Title of Invention	"PROCESS FOR THE SYNTHESIS OF PERINDOPRIL"
Abstract	Process for the synthesis of perindopril or (2S,3aS,7aS)-l-((2S)-2-{[lS)-l-(ethoxycarbonyl)butyl]amino}propanoyl)octahydro-lH-indole-2-carboxylic acid of formula (I): wherein N-[(S)-ethoxycarbonyl-l-butyl]-(S)-alanine or (2S)-2-{[(lS)-l-(ethoxycarbonyl)butyl]amino}propanoic acid of formula (II): is reacted with a sulfinyl chloride compound of formula (III): wherein R1 represents an imidazolyl, benzimidazolyl or tetrazolyl group.

Title of Invention

"PROCESS FOR THE SYNTHESIS OF PERINDOPRIL"

Abstract

Process for the synthesis of perindopril or (2S,3aS,7aS)-l-((2S)-2-{[lS)-l-(ethoxycarbonyl)butyl]amino}propanoyl)octahydro-lH-indole-2-carboxylic acid of formula (I): wherein N-[(S)-ethoxycarbonyl-l-butyl]-(S)-alanine or (2S)-2-{[(lS)-l-(ethoxycarbonyl)butyl]amino}propanoic acid of formula (II): is reacted with a sulfinyl chloride compound of formula (III): wherein R1 represents an imidazolyl, benzimidazolyl or tetrazolyl group.

Full Text	The present invention relates to process for the synthesis of perindopril. The present invention relates to a process for the synthesis of perindopril of formula (I) (Formula Removed) and its pharmaceutically acceptable salts. Perindopril and its pharmaceutically acceptable salts, and more especially- its tert- butylamine salt, have valuable pharmacological properties. Their principal property is that of inhibiting angiotensin I converting enzyme (or kininase II), which allows, on the one hand, prevention of the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and, on the other hand, prevention of the degradation of bradykinin (a vasodilator) to an inactive peptide. Those two actions contribute to the beneficial effects of perindopril in cardiovascular diseases, more especially in arterial hypertension and heart failure. Perindopril, its preparation and its use in therapeutics have been described in European patent specification EP 0 049 658. In view of the pharmaceutical value of this compound, it has been important to be able to obtain it by an effective synthesis process, readily transposable to an industrial scale, that leads to perindopril in a good yield and with excellent purity starting from reasonably priced starting materials. Patent specification EP 0 308 341 describes the synthesis of perindopril by the peptide-type coupling of (2S',3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester with N-[(S)-l-carboxybutyl]-(S)-alanine ethyl ester, followed by deprotection of the carboxylic group of the heterocycle by catalytic hydrogenation. That process has the advantage of yielding perindopril in a good yield from starting materials for which industrial synthesis has already been described. However, it also has drawbacks associated with the use of dicyclohexylcarbodiimide in the coupling step : the formation of coupling impurities, and of dicyclohexylurea, a by-product which is difficult to remove. The Applicant has now developed a new process for the synthesis of perindopril that avoids the formation of those secondary products. More specifically, the present invention relates to a process for the synthesis of perindopril and its pharmaceutically acceptable salts which is characterised in that the compound of formula (II) : (Formula Removed) is reacted with a compound of formula (III) : (Formula Removed) wherein R1 represents an imidazolyl, benzimidazolyl or tetrazolyl group, to yield the compound of formula (IV) : (Formula Removed) which is reacted with a compound of formula (V) : (Formula Removed) wherein R2 represents a hydrogen atom, or a benzyl or linear or branched (C1-C6)alkyl group, or an addition salt thereof with a mineral or organic acid, to yield, after isolation, a compound of formula (VI) : (Formula Removed) wherein R2 is as defined hereinbefore, which is hydrogenated in the presence of a catalyst such as, for example, palladium, platinum, rhodium or nickel, under a hydrogen pressure of from 1 to 30 bars, preferably from 1 to 10 bars, to yield, after deprotection of the acid function where necessary, perindopril of formula (I), which is converted, if desired, into a pharmaceutically acceptable salt, such as the tert-butylamine salt. The Example hereinbelow illustrates the invention. EXAMPLE: (2S,3aS,7aS)-l-{(2S)-2-[(lS)-l-(ethoxycarbonyl)butylamino]- propionyI}octahydro-lH-indole-2-carboxylic acid tert-butylamine salt Step A : Ethyl (2S)-2-[(4S)-4-methyl-2-oxido-5-oxo-l,2,3-oxathiazolidin-3-yl]-pentanoate Introduce into a reactor 200 g of N-[(S)-ethoxycarbonyl-l-butyl]-(S)-alanine and 1.5 litres of dichloromethane and then, at 0°C, add 325 g of 1H-imidazole-1-sulphinyl chloride. Subsequently, bring the reaction mixture to ambient temperature and then, after stirring for 1 hour, filter off the precipitate formed. The filtrate obtained is evaporated to dryness to yield the expected product in the form of an oil. Step B : (2S)-1-{(2S)-2-[(lS)-l-(Ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylic acid Introduce 200 g of (2S)-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylic acid and 1.5 litres of dichloromethane into a reactor followed by 180 ml of triethylamine. Subsequently, slowly add a solution of 315 g of the compound obtained in the above Step in 500 ml of dichloromethane and then stir for a further 1 hour at ambient temperature. After the addition of water, the reaction mixture is cooled to 15°C and the pH is adjusted to 4.2 by the addition of a 2N hydrochloric acid solution. Following extraction, the organic phases are washed and then evaporated to yield the expected product. Step C : (2S,3aS, 7aS)-l-{(2S)-2-[(lS)-l-(ethoxycarbonyl)butylamino]propionyl}-octahydro-1H-indole-2-carboxylic acid Introduce into a hydrogenation vessel 200 g of the compound obtained in the above Step in solution in acetic acid, and then 5 g of 10 % Pt/C. Hydrogenate under a pressure of 5 bars at ambient temperature until the theoretical amount of hydrogen has been absorbed. Remove the catalyst by filtration, and then cool to from 0 to 5°C and recover, by means of filtration, the solid obtained. Wash the cake and dry it to constant weight. Step D : (2S,3aS, 7aS)-l-{(2S)-2-[(lS)-l-(Ethoxycarbonyl)butylamino]propionyl}-octahydro-lH-indole-2-carboxylic acid tert-butylamine salt The compound obtained in the above Step (200 g) is dissolved in 2.8 litres of ethyl acetate, and then 40 g of tert-butylamine and 0.4 litre of ethyl acetate are added. The suspension obtained is then refluxed until complete dissolution occurs, and the solution obtained is then filtered in the heated state and cooled, with stirring, to a temperature of from 15 to 20°C. The precipitate obtained is subsequently filtered off, made into a paste again with ethyl acetate, dried and then crushed to yield the expected product in a yield of 95 %. We Claim: 1. Process for the synthesis of perindopril or (2S,3aS,7aS)-l-((2S)-2-{[lS)-l-(ethoxycarbonyl)butyl]amino}propanoyl)octahydro-lH-indole-2-carboxylic acid of formula (I): (Formula Removed) wherein N-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine or (2S)-2-{[(lS)-l-(ethoxycarbonyl)butyl]amino}propanoic acid of formula (II): (Formula Removed) is reacted with a sulfinyl chloride compound of formula (III): (Formula Removed) wherein R1 represents an imidazolyl, benzimidazolyl or tetrazolyl group, to yield ethyl (2S)-2-[(4S)-4-methyl-2-oxido-5-oxo-l,2,3-oxathiazolidin-3-yl]-pentanoate of formula (IV): (Formula Removed) which is reacted with a (2S)-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylic acid compound of formula(V): (Formula Removed) wherein R2 represents a hydrogen atom, or a benzyl or linear or branched (C1-C6)alkyl group, or an addition salt thereof with a mineral or organic acid, to yield, after isolation, a (2S)-l-((2S)-2-{[(lS)-l- (ethoxycarbonyl)butyl]amino-propanoyl)-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylic acid compound of formula (VI): (Formula Removed) wherein R2 is as defined hereinbefore, which is hydrogenated in the presence of a catalyst selected from palladium, platinum, rhodium and nickel, under a hydrogen pressure of from 1 to 30 bars, to yield, after deprotection of the acid function where necessary, perindopril or (2S,3aS,7aS)-l-((2S)-2-{{(lS)-l- (ethoxycarbonyl)butyl]amino}propanoyl)octahydro-lH-indole-2-carboxylic acid of formula (I). 2. Process as claimed in claim 1, wherein the hydrogen pressure in the hydrogenation reaction is from 1 to 10 bars.

Full Text

The present invention relates to process for the synthesis of perindopril.
The present invention relates to a process for the synthesis of perindopril of formula (I)

(Formula Removed)

and its pharmaceutically acceptable salts.
Perindopril and its pharmaceutically acceptable salts, and more especially- its tert-
butylamine salt, have valuable pharmacological properties.
Their principal property is that of inhibiting angiotensin I converting enzyme (or
kininase II), which allows, on the one hand, prevention of the conversion of the
decapeptide angiotensin I to the octapeptide angiotensin II (a vasoconstrictor) and, on the
other hand, prevention of the degradation of bradykinin (a vasodilator) to an inactive
peptide.
Those two actions contribute to the beneficial effects of perindopril in cardiovascular
diseases, more especially in arterial hypertension and heart failure.
Perindopril, its preparation and its use in therapeutics have been described in European patent specification EP 0 049 658.
In view of the pharmaceutical value of this compound, it has been important to be able to obtain it by an effective synthesis process, readily transposable to an industrial scale, that leads to perindopril in a good yield and with excellent purity starting from reasonably priced starting materials.

Patent specification EP 0 308 341 describes the synthesis of perindopril by the peptide-type coupling of (2S',3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester with N-[(S)-l-carboxybutyl]-(S)-alanine ethyl ester, followed by deprotection of the carboxylic group of the heterocycle by catalytic hydrogenation.
That process has the advantage of yielding perindopril in a good yield from starting materials for which industrial synthesis has already been described.
However, it also has drawbacks associated with the use of dicyclohexylcarbodiimide in the coupling step : the formation of coupling impurities, and of dicyclohexylurea, a by-product which is difficult to remove.
The Applicant has now developed a new process for the synthesis of perindopril that avoids the formation of those secondary products.
More specifically, the present invention relates to a process for the synthesis of perindopril and its pharmaceutically acceptable salts which is characterised in that the compound of formula (II) :
(Formula Removed)
is reacted with a compound of formula (III) :
(Formula Removed)
wherein R1 represents an imidazolyl, benzimidazolyl or tetrazolyl group, to yield the compound of formula (IV) :

(Formula Removed)
which is reacted with a compound of formula (V) :

(Formula Removed)
wherein R2 represents a hydrogen atom, or a benzyl or linear or branched (C1-C6)alkyl
group,
or an addition salt thereof with a mineral or organic acid,
to yield, after isolation, a compound of formula (VI) :

(Formula Removed)
wherein R2 is as defined hereinbefore,
which is hydrogenated in the presence of a catalyst such as, for example, palladium,
platinum, rhodium or nickel,
under a hydrogen pressure of from 1 to 30 bars, preferably from 1 to 10 bars, to yield, after
deprotection of the acid function where necessary, perindopril of formula (I), which is
converted, if desired, into a pharmaceutically acceptable salt, such as the tert-butylamine
salt.
The Example hereinbelow illustrates the invention.

EXAMPLE: (2S,3aS,7aS)-l-{(2S)-2-[(lS)-l-(ethoxycarbonyl)butylamino]-
propionyI}octahydro-lH-indole-2-carboxylic acid tert-butylamine salt
Step A : Ethyl (2S)-2-[(4S)-4-methyl-2-oxido-5-oxo-l,2,3-oxathiazolidin-3-yl]-pentanoate
Introduce into a reactor 200 g of N-[(S)-ethoxycarbonyl-l-butyl]-(S)-alanine and 1.5 litres of dichloromethane and then, at 0°C, add 325 g of 1H-imidazole-1-sulphinyl chloride. Subsequently, bring the reaction mixture to ambient temperature and then, after stirring for 1 hour, filter off the precipitate formed. The filtrate obtained is evaporated to dryness to yield the expected product in the form of an oil.
Step B : (2S)-1-{(2S)-2-[(lS)-l-(Ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylic acid
Introduce 200 g of (2S)-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylic acid and 1.5 litres of dichloromethane into a reactor followed by 180 ml of triethylamine. Subsequently, slowly add a solution of 315 g of the compound obtained in the above Step in 500 ml of dichloromethane and then stir for a further 1 hour at ambient temperature. After the addition of water, the reaction mixture is cooled to 15°C and the pH is adjusted to 4.2 by the addition of a 2N hydrochloric acid solution. Following extraction, the organic phases are washed and then evaporated to yield the expected product.
Step C : (2S,3aS, 7aS)-l-{(2S)-2-[(lS)-l-(ethoxycarbonyl)butylamino]propionyl}-octahydro-1H-indole-2-carboxylic acid
Introduce into a hydrogenation vessel 200 g of the compound obtained in the above Step in solution in acetic acid, and then 5 g of 10 % Pt/C. Hydrogenate under a pressure of 5 bars at ambient temperature until the theoretical amount of hydrogen has been absorbed. Remove the catalyst by filtration, and then cool to from 0 to 5°C and recover, by means of filtration, the solid obtained. Wash the cake and dry it to constant weight.

Step D : (2S,3aS, 7aS)-l-{(2S)-2-[(lS)-l-(Ethoxycarbonyl)butylamino]propionyl}-octahydro-lH-indole-2-carboxylic acid tert-butylamine salt
The compound obtained in the above Step (200 g) is dissolved in 2.8 litres of ethyl acetate,
and then 40 g of tert-butylamine and 0.4 litre of ethyl acetate are added.
The suspension obtained is then refluxed until complete dissolution occurs, and the
solution obtained is then filtered in the heated state and cooled, with stirring, to a
temperature of from 15 to 20°C.
The precipitate obtained is subsequently filtered off, made into a paste again with ethyl
acetate, dried and then crushed to yield the expected product in a yield of 95 %.

We Claim:
1. Process for the synthesis of perindopril or (2S,3aS,7aS)-l-((2S)-2-{[lS)-l-(ethoxycarbonyl)butyl]amino}propanoyl)octahydro-lH-indole-2-carboxylic acid of formula (I):

(Formula Removed)
wherein N-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine or (2S)-2-{[(lS)-l-(ethoxycarbonyl)butyl]amino}propanoic acid of formula (II):
(Formula Removed)
is reacted with a sulfinyl chloride compound of formula (III):
(Formula Removed)
wherein R1 represents an imidazolyl, benzimidazolyl or tetrazolyl group,
to yield ethyl (2S)-2-[(4S)-4-methyl-2-oxido-5-oxo-l,2,3-oxathiazolidin-3-yl]-pentanoate of formula (IV):

(Formula Removed)
which is reacted with a (2S)-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylic acid compound of formula(V):

(Formula Removed)
wherein R2 represents a hydrogen atom, or a benzyl or linear or branched (C1-C6)alkyl group,
or an addition salt thereof with a mineral or organic acid,
to yield, after isolation, a (2S)-l-((2S)-2-{[(lS)-l-
(ethoxycarbonyl)butyl]amino-propanoyl)-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylic acid compound of formula (VI):

(Formula Removed)
wherein R2 is as defined hereinbefore,
which is hydrogenated in the presence of a catalyst selected from palladium, platinum, rhodium and nickel,

under a hydrogen pressure of from 1 to 30 bars, to yield, after deprotection of the acid function where necessary, perindopril or (2S,3aS,7aS)-l-((2S)-2-{{(lS)-l-
(ethoxycarbonyl)butyl]amino}propanoyl)octahydro-lH-indole-2-carboxylic acid of formula (I).
2. Process as claimed in claim 1, wherein the hydrogen pressure in the hydrogenation reaction is from 1 to 10 bars.

Documents:

5718-DELNP-2005-Abstract-(18-03-2008).pdf

5718-DELNP-2005-Abstract-(19-08-2008).pdf

5718-DELNP-2005-Abstract-(31-07-2008).pdf

5718-Delnp-2005-Abstract-27-05-2008.pdf

5718-delnp-2005-abstract.pdf

5718-DELNP-2005-Claims-(18-03-2008).pdf

5718-DELNP-2005-Claims-(19-08-2008).pdf

5718-DELNP-2005-Claims-(31-07-2008).pdf

5718-delnp-2005-claims.pdf

5718-delnp-2005-complete specification (granded).pdf

5718-DELNP-2005-Correspondence-Others-(18-03-2008).pdf

5718-DELNP-2005-Correspondence-Others-(31-07-2008).pdf

5718-Delnp-2005-Correspondence-Others-27-05-2008.pdf

5718-delnp-2005-correspondence-others.pdf

5718-DELNP-2005-Description (Complete)-(18-03-2008).pdf

5718-DELNP-2005-Description (Complete)-(19-08-2008).pdf

5718-DELNP-2005-Description (Complete)-27-05-2008.pdf

5718-DELNP-2005-Description (Complete)-31-07-2008.pdf

5718-delnp-2005-description (complete).pdf

5718-DELNP-2005-Form-1(19-08-2008).pdf

5718-DELNP-2005-Form-1-(18-03-2008).pdf

5718-DELNP-2005-Form-1-(31-07-2008).pdf

5718-Delnp-2005-Form-1-27-05-2008.pdf

5718-delnp-2005-form-1.pdf

5718-delnp-2005-form-18.pdf

5718-DELNP-2005-Form-2-(18-03-2008).pdf

5718-DELNP-2005-Form-2-(19-08-2008).pdf

5718-DELNP-2005-Form-2-(31-07-2008).pdf

5718-Delnp-2005-Form-2-27-05-2008.pdf

5718-delnp-2005-form-2.pdf

5718-DELNP-2005-Form-3-(18-03-2008).pdf

5718-DELNP-2005-Form-3-(31-07-2008).pdf

5718-delnp-2005-form-3.pdf

5718-delnp-2005-form-5.pdf

5718-DELNP-2005-GPA-(18-03-2008).pdf

5718-DELNP-2005-Others-(18-03-2008).pdf

5718-delnp-2005-pct-237.pdf

5718-DELNP-2005-Petition-137-(18-03-2008).pdf

5718-DELNP-2005-Petition-138-(18-03-2008).pdf

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Patent Number

224066

Indian Patent Application Number

5718/DELNP/2005

PG Journal Number

42/2008

Publication Date

17-Oct-2008

Grant Date

26-Sep-2008

Date of Filing

09-Dec-2005

Name of Patentee

LES LABORATOIRES SERVIER

Applicant Address

12, PLACE DE LA DEFENSE, F-92415 COURBEVOIE CEDEX, FRANCE.

Inventors:

#	Inventor's Name	Inventor's Address
1	THIERRY DUBUFFET	17, ALLEE DES DCHARMILLLES, 76190 AUTRETOT, FRANCE.
2	JEAN-PIERRE LECOUVE	93, RUE DU DOCTEUR VIGNE, 76600 LE HAVRE, FRANCE.

PCT International Classification Number

C07K 5/02

PCT International Application Number

PCT/FR2004/001637

PCT International Filing date

2004-06-28

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0329 1601.7	2003-06-30	EUROPEAN UNION