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

• Published in: Chemical & pharmaceutical bulletin Vol. 47; no. 2; pp. 146 - 150
• Main Authors: YAMADA, Shin-ichi, TSUJIOKA, Ikuko, SHIBATANI, Takeji, YOSHIOKA, Ryuzo
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 1999; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: addition reaction; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; diltiazem; Exact sciences and technology; glycidamide; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Life Sciences & Biomedicine; Organic chemistry; Pharmacology & Pharmacy; Physical Sciences; Preparations and properties; ring closing reaction; Science & Technology; diltiazem; addition reaction; ring closing reaction; glycidamide; KEY INTERMEDIATE; HYDROCHLORIDE; Sulfur nitrogen heterocycle; Lactam; Benzothiazepine derivatives; Acid catalysis; Sulfonic acid; Cyclization; Epoxide; Addition reaction; Bicyclic compound; Carboxamide; Aromatic compound; Aminothiol; Chemical synthesis
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.47.146

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.