WO2006003671A1 - Procede de dedoublement de methylamino(2-chlorophenyl)acetate - Google Patents

Procede de dedoublement de methylamino(2-chlorophenyl)acetate Download PDF

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Publication number
WO2006003671A1
WO2006003671A1 PCT/IN2004/000193 IN2004000193W WO2006003671A1 WO 2006003671 A1 WO2006003671 A1 WO 2006003671A1 IN 2004000193 W IN2004000193 W IN 2004000193W WO 2006003671 A1 WO2006003671 A1 WO 2006003671A1
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WIPO (PCT)
Prior art keywords
methyl
acetate
chlorophenyl
acetone
resolution
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PCT/IN2004/000193
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English (en)
Inventor
Srinivasa Reddy Battula
Original Assignee
Srinivasa Reddy Battula
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Application filed by Srinivasa Reddy Battula filed Critical Srinivasa Reddy Battula
Priority to PCT/IN2004/000193 priority Critical patent/WO2006003671A1/fr
Publication of WO2006003671A1 publication Critical patent/WO2006003671A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/34—Preparation of optical isomers by separation of optical isomers

Definitions

  • the present invention relates to a highly efficient resolution process for 2-substituted phenyl glycine esters and/or acids, a valuable intermediate for the preparation of highly active antiplatelet aggregatory compounds known as clopidogrel
  • the present invention relates ' to a process for the preparation of 2- substituted phenylglycine esters and acids of formula -I in high yield which is a valuable intermediate for the synthesis of highly active anti platelet aggregation drug clopidogrel and also a valuable unnatural amino acids for different biochemical activities.
  • R H, alkyl(methyl,ethyl,propyl,isopropyl,butyl, phenyl)
  • the 2- substituted phenylglycine like2-chloiOphenylglycine has attained commercial importance recently because of the success of clopidogrel an anti platelet drug. This compound is reported to be resolved using with camphor sulphonic acid or tartaric acid.
  • US 5,204,469 teaches preparation of racemic methyl alpha-(4,5,6,7-tetrahydro-5- thieno[3,2c]pyridil)(2-chlorophenyl) acetate, one of whose isomers is clopidogrel which is a useful platelet anti aggregating and anti thrombotic agent, by reacting a formylating agent with methyl alpha-(2-thienylethylamino) methyl alpha-amino(2-chlorophenyl) acetate.
  • This methyl alpha- (2-thienylethylamino) methyl alpha-amino (2-chlorophenyl) acetate is formed from reaction of methyl alpha amino (2-chlorophenyl) acetate with thienyl derivative.
  • This art teaches the resolving the racemic methyl alpha amino (2-chlorophenyl) acetate using tartaric acid, acetonitrile and methyl ethyl ketone as solvents at about 60 0 C. the compound is purified with acetonitrile and methanol. The yield is about 45.79%.
  • Clopidogrel is an effective antiplatelet drug and already attained a status of "block buster drug" there is a need for a novel efficient and high yielding process which can overcome the above problems.
  • the main object of the present invention is to provide a resolution process for 2- substituted phenyl glycine esters and /or acids involving asymmetric transformation of diasteriomeric salts.
  • a further object of the present invention is to provide a resolution process for 2-substituted phenyl glycine esters and acids so as to provide a high yield of the compound even at low temperatures.
  • process of present invention involves conversion of undesired isomer also in situ to desired isomeric form thus utilizing both the isomers.
  • the use of both the isomers gives yield of at least 86%.
  • the present inventors have found a process of efficient resolution with high yield by using the technique asymmetric transformation of diastereomeric salts in situ to isomeric required form.
  • the racemic form is converted into the isomeric form using tartaric acid in defined ratio' with the racemic salt in presence of solvents acetone and methanol in defined amount.
  • the acetone used forms an intermediate with the unwanted isomer, which is converted to the racemic form by tartaric acid.
  • both the desired and undesired isomers are resolved to give high yields of (+) tartrate salts of 2-substituted phenylglycine esters and/or acids. More over the temperature used for the resolution with acetone and methanol varies from 15 to 25°C, preferably 20 0 C for 25 to 35 minutes, preferably 30 minutes when crystallization occurs. The temperature of reaction is then raised to 28-32° C, preferably 30 0 C and maintained for about 16 to 24 hrs, preferably 20 hours.
  • the resolution process is preferably carried out with the selective solvent mixture of methanol and acetone in the ratio of 4:5.
  • the resolution process of the present invention provides a yield above 86% It is believed that acetone forms an "imine" in situ with chlorophenylglycine methyl ester of the undesired isomer which in the presence of tartaric acid gets converted in to a racemic isomer. The racemic isomer is resolved further. Thus total conversion of Dextro-Levo mixture to only isomeric form is called asymmetric transformation of diasteromeric salts.
  • the ratio of the ester and/ or acid and tartaric acid used varies 0.9 to 1.4, preferably 1 : 1.1. On increasing or decreasing the molar ratio of tartaric acid with respect to the ester the yield is less and the quality of the product is also poor.
  • Both the solvents are used for the reaction .
  • the solvents required for the process are in defined ratios.
  • the ester and / or acid is dissolved in acetone and added to the solution of tartaric acid in methanol.
  • the reaction is not favorable if it is started with, premixed solvents (acetone and methanol mixture).
  • the combination of methanol and acetone in the selected ratio only help the reaction to go to completion with highest yield.
  • Methanol was replaced by ethanol and iso propyl alcohol. In case of ethanol yields are low, with iso propyl alcohol reaction completed only 50% after 40 hours of the reaction time.
  • (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl)acetate A solution of racemic methyl alpha-amino (2-chlorophenyl) acetate 199.5 gms, ( 1 mole) in 960 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms, ( 1.1 mole, 1.1 eq on ester) in 790 ml methanol at 20 0 C and maintained at 20 0 C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick, slurry. Temperature of the reaction mass was raised to 30 0 C and maintained 28-32 0 C for 20 hours under stirring.
  • Example 1 B methyl(+)-aIpha amino (2-chlorophenyI)acetate :
  • (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate of above example 2A was dissolved in 720-ml methylene chloride and cooled to 10 0 C .
  • Example 3A The process illustrated in Examples 1 and 2 provides 2-substituted phenylglycine esters with yield of over 86 % and 68.5% respectively at low and high temperatures by the use of the acetate and tartaric acid at defined ratio in solvents acetone and methanol at definite ratio.
  • Example 3A The process illustrated in Examples 1 and 2 provides 2-substituted phenylglycine esters with yield of over 86 % and 68.5% respectively at low and high temperatures by the use of the acetate and tartaric acid at defined ratio in solvents acetone and methanol at definite ratio.
  • Example 3A Example 3A:
  • (+)-tartrate of methyl (+)-a!pha amino(2-chlorophenyl)acetate
  • (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl)acetate
  • (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl)acetate
  • (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl)acetate A solution of racemic methyl alpha-amino (2-chlorophenyl) acetate 199.5 gms, (1 mole) in 960 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 150 gms, (1.0 mole) in 790 ml methanol at 20 0 C and maintained at 20 0 C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 0 C and maintained 28-32 0 C for 20 hours under stirring.
  • (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate of above example 7A was dissolved in 900 ml methylene chloride and cooled to 10 0 C .
  • D.M.- water 1200 ml was added at 10 0 C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle for 30 minutes and I O layers were separated.
  • Methyl chloride was removed by distillation under vacuume resulting oil of methyl(+)-alpha amino(2-chlorophenyl)acetate, G. C : 99% [ cc ] D +135.0 ( )
  • Example 9 (+)-tartvate of methyl (+)-alpha amino(2-chlorophenyl)acetate-.
  • (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate
  • Example 10 B methyl(+)-alpha amino(2-chlorophenyl)acetate : (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate of above example 1OA was dissolved in 900 ml methylene chloride and cooled to 10 0 C .
  • D.M. water 1200 ml was added at 10 0 C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle For 30 minutes and layers were separated.
  • (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate
  • Example H B methyl(+)-alpha amino(2-chlorophenyl)acetate : (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate of above example 1 1 A was dissolved in 900 ml methylene chloride and cooled to 10 0 C . D. M. water 1200 ml was added at 10 0 C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle for 30 minutes and layers were separated.
  • (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, ( 1 mole ) in 1000 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms,( 1.1 mole, 1.1 eq on ester) in 800 ml acetone at 20 0 C and maintained at 20 0 C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 "C and maintained 28-32 0 C for 20 hours under stirring.
  • (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in
  • (+)-tartrate of methy](+)-alpha amino(2-chlorophenyl)acetate of above example 13A was dissolved in 900 ml methylene chloride and cooled to 10 0 C .
  • D.M. water 1200 ml was added at 10 "C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle for 30 minutes and layers were separated.
  • (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate
  • Example 14 B methyl(+)-alpha amino(2-chlorophenyl)acetate : (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate of above example 14A was dissolved in 900 ml methylene chloride and cooled to 10 0 C . D.M. water 1200 ml was added at 10 0 C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle for 30 minutes and layers were separated.
  • (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate
  • (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in
  • (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate
  • examples 9- 1 The various ratios of acetone and methanol are illustrated in examples 9- 1 1. While examples 12. 13 and 14 illustrate the result using acetone alone as solvent and example 15 and 16 demonstrate the result using methanol alone. Use of acetone and isopropyl alcohol is illustrated in example 17. It is found that the yield with acetone alone as solvent is from 71.98 to 74.3 1 % which is higher than the yield achieved by the prior art methods. But the best result in terms of yield of 86% and more is achieved by the mixture of solvents methanol and acetone in defined ratio of 4:5.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de dédoublement d'esters de phénylglycine méthyl 2-substituées et/ou d'acides représentés par la formule I au moyen de la transformation asymétrique de sels diastéréomères représentés par la formule (I). Ce procédé comprend le dédoublement d'esters racémiques de phénylglycine 2-2-substitués et/ou d'acides représentés par la formule (I) avec de l'acide tartrique L(+) à un ratio molaire de 0,9 à 1,4 en présence d'un solvant choisi dans le groupe constitué d'alcools acétone, méthanol, éthanol, isopropyle ou un mélange de ces derniers.
PCT/IN2004/000193 2004-07-02 2004-07-02 Procede de dedoublement de methylamino(2-chlorophenyl)acetate WO2006003671A1 (fr)

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PCT/IN2004/000193 WO2006003671A1 (fr) 2004-07-02 2004-07-02 Procede de dedoublement de methylamino(2-chlorophenyl)acetate

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8497088B2 (en) * 2007-03-09 2013-07-30 Dsm Sinochem Pharmaceuticals Netherlands B.V. Process for the preparation of beta-lactam compounds
CN103980288A (zh) * 2014-06-03 2014-08-13 成都医路康医学技术服务有限公司 一种氯吡格雷的生产工艺
CN109734617A (zh) * 2019-01-21 2019-05-10 华东理工大学 一种取代芳环苯甘氨酸脂肪醇酯的拆分方法
CN114853623A (zh) * 2022-05-26 2022-08-05 河南优凯制药有限公司 一种s-（+）-邻氯苯甘氨酸甲酯酒石酸盐的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976680A (en) * 1972-02-25 1976-08-24 Glaxo Laboratories Limited Production of an ester of one enantiomer of an α-amino acid in the form of a salt with an optically active acid
US5204469A (en) * 1990-07-10 1993-04-20 Sanofi Process for the preparation of an n-phenylacetic derivative of tetrahydrothieno(3,2-c)pyridine and its chemical intermediate
US6080875A (en) * 1997-03-05 2000-06-27 Sanofi-Synthelabo Method for preparing 2-thienylethylamine derivatives
US20040073057A1 (en) * 2002-10-15 2004-04-15 Maheshwari Krishna K. Racemization of optically active 2-substituted phenyl glycine esters

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976680A (en) * 1972-02-25 1976-08-24 Glaxo Laboratories Limited Production of an ester of one enantiomer of an α-amino acid in the form of a salt with an optically active acid
US5204469A (en) * 1990-07-10 1993-04-20 Sanofi Process for the preparation of an n-phenylacetic derivative of tetrahydrothieno(3,2-c)pyridine and its chemical intermediate
US6080875A (en) * 1997-03-05 2000-06-27 Sanofi-Synthelabo Method for preparing 2-thienylethylamine derivatives
US20040073057A1 (en) * 2002-10-15 2004-04-15 Maheshwari Krishna K. Racemization of optically active 2-substituted phenyl glycine esters

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8497088B2 (en) * 2007-03-09 2013-07-30 Dsm Sinochem Pharmaceuticals Netherlands B.V. Process for the preparation of beta-lactam compounds
CN103980288A (zh) * 2014-06-03 2014-08-13 成都医路康医学技术服务有限公司 一种氯吡格雷的生产工艺
CN109734617A (zh) * 2019-01-21 2019-05-10 华东理工大学 一种取代芳环苯甘氨酸脂肪醇酯的拆分方法
CN114853623A (zh) * 2022-05-26 2022-08-05 河南优凯制药有限公司 一种s-（+）-邻氯苯甘氨酸甲酯酒石酸盐的制备方法

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