WO2008114270A1 - Process for the preparation of perindopril erbumine salt and novel polymorph (s) thereof - Google Patents
Process for the preparation of perindopril erbumine salt and novel polymorph (s) thereof Download PDFInfo
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- 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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- 0 CCCC(*)NC(C)C(N(C(C1)C(O)=O)C2C1CCCC2)=O Chemical compound CCCC(*)NC(C)C(N(C(C1)C(O)=O)C2C1CCCC2)=O 0.000 description 2
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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
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- 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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Abstract
A single pot process for the preparation of perindopril erbumine salt according to which condensation of (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid benzyl ester para toluene sulfonate with N-((S-)-ethoxy carbonyl -1-ethyl-(S)-alanine, catalytic hydrogenation of benzyl ester of (2S, 3aS, 7aS)-1-{2-[1-(ethoxycarbonyl)-(S)-butylamino]-(S)propionyl}- octahydro-indole-2-carboxylate and conversion of (2S,3aS, 7aS)-1-{2-[1-ethoxycarbonyl)_(S)-butylamino]-(S)-propionyl}octahydroindole-2-carboxylic acid to its perindopril erbumine salt are carried out in a single pot using a single solvent such as isopropyl acetate to obtain perindopril erbumine salt of very high purity. Also a novel polymorph S of perindopril erbumine having X-ray diffraction peaks of 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 at 2Θ values. Also processes for preparing the novel polymorph S.
Description
TITLE OF THE INVENTION
PROCESS FOR THE PREPARATION OF PERINDOPRIL ERBUMINE SALT AND NOVEL POLYMORPH (S) THEREOF
Field of invention:
The present invention relates to a single pot process for the preparation of perindopril erbumine salt of the formula (I).
Formula (I)
The present invention also relates to novel polymorph S of perindopril erbumine salt and processes for the preparation thereof
Background of Invention: 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).
It is a long lasting ACE inhibitor. 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,
Formula (III) Formula (IV)
1-hydroxybenzotriazole and dicyclohexylcarbodiimide to obtain Benzyl (2S, 3aS, 7aS)-l-{2- [l~(ethoxycarbonyl)-(S)-butyl amino ]-(S)propionyl}octahydroindole-2-carboxylate of the formula (II);
Formula (II) which is hydrogenated in the presence of the catalyst 5% Pd on charcoal to obtain (2S,3aS, 7aS)- 1 - { 2-[ 1 -ethoxycarbonyl)-(S)-butylamino] -(S)-propionyl } octahydroindole-2-carboxylic acid (i.e perindorpil acid) of the formula (V).
Formula (V)
The above product is isolated by freeze drying which is a very costly method. The perindopril is further converted into erburaine salt by treating it with tert-butyl amine in ethyl acetate at refluxed temperature followed by cooling. All the intermediates are necessarily isolated in the above process.
US 6835843 discloses a process for industrial synthesis of perindopril and its pharmaceutically acceptable salts. In the above process, (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)propionyl}octahydroindole-2-carboxylate of the formula (II) with lower acetyl impurities which are formed due to use of ethyl acetate. 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. 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.
Another method for preparing the perindopril erbumine is disclosed in US 20060178422 which discusses the problem associated with the process of US 6835843 as that the use of ethyl acetate as a solvent in the coupling step leads to formation of one major impurity namely; N-acetyl(2S, 3aS, 7aS)-2-carboxyoctahydroindole-2-carboxylic acid benzyl ester. Formation of the above impurity has been identified to be associated with the use of ethyl acetate as solvent as it acts as acetylating agent. Removal of the impurity is very difficult as the physical properties of the impurity and those of the coupled product of the formula (II) are the same. Removal of the above impurity is very difficult in the next step of debenzylation also as the impurity gets debenzylated to form N-acetyl(2S, 3aS, 7aS)-2- carboxyoctahydroindole-2-carboxylic acid which has the same physical properties as that of the product of the formula (V). Thus the perindopril erbumine salt is invariably contaminated with the N-acetyl impurity. The above mentioned US publication discloses a process for the preparation of perindopril erbumine salt that is free of N-acetyl impurity and dicyclohexyl impurity. (2S, 3aS, 7aS)-2-carboxyoctahydroindole-2-carboxylic acid benzyl ester para toluene sulfonate of the formula (III) is condensed with N((S)-ethoxy carbonyl -1 -ethyl)-
(S)alanine of the formula (IV) (1 to 1.2 moles) in the presence of 1 to 1.2 moles of 1- hydroxybenzotriazole, 1 to 1.2 moles of dicyclohexylcarbodiimide and 1 to 3 moles of triethyl amine in a non-reactive solvent other than ethyl acetate. 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). However 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. Thus the intermediates are isolated and recrystallised to achieve the purity of salt to 99 %.
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. Thus the intermediate benzyl ester is isolated and recrystallised.
All the above prior art processes disclose the preparation of perindopril erbumine of the formula (I) by condensation of (2S, 3aS, 7aS)-2-carboxyoctahydroindole-2-carboxylic acid benzyl ester para toluene sulfonate of the formula (III) with N((S)-ethoxy carbonyl -1-ethyl)- (S)alanine of the formula (IV), debenzylation of Benzyl (2S, 3aS, 7aS)-l-{2-[l- (ethoxycarbonyl)-(S)-butyl amino ]-(S)propionyl}octahydroindole-2-carboxylate of the formula (II) by catalytic hydrogenation and further conversion of perindopril acid into perindopril erbumine salt of the formula (I) by treatment with tert-butyl amine. The intermediates are isolated and recrystallized to obtain pure erbumine salt. Further different solvents are used in each step.
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.
A 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 2Θ.
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 2Θ. 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 2Θ. 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 2Θ.
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 2Θ. 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 2Θ.
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.
Object of the invention:
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.
Detailed Description of the invention:
1) According to the present invention, there is provided by a single pot process for the preparation of perindopril erbumine salt of the formula (I);
Formula (I)
the process comprising; a) preparing a benzyl ester of (2S, 3aS, 7aS)-l-{2-[l-(ethoxycarbonyl)~(S)- butylamino]-(S)propionyl}-octahydro-indole-2-carboxylic acid of the formula
(II):
Formula II by condensing (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid benzyl ester para toluene sulfonate of the formula (III) with N-((S-)-ethoxy carbonyl -1- ethyl-(S)-alanine of the formula (IV):
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
50 % volume to obtain a concentrated filtrate comprising the compound of the formula (II);
b preparing (2S,3aS, 7aS)-l-{2-[l-ethoxycarbonyl)_(S)-butylamino]-(S)- propionyl}octahydroindole-2-carboxylic acid of formula (V);
Formula (V)
by hydrogenating the concentrated filtrate comprising the compound of formula (II) in the presence of 5% Pd/C under a hydrogen pressure of 50 psi and at temperatures in the range of 20 - 25° C, removing the catalyst from the reaction mixture by filtration to obtain filtrate comprising the compound of formula (V); and
c. preparing the perindopril erbumine salt of formula (I) by treating the filtrate comprising the compound of formula (V) with tert-butyl amine at temperature in the range of 68-70 °C to obtain clear solution; cooling the reaction mixture to temperature in the range of 15-20°C with stirring to precipitate out the perindopril erbumine of formula (I) and isolating the perindopril erbumine of formula (I) by filtration followed by drying at temperatures in the range of 45-
50°C under vacuum.
The compound of the formula (I) is dried in step (c) for a period of about 8 hours.
According to the invention there is also provided a novel polymorph S of perindopril erbumine having the following X-ray diffraction pattern,
According to the present invention there is also provided 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.
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
According to the invention there is also provided 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.
According to the invention there is also provided 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
According to the invention 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.
Example 1
a) Preparation of perindopril erbumine of formula (I) using isopropyl acetate
(2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid benzyl ester para-toluene sulfonate (50 gms) was condensed with N-((S-)-ethoxy carbonyl -l-ethyl-(S)-alanine (26.5 grn) in 500ml of isopropyl acetate as a solvent, triethylamine (14.00 gm), 1-hydroxybenzotriazole (16.50 gms) and dicyclohexylcarbodimide (25.00 gms) at temperature of 25°C with stirring. The reaction completion was monitored by TLC. Once the reaction was complete, 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. To the filtrate, 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 hrs. Yield = 75% Purity = 99.85% N-acetyl impurity : 0.07 to 0.08 %
b ) Comparative Example
Preparation of perindopril erbumine of formula (I) using ethyl acetate
(2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid benzyl ester para-toluene sulfonate (50 gms) was condensed with N-((S-)-ethoxy carbonyl -l-ethyl-(S)-alanine (26.50 gm) in 500ml of ethyl acetate as a solvent, triethylamine (14.00 gm), 1-hydroxybenzotriazole (16.50 gms) and dicyclohexylcarbodimide (25.00 gms) at temperature of 25°C with stirring. The reaction completion was monitored by TLC. Once the reaction was complete, 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. To the filtrate, 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.
Yield = 70 % Purity = 99.1 % N-acetyl impurity : 0.38 %
Example 2 Polymorph S of Perindopril erbumine
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,
Polymorph S of Perindopril erbumine
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.
Yield : 88 %
Purity 99.76%
X-ray Diffraction pattern of the polymorph S is as follows,
Example 4
Polymorph S of Perindopril erbumine
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.
Yield :80 % Purity : 99.75%
X-ray Diffraction pattern of the polymorph S is as follows,
Example 5
Polymorph S of Perindopril erbumine
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.
Yield : 85 %
Purity : 99.75%
X-ray Diffraction pattern of the polymorph S is as follows,
Claims
CLAIMS :
1) A single pot process for the preparation of pcrindopril erbumine salt of the formula
(I);
Formula (1)
the process comprising; a) preparing a benzyl ester of (2S, 3aS, 7aS)-l-{2-[l-(ethoxycarbonyl)-(S)- butylamino]-(S)propionyI}-octahydro-iπdole-2-carboxylic acid of the formula
(II):
Formula II by condensing (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid benzyl ester para toluene sulfonate of the formula (III) with N-((S-)-ethoxy carbonyl -1- ethyl-(S)-alaninc of the formula (IV):
Formula (IIT) Formula (IV) in the presence of isopropyl acetate as a solvent and Lriethylamine, 1- hydroxybenzotriazole and dicyclohexylcarbodiimide at tempcraliires 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 50 % volume to obtain a concentrated filtrate comprising the compound of the formula (II); b preparing (2S,3aS, 7aS)-l-{2-ri-ethoxycarbonyl)_(S)-butylaminol-(S)- propionyl}octahydroindolc-2-carboxylic acid of formula (V);
Formula (V)
by hydrogenating the concentrated filtrate comprising the compound of formula (II) in the presence of 5% Pd/C under a hydrogen pressure of 50 psi and at temperatures in the range of 20 - 25° C, removing the catalyst from the reaction mixture by filtration to obtain filtrate comprising the compound of formula (V); and c. preparing the perindopril erbumine salt of formula (I) by treating the filtrate comprising the compound of formula (V) with tcrt-butyl amine at temperature in Lhe range of 68-70'C to obtain clear solution; cooling the reaction mixture tυ temperature in the range of 15-2O*C with stirring Io precipitate out the perindopril erbumine of formula (1) and isolating the perindopril erbumine of formula (I) by filtration followed by drying at temperatures in the range of 45-
50°C under vacuum.
2) A novel polymorph S of perindopril erbumine having the following X-ray diffraction pattern,
3) A process for the preparation of the novel polymorph S of perindopril erbumine, the process comprising 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, 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.
4) The process as claimed in claim 3, wherein preferably the process comprising 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 60-80°C, adding the hot solution of perindopril erbumine into a pre-cooled solvent such n-hexane or methyl ethyl ketone at temperature to 0°C, stirring the reaction mixture at temperature in the range of 0°C to precipitate out the polymorph S and isolating the polymorph S by filtration folloAved by drying at 30°C under vacuum for 7 days.
5) A process for the preparation of the novel polymorph S of perindopril erbumine, the process comprising dissolving perindopril erbumine of formula (I) in 3-pentanone at a
temperature in the range of 65-70°C tQ 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.
5 6) The process as claimed in claim 5, wherein preferably the process comprising dissolving perindopril erbumiiie of formula (I) in 3-pentaαone at a temperature in (he range of 68°C to obtain a clear solution, cooling the solution rapidly to 0"C with stirring to precipitate out the polymorph S and isolating the polymorph S by filtration followed by drying at 30°C under vacuum for 4 days.
10
T) A process for the preparation of the novel polymorph S of perindopril erbuminc, the process comprising dissolving the compound of 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 lhe range of 60-65°C, cooling the clear
I S solution to temperature in range of 15-2O°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.
8) The process as claimed in 7, wherein the polymorph S is preferably dried at 30°C 0 under vacuum for 7 days.
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| EP07827487A EP2137148A1 (en) | 2007-03-22 | 2007-03-22 | Process for the preparation of perindopril erbumine salt and novel polymorph (s) thereof |
| PCT/IN2007/000120 WO2008114270A1 (en) | 2007-03-22 | 2007-03-22 | Process for the preparation of perindopril erbumine salt and novel polymorph (s) thereof |
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| PCT/IN2007/000120 WO2008114270A1 (en) | 2007-03-22 | 2007-03-22 | Process for the preparation of perindopril erbumine salt and novel polymorph (s) thereof |
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| WO2012044189A1 (en) | 2010-09-29 | 2012-04-05 | Instituto Superior Técnico | A new hydrated crystalline form of perindopril erbumine, methods for its preparation and its use in pharmaceutical preparations |
| WO2014057404A1 (en) * | 2012-10-10 | 2014-04-17 | Piramal Enterprises Limited | An improved process for preparation of perindopril intermediate |
| WO2016178591A2 (en) | 2015-05-05 | 2016-11-10 | Gene Predit, Sa | Genetic markers and treatment of male obesity |
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| 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 (en) * | 2003-06-24 | 2004-12-29 | Les Laboratoires Servier | Novel crystalline forms of perindopril erbumine |
| WO2005037788A1 (en) * | 2003-10-21 | 2005-04-28 | Lupin Ltd. | Novel method for preparation of crystalline perindopril erbumine |
| WO2005108365A1 (en) * | 2004-05-07 | 2005-11-17 | Glenmark Pharmaceuticals Limited | Processes for the preparation of alpha polymorph of 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 (en) * | 2005-08-12 | 2007-02-22 | Lek Pharmaceuticals D.D. | A process for the preparation of perindopril erbumine |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012044189A1 (en) | 2010-09-29 | 2012-04-05 | Instituto Superior Técnico | A new hydrated crystalline form of perindopril erbumine, methods for its preparation and its use in pharmaceutical preparations |
| WO2014057404A1 (en) * | 2012-10-10 | 2014-04-17 | Piramal Enterprises Limited | An improved process for preparation of perindopril intermediate |
| WO2016178591A2 (en) | 2015-05-05 | 2016-11-10 | Gene Predit, Sa | Genetic markers and treatment of male obesity |
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| EP2137148A1 (en) | 2009-12-30 |
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