Development of an Efficient, Safe, and Environmentally Friendly Process for the Manufacture of GDC-0084

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• 作者：Andreas Stumpf ; Andrew McClory ; Herbert Yajima ; Nathaniel Segraves ; Remy Angelaud ; Francis Gosselin
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：April 15, 2016
• 年：2016
• 卷：20
• 期：4
• 页码：751-759
• 全文大小：462K
• 年卷期：0
• ISSN：1520-586X

文摘

An improved, efficient process with a significantly reduced process mass intensity (PMI) led to the multikilogram synthesis of a brain penetrant PI3K inhibitor GDC-0084. Highlights of the synthesis include a phase transfer catalyzed annulation in water, an efficient Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a low palladium catalyst loading, and the development of a controlled crystallization to provide the API. The process delivered GDC-0084 with low levels of both impurities and residual metals.