Convergent, Kilogram Scale Synthesis of an Akt Kinase Inhibitor

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• 作者：Pintipa Grongsaard ; Paul G. Bulger ; Debra J. Wallace ; Lushi Tan ; Qinghao Chen ; Sarah J. Dolman ; Jason Nyrop ; R. Scott Hoerrner ; Mark Weisel ; Juan Arredondo ; Takahiro Itoh ; Chengfu Xie ; Xianghui Wen ; Dalian Zhao ; Daniel J. Muzzio ; Ephraim M. Bassan ; C. Scott Shultz
• 刊名：Organic Process Research & Development
• 出版年：2012
• 出版时间：May 18, 2012
• 年：2012
• 卷：16
• 期：5
• 页码：1069-1081
• 全文大小：548K
• 年卷期：v.16,no.5(May 18, 2012)
• ISSN：1520-586X

文摘

The development of a convergent, chromatography-free synthesis of an allosteric Akt kinase inhibitor is described. The route comprised 17 total steps and was used to produce kilogram quantities of the target molecule. A key early transformation, for which both batch and flow protocols were developed, was formylation of a dianion derived by deprotonation and subsequent lithium-halogen exchange from a 2-bromo-3-aminopyridine precursor. Improved reaction yield and practicality were achieved in the continuous processing mode. Further significant process developments included the safe execution of a high temperature and pressure hydrazine displacement, separation of substituted cyclobutane diastereomers by means of chemoselective ester hydrolysis, and a late-stage Suzuki fragment coupling under mild conditions.