A Practical Synthesis of a PI3K Inhibitor under Noncryogenic Conditions via Functionalization of a Lithium Triarylmagnesiate Intermediate

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• 作者：Qingping Tian ; Zhigang Cheng ; Herbert M. Yajima ; Scott J. Savage ; Keena L. Green ; Theresa Humphries ; Mark E. Reynolds ; Srinivasan Babu ; Francis Gosselin ; David Askin ; Isao Kurimoto ; Norihiko Hirata ; Mitsuhiro Iwasaki ; Yasuharu Shimasaki ; Takashi Miki
• 刊名：Organic Process Research & Development
• 出版年：2013
• 出版时间：January 18, 2013
• 年：2013
• 卷：17
• 期：1
• 页码：97-107
• 全文大小：452K
• 年卷期：v.17,no.1(January 18, 2013)
• ISSN：1520-586X

文摘

We report a practical synthesis of PI3K inhibitor GDC-0941. The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under noncryogenic conditions to produce the corresponding aldehyde. We also investigated aminoalkylation via a benzotriazolyl-piperazine substrate as an alternative to the reductive amination route. We evaluated both palladium and nickel catalyzed processes for the borylation and Suzuki-Miyaura cross-coupling. Final deprotection and salt formation afforded the API.