PRODUCTION OF -2-(4-METHOXYPHENYL)-1,5-BENZOTHIAZEPIN-4(5H)-ONE, A KEY INTERMEDIATE FOR DILTIAZEM SYNTHESIS, BY BAKERS YEAST-MEDIATED REDUCTION

Bakers' yeast-mediated reduction of methoxyphenyl)-1,5-benzothiazepin- 3,4(2H,5H)-dione [(RS)-1] to 2-(4-methoxyphenyl)-1,5-benzo-thiazepin-4 (5H)-one, a key intermediate in the synthesis of diltiazem hydrochlori de, was investigated for industrial application. We found that an aggr egate of (RS)-1, formed by the addition of its DMF solution to water, was soluble in an aqueous medium at about 20 mg/l. Thus, the asymmetri c reduction using the (RS)-1 aggregate successively proceeded in the p resence of ethanol under aerobic conditions. In this procedure, 100 g of the substrate was reduced in 1 l of the aqueous medium to produce t he desired chiral intermediate with over 99% enantiomeric excess in 80 % yield.