Lipase-Catalyzed Asymmetric Hydrolysis of 3-Phenylglycidic Acid Ester, the Key Intermediate in the Synthesis of Diltiazem Hydrochloride

概要

論文の詳細を見る
Asymmetric hydrolytic enzymes for trans-3-(4-methoxyphenyl)glycidic acid methyl ester [(±)-MPGM], a key intermediate in the synthesis of diltiazem hydrochloride that is useful as a coronary vasodilator, were screened from 730 microorganisms. Among the microbial enzymes tested, Serratia marcescens lipase had the highest enantioselectivity (E=135) for hydrolysis of (±)-MPGM in a two-phase system water (pH 8) and a water-immiscible solvent such as toluene. Resolution of (±)-MPGM by S. marcescens lipase gave (2R, 3S)-3-(4-methoxyphenyl)glycidic acid methyl ester [(-)-MPGM] with a reaction yield of 48% and optical purity of >99.9% e.e. After the reaction, the emulsion of toluene and water was separated into two clear layers by the addition of sodium dodecyl sulfate. The crystalline (-)-MPGM was isolated with a yield of over 43% and optical purity of 100% e.e. without column tratment. Diltiazem hydrochloride synthesis using asymmetric hydrolysis of (±)-MPGM was found to be a more efficient process compared to the conventional chemical synthetic process. Some enzymatic characterizatinos on asymmetric hydrolysis in two-phases of organic solvent-water by S. marcescens lipase were investigated.
公益社団法人日本生物工学会の論文
1993-02-25