Synthesis of Filibuvir. Part III. Development of a Process for the Reductive Coupling of an Aldehyde and a β-Keto-lactone
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- 作者：Nathan D. Ide ; John. A. Ragan ; Gabriel Bellavance ; Steve J. Brenek ; Eric M. Cordi ; Grace O. Jensen ; Kris N. Jones ; Danny LaFrance ; Kyle R. Leeman ; Leo J. Letendre ; David Place ; Corey L. Stanchina ; Gregory W. Sluggett ; Holly Strohmeyer ; Jon Blunt ; Kevin Meldrum ; Stuart Taylor ; Ciaran Byrne ; Denis Lynch ; Sandra Mullane ; Maria M. O’Sullivan ; Marcella Whelan
- 刊名：Organic Process Research & Development
- 出版年：2014
- 出版时间：January 17, 2014
- 年：2014
- 卷：18
- 期：1
- 页码：45-56
- 全文大小：560K
- ISSN：1520-586X
文摘
Development of a reductive coupling of a 尾-keto-lactone and an aldehyde is described, in which the Hantzsch ester serves as an inexpensive and convenient reducing agent. Structural features in the 尾-keto-lactone rendered standard reductive coupling conditions ineffective, requiring development of a specific addition and temperature protocol. Identification of one of the reactants as Ames positive required a single-digit parts per million control strategy for this impurity in the final active pharmaceutical ingredient (API).