WO2007078176A1 - Procede de fabrication d'esters d'acide 2-chloromandelique optiquement actifs et d'acides 2-chloromandeliques par un procede enzymatique - Google Patents

Procede de fabrication d'esters d'acide 2-chloromandelique optiquement actifs et d'acides 2-chloromandeliques par un procede enzymatique Download PDF

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Publication number
WO2007078176A1
WO2007078176A1 PCT/KR2007/000085 KR2007000085W WO2007078176A1 WO 2007078176 A1 WO2007078176 A1 WO 2007078176A1 KR 2007000085 W KR2007000085 W KR 2007000085W WO 2007078176 A1 WO2007078176 A1 WO 2007078176A1
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WIPO (PCT)
Prior art keywords
optically active
chloromandelic
chloromandelic acid
acid esters
acids
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Application number
PCT/KR2007/000085
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English (en)
Inventor
Soon Ook Hwang
Sun Ho Chung
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Enzytech, Ltd.
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Application filed by Enzytech, Ltd. filed Critical Enzytech, Ltd.
Publication of WO2007078176A1 publication Critical patent/WO2007078176A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/832—Bacillus
    • Y10S435/839—Bacillus subtilis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/911—Microorganisms using fungi
    • Y10S435/913—Aspergillus
    • Y10S435/918—Aspergillus oryzae
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/911—Microorganisms using fungi
    • Y10S435/921—Candida

Definitions

  • the present invention relates to process for the preparation of optically active
  • optically active 2-chloromandelic acid ester represented by the general formula 2 and optically active 2-chloromandelic acid represented by the general formula 3 are prepared from racemic 2-chloromandelic acid ester represented by the general formula 1 in scheme 1 by hydrolases or hydrolase-producing microorganisms.
  • R is selected from substituted or unsubstituted alkyl groups or alkenyl groups wherein the alkyl contains from C i to C , benzyl groups, cycloalkyl groups comprising from C 3 to C 6 , substituted or unsubstituted arylalkyl groups, and substituted or unsubstituted heteroarylalkyl groups.
  • Optically active 2-chloromandelic acid esters are valuable chiral intermediates for synthesizing (S)-clopidogrel bisulfate with platelet aggregation inhibiting activity.
  • Tosylated or mesylated compounds can be converted to optically active 2-chlorostyrene oxide which is used for important pharmaceutical intermediates by epoxydation (Korea Patent 10-2005-0035057).
  • Noda Hirobumi et al.(JP-0072644) prepared a diastereomer salt by reacting racemic 2-chloromandelic acid with an optically active N-benzyl-1-phenylethylamine as an optical resolution agent and obtained (R)-2-chloromandelic acid by acidification of a diastereomer salt.
  • this method needs recrystallization process.
  • Hyoda Toshiharu et al.(JP-0114737) obtained (R)-2-choloromandelic acid using optically active alanine as an optical resolution agent.
  • the present invention provides the new method of preparing of optically active 2-chloromandelic acid esters and their acids by hydrolases or hydrolase-producing microorganisms. And this method can be used in practical process because seperation and recovery of 2-chloromandelic acid esters and their acids produced by this invention are easier.
  • this invention includes the process for preparing optically active 2-chloromandelic acid ester and optically active 2-chloromandelic acid by stereospecific hydrolysis of racemic 2-chloromandelic acid ester using hydrolases or hydrolase-producing mi- croorganisms. And optically active 2-chloromandelic acid ester is converted to optically active 2-chloromandelic acid by hydrolysis using agents such as sodium hydroxide.
  • hydrolases such as CAL A(Novozym
  • CAL B(Novozym 435), alcalase, and protease A or hydrolase-producing microorganisms are used as biocatalysts.
  • Racemic 2-chloromandelic acid ester was determined using gas chromatography (Donam Instrument Inc., Model 6200) equipped with HP-FFAP column(Agilent, Inc., 3O m X 0.53 mm). The oven temperature was maintained initially at 100 0 C for 5 min and then raised at the rate of 20 °C/min to 220 0 C, and maintained for 10 min. Helium gas was used as carrier and column head pressure was maintained at 6 psi, and compounds were detected using FID at 220 0 C. In this condition, the typical retention time of methyl 2-chloromandelate, ethyl 2-chloromandelate and butyl 2-chloromandelic acid was 15.31 min, 14.89 min and 17.28 min, respectively.
  • racemic 2-chloromandelic acid was added to 40ml of methanol and 35 % HCl solution. The reaction was carried out at 75 0 C for 3 hours. The reaction mixture was neutralized and racemic methyl 2-chloromandelate was gained by solvent extraction and distillation under reduced pressure. Racemic ethyl 2-chloromandelate and butyl 2-chloromandelate were synthesized using ethanol or buthanol, respectively instead of methanol. And the products were confirmed by nuclear magnetic resonance(Burker, Model DRS300).
  • Example 2-3 Preparing of optically active methyl 2-chloromandelate by hydrolysis
  • Racemic methyl 2-chloromandelate(l %(v/v)) prepared in Example 1 was added to 5 ml of 0.1 M potassium phosphate buffer(pH 7.0) and the reaction was carried out at 30 0 C using enzymes (1 %(w/v)). The reaction mixture was extracted with ethyl acetate and analyzed by above-mentioned method. The results are shown in Table 1.
  • Example 4-7 Preparing of optically active ethyl 2-chloromandelate by hydrolysis [46] [47] Instead of racemic methyl 2-chloromandelate used in Example 2, ethyl 2-chloromandelate was used as a reactant and the results are shown in Table 2.
  • Example 8 Preparing of optically active butyl 2-chloromandelate by hydrolysis [51] [52] Instead of racemic methyl 2-chloromandelate used in Example 2, butyl 2-chloromandelate was used as a reactant and CAL B was used as a biocatalyst. The reaction was carried out for 48 hours and butyl (R)-2-chloromandelate was obtained with 76 e.e% (conversion 93.1%).
  • optically active 2-chloromandelic acid ester can be produced easily by this invention, and the product with high optical purity was obtained. Also, it is easy to recover optically active esters and optically active 2-chlromandelic acids after reaction. Therefore, this method is an useful process on the industrial scale.

Abstract

La présente invention concerne procédés de préparation d'esters d'acide 2-chloromandélique optiquement actifs est représenté par la formule générale (2) et d'acides 2-chloromandéliques optiquement actifs représentés par la formule générale (2) et qui sont utilisés de manière intensive comme intermédiaires chiraux importants. De manière plus spécifique, c'est invention porte sur un procédé de préparation d'esters d'acide 2-chloromandélique optiquement actifs et d'acides 2-chloromandéliques optiquement actifs par hydrolyse stéréospécifique de l'ester d'acide 2-chloromandélique racémique utilisant des lipases ou des micro-organismes produisant des lipases en phase aqueuse ou en phase organique comprenant un solvant aqueux. Le procédé de fabrication des ester d'acide 2-chloromandélique optiquement actifs et de leurs acides est utile dans un processus pratique du fait de la production de séparation de composés de haute pureté optique.
PCT/KR2007/000085 2006-01-05 2007-01-05 Procede de fabrication d'esters d'acide 2-chloromandelique optiquement actifs et d'acides 2-chloromandeliques par un procede enzymatique WO2007078176A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020060001422A KR100722155B1 (ko) 2006-01-05 2006-01-05 효소적 방법에 의한 광학활성 2-클로로만델릭산 에스테르와 2-클로로만델릭산의 제조 방법
KR10-2006-0001422 2006-01-05

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102206686A (zh) * 2011-04-19 2011-10-05 华东理工大学 生物催化不对称还原制备(r)-邻氯扁桃酸甲酯的方法
CN108192932A (zh) * 2017-12-26 2018-06-22 上海皓元生物医药科技有限公司 一种手性醇的酶催化制备方法
CN111118073A (zh) * 2019-12-27 2020-05-08 东莞市东阳光生物合成药有限公司 酶法合成依米他韦中间体的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5580765A (en) * 1993-02-03 1996-12-03 Nitto Chemical Industry Co., Ltd. Process for producing optically active a-hydroxycarboxylic acid having phenyl group using gordona terrae
JP2001072644A (ja) * 1999-09-06 2001-03-21 Yamakawa Yakuhin Kogyo Kk 光学活性な２−クロロマンデル酸の製造方法および製造の中間体
JP2002114737A (ja) * 2000-10-11 2002-04-16 Japan Hydrazine Co Inc 光学活性ｏ−クロロマンデル酸の製造法
EP1382674A2 (fr) * 2002-07-16 2004-01-21 Daicel Chemical Industries, Ltd. Réductase de l'acide alpha-keto, méthode pour sa production et méthode pour la production d'acides alpha-hydroxy optiquement actifs qui utilise ladite réductase

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100651338B1 (ko) * 2003-01-06 2006-11-28 에스케이 주식회사 효모를 이용한 광학활성 (ｒ)-2-클로로만델릭산 및 그에스테르 유도체의 제조방법
KR100752282B1 (ko) * 2003-10-11 2007-08-29 주식회사 이큐스팜 효소를 이용한(r)-또는 (s)-폼의 2-클로로스틸렌옥사이드의 제조방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5580765A (en) * 1993-02-03 1996-12-03 Nitto Chemical Industry Co., Ltd. Process for producing optically active a-hydroxycarboxylic acid having phenyl group using gordona terrae
JP2001072644A (ja) * 1999-09-06 2001-03-21 Yamakawa Yakuhin Kogyo Kk 光学活性な２−クロロマンデル酸の製造方法および製造の中間体
JP2002114737A (ja) * 2000-10-11 2002-04-16 Japan Hydrazine Co Inc 光学活性ｏ−クロロマンデル酸の製造法
EP1382674A2 (fr) * 2002-07-16 2004-01-21 Daicel Chemical Industries, Ltd. Réductase de l'acide alpha-keto, méthode pour sa production et méthode pour la production d'acides alpha-hydroxy optiquement actifs qui utilise ladite réductase

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102206686A (zh) * 2011-04-19 2011-10-05 华东理工大学 生物催化不对称还原制备(r)-邻氯扁桃酸甲酯的方法
CN102206686B (zh) * 2011-04-19 2013-06-26 华东理工大学 生物催化不对称还原制备(r)-邻氯扁桃酸甲酯的方法
CN108192932A (zh) * 2017-12-26 2018-06-22 上海皓元生物医药科技有限公司 一种手性醇的酶催化制备方法
CN111118073A (zh) * 2019-12-27 2020-05-08 东莞市东阳光生物合成药有限公司 酶法合成依米他韦中间体的方法
CN111118073B (zh) * 2019-12-27 2022-02-15 宜昌东阳光生化制药有限公司 酶法合成依米他韦中间体的方法

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