WO2007126258A1 - Procédé de fabrication d'esters d'acides 2-halo-2-(n-substitué phényl)acétiques optiquement actifs et acides 2-halo-2-(n-substitué phényl)acétiques par méthode enzymatique - Google Patents

Procédé de fabrication d'esters d'acides 2-halo-2-(n-substitué phényl)acétiques optiquement actifs et acides 2-halo-2-(n-substitué phényl)acétiques par méthode enzymatique Download PDF

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Publication number
WO2007126258A1
WO2007126258A1 PCT/KR2007/002073 KR2007002073W WO2007126258A1 WO 2007126258 A1 WO2007126258 A1 WO 2007126258A1 KR 2007002073 W KR2007002073 W KR 2007002073W WO 2007126258 A1 WO2007126258 A1 WO 2007126258A1
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WO
WIPO (PCT)
Prior art keywords
acetic acid
halo
optically active
substituted phenyl
substituted
Prior art date
Application number
PCT/KR2007/002073
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English (en)
Inventor
Soon Ook Hwang
Sun Ho Chung
Original Assignee
Enzytech, Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Enzytech, Ltd filed Critical Enzytech, Ltd
Publication of WO2007126258A1 publication Critical patent/WO2007126258A1/fr

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Classifications

    • 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
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
    • C12P7/54—Acetic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • 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
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/59—Biological synthesis; Biological purification
    • 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
    • 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
    • Y10S435/931—Mucor
    • 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
    • Y10S435/939—Rhizopus

Definitions

  • the present invention relates to process for the preparation of optically active
  • 2-halo-2-(n-substituted phenyl)acetic acid esters and their acids by enzymes or microorganisms are prepared from racemic 2-halo-2-(n-substituted phenyl)acetic acid ester represented by the general formula 1 in scheme 1 by hydrolysis using hydrolases or hydrolase- producing microorganisms.
  • R is selected from substituted or unsubstituted alkyl groups or alkenyl groups wherein the alkyl contains from C to C , benzyl groups, cycloalkyl groups comprising from C to C , substituted or un-
  • the method related to this invention is the production of (S)-2-bromo-tolyl acetic acid ester by transesterification of 2-bromo-tolyl acetic acid ester using lipase in ocXd ⁇ o ⁇ (Tetrahedron:Asymmetry, 2004, 15, 3539-3543).
  • (S)-octyl ester was produced and by using B. cepacia-derived lipase, (R)-octyl ester was produced.
  • the maximum optical purity was only 93ee% and after the reaction, it is difficult to separate the product.
  • optically active 2-halo-2-(n-substituted phenyl)acetic acid are prepared from racemic 2-halo-2-(n-substituted phenyl)acetic acid ester by hydrolysis using hydrolases or hydrolase-producing microorganisms and this method was never reported before.
  • optically active 2-halo-2-(n-substituted phenyl)acetic acid ester and optically active 2-halo-2-(n-substituted phenyl)acetic acid which are produced by this method can be easily seperated and recovered so it has advantage in practical process.
  • this invention includes the process for preparing optically active 2-halo-2-(n-substituted phenyl)acetic acid ester and optically active 2-halo-2-(n-substituted phenyl)acetic acid using hydrolases or hydrolase-producing microorganisms. And optically active 2-halo-2-(n-substituted phenyl)acetic acid ester obtained by this invention is converted to optically active 2-halo-2-(n-substituted phenyl)acetic acid by hydrolysis using agents such as sodium hydroxide.
  • R is selected from substituted or un- substituted alkyl groups or alkenyl groups wherein the alkyl contains from C 1 to C 8 , benzyl groups, cycloalkyl groups comprising from C 3 to C 6 , substituted or un- substituted arylalkyl groups and substituted or unsubstituted heteroarylalkyl groups.
  • hydrolases such as CAL A, CAL
  • B(Novozymes Inc.), AY, AYS, F-AP15 and M(Amano Inc.) or hydrolase-producing microorganisms are used as biocatalysts.
  • the reactants and the products were analyzed as belows. Racemic 2-bromo ester and 2-chloro ester were determined using gas chromatography (Donam Instrument Inc., Model 6200) equipped with BP-I(SGE, Inc.)column and HP-FF AP(Agilent, Inc.)column respectively.
  • 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.
  • reaction mixture was extracted using dichloromethane and the water phase was acidified by HCl and extracted by isopropyl ester, then distilled under reduced pressure and finally 7.76g of product was obtained by recrystallization using toluene.
  • Racemic 2-bromo-2-(2-chloro phenyl)acetic acid prepared in Example 1 was added to methanol including H SO . The reaction was carried out at 70 0 C for 3 hours.
  • racemic 2-bromo-2-(2-chloro phenyl)acetic acid methyl ester was obtained by solvent extraction and distillation under reduced pressure.
  • Racemic 2-bromo-2-(2-chloro phenyl)acetic acid ethyl ester and 2-bromo-2-(2-chloro phenyl)acetic acid butyl ester were prepared using ethanol and butanol, respectively instead of methanol.
  • the products were confirmed by nuclear magnetic resonance(Burker Inc., Model DRX300). The result are as follows.
  • Example 5 Preparing of 2-bromo-2-(4-chloro phenyl)acetic acid alkyl ester [71] [72] Racemic 2-bromo-2-(4-chloro phenyl)acetic acid prepared in Example 4 was added to methanol including H SO . The reaction was carried out at 70 0 C for 3 hours. The reaction mixture was neutralized and racemic 2-bromo-2-(4-chloro phenyl)acetic acid methyl ester was prepared by solvent extraction. Racemic 2-bromo-2-(4-chloro phenyl)acetic acid ethyl ester was prepared under same condition by using ethanol instead of methanol.
  • Racemic 2-bromo-2-(2-chloro phenyl)acetic acid alkyl ester(l%(v/v)) prepared in Example 2 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(l%(v/v)) from Table 1.
  • the reaction mixture was extracted with ethyl acetate and analyzed by above-mentioned method.
  • optically active 2-halo-2(n-substituted phenyl)acetic acids and their esters can be produced easily and the product with high optical purity can be obtained by this invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Health & Medical Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention porte sur un procédé de fabrication d'esters d'acides 2-halo-2-(n-substitué phényl)acétiques optiquement actifs et sur des acides 2-halo-2-(n-substitué phényl)acétiques otiquement actifs qui sont utilisés intensivement comme intermédiaires chiraux influents, et représentés par les formules générales 2 et 3, ce procédé étant réalisé à partir de l'ester racémique de l'acide 2-halo-2-(n-substitué phényl)acétique représenté par la formule générale 1. Plus précisément, cette invention porte sur le procédé de préparation d'esters d'acides 2-halo-2-(n-substitué phényl)acétiques optiquement actifs et d'acides 2-halo-2-(n-substitué phényl)acétiques otiquement actifs par hydrolyse stéréospécifique des esters racémiques de l'acide 2-halo-2-(n-substitué phényl)acétique en utilisant des hydrolases ou des micro-organismes produisant des hydrolases dans un solvant auqeux comprenant une phase aqueuse ou une phase organique. Ce procédé est utile concrètement du fait que la production et la séparation des composés de haute pureté optique sont plus faciles.
PCT/KR2007/002073 2006-04-27 2007-04-27 Procédé de fabrication d'esters d'acides 2-halo-2-(n-substitué phényl)acétiques optiquement actifs et acides 2-halo-2-(n-substitué phényl)acétiques par méthode enzymatique WO2007126258A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2006-0038183 2006-04-27
KR1020060038183A KR100846676B1 (ko) 2006-04-27 2006-04-27 효소적 방법에 의한 광학활성 2-할로-2-(엔-치환된페닐)아세트산 에스테르와 2-할로-2-(엔-치환된페닐)아세트산의 제조 방법

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107796904A (zh) * 2016-08-31 2018-03-13 武汉武药制药有限公司 一种用hplc分离测定邻氯扁桃酸对映异构体的方法
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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0362556A1 (fr) * 1988-09-02 1990-04-11 Tanabe Seiyaku Co., Ltd. Procédé de préparation d'esters de l'acide 3-phénylglycidique optiquement actifs
US20020006645A1 (en) * 1997-06-09 2002-01-17 Hashimoto Shin-Ichi Method for producing optically active compound
EP1324975B1 (fr) * 2000-09-29 2005-11-16 Bristol-Myers Squibb Company Resolution dynamique d'isomeres et isomeres resolus

Family Cites Families (3)

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Publication number Priority date Publication date Assignee Title
IL81049A0 (en) 1985-12-20 1987-03-31 Wisconsin Alumni Res Found Preparation of(s)-alpha-methylarylacetic acids
JPS62205797A (ja) 1986-03-05 1987-09-10 Daicel Chem Ind Ltd 光学活性化合物の製造法
IT1247533B (it) 1991-04-26 1994-12-17 Mini Ricerca Scient Tecnolog Processo per la separazione degli isomeri ottici di acidi carbossilici alfa-sostitutivi

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0362556A1 (fr) * 1988-09-02 1990-04-11 Tanabe Seiyaku Co., Ltd. Procédé de préparation d'esters de l'acide 3-phénylglycidique optiquement actifs
US20020006645A1 (en) * 1997-06-09 2002-01-17 Hashimoto Shin-Ichi Method for producing optically active compound
EP1324975B1 (fr) * 2000-09-29 2005-11-16 Bristol-Myers Squibb Company Resolution dynamique d'isomeres et isomeres resolus

Non-Patent Citations (2)

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Title
KATO D.-I. ET AL.: "Microbial Deracemization of a-Substituted Carboxylic Acids: Substrate Specificity and Mechanistic Investigation", JOURNAL OF ORGANIC CHEMISTRY, vol. 68, no. 19, 2003, pages 7234 - 7242 *
XU H.-W. ET AL.: "Copper(II)-mediated resolution of -halo carboxylic acids with chiral O,O-dibenzoyltartaric acid: spontaneous racemization and crystallization-induced dynamic resolution", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 3, no. 23, 2005, pages 4227 - 4232 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107796904A (zh) * 2016-08-31 2018-03-13 武汉武药制药有限公司 一种用hplc分离测定邻氯扁桃酸对映异构体的方法
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

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KR20070105681A (ko) 2007-10-31

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