-440 MHz);

[0073] - broadband dual-channel sensor for solutions;

[0074] - selective channel 1 H;

[0075] - range of nuclei on the broadband channel - 31 P-15N, 19F;

[0076] - temperature range - from -150 °C to +120 °C.

[0077] For the analysis, the sample of the chemical compound produced according to Example 1 was dissolved in a commercially available deuterated solvent, d6-DMSO. The resulting solution was placed in an ampoule with a volume of 5 mL and a diameter of 5 mm. The ampoule with the dissolved sample was placed in a BrukerAvance DRX 400 MHz device, and the device was started to obtain the PMR spectrum. The results of the PMR are shown in Figure 2. The analysis of the obtained PMR spectrum is shown in Figure 3.

[0078] The obtained PMR spectrum and its analysis confirm that the chemical compound produced using the process according to the first disclosure and provided in Example 1 is the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid.

[0079] The nuclear magnetic resonance13C-NMR of the sample of the chemical compound produced according to Example 1 was performed using a two-channel BrukerAvance DRX device with the following characteristics:

[0080] - magnetic field - 9.39 T;

[0081] - operating frequency for 1 H nuclei - 400 MHz;

[0082] - two independent radio frequency channels - 10-430 MHz (6-440 MHz);

[0083] - broadband dual-channel sensor for solutions;

[0084] - selective channel 1 H;

[0085] - range of nuclei on the broadband channel - 31 P-15N, 19F;

[0086] - temperature range - from -150 °C to +120 °C.

[0087] For the analysis, the sample of the chemical compound produced according to Example 1 was dissolved in a deuterated solvent, d6-DMSO. The resulting solution was placed in an ampoule with a volume of 5 mL and a diameter of 5 mm. The ampoule containing the dissolved sample was positioned in a BrukerAvance DRX 400 MHz device, and the device was started to obtain a13C-NMR spectrum. The results of the13C-NMR are shown in Figure 4. The analysis of the obtained13C-NMR spectrum is shown in Figure 5. The structural formula of the chemical compound according to the results of the analysis of the obtained13C-NMR spectrum is as follows:

[0088] The obtained13C-NMR spectrum and its analysis confirm that the chemical compound produced using the process according to the first disclosure and provided in Example 1 is the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid.

[0089] To evaluate the effectiveness of the recrystallization of the crystals of the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from an ethanol-water mixture with an ethanol to water ratio of 2:1 , as described in the claimed process of the first disclosure, a comparative study of the technical parameters of the recrystallization of the crystals of the alpha-structural isomer of (±)-cis- 3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid was conducted: in one case, from the ethanol-water mixture with an ethanol to water ratio of 2:1 , and, in second case, from 96% ethanol. In the comparative study, the losses of the isomer of (±)-cis-3- (2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid after undergoing double recrystallization were determined using crystals of the alpha-structural isomer of (±)-cis- 3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid recrystallized from two different solvents: 96% ethanol and an ethanol-water mixture with an ethanol to water ratio of 2:1. The double recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid was performed according to the process described in Example 1 in step (b). The results of the comparative study are provided in Table 1 . Table 1

[0090] Study of the effectiveness of the recrystallization of the alpha-structural isomer of (±)- cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid

[0091] The data in Table 1 confirm that the double recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the ethanol-water mixture with an ethanol to water ratio of 2:1 results in significantly lower losses of the alpha-structural isomer of (±)- cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid than the double recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from 96% ethanol: the difference in the losses is approximately 2 times.

[0092] To evaluate the effectiveness of the purification process for the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid isolated in stage (b) accordingly to the claimed process of the first disclosure, a chromatographic analysis was conducted to determine the impurity content in the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid. The analysis was performed using standard liquid chromatography techniques.

[0093] More specifically, to prepare a test solution, 20 mg of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid was transferred to a 20.0 mL flask, combined with a solvent, thoroughly mixed until dissolved and adjusted to the 20.0 mL mark with the same solvent.

[0094] To prepare a reference solution, 1.0 mL of the prepared test solution was transferred to a 50.0 mL flask and adjusted to the 50.0 mL mark with the solvent, after that 1 .0 mL of the prepared test solution was transferred to a 20.0 mL flask and adjusted to the 20.0 mL mark with the solvent.

[0095] Mobile phase was as follows: eluent A, namely a buffer solution with pH 3.0 (0.2 M sodium perchlorate solution: 28.0 g of sodium perchlorate R was transferred to a 1000.0 mL volumetric flask, dissolved in water for chromatography R, and adjusted to the mark with the same solvent, then adjusted to pH 3.0 with diluted phosphoric acid R), and eluent B, namely acetonitrile R.

[0096] Liquid chromatography was performed under the following conditions: column: 150 mm x 4.6 mm; silica gel for chromatography, octadecylsilyl, endcapped (3 p); column temperature: 35 °C; flow rate: 1 .0 mL / min; detection: spectrophotometrically at a wavelength of 210 nm; injection: 5 pL of both the test solution and the reference solution; chromatography time: 36 min.

[0097] The following Table 2 provides the conditions for gradient elution.

[0098] Table 2

[0099] Conditions for gradient elution

[0100] The results of the analysis are considered reliable if the conditions of the chromatographic system suitability are met for the chromatograms of the reference solution:

[0101] - effectiveness of the chromatographic column: the number of theoretical plates for the peak of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the reference solution must be at least 3000;

[0102] - the relative standard deviation calculated from the area of the peak of the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from six chromatograms of the reference solution must not exceed 2.0%;

[0103] - the symmetry factor for the peak of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid must not exceed 1.5.

[0104] Peaks in the chromatogram of the test solution, the area of which is half the area of the main peak in the chromatogram of the reference solution (0.05%), were ignored.

[0105] The percentage content of an individual impurity in the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrate (X) was calculated by the following formula:

[0106] X = St / Sst * 0.1 where:

[0107] St is the area of a peak other than the main peak in the chromatogram of the test solution;

[0108] Sst is the area of the peak of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid in the chromatogram of the reference solution.

[0109] A sample of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid after step (a), a sample of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid in step (b) after the first recrystallization of the crystals of the alpha-structural isomer of (±)-cis- 3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, and a sample of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid in step (b) after the second recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid were collected as samples.

[0110] The results of the said chromatographic study of the sample of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid after step (a) are provided in Table 3.

[0111] Table 3

[0112] Chromatographic study of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid after step (a)

[0113] The data in Table 3 confirm that a significant amount of the impurities was detected in the sample of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid after step (a).

[0114] The results of the chromatographic study of the sample of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid at step (b) after the first recrystallization of the crystals of the alpha-structural isomer of (±)-cis- 3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, and the sample of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid at step (b) after the second recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid are provided in Table 4. Table 4

[0115] Chromatographic study of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid after step (b)

[0116] The data in Table 4 show that the recrystallization of the crystals of the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from the ethanol-water mixture with an ethanol to water ratio of 2:1 results in high purity of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid produced by the process of the first disclosure. After the first recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, only one impurity in amounts of 0.033 % and 0.02%, respectively, was detected, and after the second recrystallization of the crystals of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid, no impurities were detected.

[0117] Example 2

[0118] Process for production of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0119] Step (a)

[0120] A 250 mL three-necked flask is equipped with a device for removing vapors of the azeotropic mixture of water and toluene from the three-necked flask, such as a Dean- Stark nozzle. Flask is also equipped with a reflux condenser and an overhead stirrer. 18.22 g (0.1 mol) of (±)-camphoric anhydride, 10.81 g (0.1 mol) of o-phenylenediamine, 88 mL of toluene and 8.00 mL of N,N-dimethylformamide were added into the threenecked flask. The three-necked flask containing the reaction mixture solution is placed in an oil bath, the stirrer is turned on, and the reaction mixture is stirred under heating at a temperature of 100° C for 5 hours. During the reaction, vapor from the azeotropic mixture of water and toluene forms above the reaction mixture and is directed into the Dean-Stark nozzle, where it condenses.

[0121] Step (b)

[0122] Isolation of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained in step (a) is implemented as follows.

[0123] The three-necked flask containing the reaction mixture solution after step (a) is cooled to a reaction mixture solution temperature of 20°C. In the reaction mixture solution a precipitate forms, which is then filtered off using a filter. Purification of the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0124] The filtered precipitate is washed with 70% ethanol at a temperature of 15 °C, then dried in a rotary evaporator flask to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid. Then the first recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from the ethanol-water mixture with a ratio of ethanol to water of 2:1 is performed.

[0125] The recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0126] 10 g of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid is dissolved in 250 mL of ethanol under heating, then 125 mL of water was slowly added (i.e. , at the end of the addition, the ratio of ethanol to water in the solution would reach 2:1 ), then the solution was brought to a boil. Then the heated solution is slowly cooled down until the crystals are formed, and the resulting crystals were filtered off. Any other quantity of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid can be recrystallized in a similar way. Accordingly, the amount of ethanol and water required for the recrystallization can be increased or decreased.

[0127] After the first recrystallization of the crystals of the alpha-structural isomer of (±)- cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, a second recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is performed in the same way as the first recrystallization.

[0128] The yield of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid after the first recrystallization and the second recrystallization is 40%.

[0129] Example 3

[0130] Process for production of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0131] Step (a)

[0132] A 250 mL three-necked flask is equipped with a device for removing vapors of the azeotropic mixture of water and toluene from the three-necked flask, such as a Dean- Stark nozzle. Flask is also equipped with a reflux condenser and an overhead stirrer. 18.22 g (0.1 mol) of (±)-camphoric anhydride, 10.81 g (0.1 mol) of o-phenylenediamine, 104 mL of toluene and 8.00 mL of N,N-dimethylformamide were added into the threenecked flask. The three-necked flask containing the reaction mixture solution is placed in an oil bath, the stirrer is turned on, and the reaction mixture is stirred under heating at a temperature of 120 °C for 6 hours. During the reaction, vapor from the azeotropic mixture of water and toluene forms above the reaction mixture and is directed into the Dean-Stark nozzle, where it condenses.

[0133] Step (b)

[0134] Isolation of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained in step (a) is implemented as follows. The three-necked flask containing the reaction mixture solution after step (a) is cooled to a reaction mixture solution temperature of 30°C. In the reaction mixture solution, a precipitate forms, which is then filtered off using a filter.

[0135] Purification of the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0136] The filtered precipitate is washed with 70% ethanol at a temperature of 25 °C, then dried in a rotary evaporator flask to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid. Then the first recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from the ethanol-water mixture with a ratio of ethanol to water of 2:1 is performed.

[0137] The recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0138] 10 g of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid is dissolved in 250 mL of ethanol under heating, then 125 mL of water was slowly added (i.e. , at the end of the addition, the ratio of ethanol to water in the solution would reach 2:1 ), then the solution was brought to a boil. Then the heated solution is slowly cooled down until the crystals formed, and the resulting crystals were filtered off. Any other quantity of the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid can be recrystallized in a similar way. Accordingly, the amount of ethanol and water required for the recrystallization can be increased or decreased.

[0139] After the first recrystallization of the crystals of the alpha-structural isomer of (±)- cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, a second recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic is performed in the same way as the first recrystallization.

[0140] The yield of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid after the first recrystallization and the second recrystallization is 48%.

[0141] Example 4

[0142] Process for production of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0143] Step (a)

[0144] A 250 mL three-necked flask is equipped with a device for removing vapors of the azeotropic mixture of water and toluene from the three-necked flask, such as a Dean- Stark nozzle. Flask is also equipped with a reflux condenser and an overhead stirrer. 18.22 g (0.1 mol) of (±)-camphoric anhydride, 10.81 g (0.1 mol) of o-phenylenediamine, 95.72 mL of toluene and 8.00 mL of N,N-dimethylformamide were added into the threenecked flask. The three-necked flask containing the reaction mixture solution is placed in an oil bath, the stirrer is turned on, and the reaction mixture is stirred under heating at a temperature of 110° C for 5.5 hours. During the reaction, vapor from the azeotropic mixture of water and toluene forms above the reaction mixture and is directed into the

[0145] Dean-Stark nozzle, where it condenses.

[0146] Step (b) Isolation of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained in step (a) is implemented as follows.

[0147] The three-necked flask containing the reaction mixture solution after step (a) is cooled to a reaction mixture solution temperature of 25°C. In the reaction mixture solution, a precipitate forms, which is then filtered off using a filter.

[0148] Purification of the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0149] The filtered precipitate is washed with 70% ethanol at a temperature of 20 °C, then dried in a rotary evaporator flask to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid. Then the first recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from the ethanol-water mixture with a ratio of ethanol to water of 2:1 is performed.

[0150] The recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is implemented as follows.

[0151] 10 g of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid is dissolved in 375 mL of ethanol-water mixture with ethanol to water ratio of 2:1 under heating (the mixture was prepared by mixing 250 mL of ethanol and 125 mL of water), then the solution was brought to a boil. Then the heated solution is slowly cooled down until the crystals formed, and the resulting crystals were filtered off. Any other quantity of the crystals of the alpha-structural isomer of (±)-cis-3- (2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid can be recrystallized in a similar way. Accordingly, the amount of ethanol and water required for the recrystallization can be increased or decreased.

[0152] After the first recrystallization of the crystals of the alpha-structural isomer of (±)- cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, a second recrystallization of the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid is performed in the same way as the first recrystallization.

[0153] The yield of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid after the first recrystallization and the second recrystallization is 43%.

[0154] Examples of the production of the salts of the alpha-structural isomer of (±)-cis-3- (2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid are provided below.

[0155] Example 5

[0156] Process for production of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate is implemented as follows.

[0157] Steps (a) and (b) are carried out according to the procedure outlined in Example 1.

[0158] Step (c)

[0159] 27.24 g (0.1 mol) of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid produced after step (b) and 100.00 mL of 96% ethanol were added into a 500 mL conical flat-bottomed flask equipped with a reflux condenser and an overhead stirrer. 100.00 mL of 1 M aqueous hydrochloric acid solution were added dropwise to the solution under stirring. The flask is placed in a water bath, and the reaction mixture is heated to 35 °C under stirring for 1 hour until the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is formed.

[0160] Step (d)

[0161] The reaction mixture after step (c) is added into a rotary evaporator flask, where ethanol and water were evaporated, to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate. The yield of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride hydrate is 100%.

[0162] Example 6

[0163] Process for production of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate is implemented as follows.

[0164] Steps (a) and (b) are carried out according to the procedure outlined in Example

[0165] 2.

[0166] Step (c)

[0167] 27.24 g (0.1 mol) of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid produced after step (b) and 100.00 mL of 96% ethanol were added into a 500 mL conical flat-bottomed flask equipped with a reflux condenser and an overhead stirrer. 200.00 mL of 0.5 M aqueous hydrochloric acid solution were added dropwise to the solution under stirring. The flask is placed in a water bath, and the reaction mixture is heated to 40 °C under stirring for 0.5 hour until the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is formed.

[0168] Step (d)

[0169] The reaction mixture after step (c) is added into a rotary evaporator flask, where ethanol and water were evaporated, to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate. The yield of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride hydrate is 100%.

[0170] Example 7

[0171] Process for production of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate is implemented as follows.

[0172] Steps (a) and (b) are carried out according to the procedure outlined in Example

[0173] 3.

[0174] Step (c)

[0175] 27.24 g (0.1 mol) of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid produced after step (b) and 100.00 mL of 96% ethanol were added into a 500 mL conical flat-bottomed flask equipped with a reflux condenser and an overhead stirrer. 100.00 mL of 1 M aqueous hydrochloric acid solution were added dropwise to the solution under stirring. The flask is placed in a water bath, and the reaction mixture is heated to 30 °C under stirring for 1.5 hour until the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is formed. Step (d)

[0176] The reaction mixture after step (c) is added into a rotary evaporator flask, where ethanol and water were evaporated, to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate. The yield of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride hydrate is 100%.

[0177] Example 8

[0178] Process for production of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is implemented as follows.

[0179] Steps (a) and (b) are carried out according to the procedure outlined in Example 4.

[0180] Step (c)

[0181] 27.24 g (0.1 mol) of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-

[0182] 1 ,2,2-trimethylcyclopentanecarboxylic acid produced after step (b) and 100.00 mL of 96% ethanol were added into a 500 mL conical flat-bottomed flask equipped with a reflux condenser and an overhead stirrer. 100.00 mL of 1 M aqueous hydrochloric acid solution were added dropwise to the solution under stirring. The flask is placed in a water bath, and the reaction mixture was heated to 35 °C under stirring for 1 hour until the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is formed.

[0183] Step (d)

[0184] The reaction mixture after step (c) is added into a rotary evaporator flask, where ethanol and water were evaporated, to obtain the crystals, and the crystals were dried at a temperature of 120 °C to a constant weight to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride. The yield of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-

[0185] 1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is 100%.

[0186] Example 9

[0187] Process for production of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is implemented as follows.

[0188] Steps (a) and (b) are carried out according to the procedure outlined in Example 2.

[0189] Step (c)

[0190] 27.24 g (0.1 mol) of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-

[0191] 1 ,2,2-trimethylcyclopentanecarboxylic acid produced after step (b) and 100.00 mL of 96% ethanol were added into a 500 mL conical flat-bottomed flask equipped with a reflux condenser and an overhead stirrer. 200.00 mL of 0.5 M aqueous hydrochloric acid solution were added dropwise to the solution under stirring. The flask is placed in a water bath, and the reaction mixture is heated to 40 °C under stirring for 0.5 hour until the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is formed.

[0192] Step (d)

[0193] The reaction mixture after step (c) is added into a rotary evaporator flask, where ethanol and water were evaporated, to obtain the crystals, and the crystals were dried at a temperature of 120 °C to a constant weight to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride. The yield of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-

[0194] 1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is 100%.

[0195] Example 10

[0196] Process for production of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is implemented as follows.

[0197] Steps (a) and (b) are carried out according to the procedure outlined in Example 3.

[0198] Step (c)

[0199] 27.24 g (0.1 mol) of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-

[0200] 1 ,2,2-trimethylcyclopentanecarboxylic acid produced after step (b) and 100.00 mL of 96% ethanol were added into a 500 mL conical flat-bottomed flask equipped with a reflux condenser and an overhead stirrer. 100.00 mL of 1 M aqueous hydrochloric acid solution were added dropwise to the solution under stirring. The flask is placed in a water bath, and the reaction mixture is heated to 30 °C under stirring for 1.5 hour until the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is formed.

[0201] Step (d)

[0202] The reaction mixture after step (c) is added into a rotary evaporator flask, where ethanol and water were evaporated, to obtain the crystals, and the crystals were dried at a temperature of 120 °C to a constant weight to obtain the crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride. The yield of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-

[0203] 1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride is 100%.

[0204] The amount of water of crystallization in the samples of the produced alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate was calculated. The calculation was performed using the following technique: m3= m1- m2= 5,01679 - 4,76553 = 0,25126 g where: rm - mass of the crystallohydrate sample, 5.01679 g; m2 - mass of the anhydrous salt sample, 4.76553 g; m3 - mass of the evaporated water, g; n(CieH2iCIN2O2) - amount of alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride, mol;

[0205] / Wr(CieH2iCIN2O2) - molar mass of alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride, 308.8 g / mol; n(H2O) - amount of water, mol;

[0206] / Wr(H2O) - molar mass of water, 18 g / mol. m(C16H21C!N2O2) 4,76553

[0207] H(C16H21C1N2O2) 0,01543 mol

[0208] Mr(C16H21ClN2O2) 308,8 m(H2O) 0,25126

[0209] H(H20) 0,01396 MOJib

[0210] Mr(H2O) 18

[0211] The amount of water in 1 mol of the crystallohydrate: 0.01543 mol (C16H21 CIN2O2) - 0.01396 mol H2O 1 mol (C16H21 CIN2O2) - x mol H2O

[0212] > 1 X 0,01396

[0213] X0,905 mol “ 0,01543

[0214] To determine the purity of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate produced by the process described in the second disclosure, chromatographic analysis was performed using standard liquid chromatography techniques.

[0215] More specifically, to prepare a test solution, 20 mg of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate was transferred to a 20.0 mL flask, combined with a solvent, thoroughly mixed until dissolved and adjusted to the 20.0 mL mark with the same solvent.

[0216] To prepare a reference solution, 1.0 mL of the prepared test solution was transferred to a 50.0 mL flask and adjusted to the 50.0 mL mark with the solvent, after that 1 .0 mL of the prepared test solution was transferred to a 20.0 mL flask and adjusted to the 20.0 mL mark with the solvent.

[0217] Mobile phase was as follows: eluent A, namely a buffer solution with pH 3.0 (0.2 M sodium perchlorate solution: 28.0 g of sodium perchlorate R was transferred to a 1000.0 mL volumetric flask, dissolved in water for chromatography R, and adjusted to the mark with the same solvent, then adjusted to pH 3.0 with diluted phosphoric acid R), and eluent B, namely acetonitrile R.

[0218] Liquid chromatography was performed under the following conditions: column: 150 mm x 4.6 mm; silica gel for chromatography, octadecylsilyl, endcapped (3 p); column temperature: 35 °C; flow rate: 1 .0 mL / min; detection: spectrophotometrically at a wavelength of 210 nm; injection: 5 pL of both the test solution and the reference solution; chromatography time: 36 min.

[0219] The following Table 5 provides the conditions for gradient elution. Table 5

[0220] Conditions for gradient elution

[0221] The results of the analysis are considered reliable if the conditions of the chromatographic system suitability are met for the chromatograms of the reference solution:

[0222] - effectiveness of the chromatographic column: the number of theoretical plates for the peak of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride hydrate from the reference solution must be at least 3000;

[0223] - the relative standard deviation calculated from the area of the peak of the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate from six chromatograms of the reference solution must not exceed 2.0%;

[0224] - the symmetry factor for the peak of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate must not exceed 1 .5.

[0225] Peaks in the chromatogram of the test solution, the area of which is half the area of the main peak in the chromatogram of the reference solution (0.05%), were ignored.

[0226] The percentage content of an individual impurity in the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate (X) was calculated by the following formula:

[0227] X = St / Sst * 0.1 where:

[0228] St is the area of a peak other than the main peak in the chromatogram of the test solution;

[0229] Sst is the area of the peak of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate in the chromatogram of the reference solution.

[0230] The resulting chromatogram is shown in Figure 6.

[0231] Analysis of the results of the chromatographic study of the samples of the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate produced by the second disclosure shows that the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate comprises only one impurity (with a retention time of 20.090 min) in an amount of less than 0.1 %. This confirms that the produced alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate has high purity and meets the requirements of the European Pharmacopoeia Ph. Eur. 2.2.29.

[0232] The technical contribution of the present disclosure resides in the following:

[0233] - due to the features of the claimed disclosures, they enable the production of a chemical compound, such as the alpha-structural isomer of (±)-cis-3- (2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid and its salt, which was confirmed by the conducted studies, unlike the analogue (the process claimed in the declarative patent of Ukraine for invention No. UA 65046 A);

[0234] - due to a feature of performing only a single chemical reaction in the first disclosure, it requires fewer steps and actions compared to the analogue (the process claimed in the patent of Ukraine for invention No. UA 118627 C2). Additionally, it uses significantly less organic solvent and requires less time to complete the process;

[0235] - due to features of the isolation and purification of chemical compounds in the first and second disclosures, the claimed processes, compared to known methods, allow the production of products (the alpha-structural isomer (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid compound and its salts) with significantly higher purity.

[0236] The provided examples for implementing the first and second disclosures serve solely to illustrate these disclosures and are not intended to limit their scope.

Claims

CLAIMS1 . A process for production of alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)- 1 ,2,2-trimethylcyclopentanecarboxylic acid comprising the steps of:(a) reacting o-phenylenediamine compound and (±)-camphoric anhydride compound in a medium being a mixture of toluene and N,N-dimethylformamide solvents at an elevated temperature,(b) isolating the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained in step (a), and purifying the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid, characterized in that step (a) is performed at a temperature of 100-120 °C under conditions suitable for removing water formed during the reaction and the ratio of toluene and N,N-dimethylformamide at the beginning of step (a) ranging from 11 :1 to 13:1.

2. The process according to claim 1 , characterized in that step (a) is performed for at least 5 hours.

3. The process according to any one of claims 1-2, characterized in that the conditions suitable for removing water formed during the reaction in step (a) are formed by using a device for withdrawing vapors of an azeotropic mixture of water and toluene from the reaction vessel where the reaction in step (a) is performed.

4. The process according to any one of claims 1 -3, characterized in that the isolation of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained at step (a) is performed by cooling the said solution to a temperature of 20-30 °C to obtain a precipitate in the cooled solution, and filtering off the precipitate from the cooled solution.

5. The process according to claim 4, characterized in that the purification of the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid is performed by washing the precipitate filtered off from the cooled solution with 70% ethanol at a temperature of 15-25 °C, then drying the washed precipitate to obtain crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, then recrystallizing the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid at least once from an ethanol-water mixture with an ethanol to water ratio of 2:1 .

6. The process according to claim 5, characterized in that the recrystallization of the crystals of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the ethanol-water mixture is performed by homogenizing the crystals of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid in ethanol under heating, then slowly adding water under heating until the ethanol to water ratio reaches 2:1 , bringing the solution to a boil, then slowly cooling the solution until crystals form and filtering off the resulting crystals.

7. The process according to any of claims 5-6, characterized in that the recrystallization of the crystals of the alpha structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from the ethanol- water mixture is performed twice.

8. A process for production of a salt of alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid comprising the steps of:(a) reacting o-phenylenediamine compound and (±)-camphoric anhydride compound in a medium being a mixture of toluene and N,N-dimethylformamide solvents at an elevated temperature,(b) isolating the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the solution obtained in step (a), and purifying the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid, characterized in that process further comprises the following steps after step (b):(c) reacting the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid compound and an aqueous solution of hydrochloric acid by homogenizing the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid in ethanol and adding an aqueous solution of hydrochloric acid to the resulting solution at an elevated temperature,(d) evaporating the solution obtained in step (c) with isolating the salt of the alpha- structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid, wherein step (a) is performed at a temperature of 100-120 °C under conditions suitable for removing water formed during the reaction and the ratio of toluene and N,N-dimethylformamide at the beginning of step (a) ranging from 11 :1 to 13:1 , and step (c) is performed at a temperature of 30-40 °C for 0.5-1 .5 hours.

9. The process according to claim 8, characterized in that step (a) is performed for at least 5 hours.

10. The process according to any one of claims 8-9, characterized in that the conditions suitable for removing water formed during the reaction in step (a) are formed by using a device for withdrawing vapors of an azeotropic mixture of water and toluene from the reaction vessel where the reaction in step (a) is performed.11 . The process according to any one of claims 8-10, characterized in that the isolation of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from the solution obtained in step (a) is performed by cooling the said solution to a temperature of 20-30 °C to obtain a precipitate in the cooled solution, and filtering off the precipitate from the cooled solution.

12. The process according to claim 11 , characterized in that the purification of the isolated alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid is performed by washing the precipitate filtered off from the cooled solution with 70% ethanol at a temperature of 15-25 °C, then drying the washed precipitate to obtain crystals of the alpha-structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid, then recrystallizing the crystals of the alpha-structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid at least once from the ethanol-water mixture with ethanol to water ratio of 2:1 .

13. The process according to claim 12, characterized in that the recrystallization of the crystals of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid from the ethanol-water mixture is performed by homogenizing the crystals of the alpha structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid in ethanol under heating, then slowly adding water under heating until the ethanol to water ratio reaches 2:1 , bringing the solution to a boil, then slowly cooling the solution until crystals form and filtering off the resulting crystals.

14. The process according to any of claims 12-13, characterized in that the recrystallization of the crystals of the alpha structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid from the ethanol- water mixture is performed twice.

15. The process according to any of claims 8-14, characterized in that the salt of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid isolated in step (d) is the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride hydrate or the alpha structural isomer of (±)-cis-3-(2'- benzimidazolyl)-1 ,2,2-trimethylcyclopentanecarboxylic acid hydrochloride.

16. The process according to any one of claims 8-15, characterized in that in step (c) the aqueous hydrochloric acid solution is 1 M aqueous hydrochloric acid solution.

17. The process according to any one of claims 15-16, characterized in that the isolation of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride hydrate from the solution obtained in stage (c) is performed by evaporating ethanol and water to obtain crystals of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride hydrate.

8. The process according to any one of claims 15-16, characterized in that the isolation of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride from the solution obtained in step (c) is performed by evaporating ethanol and water to obtain crystals, and drying the crystals to a constant weight of the crystals to obtain the crystals of the alpha structural isomer of (±)-cis-3-(2'-benzimidazolyl)-1 ,2,2- trimethylcyclopentanecarboxylic acid hydrochloride.

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