Indian Patents. 233090:"NEW PROCESS FOR THE SYNTHESIS OF PERINDOPRIL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS"

Title of Invention	"NEW PROCESS FOR THE SYNTHESIS OF PERINDOPRIL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS"
Abstract	Process for the synthesis of the perindopril of formula (I): and its pharmaceutically acceptable salts.

Full Text	TheThe present invntion 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-butylarnine salt, have valuable pharmacological properties. Their principal property is that of inhibiting angiotensin I converting enzyme (or kinnase II), which allows, on the one hand, prevention1 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 bradylonin (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 the 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 industrial synthesis of perindopril by the coupling of (2S,3aS,7aS-octahydroindole-2-carboxylic acid benzyl ester with N-[(S)-1- carboxybutyl]-(5)-alanine ethyl ester, followed by deprotection of the carboxylic group of the heterocycle by catalytic hydrogenation. The Applicant has now developed a new process for the synthesis of perindopril. 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): (Figure Removed) wherein Bn represents a benzyl group, is reacted with a compound of formula (III) having the S configurationwherein X represents a halogen atom and BOC represents a tert-butoxycarbonyl group, in the presence of a base, to yield, after deprotection of the amino function, the compound of formula (IV) wherein Bn represents a benzyl group, (Figure Removed)-3- which is reacted with ethyl 2-oxopentanoate under hydrogen pressure, in the presence of palladium-on-carbon, to yield the compound of formula (I) directly. Among the bases that can be used in the reaction between the compounds of formulae (II) and (III) there may be mentioned, without implying any limitation, organic amines such as triethylamine, pyridine, N-methylmorpholine or diisopropylethylamine, and mineral bases such as NaOH, KOH, Na2CO3, K2CO3, NaHCO3 or KHCO3. The reaction between the compound of formula (IV) and ethyl 2-oxopenatnoate is preferably carried out in an alcoholic solvent, under a hydrogen pressure of from 1 to 5 bars, at a temperature of form 20 to 60°C. EXAMPLE ; (2S,3aS,7aS)-1-{(2S)-2-[(lS)-l-(ethoxycarbonyl)butyIamiiio]- propionyl}-octahydro-l//-indole-2-carboxylic acid tert-butylamine salt Step A : Benzyl (2S)-l-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylate Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylate and 1.5 litres of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0°C and add 107 ml of triethylamine and then 162 g of (2S)-2-[(tert-butoxycarbonyl)amino]propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-l-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3,4,5,6,7-hexahydro-l//-indole-2-carboxylate solution so obtained is used as it is in the following Step. StepB : Benzyl (2S)-l-{(2S)-2-aminopropionyl}-2,3,4,5,6,7-hexahydro-lll-indole-2-carboxylate Introduce the solution obtained in the above Step into a reactor, and then add 133 g of trifluoroacetic acid. After stirring for 1 hour 30 minutes at ambient temperature, wash the mixture with water and then with a saturated solution of sodium hydrogen carbonate and evaporate off the solvents to yield benzyl (2S)-l-{(2S)-2-aminopropionyl}-2,3,4,5,6,7-hexahydro-l//-indole-2-carboxylate. StepC: (2S,3aS, 7aS)-l-{(2S)-2-[(lS)-l-(ethoxycarbonyl)butylamino]propionyl}-octahydro-lH-indole-2-carboxylicacid Introduce into a hydrogenation vessel 200 g of the compound obtained in the above Step and 88 g of ethyl 2-oxopentanoate in solution in ethanol, followed by 5 g of 10 % Pd/C. Hydrogenate under atmospheric pressure at 30°C until the theoretical amount of hydrogen has been absorbed. Remove the catalyst by filtration and then evaporate off the solvent. (2S,3aS,7aS)-1 - {(2S)-2-[(l S)-1 -(ethoxycarbonyl)butylamino]propionyl} -octahydro- IH- indole-2-carboxylic acid is thereby obtained in a yield of 85 %. StepD: (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 acetonitrile, and then 40 g of tert-butylamine and 0.4 litres of ethyl acetate are added. The suspension obtained is then refluxed until dissolution is complete, and the solution obtained is subsequently filtered hot and cooled, with stirring, to a temperature of from 15 to 20°C. The resulting precipitate is then filtered off, made into a paste again with acetonitrile, dried and then recrystallised from ethyl acetate to give the expected product in a yield of 95 % and with an enantiomeric purity of 99 %. We claim; 1. Process for the synthesis of perindopril of formula (I) : (Formula Removed) and its pharmaceutically acceptable salts, wherein a compound of formula (II) : (Formula Removed) wherein R1 represents a hydrogen atom or a benzyl or linear or branched (C1-C6)alkyl group, is reacted with a compound of formula (III) having the S configuration : (Formula Removed) wherein X represents a halogen atom and R2 represents a tert-butoxycarbonyl or benzyl group in the presence of an organic amine selected from triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine, or a mineral base such as NaOH, KOH, NE12CO3, K2CO3, NaHCO3 or KHCO3, to yield, after deprotection of the amino function, a compound of formula (IV) : (Formula Removed) wherein Ri is as defined hereinbefore, which is reacted with a compound of formula (V) : (Formula Removed) wherein G represents a chlorine, bromine or iodine atom or a p-toluenesulphonyloxy, methanesulphonyloxy or trifluoromethanesulphonyloxy group, in the presence of an organic amine selected from triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine, or a mineral base such as NaOH, KOH, Na2CO3, K2CO3, NaHCO3 or KHCO3. to yield a compound of formula (VI): (Formula Removed) wherein R1 is as defined hereinbefore, which is hydrogenated in the presence of a catalyst such as palladium, platinum, rhodium or nickel to yield, after deprotection where necessary, the compound of formula (I). 2. Synthesis process as claimed in claim 1, wherein R1 represents a benzyl group, and the protecting group for the amino function is a tert-butoxycarbonyl group. 3. Process as claimed inclaim 1 or 2 for the synthesis of perindopril in the form of its tert-butylamine salt.

Full Text

TheThe present invntion 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-butylarnine salt, have valuable pharmacological properties.
Their principal property is that of inhibiting angiotensin I converting enzyme (or kinnase II), which allows, on the one hand, prevention1 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 bradylonin (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 the 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 industrial synthesis of perindopril by the coupling of (2S,3aS,7aS-octahydroindole-2-carboxylic acid benzyl ester with N-[(S)-1-

carboxybutyl]-(5)-alanine ethyl ester, followed by deprotection of the carboxylic group of the heterocycle by catalytic hydrogenation.
The Applicant has now developed a new process for the synthesis of perindopril.
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):
(Figure Removed)
wherein Bn represents a benzyl group, is reacted
with a compound of formula (III) having the S configurationwherein X represents a halogen atom and BOC represents a tert-butoxycarbonyl group, in the presence of a base,
to yield, after deprotection of the amino function, the compound of formula (IV)
wherein Bn represents a benzyl group,
(Figure Removed)-3-
which is reacted with ethyl 2-oxopentanoate under hydrogen pressure, in the presence of
palladium-on-carbon,
to yield the compound of formula (I) directly.
Among the bases that can be used in the reaction between the compounds of formulae (II) and (III) there may be mentioned, without implying any limitation, organic amines such as triethylamine, pyridine, N-methylmorpholine or diisopropylethylamine, and mineral bases such as NaOH, KOH, Na2CO3, K2CO3, NaHCO3 or KHCO3.
The reaction between the compound of formula (IV) and ethyl 2-oxopenatnoate is preferably carried out in an alcoholic solvent, under a hydrogen pressure of from 1 to 5 bars, at a temperature of form 20 to 60°C.
EXAMPLE ; (2S,3aS,7aS)-1-{(2S)-2-[(lS)-l-(ethoxycarbonyl)butyIamiiio]-
propionyl}-octahydro-l//-indole-2-carboxylic acid tert-butylamine salt
Step A : Benzyl (2S)-l-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylate
Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-lH-indole-2-carboxylate and 1.5 litres of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0°C and add 107 ml of triethylamine and then 162 g of (2S)-2-[(tert-butoxycarbonyl)amino]propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-l-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3,4,5,6,7-hexahydro-l//-indole-2-carboxylate solution so obtained is used as it is in the following Step.
StepB : Benzyl (2S)-l-{(2S)-2-aminopropionyl}-2,3,4,5,6,7-hexahydro-lll-indole-2-carboxylate
Introduce the solution obtained in the above Step into a reactor, and then add 133 g of trifluoroacetic acid. After stirring for 1 hour 30 minutes at ambient temperature, wash the mixture with water and then with a saturated solution of sodium hydrogen carbonate and evaporate off the solvents to yield benzyl (2S)-l-{(2S)-2-aminopropionyl}-2,3,4,5,6,7-hexahydro-l//-indole-2-carboxylate.
StepC: (2S,3aS, 7aS)-l-{(2S)-2-[(lS)-l-(ethoxycarbonyl)butylamino]propionyl}-octahydro-lH-indole-2-carboxylicacid
Introduce into a hydrogenation vessel 200 g of the compound obtained in the above Step
and 88 g of ethyl 2-oxopentanoate in solution in ethanol, followed by 5 g of 10 % Pd/C.
Hydrogenate under atmospheric pressure at 30°C until the theoretical amount of hydrogen
has been absorbed.
Remove the catalyst by filtration and then evaporate off the solvent.
(2S,3aS,7aS)-1 - {(2S)-2-[(l S)-1 -(ethoxycarbonyl)butylamino]propionyl} -octahydro- IH-
indole-2-carboxylic acid is thereby obtained in a yield of 85 %.
StepD: (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 acetonitrile, and then 40 g of tert-butylamine and 0.4 litres of ethyl acetate are added. The suspension obtained is then refluxed until dissolution is complete, and the solution obtained is subsequently filtered hot and cooled, with stirring, to a temperature of from 15 to 20°C. The resulting precipitate is then filtered off, made into a paste again with acetonitrile, dried and then recrystallised from ethyl acetate to give the expected product in a yield of 95 % and with an enantiomeric purity of 99 %.

We claim;
1. Process for the synthesis of perindopril of formula (I) :
(Formula Removed)

and its pharmaceutically acceptable salts, wherein a compound of formula (II) :
(Formula Removed)

wherein R1 represents a hydrogen atom or a benzyl or linear or branched (C1-C6)alkyl group,
is reacted with a compound of formula (III) having the S configuration :
(Formula Removed)

wherein X represents a halogen atom and R2 represents a tert-butoxycarbonyl or benzyl group in the presence of an organic amine selected from triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine, or a mineral base such as NaOH, KOH, NE12CO3, K2CO3, NaHCO3 or KHCO3,

to yield, after deprotection of the amino function, a compound of formula (IV) :

(Formula Removed)
wherein Ri is as defined hereinbefore,
which is reacted with a compound of formula (V) :
(Formula Removed)

wherein G represents a chlorine, bromine or iodine atom or a p-toluenesulphonyloxy, methanesulphonyloxy or trifluoromethanesulphonyloxy group,
in the presence of an organic amine selected from triethylamine, pyridine, N-methylmorpholine and diisopropylethylamine, or a mineral base such as NaOH, KOH, Na2CO3, K2CO3, NaHCO3 or KHCO3.
to yield a compound of formula (VI):
(Formula Removed)

wherein R1 is as defined hereinbefore, which is hydrogenated in the presence of a catalyst such as palladium, platinum, rhodium or nickel to yield, after deprotection where necessary, the compound of formula (I).
2. Synthesis process as claimed in claim 1, wherein R1 represents a benzyl group, and the protecting group for the amino function is a tert-butoxycarbonyl group.
3. Process as claimed inclaim 1 or 2 for the synthesis of perindopril in the form of its tert-butylamine salt.

Documents:

918-DELNP-2006-Abstract-(23-02-2009).pdf

918-DELNP-2006-Abstract-(28-08-2008).pdf

918-delnp-2006-abstract.pdf

918-DELNP-2006-Claims-(23-02-2009).pdf

918-DELNP-2006-Claims-(28-08-2008).pdf

918-delnp-2006-claims.pdf

918-DELNP-2006-Correspondence-Others-(23-02-2009).pdf

918-DELNP-2006-Correspondence-Others-(28-08-2008).pdf

918-delnp-2006-correspondence-others-1.pdf

918-delnp-2006-correspondence-others.pdf

918-delnp-2006-description (complete)-28-08-2008.pdf

918-delnp-2006-description (complete).pdf

918-DELNP-2006-Form-1-(23-02-2009).pdf

918-DELNP-2006-Form-1-(28-08-2008).pdf

918-delnp-2006-form-1.pdf

918-delnp-2006-form-18.pdf

918-DELNP-2006-Form-2-(23-02-2009).pdf

918-DELNP-2006-Form-2-(28-08-2008).pdf

918-delnp-2006-form-2.pdf

918-DELNP-2006-Form-3-(28-08-2008).pdf

918-delnp-2006-form-3.pdf

918-delnp-2006-form-5.pdf

918-DELNP-2006-GPA-(28-08-2008).pdf

918-delnp-2006-gpa.pdf

918-delnp-2006-pct-210.pdf

918-delnp-2006-pct-237.pdf

918-DELNP-2006-Petition-137-(23-02-2009).pdf

918-DELNP-2006-Petition-137-(28-08-2008).pdf

918-DELNP-2006-Petition-138-(28-08-2008).pdf

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Patent Number

233090

Indian Patent Application Number

918/DELNP/2006

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

26-Mar-2009

Date of Filing

22-Feb-2006

Name of Patentee

LEE 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 CHARMILLES, F-76190 AUTRETOT, FRANCE
2	JEAN-PIERRE LECOUVE	93, RUE DU DOCTEUR VIGNE, F-76600 LE HAVRE, FRANCE

PCT International Classification Number

C07K 5/06

PCT International Application Number

PCT/FR2004/002196

PCT International Filing date

2004-08-27

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	03292131.4	2003-08-29	EPO