Production of (S2,3S)-2,3-dihydro-3-hydroxy-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 (RS)-2-(4-methoxyphenyl)-1,5-benzothiazepin-3,4(2H,5H)-dione [(RS)-1] to (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzo-thiazepin-4(5H)-one, a key intermediate in the synthesis of diltiazem hydrochloride, was investigated for industrial application. We found that an aggregate 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 asymmetric reduction using the (RS)-1 aggregate successively proceeded in the presence of ethanol under aerobic conditions. In this procedure, 100 g of the substrate was reduced in 1 l of the aqueous medium to produce the desired chiral intermediate with over 99% enantiomeric excess in 80% yield.