Palbociclib Commercial Manufacturing Process Development. Part II: Regioselective Heck Coupling with Polymorph Control for Processability

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• 作者：Mark T. Maloney ; Brian P. Jones ; Mark A. Olivier ; Javier Magano ; Ke Wang ; Nathan D. Ide ; Andrew S. Palm ; David R. Bill ; Kyle R. Leeman ; Karen Sutherland ; John Draper ; Adrian M. Daly ; Joseph Keane ; Denis Lynch ; Marie O’Brien ; Joanne Tuohy
• 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：1203-1216
• 全文大小：914K
• 年卷期：0
• ISSN：1520-586X

文摘

A three-step commercial manufacturing route has been developed for palbociclib, a highly selective, reversible inhibitor of CDK 4/6. The second step, which utilizes a Heck coupling to install the enol ether side chain, is described. A highly regioselective catalyst was identified for this transformation along with reaction conditions that ensure robustness upon scale-up. Effective removal of palladium was accomplished via filtration of insoluble metal and an extractive chelation step. Finally, efficient isolation of coupled product 3 was achieved through careful polymorph control via seeding and an optimized cooling protocol that avoids nucleation of a kinetically favored, slow-filtering polymorph.