一种用于大规模制备(2R,3S)-3-(4-甲氧基苯基)缩水甘油酸甲酯的实用方法，地尔硫卓的关键中间体。

A practical procedure for the large-scale preparation of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate, a key intermediate for diltiazem.

作者信息

Furutani Toshiyuki, Imashiro Ritsuo, Hatsuda Masanori, Seki Masahiko

机构信息

Product & Technology Development Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, Japan.

出版信息

J Org Chem. 2002 Jun 28;67(13):4599-601. doi: 10.1021/jo025647b.

DOI:10.1021/jo025647b

PMID:12076164

Abstract

A practical synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), was developed. Treatment of methyl (E)-4-methoxycinnamate 3 with chiral dioxirane, generated from chiral ketone 4, provided (-)-2 in 77% ee and 89% yield. The crude mixture of (-)-2 and 4 was efficiently separated by the use of novel and simple equipment performing a lipase-catalyzed transesterification and a continuous dissolution and crystallization to furnish the optically pure (-)-2 and recovery of 4 in 74% and 91% yield, respectively.

摘要

开发了一种实用的合成方法来制备甲基 (2R,3S)-3-(4-甲氧基苯基)缩水甘油酸酯 (-)-2，它是地尔硫卓 (1) 的关键中间体。用由手性酮 4 生成的手性二氧杂环丙烷处理 (E)-4-甲氧基肉桂酸甲酯 3，得到对映体过量值为 77% 且产率为 89% 的 (-)-2。通过使用新型简单设备进行脂肪酶催化的酯交换反应以及连续溶解和结晶，有效地分离了 (-)-2 和 4 的粗混合物，分别以 74% 和 91% 的产率得到光学纯的 (-)-2 并回收 4。