WO2007054966A2 - A process for the preparation of highly pure crystalline quinapril hydrochloride - Google Patents

A process for the preparation of highly pure crystalline quinapril hydrochloride Download PDF

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Publication number
WO2007054966A2
WO2007054966A2 PCT/IN2006/000367 IN2006000367W WO2007054966A2 WO 2007054966 A2 WO2007054966 A2 WO 2007054966A2 IN 2006000367 W IN2006000367 W IN 2006000367W WO 2007054966 A2 WO2007054966 A2 WO 2007054966A2
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Prior art keywords
solution
quinapril
quinapril hydrochloride
crystalline
benzyl ester
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PCT/IN2006/000367
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French (fr)
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WO2007054966A3 (en
Inventor
Parimal Hasmukh Desai
Narendra Jagannath Salvi
Bharat Kumar Surendra Patravale
Seema Susheel Parab
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Aarti Healthcare Limited
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Publication of WO2007054966A2 publication Critical patent/WO2007054966A2/en
Publication of WO2007054966A3 publication Critical patent/WO2007054966A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the invention relates to a process for the preparation of highly pure crystalline quinapril hydrochloride of the formula (I);
  • the invention also relates to highly pure crystalline quinapril hydrochloride prepared by the above. 10. process.
  • Quinapril is chemically known as (3S)-2-[(2S)-2-[(lS)-l-(ethoxy carbonyl)-3- phenylpropyl]amino]-l-oxopropyl]-l,2,3,4 tetrahydro-3-isoquiolinecarboxylic acid. Its
  • hydrochloride salt of the formula (I) is active as angiotensin converting enzyme (ACE) inhibitors and is commercially important anti-hypertensive agent.
  • ACE angiotensin converting enzyme
  • Quinapril hydrochloride is generally available in two forms namely crystalline and amorphous. Crystalline form has improved stability as compared to amorphous form and hence improved storage life. Crystalline form is easy to handle and is desirable and preferable.
  • Quinapril was first disclosed in US 4,344,949 which describes a process for preparation of quinapril hydrochloride comprising deprotection of benzyl or t-butyl ester of quinapril by catalytic hydrogenolysis in the presence of the catalyst, 20 % Pd/C, at low pressure followed by isolation of quinapril hydrochloride by adding ether.
  • the benzyl or t- butyl ester of quinapril is unprotected by treatment with trifluoroacetic acid followed by treatment dry hydrogen chloride in dry ether and quinapril hydrochloride thus obtained is isolated by lyophilization of an aqueous solution.
  • the reaction scheme is illustrated herein below;
  • R ALkyl or Benzyl
  • Quinapril obtained by this process is .invariably contaminated with diketopiperazine derivative formed either during removal of the carboxylic acid protective group (i.e. deprotection by catalytic hydrogenolysis or treatment with trifluoroacetic acid) or during isolation of quinapril, as ⁇ quinapril degrades easily due to intramolecular cyclization to yield a diketopiperazine both in ' aqueous or organic solution as well as in the solid state. Diketopiperazine is difficult to be removed by conventional separation techniques, including fractional crystallization. Therefore isolation of quinapril is a very critical and difficult step in the manufacture of quinapril hydrochloride.
  • An object of the invention is to provide a process for the preparation of crystalline quinapril hydrochloride, which produces crystalline quinapril hydrochloride in good yield and high purity.
  • Another object of the invention is to provide a process for the preparation of crystalline quinapril hydrochloride, which is simple and easy to carry out and is efficient and economical and is f industrially feasible.
  • Another object of the invention is to provide a process for the preparation of crystalline quinapril hydrochloride, which reduces the process duration, formation of impurities like diketopiperazine and prevents degradation of the product.
  • Another object of the invention is to provide highly pure crystalline quinapril hydrochloride in good yield as obtained by the above process.
  • R Alkyl or Benzyl
  • Formula (II) by dissolving the benzyl ester in an alkyl nitrile solvent at 20 to 3O 0 C with stirring followed by cooling the solution to 0 to 5° C; adjusting the pH of the solution in the range of 0.6 to 0.9 with a 3 to 17% solution of hydrogen chloride in an organic solvent selected from dry ether or dry alkyl nitrile, the molar ratio of the benzyl ester of quinapril arid rydrogen chloride being 1.0:1.15 : to 1.0:1.35; subjecting the reaction mixture to 6 catalytic hydrogenolysis with hydrogen in the presence of 5 % Pd/C catalyst at a pressure of 40 psi to 150 psi and a temperature of 10 to 40° C to obtain quinapril hydrochloride of formula (I); removing the catalyst from the reaction mixture by filtration followed by removal of 50 % to 70 % of the solvent from the reaction mixture by distillation to obtain crystalline quinapril hydrochloride
  • the alkyl nitrile used to make the solution of the benzyl ester of quinapril is acetonitrile , or propionitrile or butyronitrile. More preferably the alkyl nitrile is acetonitrile.
  • the pH .. of the solution of the benzyl ester is adjusted to 0.8.
  • the pH of the solution of benzyl ester is adjusted preferably with a 11 % solution of hydrogen chloride.
  • the dry ether used to prepare the solution of hydrogen chloride is di-isopropyl ether.
  • the dry alley 1 nitrile used to prepare the solution of hydrogen chloride is acetontrile or propionitrile, preferably acetonitrile.
  • the crystalline quinapril hydrochloride is dried preferably in a vacuum oven.
  • benzyl ester of quinapril is prepared in known manner, for instance by the process reported in US 4,344,949 which comprises peptide condensation of ethyl ester of (S 5 S)-.
  • crystalline quinapril hydrochloride in high purity (about 99.5 % ) and in high yield ( about 85.5 %) prepared by the above process.
  • conversion of benzyl ester of quinapril to crystalline quinapril hydrochloride is of the order of 85.5 % and the process duration is reduced to the order of 20 to 24 hours.
  • Crystalline quinapril hydrochloride is obtained in high yield (about 85.5 %) and in high purity (about 99.7%).
  • Diketopiperazine impurity present in the quinapril hydrochloride is 7 reduced and is less than 0.2%.
  • Total impurity in the product is about 0.5 %.
  • the residual solvent, _acetonitrile, propionitrile or butyronitrile, present in the ⁇ crystalline quinapril hydrochloride isjn_ the range of 25.3 to 25.7 ppm, which is well below the acceptable limit (500ppm) as per the ICH guidelines.
  • the process of the invention is simple and easy to carry out, efficient and economical and is industrially feasible.
  • the high yield and high purity level of the product indicates that degradation of the product during the process is reduced. Due to the crystalline nature of the product it is stable and has improved storage life. Handling of the product is easy due to its improved stability.
  • the reaction mixture was further stirred for 1 hour while maintaining the same temperature.
  • the temperature of the reaction mixture was raised to 25° C and was transferred to a pressure vessel.
  • Example 1 The procedure of Example 1 was followed using propionitrile instead of acetonitrile to make the solution of benzyl ester of quinapril.
  • the yield and the purity of crystalline quinapril hydrochloride were 85.5 % and 99.6% Respectively.
  • Diketopiperazine and diacid contents in the product were 0.12 %._aoii_0. i lJL%_ respectively.
  • Residual propionitrile present in the crystalline quinapril hydrochloride was 25.7ppm, as quantified by chemical analysis.
  • Example 1 The procedure of Example 1 was followed using butyronitrile instead of acetonitrile to make the solution of benzyl ester of quinapril.
  • the yield and the purity of crystalline quinapril hydrochloride were 85.8 % and 99.5% respectively.
  • Diketopiperazine and diacid contents in the product were 0.11 % and 0.1 % respectively.
  • Residual butyronitrile present in the crystalline quinapril hydrochloride was 25.6ppm, as quantified by chemical analysis.
  • Example 1 The procedure of Example 1 was followed using acetonitrile instead of di-isopropyl ether to make the 11 % solution of hydrogen chloride.
  • the yield and the purity of crystalline quinapril hydrochloride were 85.9 % and 99.7% respectively.
  • Diketopiperazine and diacid contents in the product were 0.12 % and 0.1 % respectively.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

A simple, efficient and industrially feasible process for the preparation of crystalline quinapril hydrochloride in high purity and good yield is disclosed. A solution of benzyl ester of quinapril hydrochloride is prepared with an alkyl nitrile and is subjected to catalytic hydrogenolysis, after pH. adjustment of the solution to 0.8 to 1 by adding 3 to 17% solution of hydrogen chloride in dry ether or dry alkyl nitrile. The molar ratio of the benzyl ester of quinapril and hydrogen chloride is selected to be 1.0: 1.15: to 1.0: 1.35. Catalytic hydrogenolysis is carried out with hydrogen in the presence of Pd/C catalyst at a pressure of 40 to 150 psi and a temperature of 10-40° C. The solvent is distilled out to 50 to 70 % of its volume to obtain crystalline quinapril hydrochloride, which is washed with n-pentane and dried.

Description

TITLE OF THE INVENTION
A process for the preparation of highly pure crystalline quinapril hydrochloride
Technical Field:
5 The invention relates to a process for the preparation of highly pure crystalline quinapril hydrochloride of the formula (I);
Figure imgf000002_0001
Formula (I)
The invention also relates to highly pure crystalline quinapril hydrochloride prepared by the above. 10. process.
Background of Invention:
Quinapril is chemically known as (3S)-2-[(2S)-2-[(lS)-l-(ethoxy carbonyl)-3- phenylpropyl]amino]-l-oxopropyl]-l,2,3,4 tetrahydro-3-isoquiolinecarboxylic acid. Its
15 pharmaceutically acceptable salts, especially the hydrochloride salt of the formula (I) is active as angiotensin converting enzyme (ACE) inhibitors and is commercially important anti-hypertensive agent. Quinapril hydrochloride is generally available in two forms namely crystalline and amorphous. Crystalline form has improved stability as compared to amorphous form and hence improved storage life. Crystalline form is easy to handle and is desirable and preferable. 0
Quinapril was first disclosed in US 4,344,949 which describes a process for preparation of quinapril hydrochloride comprising deprotection of benzyl or t-butyl ester of quinapril by catalytic hydrogenolysis in the presence of the catalyst, 20 % Pd/C, at low pressure followed by isolation of quinapril hydrochloride by adding ether. Alternatively the benzyl or t- butyl ester of quinapril is unprotected by treatment with trifluoroacetic acid followed by treatment dry hydrogen chloride in dry ether and quinapril hydrochloride thus obtained is isolated by lyophilization of an aqueous solution. The reaction scheme is illustrated herein below;
Figure imgf000003_0001
Wherein. R = ALkyl or Benzyl
Quinapril obtained by this process is .invariably contaminated with diketopiperazine derivative formed either during removal of the carboxylic acid protective group (i.e. deprotection by catalytic hydrogenolysis or treatment with trifluoroacetic acid) or during isolation of quinapril, as^ quinapril degrades easily due to intramolecular cyclization to yield a diketopiperazine both in ' aqueous or organic solution as well as in the solid state. Diketopiperazine is difficult to be removed by conventional separation techniques, including fractional crystallization. Therefore isolation of quinapril is a very critical and difficult step in the manufacture of quinapril hydrochloride. 4 treatment with aqueous or anhydrous hydrogen chloride in the presence of aprotic or protic solvents to yield quinapril hydrochloride in solution, which is converted into acetone solvate and subsequently re-crystallized with acetonitrile. On re-crystallization acetonitrile solvate of quinapril hydrochloride is obtained. The solvate is dried to obtain amorphous quinapril hydrochloride. This process is complicated and time consuming as two solvates are necessary to' get pure compound.
The prior art processes for the preparation of crystalline quinapril hydrochloride are generally associated with lengthy and cumbersome procedures and are time consuming, costly and difficult to be carried out. The crude product formed is converted into solvates and purified by crystallization and then dried. Some of the solvents used are also unsafe and difficult to handle.
I ,
_As a result of formation of impurities like diketopiperazine due to intramolecular cyclization
H
(aminolysis) of quinapril or its benzyl ester there is considerable loss of yield of the product. For the reasons stated above, the prior art processes are also not in general suitable for commercial of industrial scale production of quinapril hydrochloride.
Object of the invention:
An object of the invention is to provide a process for the preparation of crystalline quinapril hydrochloride, which produces crystalline quinapril hydrochloride in good yield and high purity.
Another object of the invention is to provide a process for the preparation of crystalline quinapril hydrochloride, which is simple and easy to carry out and is efficient and economical and is f industrially feasible.
Another object of the invention is to provide a process for the preparation of crystalline quinapril hydrochloride, which reduces the process duration, formation of impurities like diketopiperazine and prevents degradation of the product. Another object of the invention is to provide highly pure crystalline quinapril hydrochloride in good yield as obtained by the above process.
Detailed Description of the Invention:
Recording to the invention there is provided a process for the preparation of crystalline quinapril >,> hydrochloride of the formula (I)
Figure imgf000005_0001
Formula (I) comprising the following steps :
making a solution of benzyl ester of quinapril of the formula II
Figure imgf000005_0002
Wherein R = Alkyl or Benzyl
Formula (II) by dissolving the benzyl ester in an alkyl nitrile solvent at 20 to 3O0C with stirring followed by cooling the solution to 0 to 5° C; adjusting the pH of the solution in the range of 0.6 to 0.9 with a 3 to 17% solution of hydrogen chloride in an organic solvent selected from dry ether or dry alkyl nitrile, the molar ratio of the benzyl ester of quinapril arid rydrogen chloride being 1.0:1.15 : to 1.0:1.35; subjecting the reaction mixture to 6 catalytic hydrogenolysis with hydrogen in the presence of 5 % Pd/C catalyst at a pressure of 40 psi to 150 psi and a temperature of 10 to 40° C to obtain quinapril hydrochloride of formula (I); removing the catalyst from the reaction mixture by filtration followed by removal of 50 % to 70 % of the solvent from the reaction mixture by distillation to obtain crystalline quinapril hydrochloride; and washing the crystalline quinapril hydrochloride with n-pentane and drying the same at 60 to 650C.
Preferably the alkyl nitrile used to make the solution of the benzyl ester of quinapril is acetonitrile , or propionitrile or butyronitrile. More preferably the alkyl nitrile is acetonitrile. Preferably, the pH .. of the solution of the benzyl ester is adjusted to 0.8. The pH of the solution of benzyl ester is adjusted preferably with a 11 % solution of hydrogen chloride. The dry ether used to prepare the solution of hydrogen chloride is di-isopropyl ether. The dry alley 1 nitrile used to prepare the solution of hydrogen chloride is acetontrile or propionitrile, preferably acetonitrile. The crystalline quinapril hydrochloride is dried preferably in a vacuum oven. -
The starting material, benzyl ester of quinapril is prepared in known manner, for instance by the process reported in US 4,344,949 which comprises peptide condensation of ethyl ester of (S5S)-.
•tif alpha -[(1- carboxyethyl) amino] phenylbutanoic acid with benzyl or t-butyl ester of (S)- 1,2,3 ,4j tetrahydro -3-isoquinolinecarboxylic acid in the presence of dicyclohexyl- carbodimide (DCQ and hydroxybenzotriazole.
According to the invention there is also provided crystalline quinapril hydrochloride in high purity (about 99.5 % ) and in high yield ( about 85.5 %) prepared by the above process.
According to the invention conversion of benzyl ester of quinapril to crystalline quinapril hydrochloride is of the order of 85.5 % and the process duration is reduced to the order of 20 to 24 hours. Crystalline quinapril hydrochloride is obtained in high yield (about 85.5 %) and in high purity (about 99.7%). Diketopiperazine impurity present in the quinapril hydrochloride is 7 reduced and is less than 0.2%. Total impurity in the product is about 0.5 %. The residual solvent, _acetonitrile, propionitrile or butyronitrile, present in the<crystalline quinapril hydrochloride, isjn_ the range of 25.3 to 25.7 ppm, which is well below the acceptable limit (500ppm) as per the ICH guidelines. The process of the invention is simple and easy to carry out, efficient and economical and is industrially feasible. The high yield and high purity level of the product indicates that degradation of the product during the process is reduced. Due to the crystalline nature of the product it is stable and has improved storage life. Handling of the product is easy due to its improved stability.
The following experimental examples are illustrative of the invention but not limitative of the scope thereof.
Example 1
To 1.55 Kg of benzyl ester of quinapril, 8.5 lit of acetonitrile was added at 25° C while stirring. The reaction mixture was cooled to 0 to 5° C and its pH was adjusted to 0.8-0.9 by adding 11% solution of hydrogen chloride in di-isopropyl ether while maintaining the temperature at 0 to 5° C.
The reaction mixture was further stirred for 1 hour while maintaining the same temperature. The temperature of the reaction mixture was raised to 25° C and was transferred to a pressure vessel.
To this, 150 gms of 5% Pd/C was added. The reaction mixture was flushed with nitrogen and then with hydrogen. The hydrogenolysis was carried out at 30° C and pressure of 60 psi for 20 hrs.
Figure imgf000007_0001
reaction was monitored by HPLC. The catalyst was filtered out from the reaction mixture followed by distillation of the acetonitrile to half of it's volume. The crystalline product was filtered, washed with n-pentane and dried at 60° C in vacuum oven (at 20 mm of Hg) for 48hours: The yield and the purity of crystalline quinapril hydrochloride were 86 % and 99.7% respectively. Diketopiperazine and diacid contents in the product were 0.12 % and 0.1 % respectively. Residual acetonitrile present in the crystalline quinapril hydrochloride was 25.3 ppm, as quantified by chemical analysis. Example 2
The procedure of Example 1 was followed using propionitrile instead of acetonitrile to make the solution of benzyl ester of quinapril. The yield and the purity of crystalline quinapril hydrochloride were 85.5 % and 99.6% Respectively. Diketopiperazine and diacid contents in the product were 0.12 %._aoii_0.ilJL%_ respectively. Residual propionitrile present in the crystalline quinapril hydrochloride was 25.7ppm, as quantified by chemical analysis.
Example 3
The procedure of Example 1 was followed using butyronitrile instead of acetonitrile to make the solution of benzyl ester of quinapril.
The yield and the purity of crystalline quinapril hydrochloride were 85.8 % and 99.5% respectively. Diketopiperazine and diacid contents in the product were 0.11 % and 0.1 % respectively. Residual butyronitrile present in the crystalline quinapril hydrochloride was 25.6ppm, as quantified by chemical analysis.
Example 4
The procedure of Example 1 was followed using acetonitrile instead of di-isopropyl ether to make the 11 % solution of hydrogen chloride. i
The yield and the purity of crystalline quinapril hydrochloride were 85.9 % and 99.7% respectively. Diketopiperazine and diacid contents in the product were 0.12 % and 0.1 % respectively. Residual acetonitrile present in the crystalline quinapril hydrochloride wafe 25.4ppm, as quantified by chemical analysis.

Claims

CLAIMS :
1. A process for the preparation of crystalline quinapril hydrochloride of the formula (I)
Figure imgf000009_0001
Formula (I) comprising the following steps :
making a solution of benzyl ester of quinapril of the formula II
Figure imgf000009_0002
Wherein R = Alkyl or Benzyl
Foπnula (II) by dissolving the benzyl ester in an alkyl nitrile solvent at 20 to 3O0C with stirring followed by cooling the solution to 0 to 5° C; adjusting the pH of the solution in the range of 0.6 to 0.9 with a 3 to 17% solution of hydrogen chloride in an organic solvent selected from dry ether or dry alkyl nitrile, the molar ratio of the benzyl ester of quinapril and hydrogen chloride being 1.0:1.15 : to 1.0:1.35; subjecting the reaction mixture to catalytic hydrogeno lysis with hydrogen in the presence of 5 % Pd/C catalyst at a pressure of 40 psi to 150 psi and a temperature of 10 to 40° C to obtain quinapril hydrochloride of foπnula (I); removing the catalyst from the reaction mixture by filtration followed by removal of 10
50 % to 70 % of the solvent from the reaction mixture by distillation to obtain crystalline quinapril hydrochloride; and washing the crystalline quinapril hydrochloride with n- pentane and drying the same at 60 to 650C.
2. The process as claimed' in claim 1, wherein the alkyl nitrile used to make the solution of the benzyl ester of quinapril is acetonitrile or propionitrile or butyronitrile, preferably acetonitrile.
3. The process as claimed in claim 1, wherein the pH of the solution of the benzyl ester is adjusted preferably to 0.8.
4. The process as claimed in claim 1, wherein the pH of the solution of benzyl ester is adjusted preferably with a 11 % solution of hydrogen chloride.
5. The process as claimed in claim 1, wherein the dry ether used to prepare the solution of hydrogen chloride is di-isopropyl ether.
6. The process as claimed in claiml, wherein the dry alkyl nitrile used to prepare the solution of hydrogen chloride is acetontrile or propionitrile, preferably acetonitrile.
7. The process as claimed in any one of the claims 1 to 6, wherein the crystalline quinapril hydrochloride is dried in a vacuum oven.
8. Crystalline quinapril hydrochloride in high purity (about 99.7 %) and high yield (about 85.5 %) prepared by the process as claimed in any of the claims 1 to 7.
PCT/IN2006/000367 2005-09-13 2006-09-13 A process for the preparation of highly pure crystalline quinapril hydrochloride WO2007054966A2 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4037960A1 (en) * 1990-11-29 1992-06-04 Goedecke Ag Aminoacid derivs. prepn. which are ACE inhibitors - by selective hydrolysis of benzyl ester using aluminium chloride, condensing the prod. with another benzyl ester and then hydrogenating
EP0992495A1 (en) * 1997-05-29 2000-04-12 Esteve Quimica, S.A. Process for obtaining quinapryl hydrochloride and solvates useful for isolating and purifying quinapryl hydrochloride

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4037960A1 (en) * 1990-11-29 1992-06-04 Goedecke Ag Aminoacid derivs. prepn. which are ACE inhibitors - by selective hydrolysis of benzyl ester using aluminium chloride, condensing the prod. with another benzyl ester and then hydrogenating
EP0992495A1 (en) * 1997-05-29 2000-04-12 Esteve Quimica, S.A. Process for obtaining quinapryl hydrochloride and solvates useful for isolating and purifying quinapryl hydrochloride

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