RU2433998C1 - Method of producing perindopril and pharmaceutically acceptable salts thereof - Google Patents

Abstract

FIELD: chemistry. ^ SUBSTANCE: invention relates to an improved method of producing perindopril of formula (I) or pharmaceutically acceptable salts thereof, protected compound ^ (I), (IV). The method involves removal of protective groups from a protected compound of formula (IV), where R1, R2 and R3 independently denote H, alkyl, aryl and Cl, via treatment thereof with palladium derivatives with aryl phosphines or biphosphines in protonic or aprotic solvents to obtain perindopril (I), which, if necessary, is treated with a base to obtain its pharmaceutically acceptable salt, followed by, if necessary, recrystallisation thereof from acetonitrile or a mixture of acetonitrile and ethanol. ^ EFFECT: high yield ratio. ^ 23 cl, 3 dwg, 7 ex

Description

The present invention relates to an improved method for producing perindopril and its pharmaceutically acceptable salts, which can be used for the manufacture of pharmaceutical preparations.

Perindopril and its pharmaceutically acceptable salts, preferably its tert-butylamine salt, exhibit valuable pharmacological properties in the treatment of cardiovascular diseases, normalizing blood pressure

EP 1279665 (and its modifications EP 1362864, WO 03010142, WO 2005003153) describes a method for producing perindopril and its pharmaceutically acceptable salts, according to which perindopril is produced by condensation of N - [(S) -1-carbethoxybutyl] - (5) - alanine, due to activation of the carboxyl group by phosgene or its derivatives, and octahydroindole-2-carboxylic acid.

The disadvantage of this method is the use of highly toxic phosgene and its derivatives, which leads to certain difficulties in the implementation process in the industry of this invention.

A known method of producing perindopril and its pharmaceutically acceptable salt of perindopril erbumin (WO 2005/068425), which consists in protecting the nitrogen atom and the carboxyl function of N - [(S) -1-carbethoxybutyl] - (S) -alanine with trimethylsilyl groups, followed by activation of the carboxyl group by transferring it to the corresponding chloro or bromohydride. Further interaction of the anhydride with protected (benzyl, trimethylsilyl, tert-butyl ether) octahydroindole-2-carboxylic acid leads to perindopril ester. Removing the protecting group and obtaining the salt with tert-butylamine give perindopril erbumin.

This method also has a number of significant disadvantages: a large number of stages and the need to purify the final product from organosilicon derivatives.

US Pat. No. 4,914,214 describes a process for the preparation of perindopril and its tert-butylamine salt, according to which N - [(S) -1-carbethoxybutyl] - (S) -alanine is condensed with octahydroindole-2-carboxylic acid benzyl ester followed by deprotection ( benzyl) by hydrogenation in the presence of a noble metal catalyst (palladium) on coal. In addition to benzyl, mono-, di-, triaryl-substituted (alkyl, alkoxy, halo, nitro) benzyl groups can also be used as a protective group; diphenylmethyl and triphenylmethyl or their derivatives. In the synthesis of perindopril, the corresponding hexahydroindole-2-carboxylic acid and dihydroindole-2-carboxylic acid can be used (patents WO 2004078708, WO 2004078107, EP 1362864, WO 2005003153, EP 1367062, EP 1256590, WO 2005023842, WO 20050661).

The disadvantage of this method is the use of hydrogen in the hydrogenation process, which has the ability to form an explosive mixture with air.

In the patent RU 2339645, this method was improved by eliminating some of the disadvantages listed above, the multi-stage process and the formation of undesirable impurities. In this case, the removal of the protective group is carried out in the presence of a base, which is added directly to the reaction mixture obtained in the process of removal of the protective group, which leads to a reduction in the stages of the technological process.

The disadvantage of this method is the use of hydrogen, since the removal of the protective group includes a hydrogenation process in the presence of a noble metal catalyst, preferably palladium on carbon.

The perindopril tert-butylamine salt obtained by the above methods is used in the manufacture of pharmaceutical preparations in the form of various crystalline forms or in the form of a monohydrate. The following forms of perindopril tert-butylamine salt and methods for their preparation are known, which are protected by patents: α-crystalline form (PCT WO 01/87835), β-crystalline form (PCT WO 01/87836), γ-crystalline form (PCT WO 01 / 87835), perindopril monohydrate (RU 2339645).

The main objective of the invention is to develop a simple and safe method for producing perindopril and its pharmaceutically acceptable salts, easily and quickly practiced in an industrial environment.

The authors of the present invention have developed an environmentally friendly and explosion-proof method for producing perindopril and its pharmaceutically acceptable salts, which eliminates the use of highly toxic and explosive reagents, which includes the stages of esterification (A), condensation (B), removal of the protective group (C) and salt formation (G), however, the last two stages can be combined into one (figure 1).

The invention relates primarily to a method for producing perindopril (I) or its pharmaceutically acceptable salts from a protected compound (IV)

characterized in that the removal of the protective group from the protected compound (IV), in which R ¹ , R ² and R ³ are preferably hydrogen, alkyl, aryl or chlorine in any combination, and the protective group is an alkenyl group, is carried out by processing the protected compounds (IV) with palladium derivatives with arylphosphines or biphosphines, whereby perindopril (I) is obtained, which, if necessary, is treated with a base, preferably tert-butylamine, and a salt, preferably a tert-butylamine salt of perind, is obtained App.

Derivatives of palladium with arylphosphine or biphosphine are used as a catalyst, while palladium derivatives, both obtained in situ and introduced into the reaction mixture with a zero oxidation state of the metal, preferably Рd (0) / РРh ₃ , Рd (0) /, can be used. P (o-tolyl) ₃ , Pd (0) / (2-biphenyl) ditret-butylphosphine, Pd (0) / BINAP, etc.

The deprotection is carried out in an organic solvent, in which case both protic solvents, preferably C ₁ -C ₄ aliphatic linear or branched alcohols, and aprotic solvents, preferably 1,4-dioxane, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform can be used.

In order to reduce the number of process steps, a salt, preferably tert-butylamine salt of perindopril, can be obtained directly from compound (IV), while the deprotection is carried out in the presence of a base, preferably tert-butylamine, directly in the reaction mixture obtained during the processing compounds (IV) with palladium derivatives.

The authors found that a specific perindopril salt - tert-butylamine salt can be obtained in a well-defined, highly reproducible crystalline form, characterized by an IR spectrum (Fig. 2) and a powder X-ray diffraction diagram (Fig. 3), expressed in terms of: interplanar distance d , Bragg's 2 θ angle, intensity and relative intensity (expressed as a percentage of the most intense beam) presented in the table.

Characterization of the crystalline form of tert-butylamine salt of perindopril Angle 2 θ, ° Interplanar distance, d Intensity Relative intensity,% 9.160 9.65 4033.33 43.3 11.080 7.98 1063.33 11,4 13.880 6.38 508.33 5.5 14.700 6.02 1465.00 15.7 15.460 5.73 2380.00 25.6 16.620 5.33 9310.00 one hundred 17.460 5.08 1645.00 17.7 18.140 4.89 921.67 9.9 20.080 4.42 1288.33 13.8 20.720 4.28 2148.33 23.1 21.520 4.13 1143.33 12.3 22.180 4.01 3083.33 33.1 22.660 3.92 1985.00 21.3 24.240 3.67 1500.00 16.1 24.840 3,58 793.33 8.5 25.960 3.43 835.00 9.0 27.780 3.21 1150.00 12,4

The X-ray powder diffraction spectrum was measured under the following conditions: Thermo ARL X'TRA diffractometer, semiconductor detector, CuKα radiation, voltage 45 kV, current 35 mA, continuous shooting at 2 ° / min, step 0.02 °, tube slit widths 2 and 4 mm , detectors - 0.5 and 0.2 mm. The experimental data were processed using WinXRD 2.0 software.

This crystalline form can be obtained by recrystallization, preferably, of the perindopril tert-butylamine salt obtained by any known method, as well as by recrystallization of other crystalline forms (for example, the α, β, γ form) of this salt from acetonitrile, preferably from a mixture of acetonitrile and ethanol, while the ethanol content in the mixture should not exceed 30% by volume. The addition of ethanol allows to reduce the total volume of solvent required for recrystallization, while increasing the ethanol content over 30% by volume leads to a sharp reduction in the yield of the target product.

The invention also relates to compound (IV), which can be obtained by condensation of acid (II) and ester (III), which, in turn, is obtained by etherification of octahydroindole-2-carboxylic acid with an alcohol in which R ¹ , R ² and R ³ are preferably hydrogen, as well as alkyl, aryl or chlorine in any combination

The following examples illustrate the invention, but do not limit it.

Example 1

A. Preparation of (2S, 3aS, 7aS) octahydroindole-2-carboxylic acid allyl ether paratoluenesulfonate.

4.23 g (0.025 mol) (2S, 3aS, 7aS) -perhydroindole-2-carboxylic acid, 16.9 ml (0.25 mol, 14.5 g) of allyl alcohol and 5.71 g (0.03 mol) ) paratoluene sulfonic acid (in the form of a monohydrate) in 200 ml of benzene is boiled with a Dean-Stark trap until the water separation ceases (~ 24 hours). The resulting mixture was cooled and evaporated to dryness, diluted with 20 ml of hexane and the precipitate formed was filtered off. The resulting product was recrystallized from methyl tert-butyl ether. The output is quantitative. T. pl. 110 ° C. ¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 1.23 m (1H), 1.36 m (3H), 1.61 m (1H), 1.86 m (1H), 2.01 m (1H), 2.04 s (3H, CH ₃ ), 2.32 m (1H), 3.61 m (1H), 4.50 m (1H), 4.70 m (2H, CH ₂ -O), 5.27 d ( 1H, J 10.8 Hz, CH ₂ = CH), 5.36 d (1H, J 16.8 Hz, CH ₂ = CH), 5.93 m (1H, CH ₂ = CH), 7.11 d (1H, J 7.9 Hz, Ar), 7.49 d (1H, J 7.9 Hz, Ar), 8.51 s (1H), 9.78 s (1H).

B. Preparation of (2S, 3aS, 7aS) -1- {2- [1 (ethoxycarbonyl) - (S) -butylamine] -S-propionyl} octahydroindole-2-carboxylic acid allyl ester.

To a suspension of 2.39 g (0.011 mol) of N - [(S) -1-carbethoxybutyl] - (S) -alanine and 1.485 g (0.011 mol) of 1-hydroxybenzotriazole in 20 ml of ethyl acetate was added 4.2 ml at room temperature ( 3.05 g, 0.03 mol) of triethylamine, 2.27 g (0.011 mol) of N, N'-dicyclohexylcarbodiimide and after 10 minutes 3.81 g (0.01 mol) of allyl ether paratoluenesulfonate (2S, 3aS, 7aS) -Octohydroindole-2-carboxylic acid. The resulting mixture was stirred for 12 hours, then the precipitated urea precipitate was filtered off and the filtrate was washed with soda, water and brine. Dry with sodium sulfate and evaporate to dryness. The resulting residue was dissolved in cold hexane and filtered off from urea residues, evaporated. 4.01 g (98%) of the product (perindopril allyl ether) are obtained in the form of a yellowish oil. The product is used without further purification in the next step.

C. 0.511 g (1.25 mmol) of perindopril allyl ether and 8 mg (0.03 mmol) of triphenylphosphine are dissolved in 10 ml of 1,4-dioxane, purged with nitrogen and 9 mg (0.0078 mmol) of tetrakis (triphenylphosphine) palladium are added. Then, after 24 hours, the reaction mixture was evaporated to dryness to obtain technical perindopril, which was dissolved in a water / cyclohexane mixture, the organic layer was separated, and the aqueous layer was evaporated to obtain perindopril. Yield: 285 mg (62%).

G. 285 mg (0.77 mmol) of perindopril was dissolved in ethanol (2 ml) and tert-butylamine (0.2 ml) was added, the resulting mixture was evaporated and the residue was recrystallized from acetonitrile. Yield: 272 mg (80%).

Example 2

0.511 g (1.25 mmol) of perindopril allyl ether (prepared as described in Example 1 of Step A-B) and 8 mg (0.03 mmol) of triphenylphosphine are dissolved in 10 ml of 1,4-dioxane, purged with nitrogen and 9 mg ( 0.0078 mmol) tetrakis (triphenylphosphine) palladium. Then 0.26 ml (0.183 g, 2.5 mmol) of tert-butylamine are added. After 2 hours, precipitation was observed, the reaction mixture was stirred for another 22 hours and evaporated to dryness. The resulting product was diluted with 10 ml of ethyl acetate, brought to a boil, cooled and the precipitate was filtered off. Recrystallized from acetonitrile / ethanol (9/1). Yield: 0.424 g (77%).

Example 3

0.606 g (1.25 mmol) of perindopril 3-phenylallyl ether (obtained by analogy with Example 1 of Step A-B) and 19 mg (0.03 mmol) of 1,1-binaphthalene-2,2-diyl-bis-diphenylphosphine ( BINAP) was dissolved in 10 ml of tetrahydrofuran, purged with nitrogen and 5.5 mg (0.0078 mmol) of bis (triphenylphosphine) palladium dichloride was added. After 24 hours, the reaction mixture was evaporated to dryness. The resulting product was diluted with 10 ml of ethyl acetate, 0.26 ml (0.183 g, 2.5 mmol) of tert-butylamine was added, brought to a boil, cooled and the precipitate formed was filtered off. Recrystallized from acetonitrile / ethanol (9/1). Yield: 0.292 g (53%).

Example 4

528 mg (1.25 mmol) of perindopril but-2-enyl ether (obtained by analogy with Example 1 of Step A-B) and 9 mg (0.03 mmol) of tris (o-methylphenyl) phosphine are dissolved in 10 ml of ethanol, purged nitrogen and 5.5 mg (0.0078 mmol) bis (triphenylphosphine) palladium dichloride are added. Then it is heated to a boil and the reaction mixture is kept at this temperature for 10 hours, cooled and evaporated to dryness. The resulting product was diluted with 10 ml of ethyl acetate, 0.26 ml (0.183 g, 2.5 mmol) of tert-butylamine was added, brought to a boil, cooled and the precipitate formed was filtered off. Recrystallized from acetonitrile as in Example 1. Yield: 0.397 g (72%).

Example 5

546 mg (1.25 mmol) of perindopril pent-2-enyl ester (obtained by analogy with Example 1 of Step A-B) and 9 mg (0.03 mmol) of triphenylphosphine are dissolved in 10 ml of isopropanol, purged with nitrogen and 5.5 is added mg (0.0078 mmol) bis (triphenylphosphine) palladium dichloride. Then it is heated to 70 ° C and the reaction mixture is kept at this temperature for 10 hours, cooled and evaporated to dryness. The resulting product was diluted with 10 ml of ethyl acetate, 0.26 ml (0.183 g, 2.5 mmol) of tert-butylamine was added, brought to a boil, cooled and the precipitate formed was filtered off. Recrystallized from acetonitrile / ethanol (7/1). Yield: 0.376 g (68%).

Example 6

554 mg (1.25 mmol) of perindopril 3-chlorallyl ether (obtained by analogy with Example 1 of Step A-B) and 9 mg (0.03 mmol) of (2-biphenyl) ditret-butylphosphine are dissolved in 10 ml of 1,4- of dioxane, purged with nitrogen and 5.5 mg (0.0078 mmol) of bis (triphenylphosphine) palladium dichloride are added. Then it is heated to 70 ° C and the reaction mixture is kept at this temperature for 10 hours, cooled and evaporated to dryness. The resulting product was diluted with 10 ml of ethyl acetate, 0.26 ml (0.183 g, 2.5 mmol) of tert-butylamine was added, brought to a boil, cooled and the precipitate formed was filtered off. Recrystallized from acetonitrile / ethanol (15/1). Yield: 0.353 g (64%).

Example 7

623 mg (1.25 mmol) of 3- (4-methylphenyl) allyl ether of perindopril (obtained by analogy with Step 1, A-B) and 9 mg (0.03 mmol) of (2-biphenyl) ditret-butylphosphine are dissolved in 10 ml of ethyl acetate, purged with nitrogen and 5.5 mg (0.0078 mmol) of bis (triphenylphosphine) palladium dichloride are added. Then the reaction mixture is kept for 24 hours and evaporated to dryness. The resulting product was diluted with 10 ml of ethyl acetate, 0.26 ml (0.183 g, 2.5 mmol) of tert-butylamine was added, brought to a boil, cooled and the precipitate formed was filtered off. Recrystallized from acetonitrile / ethanol (12/1). Yield: 0.259 g (47%).

Claims (23)

1. A method of producing perindopril (I) and its pharmaceutically acceptable salts from a protected compound

characterized in that the removal of the protective group from the protected compound (IV), in which R ¹ , R ² and R ³ are hydrogen, alkyl, aryl or chlorine in any combination, and the protective group is an alkenyl group, is carried out by processing the protected compound (IV) derivatives of palladium with arylphosphines or biphosphines in protic or aprotic solvents, and perindopril is obtained (I), which, if necessary, is treated with a base, and a pharmaceutically acceptable salt of perindopril is obtained, which if necessary they recrystallize. 2. The method according to claim 1, characterized in that the protected compound (IV) is obtained by condensation of acid (II) with ether (III), which, in turn, is obtained by esterification of octahydroindole-2-carboxylic acid with an alcohol in which R ¹ , R ² and R ³ represent hydrogen, as well as alkyl, aryl or chlorine in any combination

3. The method according to claim 1, characterized in that the palladium derivatives are a complex of palladium with triphenylphosphine. 4. The method according to claim 1, characterized in that the palladium derivatives are a complex of palladium with tri (o-methylphenyl) phosphine. 5. The method according to claim 1, characterized in that the palladium derivatives are a complex of palladium with 1,1-binaphthalene-2,2-diyl-bis-diphenylphosphine. 6. The method according to claim 1, characterized in that the palladium derivatives are a complex of palladium with (2-biphenyl) -ditre-butylphosphine. 7. The method according to claim 1, characterized in that R ¹ , R ² , R ³ represent hydrogen. 8. The method according to claim 1, characterized in that R ¹ represents phenyl, and R ² , R ³ is hydrogen. 9. The method according to claim 1, characterized in that R ¹ represents 4-methylphenyl, and R ² , R ³ is hydrogen. 10. The method according to claim 1, characterized in that R ¹ represents methyl, and R ² , R ³ is hydrogen. 11. The method according to claim 1, characterized in that R ¹ represents ethyl, and R ² , R ³ is hydrogen. 12. The method according to claim 1, characterized in that R ¹ represents chlorine, and R ² , R ³ is hydrogen. 13. The method according to claim 1, characterized in that C ₁ -C ₄ alcohols are used as a solvent in the deprotection step. 14. The method according to claim 1, characterized in that ethanol is used as a solvent in the deprotection step. 15. The method according to claim 1, characterized in that isopropanol is used as a solvent in the deprotection step. 16. The method according to claim 1, characterized in that aprotic solvents are used as the solvent in the deprotection step. 17. The method according to claim 1, characterized in that 1,4-dioxane is used as a solvent in the deprotection step. 18. The method according to claim 1, characterized in that tetrahydrofuran is used as a solvent in the deprotection step. 19. The method according to claim 1, characterized in that the stage of removal of the protective group is carried out in the presence of a base in an amount greater than or equal to 1 equivalent, obtaining a salt. 20. The method according to any one of claims 1, 19, characterized in that to obtain a pharmaceutically acceptable salt of perindopril, tert-butylamine is used as the base and a tert-butylamine salt of perindopril is obtained. 21. The method according to claim 20, characterized in that the tert-butylamine salt of perindopril is recrystallized from acetonitrile. 22. The method according to claim 20, characterized in that the tert-butylamine salt of perindopril is recrystallized from a mixture of acetonitrile and ethanol with an ethanol content of not higher than 30 vol.%. 23. The method according to any of paragraphs.21, 22, characterized in that the perindopril tert-butylamine salt is converted into a crystalline form characterized by the following X-ray powder diffraction pattern, measured using a Thermo ARL X'TRA diffractometer and expressed in terms of: interplanar distance d , Bragg angle 2 θ, intensity and relative intensity.

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