WO2004087932A2 - Resolution enzymatique de (±) methyl trans-3-phenyl glycidate - Google Patents

Resolution enzymatique de (±) methyl trans-3-phenyl glycidate Download PDF

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Publication number
WO2004087932A2
WO2004087932A2 PCT/IN2003/000239 IN0300239W WO2004087932A2 WO 2004087932 A2 WO2004087932 A2 WO 2004087932A2 IN 0300239 W IN0300239 W IN 0300239W WO 2004087932 A2 WO2004087932 A2 WO 2004087932A2
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WIPO (PCT)
Prior art keywords
phenylglycidate
trans
methyl
alkyl
transesterification
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PCT/IN2003/000239
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English (en)
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WO2004087932A3 (fr
Inventor
Ranjith Dr. Nair
Dhanalakshmi Dr. Kasi
Somasundaram Muthuramalingam
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Shasun Chemicals And Drugs Limited
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Application filed by Shasun Chemicals And Drugs Limited filed Critical Shasun Chemicals And Drugs Limited
Priority to AU2003253250A priority Critical patent/AU2003253250A1/en
Publication of WO2004087932A2 publication Critical patent/WO2004087932A2/fr
Publication of WO2004087932A3 publication Critical patent/WO2004087932A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • 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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • 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
    • C12P41/004—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 alcohol- or thiol 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
    • C12P7/62—Carboxylic acid esters

Definitions

  • This invention relates to the enzymatic resolution of trans-3- 5 phenylglycidyl esters with high enantiomeric excess using lipozyme (a class of hydrolytic enzyme) and the synthesis of novel chiral alkyl trans- phenylglycidates.
  • the process involves transesterification of methyl trans-3 -phenylglycidate with various alcohols at ambient temperature to obtain (2R, 3S) methyl ⁇ raws-phenylglycidate and (2S, 3, R) alkyl transit) phenylglycidate. Study is also focussed on the effect of solvents, reaction conditions, length of the alkyl chain on the entioselectivity of the glycidate. BACKGROUND OF THE INVENTION
  • esters of 3-phenylglycidic acid are known compounds, 15 described in literature and widely used as synthetic intermediates.
  • Methyl trans-3 -phenylglycidate is a useful intermediate for the synthesis of C-13 side chain (phenyl isoserine) of taxol, an anticancer drug.
  • C-13 side chain phenyl isoserine
  • Synthesis of taxol using phenyl isoserine has been reported in Product Letters, Volume 6, 147. 20
  • the presence of the taxol side chain is very important for the antitumor activity of taxol.
  • it is very essential to develop an enantioselective synthesis route for phenylisoserine, which can be adopted for large : scale production.
  • the convenient and economical way of synthesising phenylisoserine is from optically active trans-3- 25 phenylglycidic esters.
  • chiral glycidates can be made by the resolution of the racemic mixture by chemical or enzymatic methods.
  • Previously W. E. Ladner and G. M. Whitesides had employed enzymatic hydrolysis in the resolution of carboxylic acid esters to chiral epoxy alcohols: J. Am Chem. So ⁇ , 106, 7250-7251 and US Pat. No 4,732,853 (1988).
  • US Pat. No 4923810 (1990) by A. E. Walts and E. M. Fox describes the resolution of glycidyl esters to high enantiomeric excess employing lipases to selectively hydrolyse one enantiomer of the glycidyl esters.
  • Lipase catalysed esterifications and transesterifications in organic solvents were pioneered by Klibanov et al. (Zaks and Klibanov in Science, 224, 1249-1251; A. M. Klibanov in Trends in Biochemical Sciences, 1989, 14, 141-144 and A. M. Klibanov in Ace. Chem. Res. 1990, 23, 1 14-120).
  • Enzymatic transformations in organic solvents offer advantages like carrying out transesterifcation reactions instead of hydrolysis.
  • the selectivity of lipase can be enhanced by changing the organic solvent, which is sometimes called as solvent (medium) engineering. Also moisture sensitive compounds could be resolved in organic solvents. Additionally, the separation of the hydrophilic product from organic solvents is easier than from water.
  • Tanabe in JP06/078790 reports a similar process of kinetic resolution of phenylglycidates catalysed by esterases in which alcohol (C2-C10) are use m the transesterification reaction.
  • (2R, 3S)-3-(4- methoxyphenyl)glycidate was obtained with high optical purity; however this method involved chromatographic techniques for the separation of the esters formed.
  • Tanabe Seiyaku Co. Limited in JP08259552A2 describes a process to_obtain optically active phenylglycidate by subjecting a racemic mixture of trans-3 phenylglycidate with an alcohol in the presence of esterases enzyme.
  • the entire process may not be cost- effective at industrial scales, as it does not utilize supported enzymes for the transesterification.
  • US patent no. 6187936 Bl discloses the process for the enzymatic kinetic resolution of 3-phenylglycidates by transesterification with aminoalcohols.
  • optically active (2R, 3S) methyl trans 3 ⁇ phenyl glyci dates were obtained and the separation of the other amino ester formed during the above transesterification was achieved by acidification.
  • This process does not mention about the optical and chemical yield of the amino esters thus formed.
  • the lower alcohols used in the process may not facilitate the easy separation of the esters formed, possibly making it difficult to determine the chemical and optical purity of the isomers.
  • the research is focussed on the use of immobilized enzymes for various transformations.
  • the object of the present invention is therefore to provide a novel process for enzymatic resolution of trans-3-phenylglycidyl esters with high enantiomeric excess.
  • the present invention comprises of a method for preparing (2S,3R) alkyl trans-3 -phenylglycidate or (2R,3S) methyl trans-3 -phenylglycidate comprising:
  • the reaction is carried out at ambient temperature.
  • the transesterification agent is an alcohol selected from butanol, pentanol, hexanol, octanol and decanol, preferably octanol.
  • the organic solvent is selected from toluene, tetrahydrofuran (THF) and chloroform and more preferably toluene.
  • step (ii) (2S,3R) alkyl trans-3 -phenylglycidate is isolated from
  • the methanol released from the trans-esterification reaction is removed under vacuum.
  • the molar ratio of ⁇ methyl ?ra «5-3-phenylglycidate to trans- esterification agent is 1.0
  • This invention also includes novel (2S, 3 R) alkyl trans- phenylglycidates of the formula:
  • R phenyl, hexyl, octyl and decyl
  • the present invention relates to a method for preparing chiral trans-3 -phenylglycidate esters with high enantiomeric excess, by enzymatic transesterifcation.
  • the reaction was carried out in different solvents such as chloroform, THF and toluene. All these reactions were performed at 25 - 30°C temperature.
  • the quantity of enzyme used in the initial study was about 15 % by weight with respect to the substrate.
  • Octanol was used as the transesterification agent.
  • the reaction time was kept constant and the progress of the reaction was monitored by chiral HPLC.
  • the amount of enzyme required for the reaction was studied and optimised as shown in Table 3.
  • the resolution of ( ⁇ )-methyl trans-3- phenyl glycidate was carried out by varying the enzyme quantity like 15 %, 10 % and 5 % with respect to the substrate with octanol as a transesterification agent and toluene as the solvent.
  • Example: 1 General procedure for the transesterification of racemic methyl trans-3-phenyl glycidate with octanol in toluene Racemic methyl trans-3 -phenylglycidate (10 g) was taken in toluene (6v). 0.5 g of lipozyme and ocatanol (1 equiv.) were added and stirred at 25 - 30 °C. Me ⁇ anol formed in the reaction was removed by applying vacuum to the reaction mixture. The progress of the reaction was monitored by chiral HPLC.
  • Example 2 Procedure for enhancing the optical purity of (2R, 3S) methyl *r «s-3-phenyl glycidate by transesterification of racemic methyl trans-3- ⁇ enyl glycidate with octanol in toluene
  • Racemic methyl raw.s-3-phenylglycidate (10 g) was taken in toluene (6v). 0.5 g of lipozyme and ocatanol (1 equiv.) were added and stirred at 25 - 30°C. Methanol formed in the reaction was removed by applying vacuum to the reaction mixture. The progress of the reaction was monitored by chiral HPLC.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne un procédé de préparation de (2S,3R) alkyl trans-3-phénylglycidate ou de (2R,3S) méthyl trans-3-phénylglycidate qui consiste en: la résolution enzymatique par trans-estérification de ± méthyl trans-3-phénylglycidate à excédent d'énantiomère, au moyen de lipozyme en présence d'un agent de transestérification et d'un solvant organique, en vue de l'obtention de (2R,3S) méthyl trans-3-phénylglycidate et de (2S,3R) alkyl trans-3-phénylglycidate ; et l'isolement de (2S,3R) alkyl trans-3-phénylglycidate dans le (2R,3S) méthyl trans-3-phénylglycidate.
PCT/IN2003/000239 2003-04-02 2003-07-14 Resolution enzymatique de (±) methyl trans-3-phenyl glycidate WO2004087932A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003253250A AU2003253250A1 (en) 2003-04-02 2003-07-14 Enzymatic resolution of (plus or minus) methyl trans-3-phenyl glycidate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN278/MAS/2003 2003-04-02
IN278CH2003 2003-04-02

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WO2004087932A2 true WO2004087932A2 (fr) 2004-10-14
WO2004087932A3 WO2004087932A3 (fr) 2005-01-13

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5998637A (en) * 1997-02-27 1999-12-07 Tanabe Seiyaku Co., Ltd. Process for preparing optically active trans-3-substituted glycidic acid ester

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5998637A (en) * 1997-02-27 1999-12-07 Tanabe Seiyaku Co., Ltd. Process for preparing optically active trans-3-substituted glycidic acid ester

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