WO2007004165A2

WO2007004165A2 - Process for the preparation of perindopril

Info

Publication number: WO2007004165A2
Application number: PCT/IB2006/052191
Authority: WO
Inventors: Asok Nath; Mohan Prasad
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2005-06-30
Filing date: 2006-06-29
Publication date: 2007-01-11
Also published as: WO2007004165A3

Abstract

The present invention relates to an improved process for the preparation of silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole. Also provided is an improved process for the preparation of perindopril and its pharmaceutically acceptable salts.

Description

PROCESS FOR THE PREPARATION OF PERINDOPRIL

Technical Field of the Invention

Background of the Invention

Perindopril is chemically described as (2S, 3aS, 7aS)-l-[(2S)-2-[[(ls)-l- (ethoxy carbony l)buty 1] amino] - 1 -oxopropy 1] octahy dro- 1 - 1 H-indole-2-carboxy lie acid and is represented by Formula I.

Formula I

Perindopril and its pharmaceutically acceptable salts are known to have therapeutic applications as angiotensin converting enzyme ("ACE") inhibitors. The angiotensin converting enzyme is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to angiotensin II. In addition it is known to degrade to bradykinin. Angiotensin II is a vasoconstrictor that also stimulates aldosterone secretion by the adrenal cortex. Perindopril and its pharmaceutically acceptable salts, in particular the tert-butyl amine salt, inhibit the conversion of the angiotensin I decapeptide to angiotensin II octapeptide, which is responsible in certain cases for arterial hypertension, by acting on the conversion enzyme. The use of perindopril and its pharmaceutically acceptable salts in therapeutic applications makes it possible to reduce or even suppress the activity of these enzymes, which are responsible for the hypertensive disorder or for cardiac insufficiency. In addition, it has been discovered that ACE inhibitors are also useful in treating cognitive diseases.

Various methods are reported in literature for the preparation of perindopril and its pharmaceutically acceptable salts such as those described in U.S. Patent Nos. 4,508,729; 4,914,214, the relevant portions of which are herein incorporated by reference and PCT Publication Nos. WO 01/58868; WO 04/046172; WO 03/064388; WO 04/075889 and German Patent No. 19721290.

U.S. Patent No. 4,508,729 describes a process for the preparation of perhydroindole derivatives including perindopril, in their racemic form or as optical isomers, and their salts with therapeutically compatible acids and bases. The process includes subjecting an alkyl ester of an azabicycloalkane carboxylic acid to reductive alkylation with an alpha keto carboxylic acid, or its ester, followed by subjecting the intermediate, thus obtained, to deprotection, if necessary, to convert it into the corresponding perhydroindole compound. U.S. Patent No. 4,914,214 describes a process for the preparation of perindopril tert-butyl amine via the condensation of ester of (2S, 3aS, 7aS)-2-carboxyperhydroindole with the (S, S) diastereoisomer of N-[(S)-l-carbethoxybutyl]-(S)-alanine, in an alkaline medium, in the presence of a catalyst for peptide synthesis such as dicyclohexylcarbodiimide and 1-hydroxybenzotraizole. Next the carboxylic group is deprotected to obtain perindopril and is treated with tert-butyl amine to obtain perindopril erbumine.

WO 01/58868 describes a process for the preparation of perindopril or pharmaceutically acceptable salts thereof. The process includes reacting a p-toluene sulphonate salt of benzyl ester of (2S, 3aS, 7aS)-2-carboxyperhydroindole with (S, S) diastereoisomer of N-[(S)-l-carbethoxybutyl]-(S)-alanine, in the presence of dicyclohexylcarbodiimide, followed by deprotection of the benzyl ester by catalytic hydrogenation to yield perindopril, which is low in the impurities associated with dicyclohexylcarbodiimide. The perindopril, thus obtained may be converted into a pharmaceutically acceptable salt, if desired. However, these known processes for the preparation of perindopril or its pharmaceutically acceptable salts often result in undesirable associated impurities such as diketopiperazine analogues.

WO 04/046172 describes a process for the preparation of a pharmaceutically acceptable salt of perindopril, including perindopril erbumine, by the deprotection of a protected precursor compound of perindopril. The carboxyl group attached to the heterocyclic ring is deprotected so as to obtain the corresponding free acid, the deprotection is carried out in the presence of a base, which forms a pharmaceutically acceptable salt with said free acid formed by said deprotection. WO 03/064388 describes a process for the preparation of perindopril and its tert- butyl amine salt free of contaminations from dicyclohexylcarbodiimide. The process includes reacting N-[(S)-l-carbethoxybutyl]-(S)-alanine with a suitable carbonic acid derivative to obtain the corresponding amide, activating the compound obtained with thionyl chloride, reacting the activated compound with (2S, 3aS, 7aS)-2- carboxyperhydroindole, and reacting with tert-butylamine, if desired.

WO 04/075889 describes a process for the preparation of perindopril or its derivatives and/or pharmaceutically acceptable salts thereof. The process includes reacting the halogen derivative of N-[(S)-l-carbethoxybutyl]-(S)-alanine with benzyl ester of (2S, 3aS, 7aS)-2-carboxyperhydroindole followed by catalytic hydrogenation and deprotection to obtain perindopril.

It is apparent from the above that while several methods for the preparation of perindopril and its pharmaceutically acceptable salts either involve the use of hazardous and costly coupling agents like dicyclohexylcarbodiimide and 1-hydroxybenzotraizole thus leading to the formation of impurities associated with dicyclohexylcarbodiimide or essentially require acidic or alkaline conditions. Besides this, most of the methods reported in the literature involve the step of deprotection of the precursor compound, to obtain perindopril, which is then converted into perindopril erbumine.

Thus there is a need for an improved industrially advantageous method for the preparation of perindopril and its pharmaceutically acceptable salts which avoid the drawbacks associated with the methods reported in the literature. DE 19721290 describes a process for the preparation of several ACE inhibitors, including perindopril erbumine, via the silylation of N-[(S)-l-carbethoxybutyl]-(S)- alanine, followed by activation of the silylated compound with thionyl chloride. The activated silylated compound is then reacted with (2S, 3aS, 7aS)-2-carboxyperhydroindole to obtain perindopril.

Journal of Medicinal Chemistry, (1987) 30, 992 describes a method of preparation of silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II

Formula Il by refluxing a reaction mixture containing (2S, 3aS, 7aS)-2-carboxyperhydroindole of Formula III

with hexamethyldisilazane and chlorotrimethylsilane in acetonitrile. The resulting solution was cooled in an ice-bath followed by the addition of (acetylthio)-2-methyl propionyl chloride in acetonitrile. After the completion of the reaction a major portion of chlorotrimethylsilane and acetonitrile are allowed to escape from the reaction mixture by refluxing, followed by extraction of the pure product by aqueous work-up and several recrystallizations. The article describes the use of silylated (2S, 3aS, 7aS)-2- carboxyperhydroindole compound of Formula III for the preparation of ACE inhibitors such as indolapril and quinapril. However, its use for the preparation of perindopril of Formula I, or its pharmaceutically acceptable salts, is not reported in the literature.

The process described in the literature for the preparation of silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II involves the use of a corrosive, highly flammable reagent, chlorotrimethylsilane, to enhance the reaction which is not suitable for an industrial scale preparation.

Summary of the Invention

In one general aspect there is provided a process for the preparation of silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II

The process includes reacting (2S, 3aS, 7aS)-2-carboxyperhydroindole of Formula III

with a silylating agent in the presence of one or more catalysts. Embodiments of the process may include one or more of the following features. For example, the (2S, 3aS, 7aS)-2-carboxyperhydroindole of Formula III is used as a solution directly from a reaction in which it is formed.

Silylating agents may be one or more of silazanes, silanes and alkylsilyl triflates. For example, the silazane may be hexamethyldisilazane.

Catalysts may be one or more of imidazole, trimethylsilylimidazole, dicyclohexylimidazole and l,8-diazabicyclo[5.4.0]undec-7-ene. For example, the catalyst may be imidazole.

The reaction may be carried out in the presence of one or more suitable solvents. Suitable solvents may be partially water miscible or water immiscible organic solvents and mixtures thereof. The water immiscible solvents may be one or both of dialkyl ethers and chlorinated hydrocarbons. The water immiscible solvent may be methylene chloride.

In another general aspect there is provided a process for the conversion of silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II

to perindopril of Formula I

Formula I or its pharmaceutically acceptable salts. The process includes condensing the silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II with N-[(S)-1- carbethoxybutyl]-(S)-alanine chloride hydrochloride of Formula IV

Formula IV to obtain perindopril of Formula I.

Embodiments of the process may include one or more of the following features. For example, the compound of Formula IV may be used as a solution directly from a reaction in which it is formed or the compound of Formula II may be used as a solution directly from a reaction in which it is formed. In addition, the compound of Formula IV may be added to the reaction mixture at a temperature of about O⁰C.

The perindopril of Formula I may be converted to its pharmaceutically acceptable salt by reaction with one or more suitable bases in one or more suitable solvents. Suitable bases may be mono-, di- and tri-alkyl amines. For example, the suitable base may be tert- butylamine.

Suitable solvents may be one or more of water, alkyl acetates, chlorinated hydrocarbons, alcohols, ketones and/or mixtures thereof. The alkyl acetate may be ethyl acetate, n-propyl acetate and iso-propyl acetate and/ or mixtures thereof. For example, the alkyl acetate may be ethyl acetate.

Detailed Description of the Invention

The (2S, 3aS, 7aS)-2-carboxyperhydroindole of Formula III can be prepared by any of the processes known in the prior art including those described in U.S. Patent Nos. 4,935,525; 4,914,214; 4,902,817; 6,818,788, the relevant portions of which are herein incorporated by reference only.

Suitable silylating agents used for the preparation of silylated (2S, 3aS, 7aS)-2- carboxyperhydroindole compound of Formula II may include silazanes, such as hexamethyldisilazane and the like; silanes, such as trialkylsilane, hydrosilanes, disilanes and the like; alkylsilyl triflates, such as tert-butyldimethylsilyl triflate, triisopropylsilyl triflate, triethylsilyl triflate and the like. For example, hexamethyldisilazane may be used as the silylating agent.

Catalysts used for the preparation of silylated (2S, 3aS, 7aS)-2- carboxyperhydroindole compound of Formula II may be any catalyst that can be used for peptide synthesis including imidazole, trimethylsilylimidazole, dicyclohexyimidazole, 1,8- diazabicyclo[5.4.0]undec-7-ene and the like. The preparation of the silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II may be carried out in one or more suitable solvents. Suitable solvents may include partially water miscible or water immiscible organic solvents, Suitable partially water miscible or water immiscible organic solvents include hydrocarbons such as hexanes, heptanes, aromatic hydrocarbons and the like; dialkyl ethers such as diethyl ether, diisopropyl ether and the like; chlorinated hydrocarbons such as chloroform, methylene chloride and the like; ketones such as acetone, diethyl ketone and the like; cyclic ethers, such as tetrahydrofuran and the like; nitriles, such as acetonitrile and the like; dipolar aprotic solvents, such as dimethylformamide, dimethyl sulphoxide and the like; and mixtures thereof. For example, the reaction may be carried out by refluxing in methylene chloride for about 1 to 5 hours.

After completion of the reaction, the reaction mixture may be cooled to O⁰C. One or more bases may be added to the reaction mixture. Suitable bases may include mono-, di- and trialkyl amines. Examples of mono-alky lamines may include ethylamine, n- propylamine and the like. Examples of dialkylamines may include diethyl amine, di-n- ethylamine, di-n-propyl amine and the like. Examples of trialkyl amines may include triethylamine, tri-iso-propylamine and the like. For example, the base used may be triethylamine. The reaction mixture may be further cooled to between about -15 to about 35⁰C. For example, the reaction mixture is cooled to about -25⁰C.

The silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II,

Formula Il

may be converted to perindopril of Formula I,

Formula I by condensation of silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of

Formula II with N-[(S)-l-carbethoxybutyl]-(S)-alanine chloride hydrochloride of Formula

to obtain perindopril of Formula I, without involving any deprotection step, which may be optionally converted into its pharmaceutically acceptable salt by reaction with one or more suitable bases.

The intermediate of Formula IV may be prepared by any of the processes known in the literature such as those described in U.S. Patent Nos. 4,914,214; 4,902,817; 6,818,788, the relevant portions of which are herein incorporated by reference. The compound of Formula IV obtained as a solution directly from a reaction in which it is formed and used as such without isolation.

The silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II used in the preparation of perindopril may be prepared by the method described in the first aspect of the invention. It may also be prepared by any of the methods reported in the literature such as the Journal of Medicinal Chemistry, 1987, 30, 992.

In the present invention the intermediate compounds of Formula II used for the preparation of perindopril may be utilized without first being isolated. The condensation of the compound of Formula II with a compound of Formula IV to obtain crude perindopril of Formula I may be carried out at a temperature range of between about -25⁰C to about O⁰C for a period of about 2 to about 20 minutes.

Perindopril of Formula I may be converted into a pharmaceutically acceptable salt by adding one or more suitable bases. The conversion of perindopril of Formula I to its pharmaceutically acceptable salts may be carried out in the in the presence of one or more suitable solvents.

Suitable bases may include mono-, di- and tri-alkyl amines. Examples of mono-, di- and tri-alkyl amines may include ethyl amine, n-propyl amine, tert-butyl amine, diethyl amine, di-isopropyl amine, tri-ethylamine, tri-isopropyl amine and the like. For example, tert-butylamine may be used.

Suitable solvents may include one or more of water, alkyl acetates, chlorinated hydrocarbons, alcohols, ketones and/or mixtures thereof. Examples of alkyl acetates may include ethyl acetate, n-propyl acetate, iso-propyl acetate and the like. Examples of chlorinated hydrocarbons may include chloroform, methylene chloride and the like. Examples of alcohols may include methanol, ethanol, isopropanol and the like. Examples of ketones may include acetone, diisopropyl ketone and the like. For example, the crude perindopril may be dissolved in ethyl acetate.

The reaction mixture containing crude perindopril and one or more suitable bases may be heated to reflux to dissolve the solid. The reaction mixture may be slowly cooled, filtered and dried to obtain the pharmaceutically acceptable salt of perindopril.

The process of the present invention provides a one pot method for the preparation of perindopril of Formula I, or its pharmaceutically acceptable salts, starting from silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II.

The present inventors have found that the silylated (2S, 3aS, 7aS)-2- carboxyperhydroindole compound of Formula II may also be used for the preparation of other ACE inhibitors such as trandolapril.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

Example 1

To a slurry of N-[(S)-l-carbethoxybutyl]-(S)-alanine (30 g) in methylene chloride (125 ml) dry HCl gas at O⁰C to 5⁰C was purged for 30 minutes. To this phosphorus pentachloride (36 g) was added at O⁰C to 5⁰C over a period of 30 minutes. After the addition, the reaction mixture was stirred at O⁰C to 5⁰C for 2 hours and methylene chloride was removed under reduced pressure. Hexane (150 ml) was added to the residue and the contents were stirred at O⁰C to 5⁰C for 15 minutes. The precipitated solid was filtered and washed with hexane (2x30 ml) to get N-[(S)-l-carbethoxybutyl]-(S)-alanine chloride hydrochloride which was directly used in the condensation reaction. To a slurry of (2S, 3aS, 7aS)-2-carboxyperhydroindole (25 g) in methylene chloride (250 ml) hexamethyldisilazane (24 g) and imidazole (0.5 g) were added. The reaction mixture was refluxed for 3 hours and then cooled to O⁰C. Triethylamine (30 g) was then added to the reaction mixture and it was further cooled to -25⁰C. To this reaction mixture wet N-[(S)-l-carbethoxybutyl]-(S)-alanine chloride hydrochloride obtained above was added at -25⁰C to O⁰C over a period of 5-10 minutes. After addition, the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water and concentrated to get crude perindopril.

The crude perindopril was dissolved in ethyl acetate (300 ml) and then tert- butylamine (10 g) was added. The mixture was heated to reflux to dissolve all solids. It was slowly cooled to 15⁰C over 2 hours and filtered. The wet solid was washed with ethyl acetate and dried at 45⁰C to 5O⁰C under reduced pressure to get perindopril tert- butylamine (40 g).

Claims

We Claim: 1. A process for the preparation of silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II

Formula Il

comprising reacting (2S, 3aS, 7aS)-2-carboxyperhydroindole of Formula III

with a silylating agent in the presence of one or more catalysts. 2. The process according to claim 1, wherein (2S, 3aS, 7aS)-2- carboxyperhydroindole of Formula III is used as a solution directly from a reaction in which it is formed. 3. The process according to claim 1, wherein the silylating agent comprises one or more of silazanes, silanes and alkylsilyl triflates. 4. The process according to claim 3, wherein the silazane comprises hexamethyldisilazane.

5. The process according to claim 1, wherein the one or more catalysts comprise one or more of imidazole, trimethylsilylimidazole, dicyclohexylimidazole and 1,8- diazabicyclo[5.4.0]undec-7-ene. 6. The process according to claim 5, wherein the one or more catalysts comprise imidazole. 7. The process according to claim 1, wherein the reaction is carried out in the presence of one or more suitable solvents.

The process according to claim 7, wherein the one or more suitable solvents comprises partially water miscible or water immiscible organic solvents and mixtures thereof. 9. The process according to claim 8, wherein the water immiscible solvents comprise one or both of dialkyl ethers and chlorinated hydrocarbons. 10. The process according to claim 9, wherein the water immiscible solvents comprise methylene chloride. 11. A process for the conversion of silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II

Formula Il

to perindopril of Formula I

Formula I or its pharmaceutically acceptable salts, the process comprising condensing the silylated (2S, 3aS, 7aS)-2-carboxyperhydroindole compound of Formula II with N-[(S)-1- carbethoxybutyl]-(S)-alanine chloride hydrochloride of Formula IV

Formula IV to obtain perindopril of Formula I. 12. The process according to claim 11, wherein the compound of Formula IV is used as a solution directly from a reaction in which it is formed. 13. The process according to claim 11, wherein the compound of Formula II is used as a solution directly from a reaction in which it is formed. 14. The process according to claim 11, wherein the compound of Formula IV is added to the reaction mixture at a temperature of about O⁰C. 15. The process according to claim 11, wherein the perindopril of Formula I is converted to its pharmaceutically acceptable salt by reaction with one or more suitable bases in one or more suitable solvents. 16. The process according to claim 15, wherein the one or more suitable bases comprise mono-, di- and tri-alkyl amines. 17. The process according to claim 16, wherein the one or more suitable bases comprises tert-butylamine.

18. The process according to claim 15, wherein the one or more suitable solvents comprise one or more of water, alkyl acetates, chlorinated hydrocarbons, alcohols, ketones and mixtures thereof. 19. The process according to claim 18, wherein the alkyl acetate comprises one or more of ethyl acetate, n-propyl acetate and iso-propyl acetate and mixtures thereof. 20. The process according to claim 19, wherein the alkyl acetate comprises ethyl acetate.