Efficient Alternative Synthetic Route to Diltiazem via (2R, 3S)-3-(4-Methoxyphenyl)glycidamide

Abstract

An effective new route to diltiazem, a representative coronary vasodilator, through (-)-(2R, 3S)-3-(4-methoxyphenyl)glycidamide [(-)-2] has been achieved. The glycidamide (-)-2 was prepared in 43% overall yield by a combination of the enzymatic resolution of methyl (±)-(2RS, 3SR)-3-(4-methoxyphenyl)glycidate [(±)-1] with lipase and the following amidation of (-)-1 with ammonia. A one-pot synthesis through the treatment of (-)-2 with 2-aminothiophenol and a following ring closing reaction efficiently gave a key intermediate of diltiazem synthesis, (2S, 3S)-2, 3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1, 5-benzothiazepin-4(5H)-one [cis-(+)-5] in 80% overall yield.