Process Research and Development for the Kilogram Manufacture of the SRC Kinase Inhibitor AZD0530

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• 作者：J. Gair Ford ; Simon M. Pointon ; Lyn Powell ; Paul S. Siedlecki ; John Baum ; Richard Chubb ; Robin Fieldhouse ; James Muxworthy ; Alex Nivlet ; Rachel Stenson ; Eleanor Warwick
• 刊名：Organic Process Research & Development
• 出版年：2010
• 出版时间：September 17, 2010
• 年：2010
• 卷：14
• 期：5
• 页码：1078-1087
• 全文大小：273K
• 年卷期：v.14,no.5(September 17, 2010)
• ISSN：1520-586X

文摘

Process research and development of a synthetic route towards a novel SRC kinase inhibitor is described. The Medicinal Chemistry route was very long and suffered from extensive use of chlorinated solvents and chromatography. A number of steps in the Medicinal Chemistry route were also unattractive for large-scale use for a variety of reasons. The route was modified to produce a shorter synthetic scheme that started from more readily available materials. By using the modified route, the title compound was manufactured on kilogram scale without recourse to chromatography and in significantly fewer steps. The scaled synthesis required two Mitsunobu couplings, which were developed and scaled successfully. An interesting hydrazine impurity was identified in the second Mitsunobu coupling; a mechanism for its formation is proposed, and a method for its control is described. The formation and control of some other interesting impurities are also described.