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WO2007069841A1 - Procede de preparation de cyclopropane carboxamide optiquement actif, et de ses derives - Google Patents

Procede de preparation de cyclopropane carboxamide optiquement actif, et de ses derives Download PDF

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Publication number
WO2007069841A1
WO2007069841A1 PCT/KR2006/005402 KR2006005402W WO2007069841A1 WO 2007069841 A1 WO2007069841 A1 WO 2007069841A1 KR 2006005402 W KR2006005402 W KR 2006005402W WO 2007069841 A1 WO2007069841 A1 WO 2007069841A1
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WO
WIPO (PCT)
Prior art keywords
substituted
carboxylic acid
acid ester
unsubstituted
cyclopropane
Prior art date
Application number
PCT/KR2006/005402
Other languages
English (en)
Inventor
Ji-Shick Kim
Jae-Min Son
Kyoung-Rok Roh
Ji-Sang Yoo
Jong-Won Jang
Original Assignee
Choongwae Pharma Corporation
Chemico Ltd.
Chiroad Inc.
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 Choongwae Pharma Corporation, Chemico Ltd., Chiroad Inc. filed Critical Choongwae Pharma Corporation
Priority to AT0951906A priority Critical patent/AT509135A1/de
Publication of WO2007069841A1 publication Critical patent/WO2007069841A1/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
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • 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
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
    • 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

Definitions

  • the present invention relates to a process for preparing an optically active cyclopropane carboxamide and derivatives thereof by using an enzyme.
  • 2,2-dimethylcyclopropanecarboxylic acid is used as a dihydropeptidase I inhibitor and pyrethroids-based insecticides having exceptionally low toxicity to mammals (British Patent No. 1,260,847), and also is a chiral building block which is an important material having a significant industrial meaning in the development of various applications, where it is used as a key intermediate for cilastatin which inhibits the decomposition of a carbapenem-based antibiotic in the kidney (European Patent Specifications EP0048301 and EP0048025) and as an optical resolving reagent.
  • the conventional preparation methods can be largely classified into two categories, that is: a method wherein optically active amines, hydroxyl group-containing L- menthol, or (S)-mandelic acid ester is used to prepare an ester, then recrystallization was repeatedly carried out; and a method wherein an (S)-isomer of a product is prepared through a biotrasformation process.
  • Both of the two methods have problems such as low optical purity of the product, low yield, use of an expensive reagent for optical resolution and repeated recrystallization; several problems among which are necessarily accompanied. Thus, it can be said that they have industrial limitations.
  • 5,166,417 discloses optical resolution by preparing a diastereomer using optically active l-(3-methoxyphenyl)ethylamine and subsequent recrystallization, but requirement of a very expensive chiral amine, low yield of about 21%, optical purity 93% or below of the produced (S)-dimethyl cyclopropane carboxylic acid render it less suitable for commercialization.
  • Japanese Published Patent Application No. 80-051023 discloses a process for preparing (S)-dimethyl cyclopropane carboxylic acid by means of optical resolution using quinine, but this method has disadvantages that quinine is very expensive as well as not available stably and besides that the yield is low.
  • British Patent No. 1260847 discloses a process using D- or L-phenethylamine for optical resolution, but it has problems that the (S)-dimethyl cyclopropane carboxylic acid produced by this process has an optical purity as low as 49% and that the yield is low, thus it is not good for industrial availability.
  • U.S. Pat. No. 5,243,070 discloses a process for preparing dimethylcyclo- propanecarboxamide which comprises preparing a racemate of dimethylcyclo- propanecarboxylic acid ester by reacting dimethylcyclopropanecarboxylic acid with optically active mandelic acid methyl ester, seperating optical isomers by means of re- crystallization of the racemate, hydrolyzing the product to prepare (S)-dimethylcyclopropane carboxylic acid, and performing a resolution of a chiral resolving reagent and isomers.
  • This however, has drawbacks that the used (S)-mandelic acid methyl ester is a highly expensive reagent, and at least three times of recrystallization should be repeated in order to increase the optical purity.
  • WO 2004/005241 discloses a process for preparing
  • Korean Published Patent Application No. 10-2004-0004744 discloses a process for preparing (S)-dimethylcyclopropane carboxamide, which comprises reacting dimethyl- cyclopropane carboxylic acid with alcohol to prepare a racemate of dimethylcy- clopropane carboxylic acid ester, subjecting the product to biological resolution using a microorganism to prepare (S)-dimethylcyclopropane carboxylic acid and (R)-dimethylcyclopropane carboxylic acid, and then further performing addition reacting of the prepared (S)-dimethylcyclopropane carboxylic acid with various chlorinating reagents and ammonia.
  • the present inventors have found that when a racemate of cyclopropane carboxylic acid ester is reacted with the lipase from Candida antarctica as an enzyme in an organic solvent having ammonia gas dissolved therein, only an (S)-isomer of substituted cyclopropane carboxylic acid ester specifically participates in the reaction, thereby in the reaction solution an (S)-isomer of cyclopropane carboxamide and an (R)-isomer of cyclopropane carboxylic acid ester is prepared.
  • the object of the present invention is to provide an (S)-cyclopropane carboxamide and derivatives thereof with a high optical purity and a high yield, which is industrially economical, by using a hydrolysis enzyme at a high concentration, even without using expensive optical resolving reagents such as conventionally used optically active amines or L- menthol, and without performing complicated biotransformation processes.
  • the present invention relates to a novel process for preparing cyclopropane carboxamide and derivatives thereof represented by the following formula 1 (hereinafter, optically active cyclopropane carboxamide) by using an enzyme. More specifically, the present invention relates to a process for preparing optically active cyclopropane carboxamide and cyclopropane carboxylic acid ester, which comprises the steps of (1) reacting a racemate of cyclopropane carboxylic acid ester represented by formula 3 with a lipase from Candida antarctica at a constant reaction temperature in an organic solvent having ammonia gas dissolved therein; and (2) separating (S)-cyclopropane carboxamide represented by formula 1 and (R)-cyclopropane carboxylic acid ester represented by formula 2:
  • R and R may be the same or different, and independently represent hydrogen, substituted or unsubstituted straight or branched Cl to C7 alkyl, substituted or un- substituted straight or branched Cl to C7 alkenyl, benzyl, substituted or unsubstituted C3 to C7 cycloalkyl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl;
  • R and R may be the same or different, independently represent hydrogen
  • R is Cl to C7 straight or branched alkyl, halogen compound-substituted Cl to C7 straight or branched alkyl, or substituted or unsubstituted straight or branched Cl to C7 alkoxy group-substituted Cl to C7 straight or branched alkyl.
  • lipases which act as an enzyme in the optical resolution
  • examples of the which used include lipases from Candida cylindracea, Pseudomonas sp., Candida rugosa, and Candida antarctica, etc.
  • These are different in the kinds of the reactive compounds, the kinds of the reactive optical isomers and the reactivity according to their origin.
  • Most of the lipases do not catalyze the reaction of the present invention. Even in the case of partially hydroyzing, low optical purities render the enzyme meaningless.
  • the present inventors have found that in the enzymatic optical resolution, only a lipase from Candida antarctic gives a high conversion rate and high optical purity.
  • racemate (3) of cyclopropane carboxylic acid ester can be easily prepared by esterification of the racemate (4) of cyclopropane carboxylic acid with various alcohols.
  • the reaction mixture having the compound without separating the reaction mixture, to the reaction mixture having the compound, added is at least one alcohol derivative selected from 2-chloroethanol, 2,2-dichloroethanol, 2,2,2-trichloroethanol, 2-fluoroethanol, 2,2-difluoroethanol, 2,2,2-trifluoroethanol, 2-bromoethanol, 2,2-dibromoethanol, 2,2,2-tribromoethanol and 2-methoxyethanol, to produce the racemate (3) of cyclopropane carboxylic acid ester with a high yield of 85% or higher.
  • a lipase from Candida antarctica as an enzyme, to perform amination and optical resolution in an organic solvent having ammonia gas dissolved therein.
  • the organic solvent is a solvent mixture comprising one or more solvents selected from alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol, isoamyl alcohol, tert-butanol, pentanol, hexanol, heptanol and octanol; an oxane solvent such as 1,4-dioxane and trioxane; an amide solvent such as diethylformamide and dimethylformamide; dimethylsulf oxide; an aromatic solvent such as benzene, toluene and xylene; and a non-polar solvent such as hexane, heptane, octane, and cy- clohexane.
  • alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol, isoamyl alcohol, tert-butanol, pentanol, hex
  • the specific enzymatic optical resolution by the lipase from Candida antarctica according to the present invention can be performed by any carboxylic acid ester compound having cyclopropane carboxylic acid moiety,
  • R and R in cyclopropane moiety of formula 1 can be anything.
  • R and R may be the same or different, and each are preferably selected form hydrogen, substituted or unsubstituted straight or branched Cl to C7 alkyl, substituted or unsubstituted straight or branched Cl to C7 alkenyl, benzyl, substituted or unsubstituted C3 to C7 cycloalkyl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl.
  • R and R are the same or different, and are independently selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, fluoromethyl, difluoromethyl or trifluoromethyl. It is still more preferable when both of R and R are methyl.
  • the most significant factor which affects the specific enzymatic optical resolution by the lipase from Candida antarctica according to the present invention is the characteristics of the substituents R through R in the racemate of cyclopropane carboxylic acid ester.
  • R and R may be the same or different, and each can be selected from hydrogen, substituted or unsubstituted straight or branched Cl to C7 alkyl, substituted or unsubstituted straight or branched Cl to C7 alkenyl, benzyl, substituted or unsubstituted C3 to C7 cycloalkyl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heteroarylalkyl, and R is can be selected from Cl to C7 straight or branched alkyl.
  • R is preferably selected from halogen compound-substituted Cl to C7 straight or branched alkyl, or substituted or unsubstituted straight or branched Cl to C7 alkoxy group-substituted Cl to C7 straight or branched alkyl.
  • R and R are each hydrogen, and R is selcted from fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, di- bromomethyl, tribromomethyl, methoxymethyl, and ethoxymethyl.
  • Candida antarctica mentioned above is easily available because it is commercially available.
  • the concentration of the lipase from Candida antarctica in the reaction is preferably 1 to 30 parts by weight, based on 100 parts by weight of the racemate of cyclopropane carboxylic acid ester as a substrate, and more preferably about 5 parts by weight. It is preferable to use an enzyme in the immobilized form, for the reaction convenience and economy.
  • the specific enzymatic optical resolution of cyclopropane carboxylic acid by a lipase from Candida antarctica according to the present invention is subject to reaction under the reaction temperature maintained constant, wherein the reaction temperature is preferably 10 to 8O 0 C. When considering the optical purity, the reaction temperature of 20 to 45 0 C is the most preferable.
  • concentration of the racemate of cyclopropane carboxylic acid ester as a substrate used for the enzymatic optical resolution is suitably 3% to 70%, and when considering the process efficiency, preferably 5% to 40%.
  • a simple post-treatment process following the specific enzymatic optical resolution can be carried out to separate optically active cyclopropane carboxamide and cyclopropane carboxylic acid ester.
  • the mixed reaction solution is filtered to recover the enzyme, and the organic solvent and low-boiling point organic materials are distilled off from the filtrate, thereby obtaining (S)-2,2-dimethylcyclopropane carboxamide.
  • the product is purified by recrystallization in methanol.
  • the enzyme used in the enzymatic reaction is isolated by using a filter, etc. after completion of the reaction, and can be reused after washing.
  • the preparation process according to the present invention has advantages that it is a novel process for preparing an (S)-cyclopropane carboxamide and derivatives thereof with a high optical purity and a high yield, which is industrially economical, by hy- drolyzing enzyme at a high concentration, even without using expensive optical resolving reagents such as conventionally used optically active amines or L-menthol, and without performing complicated biotransformation processes.
  • Mode for the Invention is a novel process for preparing an (S)-cyclopropane carboxamide and derivatives thereof with a high optical purity and a high yield, which is industrially economical, by hy- drolyzing enzyme at a high concentration, even without using expensive optical resolving reagents such as conventionally used optically active amines or L-menthol, and without performing complicated biotransformation processes.
  • Candida antarctica Type B lipase As shown in Table 2, after the screening of the enzymes using a racemate of 2,2-dimethylcyclopropane carboxylic acid 2,2,2-trifluoroethyl ester as a substrate, only Candida antarctica Type B lipase (Example 1) leads to a production of the optical isomers of (S)-dimethylcyclopropane carboxamide with a high optical purity to be industrially useful, while other lipases, proteases and esterase did not cause the reactions. Thus, it could be confirmed that the lipase from Candida antarctica, which is a stere- ospecific enzyme, as an enzyme for the preparation process according to the present invention is remarkably effective.

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  • Chemical & Material Sciences (AREA)
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  • Wood Science & Technology (AREA)
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Abstract

L'invention porte sur un procédé de préparation de cyclopropane carboxamide optiquement actif, dans une structure spécifique utilisant une enzyme.
PCT/KR2006/005402 2005-12-12 2006-12-12 Procede de preparation de cyclopropane carboxamide optiquement actif, et de ses derives WO2007069841A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT0951906A AT509135A1 (de) 2005-12-12 2006-12-12 Verfahren zur herstellung von optisch aktivem cyclopropancarboxamid und derivaten davon

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KR1020050122129A KR100650797B1 (ko) 2005-12-12 2005-12-12 광학활성 사이클로프로판 카복사미드의 제조방법
KR10-2005-0122129 2005-12-12

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013126337A1 (fr) * 2012-02-24 2013-08-29 Bristol-Myers Squibb Company Procédé pour séparer des diesters de cyclopropyle

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100884558B1 (ko) 2008-09-11 2009-02-19 디에이치씨 (주) 고수율 및 고 광학순도의 광학활성 아미드의 제조방법

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5360731A (en) * 1991-03-06 1994-11-01 Lonza Ltd. Bacteria capable of stereospecifically hydrolyzing R-(-)-2,2-dimethylcyclopropanecarboxamide
US5427934A (en) * 1991-07-26 1995-06-27 Lonza Ltd. Genetic engineering process for the production of S-(+)-2,2-dimethylcyclopropanecarboxamide by microorganisms
WO1998029561A1 (fr) * 1996-12-27 1998-07-09 Smithkline Beecham Plc Resolution enzymatique d'esters d'acide acetique de benzodiazepine par une lipase
WO2003083126A2 (fr) * 2002-03-22 2003-10-09 Dow Global Technologies Inc. Resolution enzymatique d'esters et d'acetates d'ether de propylene glycol alkyle (ou aryle)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100511534B1 (ko) * 2002-07-05 2005-08-31 임광민 아미드 화합물의 새로운 제조방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5360731A (en) * 1991-03-06 1994-11-01 Lonza Ltd. Bacteria capable of stereospecifically hydrolyzing R-(-)-2,2-dimethylcyclopropanecarboxamide
US5427934A (en) * 1991-07-26 1995-06-27 Lonza Ltd. Genetic engineering process for the production of S-(+)-2,2-dimethylcyclopropanecarboxamide by microorganisms
WO1998029561A1 (fr) * 1996-12-27 1998-07-09 Smithkline Beecham Plc Resolution enzymatique d'esters d'acide acetique de benzodiazepine par une lipase
WO2003083126A2 (fr) * 2002-03-22 2003-10-09 Dow Global Technologies Inc. Resolution enzymatique d'esters et d'acetates d'ether de propylene glycol alkyle (ou aryle)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013126337A1 (fr) * 2012-02-24 2013-08-29 Bristol-Myers Squibb Company Procédé pour séparer des diesters de cyclopropyle

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AT509135A1 (de) 2011-06-15
KR100650797B1 (ko) 2006-11-27

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