Palbociclib Commercial Manufacturing Process Development. Part I: Control of Regioselectivity in a Grignard-Mediated SNAr Coupling

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• 作者：Shengquan Duan ; David Place ; Hahdi H. Perfect ; Nathan D. Ide ; Mark Maloney ; Karen Sutherland ; Kristin E. Price Wiglesworth ; Ke Wang ; Mark Olivier ; Fangming Kong ; Kyle Leeman ; Jon Blunt ; John Draper ; Marie McAuliffe ; Maria O’Sullivan ; Denis Lynch
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：July 15, 2016
• 年：2016
• 卷：20
• 期：7
• 页码：1191-1202
• 全文大小：672K
• 年卷期：0
• ISSN：1520-586X

文摘

This is the first in a series of three papers describing commercial manufacturing process development for palbociclib (1). This manuscript focuses on the S_NAr coupling between aminopyridine 3 and chloropyrimidine 7. The regioselectivity of the S_NAr coupling was studied from a synthetic and mechanistic perspective. Grignard bases were identified as the preferred class of bases for this reaction, allowing for a simplified process and reduced usage factor for aminopyridine 3. The development of this S_NAr reaction into a scalable commercial manufacturing process is also described.