WO1999045134A1 - RESOLUTION OPTIQUE DE α-ALKYL-β-THIOLACTONES UTILISANT UNE ENZYME HYDROLYTIQUE - Google Patents

RESOLUTION OPTIQUE DE α-ALKYL-β-THIOLACTONES UTILISANT UNE ENZYME HYDROLYTIQUE Download PDF

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Publication number
WO1999045134A1
WO1999045134A1 PCT/KR1998/000040 KR9800040W WO9945134A1 WO 1999045134 A1 WO1999045134 A1 WO 1999045134A1 KR 9800040 W KR9800040 W KR 9800040W WO 9945134 A1 WO9945134 A1 WO 9945134A1
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WIPO (PCT)
Prior art keywords
alkyl
thiolactone
reaction
mixture
enantiomers
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Ceased
Application number
PCT/KR1998/000040
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English (en)
Inventor
Byung Gee Kim
Bum Yeol Hwang
Young Gyu Kim
Hee Bong Lee
Eun Young Hwang
Sang Hyup Lee
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Hanwha Corp
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Hanwha Corp
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Priority to PCT/KR1998/000040 priority Critical patent/WO1999045134A1/fr
Publication of WO1999045134A1 publication Critical patent/WO1999045134A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • C12P11/00—Preparation of sulfur-containing organic compounds
    • 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

Definitions

  • the present invention relates to a process for preparing an (R)- -alkyl- ⁇ -thiolactone or an (S)- a -alkyl- ⁇ -mercaptopropionic acid by stereo-selectively hydrolyzing a mixture of R and S enantiomers of a -alkyl- ⁇ -thiolactone using a hydrolytic enzyme.
  • n 1 or 2
  • R 2 , R 3 and R 4 independently of one another represent alkyl, cycloalkyl, etc.
  • reaction yield and optical purity of the product in the prior art process are 22-46% and 80-98%, respectively, which are somewhat insufficient to meet further application of this product.
  • some protection- deprotection reactions and complex condensation reactions should be carried out additionally.
  • the present invention uses a mixture of R and S enantiomers of -alkyl- ⁇ -thiolactone, preferably a -alkyl- ⁇ -thiolactone racemate represented by the following formula 2 as a starting material, from which (R)- a -alkyl- ⁇ -thiolactone represented by the following formula 3 or (S)- a -alkyl- ⁇ -mercaptopropionic acid represented by the following formula 4 is obtained :
  • R represents C ⁇ -C 6 alkyl
  • (S)-form thiolactone is selectively hydrolyzed by a hydrolytic enzyme to produce (R)- a -alkyl- ⁇ -mercaptopropionic acid represented by the following formula 5, which is removed during the subsequent separation procedure.
  • the (S)- a -alkyl- ⁇ -mercaptopropionic acid is obtained when only the (R)-form thiolactone among the mixture is hydrolyzed due to the stereo-selectivity of the hydrolytic enzyme used.
  • the remained (S)- a -alkyl- ⁇ -thiolactone represented by the following formula 6 is removed during the separation procedure.
  • R represents C ⁇ -C 6 alkyl
  • (R)- a -alkyl- ⁇ -thiolactone compounds obtained according to the present invention (R)- a -methyl- ⁇ -thiolactone wherein methyl is attached to the -position °f thiolactone can be used as a useful and economic intermediate for synthesizing optically active medicines such as captopril, zofenopril, etc.
  • the reaction system according to the present invention consists essentially of a mixture of R and S enantiomers of a -alkyl- ⁇ -thiolactone, preferably a -alkyl- ⁇ -thiolactone racemate, as the starting material (in other words, substrate for the enzymatic reaction), a hydrolytic enzyme such as lipase, etc., an organic solvent and a small quantity of buffer solution to maintain the enzyme activity. If desired, surfactants may be added to the reaction solution in order to increase the enzyme activity.
  • organic solvent one or more selected from a group consisting of n-hexane, cyclohexane, n-heptane, cyclohexanone, n-octane, benzene, toluene, acetone, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, dioxane, diethylether, dimethylformamide and tetrahydrofuran can be used in an amount of 10 to 500 times by weight with respect to the starting material.
  • the reaction solution becomes so concentrated that the reaction rate is lowered at the point near the reaction completion and that the optical purity of the product is deteriorated when the solvent is used in an amount of less than 10 times by weight. Also, it is uneconomic due to the use of excess solvent when the solvent is used in an amount of more than 500 times by weight.
  • Buffer solutions which can be used in the present invention include phosphate buffer, bicarbonate buffer and Tris-HCl buffer having pHs ranging from 6.0 to 8.5.
  • the reaction rate becomes very slow when the buffer solution is used in a less amount than that of the starting material, and the stereo-selectivity may be deteriorated when the buffer solution is used in an excess amount of more than 50 times by weight, it is preferable to use it in an amount of 1 to 50 times by weight with respect to the starting material.
  • the surfactant one or more selected from a group consisting of Triton X-100[PEG(9-10) p-t-octylphenol, Sigma], Triton X-114[PEG(7-8) p-t-octylphenol, Sigma], Twin 80[PEG(20) sorbitan monooleate, Sigma], Twin 20[PEG(20) sorbitan monolaurate, Sigma], sodium dodecyl sulfate(SDS), lithium dodecyl sulfate(LDS), sodium cholate, sodium deoxy cholate, octyl glucoside[octyl- ⁇ -D-glucopyranoside, Aldrich], Brij 35[PEG(23) lauryl alcohol, Sigma], CHAPS[3-[(3-cholamidopropyl)-dimethylammonio]-l- propane-sulfonate, Sigma] and Xwittergent 3-14[N-alkyl-N
  • Hydrolytic enzymes which can be used in the present invention to cany out the optical resolution include lipases, proteases and esterases.
  • a lipase derived from Pseudomonas cepacea, a lipase derived from Penicillium roqueforti, a cholesterol esterase, a lipase derived from Penicillium camembertii, a lipase derived from Aspergillus, a lipase derived from Rhizopus japonicus, a lipase derived from calf tongue root and chymopapain can be mentioned.
  • Free enzymes or immobilized enzymes on a support may be employed in the reaction solution.
  • the suitable support for the enzyme immobilization one or more selected from a group consisting of ceramic, celite, silica gel, alumina, borosilicate, calcium carbonate and zeolite can be mentioned.
  • said enzyme may be suspended in the reaction system or may be filled into a column. In the latter case, the reaction can be proceeded by passing the reaction solution through the column filled with an enzyme immobilized on a support at an appropriate flow rate, then by recycling the eluant. The reaction may not be carried out smoothly and accordingly, the yield may be lowered when the enzyme is used in an amount of less than 0.1 times by weight with respect to the starting material.
  • the separation process may be cumbersome and uneconomic. Therefore, it is preferable to use the enzyme in the amount ranging from 0.1 to 100 times by weight with respect to the starting material. It is more preferable to use the enzyme in the amount ranging from 0.3 to 15 times by weight.
  • the present reaction is carried out at temperatures ranging from -20 to 70 °c for 8 to 72 hours.
  • temperatures ranging from -20 to 70 °c for 8 to 72 hours.
  • weak basic work-up may be carried out to separate the desired (R)- a -alkyl- ⁇ -thiolactone or (S)- a -alkyl- ⁇ -mercaptopropionic acid, which are then analyzed by HPLC.
  • an efficient analysis can be achieved when ChiralPack AS HPLC column(manufactured by Daicel Co., Japan) is used with n-hexane as an eluent at 0.7 m ⁇ /min of gradient flow rate.
  • the eluent and column type can be varied and easily selected by a person having ordinary skill in the art upon considering the kind of substituents.
  • Example 7 10 m g of a -ethyl- ⁇ -thiolactone racemate was dissolved in 2 m ⁇ > of cyclohexane and then 500 ⁇ of phosphate buffer solution (1M, pH 7.5) was added thereto. 5 ra g of the lipase derived from Pseudomonas cepacect was added to the reaction solution and the reaction was started at 45 °Q . The reaction was stopped after 8 hours and the desired product was separated in the same procedure as Example 1 to obtain (R)- a -ethyl- ⁇ -thiolactone with a yield of 45% (99.0% ee, purity by HPLC).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (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

La présente invention a trait à un procédé de préparation d'une (R)-α-alkyl-β-thiolactone ou d'un acide (S)-α-alkyl-β-mercaptopropionique par une hydrolyse stéréosélective d'un mélange d'énantiomères R et S d'une α-alkyl-β-thiolactone utilisant une enzyme hydrolytique.
PCT/KR1998/000040 1998-03-04 1998-03-04 RESOLUTION OPTIQUE DE α-ALKYL-β-THIOLACTONES UTILISANT UNE ENZYME HYDROLYTIQUE Ceased WO1999045134A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR1998/000040 WO1999045134A1 (fr) 1998-03-04 1998-03-04 RESOLUTION OPTIQUE DE α-ALKYL-β-THIOLACTONES UTILISANT UNE ENZYME HYDROLYTIQUE

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR1998/000040 WO1999045134A1 (fr) 1998-03-04 1998-03-04 RESOLUTION OPTIQUE DE α-ALKYL-β-THIOLACTONES UTILISANT UNE ENZYME HYDROLYTIQUE

Publications (1)

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WO1999045134A1 true WO1999045134A1 (fr) 1999-09-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105506052A (zh) * 2015-11-23 2016-04-20 浙江理工大学 一种提高有机相中游离脂肪酶催化拆分性能的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289804A2 (fr) * 1987-04-09 1988-11-09 Toyo Jozo Co., Ltd. Procédé de préparation de composés mercaptan optiquement actifs
US5106736A (en) * 1991-04-23 1992-04-21 E.R. Squibb & Sons, Inc. Enzymatic process for enantiomer-specific perparation of mercapto alkanoic acid compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289804A2 (fr) * 1987-04-09 1988-11-09 Toyo Jozo Co., Ltd. Procédé de préparation de composés mercaptan optiquement actifs
US5106736A (en) * 1991-04-23 1992-04-21 E.R. Squibb & Sons, Inc. Enzymatic process for enantiomer-specific perparation of mercapto alkanoic acid compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105506052A (zh) * 2015-11-23 2016-04-20 浙江理工大学 一种提高有机相中游离脂肪酶催化拆分性能的方法

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