WO2006131828A1

WO2006131828A1 - A process for the preparation of perindopril

Info

Publication number: WO2006131828A1
Application number: PCT/IB2006/001583
Authority: WO
Inventors: Brajesh Kumar Sinha; Pandu Ranga Rao Vaddi; Shankar Reddy Budidet; Ramesh Dandala; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2005-06-08
Filing date: 2006-06-01
Publication date: 2006-12-14

Abstract

The present invention provides an improved process for the preparation of Perindopril of Formula (I) and its pharmaceutically acceptable salts.

Description

A PROCESS FOR THE PREPARATION OF PERINDOPRIL

FIELD OF THE INVENTION

Tlic present invention is an improvement in the industrial preparation of (2S,3c/S,7c/S)-l-[2-[l-(ethoxycarbonyl)-(S)-butylamine]-(S)-propionyl]- octahydroindole-2-carboxylic acid of Formula I

Formula I

and its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION

Perindopril, and its pharmaceutically acceptable salts thereof, more specifically the tert-Butylamine salt, have valuable pharmacological properties. Their principal property lies in the inhibition of the enzyme that converts angiotensin I (or kininase II), which enables on the one hand prevention of the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (vasoconstrictor) and on the other hand prevention of the degradation of bradykinin (vasodilator) to inactive peptide. These two actions contribute to the beneficial effects of perindopril in cardiovascular disorders, especially arterial hypertension and cardiac insufficiency.

Perindopril, its preparation and its therapeutic use have been for the first time, described in US 4,508,729.

Several methods for the preparation of perindopril of Formula (I) are already known, but on an industrial scale these processes have significant disadvantages.

EP 308 341 Bl describes the industrial synthesis of perindopril by catalytic hydrogenatiυn of (2S)-2,3-dihydroindole-2-carboxylic acid, followed by coupling Of the resulting (2S,3øS, 7αiS)-octahydroindole-2-carboxylic acid benzyl ester with N-[(S)-l-carboxybutyl]-(S)-alanine ethyl ester, and then deprotection of the carboxylic group of heterocycle by catalytic hydrogenation. This process has the advantage of yielding perindopril in a good yield. However, the purity of the perindopril obtained by this process is not satisfactory, and necessitates a purification step in order to obtain perindopril of a quality that would allow its use as a pharmaceutical active agent. Indeed, under the conditions described in the patent specification the perindopril obtained is contaminated by significant amounts of the impurities (dicyclohexyl urea derivatives) of the following formulae which are also pharmacoepial impurities.

EP 309 324 Bl describes a process for obtaining a compound of formula (I) by reacting alanine benzyl ester with ethyl α-bromovalerate in dimethylformamide in

15 the presence of triethylamine to obtain carboethoxy benzyl ester followed by deprotection to give perindopril. The major drawbacks of this process are the number of steps involved and the low yield of the (S, S) isomer. Indeed, since the reaction is not diastereoselective, a purification step is required in order to obtain the pure (S, S) isomer, which comprises fractional crystallization in the presence

20 of maleic acid.

EP 1 333 026 Al describes the synthesis of perindopril by acylating the N-[(S)-1- carboethoxybutyl]-(S)-alanine with a suitable carbonic acid like methyl chloroformate, ethyl chloroformate, and benzyl chloroformate respectively in an

^"1 S inert organic solvent and in the presence of a base. The N-protected carbonic acid derivative is then activated with thionyl chloride which is subsequently coupled with 2-carboxyperhydroindole derivative which after deprotection gives perindopril.

It would be apparent from the above processes that while there are several known methods available for synthesis of perindopril, however, most of the methods either involve utilization of hazardous or costly coupling agent like dicyclohexylcarbodiimide. Further, it is difficult to remove completely the byproduct, dicyclohexylurea derivatives from the- final perindopril obtained. These in turn lead to complexities in the manufacture and render the methods to obtain perindopril less cost-effective.

Given the pharmaceutical interest in this compound, it is important to be able to obtain it by cost effective process that can be readily applied on an industrial scale, yielding perindopril in a good yield and, especially, with an excellent degree of purity.

The inventors have now developed a new industrial process that, requires less laborious purification, yielding perindopril in a single reaction step with a purity that is compatible with its use as a pharmaceutical active ingredient, totally free of the above mentioned pharmacoepial impurities.

OBJECTIVES OF INVENTION

The objective of the present invention is to develop an improved process for the preparation of perindopril without requiring laborious purification and free of pharmacoepial impurities which in turn can be used as Active Pharmaceutical Ingredient.

SUMMARY OF INVENTION

Accordingly, the present invention relates to an improved process for the preparation of Perindopril of Formula I Formula 1

which comprises reacting the compound of Formula II

R O

OH Formula II

O^ CH₃ H₃C-/ O wherein R represents H or a protecting group

with a carbonic acid derivative of compound Formula III

Cl- C- O- R'

Formula III O

wherein R' represents aryl, substituted aryl and subsequent N-acylation of compound of Formula IV

Formula IV

wherein R" represents benzyl, substituted benzyl in the presence of base to obtain a compound of Formula V Formula V

wherein R, R" are defined as above,

which on deprotection by catalytic hydrogenation gives compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes an improved process for the preparation of perindopril free of pharmacoepial impurities without requiring laborious purification steps.

The aim of the present invention is to eliminate the formation of dicyclohexyl carbodiimide related pharmacoepial impurities. This has been achieved by avoiding dicyclohexylcarbodiimide in the synthesis of perindopril.

The inventors have found that by activating the compounds of general Formula Ii with the compounds of general Formula III, like 4-nitrophenyl chloroformate in the presence of a base and subsequently achieving N-acylation of the perhydroindole moiety.

The condensations of compound of Formula II with compounds of Formula III and subsequent N-acylation of compound of Formula IV with the compound resulting from condensation of compounds of Formula II and III, is carried out in the presence or absence of 1 -hydroxybenzotriazole derivative.

The above coupling reaction is effected in halogenated aliphatic hydrocarbons, aromatic hydrocarbons, esters, ethers, alcohols, nitriles, ketones, more preferably acelυnilrile. More particularly, the present invention relates to a process, which comprises coupling of the protected perhydro indole moiety of Formula IV with compounds of genera] Formula II, followed by deprotection yielding perindopril in a single reaction step.

Examples of bases are alkali metal hydroxides, alkali carbonate, alkali hydrogen carbonate, organic bases like teritiary amines like triethylamine, N-methyl morpholine, diisopropyl amine and 4-dimethylaminopyridine.

Aryl group as referred" herein refers to phenyl, substituted aryl refers to 4- nitrophenyl cloro formate.

Examples of carbonic acid derivative used in the present invention are phenyl chloroformate, 4-methoxyphenylchloroformate, 4-chlorophenylchloroformate, 2,4-dinitrophenylchloiOformate, ^" 4-trifluoromethylphenylchloroformate, 4- nitroplienylchloroformate, 2-nitrophenylchloroformate, more preferably 4- nitrophenylchloro formate.

Examples of benzotriazole derivative are 1-hydroxybenzotriazole,. l-hydroxy-5- chlorobenzotriazole and l-hydroxy-7-azabenzotriazole, 3-hydroxy-3,4- dihydroxybenzotriazole-4-one.

The reaction is carried out at a temperature ranging between -20 °C and 60 ⁰C, more preferably at 0-30 ⁰C.

After completion of the reaction, the reaction mass is washed with DM water, aqueous base, aqueous acid and finally with aqueous sodium bicarbonate solution. Organic layer is concentrated under reduced pressure, which on deprotection leads Io perindopril.

Deprotection is conveniently carried out using Pd/C in an organic solvent selected IVo m hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, esters, alcohols, ethers, ketones, water and their mixtures, more preferably methyl tert.butylether.

The present invention is exemplified by the following examples which are provided for illustration purposes, and does not limit the scope of invention.

Example 1 Step 1

4-NitiOphenylchloroformate (5 g, 0.0248 moles) in acetonitrile (30 ml) was added dropwise to the mixture of N-/^"f5^-l-carbethoxybutyl]-fS'j-alanine (5.78 g, 0.0266 moles), 4-(dimethylamino)pyridine (3.12 g, 0.0255 moles) and acetonitrile (60 ml) at 10-15 ⁰C. The reaction mass was slowly warmed to 20 ⁰C and stirred for

30 min at 20-25 ⁰C. To the reaction mass, 4-(dimethylamino)pyridine (2.83 g,

0.0231 moles) was added and stirred for 5 min at 20-25 ⁰C. (2S,3aS,7aS)- Oclahydro-l /-/-indole-2-carboxylic acid benzyl ester p-toluenesulfonic acid salt

( 10 g, 0.0231 moles) was added to the reaction mass and stirred at 20-30⁰C till completion of reaction.

The reaction mass was concentrated to remove acetonitrile under reduced pressure. The concentrated reaction mass was treated with methyl tert-butyl ether

(.60 ml), filtered and washed with methyl tert-butyl ether (20 ml). Thereafter, the filtrate was washed with DM water, 3% w/w aqueous ammonium hydroxide solution, 10% w/w aqueous acetic acid solution and 5% w/w aqueous sodium bicarbonate solution. The organic layer was treated with activated carbon at 20-30 ⁰C for 30 min and filtered. The filtrate contains (2S,3aS,7aS)-l-[(2S)-2-

[[ 1 S)- 1 -(ethoxycarbonyl)butyl]amino]propanoyl] octahydro - 1 H-indole-2- earboxylic acid benzyl ester.

Step Il The methyl tert-butyl ether filtrate containing (2S,3aS,7aS)-l-[(2S)-2-[[lS)-l- (elhoxycarbonyl)butyl]amino]propanoyl]octahydiO-lΗ-indole-2-carboxylic acid benzyl ester was subjected to hydro genation over 5% palladium on charcoal (1.5 g. 50% Wet) using 3-5 Kg / cm2. of hydrogen pressure for 2 h at 20-30 ⁰C, The reaction mass was filtered and washed with methyl tert-butyl ether. The filtrate was treated with activated carbon at 20-30 °C for 30 min and filtered through hyflo and washed with methyl tert-buty ether. The filtrate was concentrated under reduced pressure (10-70 mm Hg)'below 30 ⁰C to yield Perindopril acid (7.7 g).

Perindopril acid (7.7 g) was dissolved in ethyl acetate (100 ml) and to the solution tert-butylamine ( 1.86 g, 0.025 moles) in ethyl acetate (20 ml) was added dropwise at 25-3O⁰C and stirred for 1 h. The reaction mass was heated to 73-76⁰C to obtain a clear solution and cooled to 17-20⁰C. The reaction mass was stirred for 1 h at 17-20°C, filtered, washed with cold ethyl acetate (10 ml) and dried to yield pure Perindopril Erbumine (7.6 g).

Example 2

Step I

4-NiliOphenylchloroformate (7g, 0.0347 mole) in ethyl acetate (30 ml) was added to a mixture of N-[(S)-l-carbethoxybutyl]-(S)-alanine (6.65 g, 0.0306 mole), trielhylamine (5.6 g 0.0553 mole) and ethyl acetate (60 ml) at 0-10 ⁰C. The reaction mass was slowly warmed to 20 ⁰C and stirred for 1 h at 20-25 ⁰C. To the reaction mass, 1 -Hydroxybenzotriazole (4.15 g, 0.0307 mole) was added and stirred for 10 min at 20-25 ⁰C. Triethylamine (2.5 g, 0.0247 mole) followed by (2S,3aS,7aS)-octahydro-lH-indole-2-carboxylic acid benzyl ester /?-toluene sulfonic acid salt (12 g, 0.0278 mole) were added to the reaction mass and maintained for at 20-30 ⁰C till completion of the reaction.

The reaction mass was filtered and the filtrate was washed with DM water and aqueous triethylamine. To the organic layer, dimethylaminopyridine (4.24 g) was added and stirred for 3 hrs at 30 -35 ⁰C. The reaction mass was washed with DM water followed by aqueous triethylamine till 4-nitrophenol was removed completely. The organic layer was concentrated under reduced pressure to yield 10.5 g of (2S,3aS,7.aS)-l-[(2S)-2-[[(lS)-l-(ethoxycarbonyl)butyl]amino]-l- oxopropyl]octahydro-lH-indole-2-carboxylic benzyl ester.

5 Step II

(2S,3aS,7aS)- 1 -[(2S)-2-[[(l S)- 1 -(Ethoxycarbonyl)butyl] amino]- 1 -oxopropyl]- octahydro-l H-indole-2-carboxylic benzyl ester (10.5 g, 0.0229 mole) was dissolved in ethanol (70 ml) and subjected to hydrogenation over 5% palladium on ϋ charcoal (50% w/w Wet, 3 g) using 5-7 Kg hydrogen pressure for 2 h at 20-30 ⁰C. The reaction mass was filtered over hyflo and washed with ethanol (20 ml). The filtrate was concentrated under reduced pressure to yield Perindopril acid (7.5 g). Perindopril acid (7.5 g, 0.023 mole) was dissolved in ethyl acetate (90 ml) and treated with activated carbon (0.6 g) at 20-30 ⁰C for 30 min and filtered. Tert- 5 Butyl amine (1.85 g, 0.0253 mole) in ethylacetate (30 ml) was added dropwise to the filtrate at 20-30 ⁰C and maintained for 1 h. The reaction mass was heated to 70-75 ⁰C and filtered. The filtrate was cooled to 0-5 ⁰C and stirred for 1 h. The separated product was filtered, washed with cold ethyl acetate (15 ml) and dried to yield Perindopril tert-butylamine salt (6.5 g).

Claims

WE CLAIM

An improved process for the preparation of Perindopril of Formula I

Formula I

which comprises reacting the compound of Formula II

Formula II

wherein R represents H or a protecting group

with a carbonic acid derivative of Formula III

Cl- C- O- R'

Formula III O

Formula IV

wherein R" represents benzyl, substituted benzyl

in the presence of base to obtain a compound of Formula V Formula V

wherein R, R" are defined as above,

which on deprotection by catalytic hydrogenation gives compound of Formula I.

2) The process according to claim 1, wherein the carbonic acid derivative is selected from aryl and substituted aryl chloro formates.

3 ) The process according to claim 2, wherein the carbonic acid derivative employed for the activation of compounds of Formula II is phenyl chloro formate, 4-methoxyphenylchloroformate, 4-chloroplienylchloroformate, 2,4-dinitrophenylchloro formate, 4-trifluoromethylphenylchloroformate, 4- nitrophenylchloroformate, 2-nitrophenylchlororformate, more preferably 4- nitrophenylchloro form ate.

4) The process according to claim 1 , which comprises carrying out the acylation of the compound of Formula IV in the presence of a base, preferably alkali metal hydroxides, alkali carbonate, alkali hydrogen carbonate, organic bases like triethylamine, 4-dimethylaminopyridine, diisopropylamine, N-methyl morpholine, more preferably 4-dimethylamino pyridine.

5} The process according to claim 1, wherein the solvents used are hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, esters, alcohols, ethers, ketones, nitriles more preferably acetonitrile. 6) The process according to claim 1, wherein the deprotection of the N- carbonyloxy benzyl perindopril ester of Formula V is carried out in the presence of Pd/C.

7) The deprotection according to claim 6, is carried out in hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, esters, alcohols, ethers, ketones, water and their mixtures, more preferably methyl tert.butyl ether.

8) The process according to claim 1, wherein the N-acylation is carried out in the presence or absence of 1 -hydroxy benzotriazole derivative.

9) The process according to claim 8, wherein 1-hydroxybenzotriazole derivative is selected from 1-hydroxybenzotriazole, l-hydroxy-5-chlorobenzotriazole, 1- hydroxy-7-azabenzotriazole, 3-hydroxy-3,4-dihydroxybenzotriazole-4-one, more preferably 1-hydroxybenzotriazole.