Microbial Asymmetric Reduction of (RS)-2-(4-Methoxyphenyl)-1,5-benzothiazepin-3,4(2H, 5H)-dione, the Key Intermediate in the Synthesis of Diltiazem Hydrochloride

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Microbial production of (2S, 3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one [(2S, 3S)-2], a key intermediate in the synthesis of diltiazem hydrochloride, was examined. The reduction of (RS)-2-(4-methoxyphenyl)-1,5-benzothiazepin-3,4(2H, 5H)-dione [(RS)-1] by various microorganisms produced a mixture of stereoisomers with the (2S, 3S) stereoisomer being the major product. Among the microorganisims tested, baker's yeast afforded the highest conversion yleld and excellent stereoselectivity for the production of (2S, 3S)-2. When asymmetric reduction using baker's yeast was carried out at the substrate concentration of 3.34 mM with the addition of N, N-dimethylformamide solution containing 0.0334-0.334 M (RS)-1 to the reaction mixture, the reaction gave (2S, 3S)-2 with a conversin yield of 92-94% and an optical purity of >99.9% enantiomeric excess. Crystals of (2S, 3S)-2 were isolated with a total yield of 85%. 3-Hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one S-oxide [oxide-1] and (2RS, 3SR)-2 were formed as by-products in the reaction mixture. The optimum conditions for (2S, 3S)-2 production containing a minimum amount of by-products were pH 7.0 and 42℃. The decrease of the conversion yield of (2S, 3S)-2 was attributable to the conversion to oxide-1 with increasing substrate concentration. It was concluded that the production method of diltiazem hydrochloride using microbial asymmetric reduction was an excellent method from the viewpoint of yield.
社団法人日本生物工学会の論文
1995-01-25

Microbial Asymmetric Reduction of (RS)-2-(4-Methoxyphenyl)-1,5-benzothiazepin-3,4(2H, 5H)-dione, the Key Intermediate in the Synthesis of Diltiazem Hydrochloride

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