WO2004005241A1 - Procede de production d'un amide optiquement actif - Google Patents

Procede de production d'un amide optiquement actif Download PDF

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Publication number
WO2004005241A1
WO2004005241A1 PCT/KR2003/001328 KR0301328W WO2004005241A1 WO 2004005241 A1 WO2004005241 A1 WO 2004005241A1 KR 0301328 W KR0301328 W KR 0301328W WO 2004005241 A1 WO2004005241 A1 WO 2004005241A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
optically active
substituent
reaction
Prior art date
Application number
PCT/KR2003/001328
Other languages
English (en)
Inventor
Kwang-Min Lim
Original Assignee
Cls Laboratories, 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 Cls Laboratories, Inc. filed Critical Cls Laboratories, Inc.
Priority to AU2003237069A priority Critical patent/AU2003237069A1/en
Publication of WO2004005241A1 publication Critical patent/WO2004005241A1/fr

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Classifications

    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16B—DEVICES FOR FASTENING OR SECURING CONSTRUCTIONAL ELEMENTS OR MACHINE PARTS TOGETHER, e.g. NAILS, BOLTS, CIRCLIPS, CLAMPS, CLIPS OR WEDGES; JOINTS OR JOINTING
    • F16B15/00—Nails; Staples
    • F16B15/02—Nails; Staples with specially-shaped heads, e.g. with enlarged surfaces
    • 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
    • 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
    • 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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16B—DEVICES FOR FASTENING OR SECURING CONSTRUCTIONAL ELEMENTS OR MACHINE PARTS TOGETHER, e.g. NAILS, BOLTS, CIRCLIPS, CLAMPS, CLIPS OR WEDGES; JOINTS OR JOINTING
    • F16B2200/00—Constructional details of connections not covered for in other groups of this subclass
    • F16B2200/95—Constructional details of connections not covered for in other groups of this subclass with markings, colours, indicators or the like

Definitions

  • the present invention relates to a new process for producing a pharmaceutical intermediate, more specifically an optically active amide intermediate for production of cilastatin.
  • Cilastatin is administered in treatment together with imipenem which is a carbapenem antibiotic, to prevent imipenem from being deactivated by dehydropeptidase-1 and maintain its antibiotic activity, and is represented by the following formula: cilastatin
  • European Published Patent Application No. 048301 discloses a method in which cilastatin can be easily synthesized by condensing an intermediate compound (I) with ⁇ -keto-acid compound (A) to produce a compound (B), followed by an addition of L-cysteine, an amino acid.
  • optical resolution is a main step of some conventional methods.
  • U.S. Pat. Nos. 5,166,417 and 5,243,070 disclose a method for producing the compound (I) as shown in the following reaction scheme.
  • an enantiomer mixture of the carboxylic acid (D) is converted into a diastereomer mixture by a chiral resolving agent.
  • the diastereomers are separated from each other by way of chemical resolution and then the chiral resolving agent is removed, so that an optically active carboxylic acid (G) is obtained.
  • the obtained material (G) is transformed into the amide compound (I).
  • the above method has two drawbacks. First, it requires carrying out very complicated resolution and separation reactions, which include combining a racemate and a chiral resolving agent, resolving the diastereomers and separating the chiral resolving agent from the optically active isomers. Therefore, in order to achieve a product with 98% or more of optical purity, it is inevitable that its yield becomes lower to around 20%. In addition, the chiral resolving agent may remain in the product as an impurity, resulting in quality deterioration. Secondly, the fact that the chiral resolving agent used in the method should be recycled due to its expensive price causes the method to become more complicated and increases the unit cost of production.
  • U.S. Pat. No. 5,273,903 discloses a method for producing the compound (I) using biological resolution of a racemate. As shown in the following reaction scheme, a racemate (H) of the compound (I) is subjected to a selective-hydrolysis by an amidase, followed by separation of the optically active compound (I).
  • this method also has some drawbacks.
  • the concentration of the reactant in the enzyme reaction is merely around lwt%, the unit productivity of the object compound is so small and a large quantity of waste material is produced, which is highly unfavorable from a commercial point of view.
  • the enzyme is difficult to be recycled and thus becomes a waste product, resulting in raising the unit cost of the product.
  • the object of the present invention is to provide a process for producing an optically active intermediate for synthesis of cilastatin with a high optical purity and a good product yield in a simple and moderate way.
  • the present invention relates to a process for producing S-2,2- dimethylcyclopropanecarboxamide represented by the formula (I) as indicated below.
  • the process includes the steps of: (i) obtaining an ester compound of formula (II) by condensation of a compound of formula (D) with an alcohol;
  • R represents straight or branched Cwo alkyl with or without substituent(s), phenyl with or without substituent(s) or aryl with or without substituent(s).
  • Step 1 Preparation of the compound of formula (II).
  • the compound of formula (II) is obtained by condensing a compound (D) with an alcohol in the presence of an acid catalyst.
  • R represents straight or branched C MO alkyl with or without substituent(s), phenyl with or without substituent(s) or aryl with or without substituent(s).
  • the acid catalyst examples include hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoro acetic acid, methansulfonic acid, toluensulf ⁇ nic acid, trifluoromethansulfonic acid, phosphoric acid, PPA (polyphosphoric acid), silica impregnated with metal such as titanium, and zeolite.
  • the catalyst may be used in an amount of 0.000005 ⁇ 0.5 eq. on the basis of the compound of formula (D).
  • the reaction may be performed in the presence or absence of an aromatic solvent such as benzene, toluene and xylene, or a halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene, dichlorobenzene and trichlorobenzene.
  • aromatic solvent such as benzene, toluene and xylene
  • a halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene, dichlorobenzene and trichlorobenzene.
  • the compound of formula (II) is subjected to a selective hydrolysis using an enzyme to provide an optically active carboxylic acid of formula (G) and its counter- isomer, unreacted ester compound of formula (K). Then, the compound of formula (G) is isolated, which may be easily performed.
  • R represents straight or branched C O alkyl with or without substituent(s), phenyl with or without substituent(s), or aryl with or without substituent(s).
  • the enzyme refers to a hydrolase for hydrolyzing an ester, such as a lipase, a protease or an esterase, especially an enzyme capable of asymmetric hydrolysis of a racemic ester.
  • an ester such as a lipase, a protease or an esterase
  • the enzyme may be used in an immobilized form in terms of recovery, stability, optical selectivity and reaction efficiency.
  • the reaction it is preferable to perform the reaction in a high reaction concentration of 10wt% or more, which enables the product amount per unit to be 10 times more than that in the case of using conventional amidases. It indicates that the optically active compound (G) may be produced with a high efficiency in this process.
  • the compound of formula (G) may be effectively obtained with a quantitative yield of about 49% (theoretical yield: 50%) and a high optical purity of about 99%, while the yield and optical purity are about 20% and 93% ⁇ 98% respectively in the case of using conventional chemical resolution processes.
  • Examples of a solvent for the process are distilled water, phosphate buffer, and buffer including an organic or inorganic acid salt.
  • an organic solvent may be added into the solvent for improving the reactivity or solubility of the ester, or facilitating the recovery of the enzyme.
  • Step 3 Preparation of the compound of formula (I).
  • the compound of formula (I) is obtained by reacting the compound of formula (G) with ammonia.
  • the carboxylic acid of the compound of formula (G) is chlorinated using a chlorinating agent and reacted with ammonia to obtain the compound of formula (I).
  • chlorinating agent examples include chlorine, SOCl 2 , SO 2 Cl 2 , POCl 3 and PC1 5 , and the agent may be used in an amount of 1.0—2.0 eq. based on the compound of formula (G).
  • the reaction may be carried out in the presence or absence of a solvent and examples of the solvent are dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene and trichlorobenzene.
  • the reaction temperature is 100 ° C or below, preferably -30 ° C ⁇ 60 ° C .
  • the reaction becomes slow at a temperature of below -30 ° C, and side reactions may occur at a temperature of above 100 ° C .
  • optically active amide of formula (I) is an intermediate and useful for producing cilastatin (Ref. European Published Patent Application No. 048301).
  • the pH of the reaction was maintained at 7 by using 50% sodium hydrogen carbonate aqueous solution.
  • the esterase was filtered by a filter paper and 35% hydrochloric acid was slowly added to the filtrate in order to set the pH to 2.
  • 600mL of ethyl acetate was further added to the mixture and the mixture was agitated for 15 minutes.
  • the organic phase was separated from the aqueous phase then distilled so that the solvent and organic materials with low boiling point were recovered and S-2,2-dimethylcyclopropane carboxylic acid was obtained (yield : 49.1%, purity : 99.0%, optical purity : 99.1%).
  • Rf 0.5 (n-hexane/ethyl acetate, 2/1)
  • the present invention provides a method for preparing an optically active intermediate compound for cilastatin, in which the intermediate compound can be simply prepared with a high yield of 99.0% or more and a high optical purity of 99.5% without undergoing any dangerous processes.
  • a highly pure cilastain can be prepared in an economical and safe way according to the present invention.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Mechanical Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation d'un composé intermédiaire médical de la formule (1). Selon l'invention, on peut préparer sans difficulté un composé intermédiaire de la cilastatine avec un rendement supérieur ou égal à 99,0% et une pureté optique élevée de 99,5% sans devoir recourir à un quelconque processus dangereux.
PCT/KR2003/001328 2002-07-05 2003-07-04 Procede de production d'un amide optiquement actif WO2004005241A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003237069A AU2003237069A1 (en) 2002-07-05 2003-07-04 Process for producing optically active amide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2002-0039087A KR100511534B1 (ko) 2002-07-05 2002-07-05 아미드 화합물의 새로운 제조방법
KR10-2002-0039087 2002-07-05

Publications (1)

Publication Number Publication Date
WO2004005241A1 true WO2004005241A1 (fr) 2004-01-15

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2003/001328 WO2004005241A1 (fr) 2002-07-05 2003-07-04 Procede de production d'un amide optiquement actif

Country Status (3)

Country Link
KR (1) KR100511534B1 (fr)
AU (1) AU2003237069A1 (fr)
WO (1) WO2004005241A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100593569C (zh) * 2007-11-28 2010-03-10 浙江工业大学 蜡状芽孢杆菌及其制备手性2,2-二甲基环丙甲酸/酰胺
CN102533923A (zh) * 2011-12-19 2012-07-04 浙江工业大学 有机溶剂共溶剂生物拆分制备(s)-(+)-2,2-二甲基环丙烷甲酸的方法
CN103086910A (zh) * 2011-11-03 2013-05-08 Dhc有限公司 光学活性酰胺的制造方法
CN104193645A (zh) * 2014-07-15 2014-12-10 上海应用技术学院 一种手性二甲基环丙甲酰胺的制备方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100650797B1 (ko) * 2005-12-12 2006-11-27 (주)케미코월드 광학활성 사이클로프로판 카복사미드의 제조방법
KR100654923B1 (ko) * 2005-12-15 2006-12-06 (주)씨엘에스랩 고순도의 광학활성아미드를 연속적으로 제조하는 방법
KR100884558B1 (ko) 2008-09-11 2009-02-19 디에이치씨 (주) 고수율 및 고 광학순도의 광학활성 아미드의 제조방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0155779A1 (fr) * 1984-02-28 1985-09-25 Sumitomo Chemical Company, Limited Procédé pour la purification optique d'un amide 2,2-diméthylcyclopropanecarboxylique optiquement actif
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0155779A1 (fr) * 1984-02-28 1985-09-25 Sumitomo Chemical Company, Limited Procédé pour la purification optique d'un amide 2,2-diméthylcyclopropanecarboxylique optiquement actif
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAMOTSU FUJISAWA ET AL.: "Regioselective ring cleavage of chiral beta-trichloromethyl-beta-propiolac tone with organoluminum compounds for the synthesis of optically active intermediates", TETRAHEDRON LETTERS, vol. 39, no. 52, 1998, pages 9735 - 9738 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100593569C (zh) * 2007-11-28 2010-03-10 浙江工业大学 蜡状芽孢杆菌及其制备手性2,2-二甲基环丙甲酸/酰胺
CN103086910A (zh) * 2011-11-03 2013-05-08 Dhc有限公司 光学活性酰胺的制造方法
CN102533923A (zh) * 2011-12-19 2012-07-04 浙江工业大学 有机溶剂共溶剂生物拆分制备(s)-(+)-2,2-二甲基环丙烷甲酸的方法
CN104193645A (zh) * 2014-07-15 2014-12-10 上海应用技术学院 一种手性二甲基环丙甲酰胺的制备方法

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Publication number Publication date
KR100511534B1 (ko) 2005-08-31
KR20040004744A (ko) 2004-01-14
AU2003237069A1 (en) 2004-01-23

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