Development of the Commercial Route for the Manufacture of a 5-Lipoxygenase Inhibitor PF-04191834
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- 作者：Brian Chekal ; David Damon ; Danny LaFrance ; Kyle Leeman ; Carlos Mojica ; Andrew Palm ; Michael St. Pierre ; Janice Sieser ; Karen Sutherland ; Rajappa Vaidyanathan ; John Van Alsten ; Brian Vanderplas ; Carrie Wager ; Gerald Weisenburger ; Gregory Withbroe ; Shu Yu
- 刊名：Organic Process Research & Development
- 出版年：2015
- 出版时间：December 18, 2015
- 年：2015
- 卷：19
- 期：12
- 页码：1944-1953
- 全文大小：646K
- ISSN：1520-586X
文摘
A de novo three-step-one-pot process for the formation of PF-04191834 was developed. This methodology employed inexpensive, odorless, and readily available commodity chemical iso-octyl-3-mercaptopropionate as a sulfur source, which could be a general alternative to the popular TIPS-SH in the formation of diarylthioethers via Migita coupling. A kinetic study revealed that, at high temperature, reductive elimination could be the rate-limiting step in the catalytic cycle, which opens pathways for the generation of undesired impurities. By proper control of the reaction conditions, the desired API was synthesized in >70% crude yield and in 55% isolated yield after vigorous purifications. This process was successfully demonstrated on a 20 kg scale.