PREPARATION OF Y-2-(4-METHOXYPHENYL)-1,5-BENZOTHIAZEPIN-4(5H)-ONE BY MICROBIAL CONVERSION

Microbial production of 3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)- 1,5- benzothiazepin-4(5H)-one [(2S,3S)-DHMB], a key intermediate in th e synthesis of diltiazem hydrochloride, was investigated. In the cours e of the screening of microorganisms for the hydrolysis of y-2-(4-meth oxyphenyl)-1,5-benzothiazepin-4(5H)-one (AMB), the genera Alcaligenes, Arthrobacter, Bacillus, and Rhodococcus were found to give (2S,3S)-DH MB from AMB directly at high conversion levels (67-77%) with excellent enantioselectivity [>99% enantiomeric excess (e.e.)]. By using Bacill us sphaericus FERM P-6746, which afforded the highest conversion, the following reaction pathway was postulated: (RS)-2-(4-methoxyphenyl)-1, 5-benzothiazepin-3 ,4(2H,5H)-dione [(RS)-MBD] was an intermediate, fro m which the selective reduction subsequently proceeded. This hydrolyti c enzyme was induced by AMB. This microbial conversion process provide s an efficient method for the synthesis of diltiazem hydrochloride bec ause fewer processes are required and the product can be obtained with a high yield.