Chem. Pharm. Bull., 47(2), 146-150, February 1999

Regular Articles

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

Shin-ichi YAMADA, Ikuko TSUJIOKA, Takeji SHIBATANI, and Ryuzo YOSHIOKA^*

Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 16-89, Kashima-3-chome, Yodogawa-ku, Osaka 532-8505,
Japan. Received July 8, 1998; accepted November 20, 1998

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.

Key words diltiazem; glycidamide; addition reaction; ring closing reaction