WO2008114270A1 - Procédé de préparation d'un sel de périndopril erbumine et son ou ses nouveaux polymorphes - Google Patents

Procédé de préparation d'un sel de périndopril erbumine et son ou ses nouveaux polymorphes Download PDF

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Publication number
WO2008114270A1
WO2008114270A1 PCT/IN2007/000120 IN2007000120W WO2008114270A1 WO 2008114270 A1 WO2008114270 A1 WO 2008114270A1 IN 2007000120 W IN2007000120 W IN 2007000120W WO 2008114270 A1 WO2008114270 A1 WO 2008114270A1
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Prior art keywords
formula
polymorph
perindopril erbumine
range
temperature
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PCT/IN2007/000120
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English (en)
Inventor
Parimal Hansmukh Desai
Narenda Jagannath Salvi
Bharatkumar Surendra Patravale
Seetharaman Subramanian
Nitin Baburao Kajale
Avikumar Digamber Dabe
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Aarti Healthcare Limited
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Priority to PCT/IN2007/000120 priority Critical patent/WO2008114270A1/fr
Priority to EP07827487A priority patent/EP2137148A1/fr
Publication of WO2008114270A1 publication Critical patent/WO2008114270A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a single pot process for the preparation of perindopril erbumine salt of the formula (I).
  • the present invention also relates to novel polymorph S of perindopril erbumine salt and processes for the preparation thereof
  • Perindopril is known by the chemical name (2S,3aS,7aS)-l- ⁇ 2- [l-(ethoxycarbonyl)-(S)-butyl amine ⁇ -(S)-propionyl ⁇ -octahydroindole-2-carboxylic acid of the formula (V).
  • Perindopril is the free acid form which is a prodrug and metabolizes in vivo by hydrolysis of ester group to form perindoprilate, the biologically active metabolite. Perindopril exerts an inhibiting activity on kininase II which is responsible for hypertensive disorder or cardiac insufficiency. Perindopril and its synthesis was first disclosed in US4508729. The process disclosed in US 4508729 is not industrially feasible.
  • US 4914214 disclose an industrially feasible process for synthesis of perindopril and its salt specifically the erbumine salt.
  • (2S, 3aS, 7aS)-2-carboxyoctahydroindole-2-carboxylic acid benzyl ester para toluene sulfonate of the formula (III) is condensed with N((S)-ethoxy carbonyl -l-ethyl)-(S)alanine of the formula (IV) in the presence of ethyl acetate,
  • US 6835843 discloses a process for industrial synthesis of perindopril and its pharmaceutically acceptable salts.
  • (2S, 3aS, 7aS)-2- carboxyoctahydroindole-2-carboxylic acid benzyl ester para toluene sulfonate of the formula (III) is condensed with N((S)-ethoxy carbonyl -l-ethyl)-(S)alanine of the formula (IV) in the presence of ethyl acetate, 0.4 to 0.6 mol of 1-hydroxybenzotriazole per mole of benzyl ester and 1 to 1.2 mol of dicyclohexylcarbodiimide per mole of benzyl ester in the absence of triethyl amine to obtain Benzyl (2S, 3aS, 7aS)-l- ⁇ 2-[l-(ethoxycarbonyl)-(S)-butyl amino ]- (S)
  • the compound of formula (II) is catalytically hydrogenated in the presence of bi-phasic solvent system containing methylcyclohexane and water and converted further into erbumine salt.
  • bi-phasic solvent system containing methylcyclohexane and water and converted further into erbumine salt.
  • the use of biphasic solvent system in catalytic hydrogenation lowers the rate of reaction and increases the reaction completion time.
  • Biphasic solvent system makes a slow separation of catalyst by filtration. Further, the product obtained is to be isolated by lyophilisation which is a costly method.
  • the Benzyl (2S, 3aS, 7aS)-l- ⁇ 2-[l-(ethoxycarbonyl)-(S)-butylamino]-(S)propionyl ⁇ octahydroindole-2-carboxylate of the formula (II) is isolated free of N-acetyl impurity and dicyclohexyl urea.
  • the product is deprotected by catalytic hydrogenation using palladium on charcoal and the perindopril acid of the formula (V) is isolated by solvent extraction and further converted into erbumine salt of the formula (I).
  • the publication does not disclose any information on the purity of the compounds obtained by using non-ethyl acetate solvents.
  • US7157485 discloses a process for the preparation of (2S, 3aS, 7aS)-l- ⁇ 2-[l- (ethoxycarbonyl)-(S)-butyl amino ]-(S)propionyl ⁇ octahydroindole-2-carboxylic acid of the formula (V) and its pharmaceutically acceptable salts.
  • (2S, 3aS, 7aS)-2- carboxyoctahydroindole-2-carboxylic acid benzyl ester para toluene sulfonate of the formula (III) is condensed with N((S)-ethoxy carbonyl -l-ethyl)-(S)alanine of the formula (IV) in the tetrahydrofuran, dicyclohexylcarbodiimide and triethyl amine to obtain Benzyl (2S, 3aS, 7aS)- 1 - ⁇ 2-[ 1 -(ethoxycarbonyl)-(S)-butyl amino ]-(S)propionyl ⁇ octahydroindole-2- carboxylate of the formula (II).
  • the benzyl ester is recrystallised and catalytically hydrogenated in the presence of acetic acid and catalyst, Pt/C to obtain perindopril acid of the formula (V) which is converted further into erbumine salt.
  • perindopril acid of the formula (V) which is converted further into erbumine salt.
  • WO2004/099138 discloses a process for the preparation of perindopril and its pharmaceutically acceptable salts thereof.
  • (2S, 3aS, 7aS)-2-carboxyoctahydroindole benzyl ester benzene sulphonic acid salt is basified with liquid ammonia in dichloromethane. The organic layer is separated and washed with water till pH is neutral.
  • the organic layer is treated with N((S)-ethoxy carbonyl -l-ethyl)-(S)alanine of the formula (IV) in the hydroxyl benzotriazole and dicyclohexylcarbodiimide to obtain Benzyl (2S, 3aS, 7aS)-l- ⁇ 2-[l- (ethoxycarbonyl)-(S)-butyl amino ]-(S)propionyl ⁇ octahydroindole-2-carboxylate of the formula (II).
  • the product is purified by treating it with di-isopropyl ether and filtered through hyflo bed.
  • the organic layer is concentrated to obtain pure product in the form of an oil.
  • the oil is catalytically hydrogenated in the presence of ethyl acetate and catalyst, Pt/C to obtain perindopril acid of the formula (V) which is converted further into its erbumine salt.
  • perindopril acid of the formula (V) which is converted further into its erbumine salt.
  • US2005059609 discloses alpha crystalline form of perindopril erbumine prepared by treating the erbumine with ethyl acetate as a solvent.
  • Alpha crystalline form is characterized by X-ray diffraction peak of 7.68, 8.144, 9.037, 10.947, 13.150, 13.687, 14.627, 15.412, 16.573, 17.357, 18.109, 19.922, 20.609, 21.412, 21.832, 22.588, 23.323, 24.200, 24.727, 25.957, 26.932, 27.836, 28.966, 29.213 at 20.
  • WO2005/108365 discloses another process to prepare alpha crystalline form of perindopril erbumine in which perindopril erbumine is treated with one or more ketone.
  • beta crystalline form of perindopril erbumine is disclosed in US2005203165. It is prepared by heating perindopril erbumine in dichloromethane.
  • the characteristic XRD peaks of beta crystalline form are 5.169, 8.379, 9.350, 14.746, 15.411, 15.931, 16.711, 18.161, 20.564, 21.285, 21.781, 22.632, 22.308, 23.797, 24.276, 25.190, 25.924, 26.646, 27.620, 28.306 at 2 ⁇ .
  • Another new polymorph namely, gamma crystalline form of perindopril erbumine is disclosed in US 2004/0248817.
  • the above polymorph is prepared by heating the solvent of perindopril erbumine in chloroform.
  • the gamma crystalline form is characterized by XRD peaks of 6.298, 7.480, 8.700, 9.276, 10.564, 11.801, 12.699, 13.661, 14.095, 14.332, 14.961, 15.793, 16.212, 16.945, 17.291, 17.825, 18.100, 18.715, 19.017, 19.362, 19.837, 20.609, 21.232, 21.499, 21.840, 22.129, 22.639, 23.000, 23.798, 24.170, 25.066, 25.394, 26.034, 26.586. 27.541, 28.330 and 29.589 at 20.
  • JP2006169169 discloses a new type I crystal form of perindopril erbumine and method to prepare the same.
  • New crystal type I is characterized by XRD peaks of 8.47, 9.53, 14.09, 14.92, 15.22, 15.45, 15.80, 18.64, 19.97, 20.68, 21.10, 21.45, 22.12, 23.19 at 2 ⁇ .
  • the Type I crystals of perindopril erbumine are prepared by treating the erbumine with tetrahydrofurane.
  • EP 1647547 discloses new crystalline forms of perindopril erbumine monohydrate, perindopril erbumine sesquihydrate and perindopril erbumine dihydrate. Sesquihydarte has characteristic XRD peaks of 8.976, 9.425, 14.821, 15.253, 19.924, 20.582, 20.960, 21.324, 21.93 at 2 ⁇ .
  • the aqueous solution of perindopril erbumine (2 to 20 %) is frozen and dried by lyophililzation in vacuo to obtain its sesquihydate form.
  • the aqueous solution of perindopril erbumine containing upto 20 % of a volatile water-miscible polar organic solvent is frozen and dried by lyophilization to obtain its dihydrate form having characteristic XRD peaks of 9.470, 15.488, 15.760, 16.050, 21.036, 21.46 at 20.
  • the monohydrate form of perindopril erbumine is prepared by treating the perindopril erbumine with water and acetone in the ratio of 30:70 to 70:30 and the solution is cooled to -80°C. The solid obtained is dried by lyophilization.
  • WO2005/037788 discloses a process to prepare crystalline perindopril erbumine.
  • the solution of perindopril in a solvent selected from N,N dimethyl formamide or dimethyl acetals of lower aliphatic ketones is treated with tert. Butyl amine.
  • the crystalline form is having characteristic XRD peaks of 8.628, 9.945, 11.863, 14.618, 15.487, 16.294, 17.434, 18.296, 19.023, 20.744, 21.570, 22.965, 24.950, 26.690, 28.531, 29.823, 32.194, 32.918, 34.196, 35.140, 36.151, 37.578, 40.129, 43.534 at 2 ⁇ .
  • EP 1636185 discloses new polymorph of perindopril erbumine forms namely, d and e. Crystalline forms d and e are obtained by crystallizing perindopril erbumine from methyl tert- butyl ether as crystallizing solvent at specific conditions. Crystalline form e is converted into crystalline form d by removing water, practically by azeotropic distillation.
  • Form d has characteristic XRD peaks of 5.27, 8.93, 9.75, 10.65, 14.65, 14.97, 15.27, 15.95, 17.27, 18.63, 19.99, 20.37, 21.31, 21.83, 22.49, 23.15, 23.65, 23.99, 24.71, 25.33, 15.75, 26.43, 26.77, 28.19 at 2 ⁇ .
  • Further Form e has characteristic peaks of 5.28, 8.43, 8.87, 9.45, 10.01, 13.58, 14.21, 14.79, 15.31, 15.84, 16.43, 16.84, 17.65, 18.65, 19.87, 21.21, 21.79, 22.79, 23.52, 24.5, 25.83, 26.55, 27.25, 28.11 at 2 ⁇ .
  • perindopril erbumine and its polymorphs In view of the therapeutic value of perindopril erbumine and its polymorphs, there is still the need and scope for obtaining perindopril erbumine or polymorph thereof with higher purity. It is also important from a commercial point of view to develop processes for the preparation of perindopril erbumine and polymorph which can be used at as industrial scale, especially in a form that allows rapid filtration and drying. The products are also to be reproducible and sufficiently stable to allow their storage for long periods without employing controlled conditions like requirements of temperature, light, humidity or oxygen level.
  • An object of the invention is to provide a novel polymorph S of perindopril erbumine, which is stable, reproducible and pure.
  • Another object of the invention is to provide processes to prepare the above polymorph form S of perindopril erbumine.
  • Yet another object of the invention is to provide a single pot process for the preparation of perindopril erbumine using single solvent, in which process is industrially feasible.
  • Yet another object of the invention is to provide a single pot process for the preparation of perindopril erbumine using a single solvent, in which the intermediates are not isolated and recrystallised, to achieve a purity level of 99.85 %, the process being simple, easy and convenient to carry out.
  • Yet another object of the invention is to provide a single pot process for the preparation of perindopril erbumine using single solvent, in which the duration of the process is reduced thereby making the process cost-effective.
  • Yet another object of the invention is to provide a single pot process for the preparation of perindopril erbumine using a single solvent, in which the product obtained has a purity of 99.85 % without additional purification steps thereby making the process efficient and economical.
  • Yet another object of the invention is to provide a single pot process for the preparation of perindopril erbumine using a single solvent, in which solvent can be recovered and reused, thereby reducing effluent generation and making the process eco-friendly.
  • Formula (III) Formula (IV) in the presence of isopropyl acetate as a solvent and triethylamine, 1- hydroxybenzotriazole and dicyclohexylcarbodiimide at temperatures in the range of 25 - 30°C; cooling the reaction mixture to temperatures in the range of 5 to 10°C; filtering the reaction mixture and concentrating the filtrate to its
  • step (c) The compound of the formula (I) is dried in step (c) for a period of about 8 hours.
  • a novel polymorph S of perindopril erbumine having the following X-ray diffraction pattern,
  • a process for the preparation of the above novel polymorph S of perindopril erbumine salt by dissolving perindopril erbumine of formula (I) in isopropyl acetate or ethyl acetate in the molar ratio of 1 :15 wt/v at a temperature in the range of 50-80°C to obtain clear solution, adding the hot solution of the perindopril erbumine into a pre-cooled solvent such as n-Hexane or methyl ethyl ketone at temperature to 0-5°C, stirring the reaction mixture at temperature in the range of 0-5° C to precipitate out the polymorph S and isolating the polymorph S by filtration followed by drying at 30 ° C under vacuum.
  • a pre-cooled solvent such as n-Hexane or methyl ethyl ketone
  • the perindopril erbumine is dissolved in isopropyl acetate or ethyl acetate preferably at temperature in the range of 60-80°C.
  • n-Hexane or methyl ethyl ketone is preferably cooled at temperature of 0 ° C.
  • the reaction mixture is preferably stirred at temperature of 0°C to precipitate out the polymorph S.
  • the polymorph S is preferably dried at 30°C under vacuum for 7 days
  • a process for the preparation of the above novel polymorph S of perindopril erbumine by dissolving perindopril erbumine of formula (I) in 3-pentanone at a temperature in the range of 65-70°C to obtain a clear solution, cooling the solution rapidly to 0-5 ° C with stirring to precipitate out the polymorph S and isolating the polymorph S by filtration followed by drying at 30°C under vacuum.
  • the perindopril erbumine is dissolved in 3-pentanone preferably at a temperature of 68°C to obtain clear solution.
  • the solution is cooled rapidly preferably at temperature of 0°C with stirring to precipitate out the polymorph S.
  • the polymorph S is preferably dried at 30°C under vacuum for 4 days.
  • a process for the preparation of the above novel polymorph S of perindopril erbumine by dissolving the compound of the formula (V) in isopropyl acetate with stirring to obtain a clear solution, adding tertiary butyl amine to the solution, heating the reaction mixture at a temperature in the range of 60- 65° C, cooling the clear solution to temperature in range of 15 - 20°C with stirring to precipitate out the polymorph S and isolating the polymorph S by filtration followed by washing with isopropyl acetate and drying the polymorph at 30°C under vacuum.
  • the polymorph S is preferably dried at 30°C under vacuum for 7 days
  • the process of preparing the perindopril erbumine salt is carried out in a single pot using a single solvent and without isolating the intermediates.
  • Perindopril erbumine of the formula (I) prepared by the process of the invention is 99.85% pure without the need for additional purification steps and the yield is 75 % thereby making the process efficient and economical.
  • Being a single pot process without isolation of intermediates and recrystallization and yet achieving a purity of 99.85 % the process is simple, easy and convenient to carry out.
  • the duration of the process is reduced by about 30 - 35 % thereby making the process cost-effective.
  • the present process for the preparation of perindopril erbumine uses single solvent namely iso-propyl acetate.
  • the solvent can be recovered and reused thereby reducing or eliminating effluent generation and making the process eco- friendly and thus industrially feasible.
  • the invention also gives novel polymorph S.
  • the polymorphic form S was studied for its stability by using XRD and found to be stable for at least six months.
  • the invention also provides alternative processes for the preparation of the polymorph.
  • the reaction mixture was cooled to temperature in the range of 5-10 ° C with stirring for 30 minutes.
  • the reaction mixture was filtered.
  • the filtrate was concentrated to its 50% of volume to obtain the concentrated filtrate comprising benzyl ester of (2S, 3aS, 7aS)-l- ⁇ 2-[l-(ethoxycarbonyl)-(S)- butylamino]-(S)propionyl ⁇ -octahydro-indole-2-carboxylate.
  • the concentrated filtrate was hydrogenated in the presence of 5% Pd/C (5.0 gm) under a hydrogen pressure of 50 psi at temperature of 20°C.
  • the reaction was monitored by TLC.
  • reaction mixture was filtered to remove the catalyst.
  • tertiary butyl amine (10.0 gm) was added with stirring and then reaction mixture was heated to 68-70°C to obtain a clear solution.
  • the reaction mixture was cooled to temperature of 15-20°C with stirring for 1 hour to precipitate out perindopril erbumine.
  • the reaction mixture was cooled to temperature in the range of 5- 10° C with stirring for 30 minutes.
  • the reaction mixture was filtered.
  • the filtrate was concentrated to its 50% of volume to obtain the concentrated filtrate comprising benzyl ester of (2S, 3aS, 7aS)-l- ⁇ 2-[l-(ethoxycarbonyl)-(S)- butylamino]-(S)propionyl ⁇ -octahydro-indole-2-carboxylate.
  • the concentrated filtrate was hydrogenated in the presence of 5% Pd/C (5.0 gm) under a hydrogen pressure of 50 psi at temperature of 20° C.
  • the reaction was monitored by TLC. Once the reaction was over, the reaction mixture was filtered to remove the catalyst.
  • tertiary butyl amine (10.0 gm) was added with stirring and then reaction mixture was heated to 68-70°C to obtain a clear solution.
  • the reaction mixture was cooled to temperature of 15-20°C with stirring for 1 hour to precipitate out perindopril erbumine.
  • the erbumine salt was filtered and was dried at 45-50°C under vacuum for 8 lirs.
  • Perindopril erbumine (5 gms) obtained according to the Example 1 (a) was dissolved in 75 ml of isopropyl acetate by heating the reaction mixture at temperature of 80°C to obtain the clear solution.
  • 75 ml n- hexane was cooled to 0°C.
  • the hot solution of perindopril erbumine was added to the pre-cooled n-hexane at 0°C with stirring to precipitate out polymorph S.
  • the polymorph was filtered and was dried under vaccum at 30°C for 7 days. Yield : 80% Purity : 99.85% X-ray Diffraction pattern of the polymorph S is as follows,
  • Perindopril erbumine (5gms) obtained according to Example 1 (a) was dissolved in 55 ml of ethyl acetate by heating the reaction mixture at temperature of 80°C to obtain the clear solution. 50 ml. of methyl ethyl ketone was cooled to 0°C. The hot solution of perindopril erbumine was added to the pre-cooled methyl ethyl ketone at 0°C with stirring to precipitate out polymorph S. The polymorph was filtered and was dried under vacuum at 30°C for 7 days.
  • Perindopril erbumine (5 gms) obtained according to Example 1 (a) was dissolved in 270 ml of 3-pentanone at temperature of 68°C to obtain a clear solution. The solution was rapidly cooled to 0°C with stirring to precipitate out polymorph S. The polymorph was filtered and was dried under vacuum at 30° C for 4 days.
  • Perindopril (5 gms) obtained according to Example l(a) was dissolved in 70 ml of isopropyl acetate with stirring to obtain a clear solution. To the solution, 1.2 gms of tertiary butyl amine was added. The reaction mixture was heated at temperature in the range of 64-65°C for 30 minutes. The reaction mixture was cooled to 18°C with stirring to precipitate out polymorph S. The polymorph was filtered and was dried under vaccum at 30°C for 7 days.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne un procédé en un seul pot pour la préparation d'un sel de périndopril erbumine. Selon ce procédé, la condensation du para toluène sulfonate de l'ester benzylique de l'acide (2S, 3aS, 7aS)-octahydroindole-2-carboxylique avec la N-((S-)-éthoxy carbonyl-1-éthyl-(S)-alanine, l'hydrogénation catalytique de l'ester benzylique du (2S, 3aS, 7aS)-1-{2-[1-(éthoxycarbonyl)-(S)-butylamino]-(S)propionyl}- octahydro-indole-2-carboxylate et la conversion de l'acide (2S,3aS,7aS)-1-{2-[1-éthoxycarbonyl)_(S)-butylamino]-(S)-propionyl}octahydroindole-2-carboxylique en son sel de périndopril erbumine sont réalisées dans un seul pot au moyen d'un seul solvant tel que l'acétate d'isopropyle pour obtenir un sel de périndopril erbumine de très grande pureté. L'invention concerne également un nouveau polymorphe S de périndopril erbumine qui présente des pics de diffraction des rayons X de 9,10, 14,64, 15,37, 16,58, 17,39, 19,99, 20,62, 21,50, 22,15, 22,60, 24,20, 27,55 ± 0,2 aux valeurs 2Θ. L'invention concerne également des procédés de préparation du nouveau polymorphe S.
PCT/IN2007/000120 2007-03-22 2007-03-22 Procédé de préparation d'un sel de périndopril erbumine et son ou ses nouveaux polymorphes WO2008114270A1 (fr)

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PCT/IN2007/000120 WO2008114270A1 (fr) 2007-03-22 2007-03-22 Procédé de préparation d'un sel de périndopril erbumine et son ou ses nouveaux polymorphes
EP07827487A EP2137148A1 (fr) 2007-03-22 2007-03-22 Procédé de préparation d'un sel de périndopril erbumine et son ou ses nouveaux polymorphes

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2012044189A1 (fr) 2010-09-29 2012-04-05 Instituto Superior Técnico Forme cristalline hydratée inédite de l'erbumine de périndopril, ses procédés de préparation et son utilisation dans des préparations pharmaceutiques
WO2014057404A1 (fr) * 2012-10-10 2014-04-17 Piramal Enterprises Limited Procédé amélioré de préparation d'un intermédiaire de périndopril
WO2016178591A2 (fr) 2015-05-05 2016-11-10 Gene Predit, Sa Marqueurs génétiques et traitement de l'obésité masculine

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US4914214A (en) * 1987-09-17 1990-04-03 Adir Et Cie Process for the industrial synthesis of perindopril
US20040248817A1 (en) * 2000-07-06 2004-12-09 Bruno Pfeiffer Gamma crystalline form of perindopril tert-butylamine salt
US6835843B2 (en) * 2000-04-06 2004-12-28 Les Laboratoires Servier Method for synthesis of perindopril and its pharmaceutically acceptable salts
WO2004113293A1 (fr) * 2003-06-24 2004-12-29 Les Laboratoires Servier Nouvelles formes cristallines de perindopril erbumine
US20050059609A1 (en) * 2000-07-06 2005-03-17 Bruno Pfeiffer New alpha crystalline form of perindopril tert-butylamine salt
WO2005037788A1 (fr) * 2003-10-21 2005-04-28 Lupin Ltd. Nouvelle methode de preparation de perindopril erbumine cristalline
WO2005108365A1 (fr) * 2004-05-07 2005-11-17 Glenmark Pharmaceuticals Limited Procedes de preparation d'une forme polymorphe alpha du perindopril erbumine
US20060178422A1 (en) * 2004-05-31 2006-08-10 Ashok Kumar Process for making (2S, 3aS, 7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl) butyl] amino]-1-oxopropyl] octahydro-1H-indole-2-carboxylic acid
WO2007020012A1 (fr) * 2005-08-12 2007-02-22 Lek Pharmaceuticals D.D. Procede de preparation de perindopril erbumine

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4914214A (en) * 1987-09-17 1990-04-03 Adir Et Cie Process for the industrial synthesis of perindopril
US6835843B2 (en) * 2000-04-06 2004-12-28 Les Laboratoires Servier Method for synthesis of perindopril and its pharmaceutically acceptable salts
US20040248817A1 (en) * 2000-07-06 2004-12-09 Bruno Pfeiffer Gamma crystalline form of perindopril tert-butylamine salt
US20050059609A1 (en) * 2000-07-06 2005-03-17 Bruno Pfeiffer New alpha crystalline form of perindopril tert-butylamine salt
WO2004113293A1 (fr) * 2003-06-24 2004-12-29 Les Laboratoires Servier Nouvelles formes cristallines de perindopril erbumine
WO2005037788A1 (fr) * 2003-10-21 2005-04-28 Lupin Ltd. Nouvelle methode de preparation de perindopril erbumine cristalline
WO2005108365A1 (fr) * 2004-05-07 2005-11-17 Glenmark Pharmaceuticals Limited Procedes de preparation d'une forme polymorphe alpha du perindopril erbumine
US20060178422A1 (en) * 2004-05-31 2006-08-10 Ashok Kumar Process for making (2S, 3aS, 7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl) butyl] amino]-1-oxopropyl] octahydro-1H-indole-2-carboxylic acid
WO2007020012A1 (fr) * 2005-08-12 2007-02-22 Lek Pharmaceuticals D.D. Procede de preparation de perindopril erbumine

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012044189A1 (fr) 2010-09-29 2012-04-05 Instituto Superior Técnico Forme cristalline hydratée inédite de l'erbumine de périndopril, ses procédés de préparation et son utilisation dans des préparations pharmaceutiques
WO2014057404A1 (fr) * 2012-10-10 2014-04-17 Piramal Enterprises Limited Procédé amélioré de préparation d'un intermédiaire de périndopril
WO2016178591A2 (fr) 2015-05-05 2016-11-10 Gene Predit, Sa Marqueurs génétiques et traitement de l'obésité masculine

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