Process Development of a Potent Glucosylceramide Synthase Inhibitor

被引：28

作者：

Cooper, Christopher G. F. ^{[1
]}

Lee, Edward R. ^{[1
]}

Silva, Richard A. ^{[1
]}

Bourque, Andre J. ^{[1
]}

Clark, Scott ^{[1
]}

Katti, Sanjeev ^{[1
]}

Nivorozhkin, Vitaly ^{[1
]}

机构：

[1] Genzyme Corp, Waltham, MA 02451 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2012年 / 16卷 / 05期

关键词：

INSULIN SENSITIVITY; REDUCTION; DISEASE; ETHERS;

D O I：

10.1021/op2001222

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

An economic, scalable process for the production of glucosylceramide synthase (GCS) inhibitor 7 has been developed. Herein we report a three-step synthesis to aldehyde 4 with high yield and purity that employs the selective cleavage of an endocyclic C-O bond of a THP ether using borane/THF as the key step. This particular methodology has not been used previously from a development standpoint and offers an attractive way towards introducing pentanol side chains. Aldehyde 4 is then coupled with deoxynojirimycin via flow hydrogenation using an H-Cube to safely produce the free base of 7, which is isolated as an MSA salt in 50% overall yield. Herein we discuss the evolution of this process from its original form and the thermodynamics of its associated chemistry.

引用

页码：1090 / 1097

页数：8

共 20 条

[1] Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity [J].