The Synthesis of a Novel Inhibitor of B-Raf Kinase

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• 作者：Donatienne Denni-Dischert ; Wolfgang Marterer ; Markus B&auml ; nziger ; Naeem Yusuff ; David Batt ; Tim Ramsey ; Peng Geng ; Walter Michael ; Run-Ming B. Wang ; Francis Taplin ; Jr. ; Richard Versace ; David Cesar
• 刊名：Organic Process Research & Development
• 出版年：2006
• 出版时间：January 2006
• 年：2006
• 卷：10
• 期：1
• 页码：70 - 77
• 全文大小：116K
• 年卷期：v.10,no.1(January 2006)
• ISSN：1520-586X

文摘

A scaleable synthetic route to [4,7']bis-isoquinolinyl-1-yl-(2-tert-butyl-pyrimidine-5-yl)amine (1), an inhibitor of B-Raf kinaseis described. The key step in the synthesis is the Pd-catalyzedNegishi coupling of 4-bromo-1-chloroisoquinoline with trifluoromethanesulfonic acid isoquinoline-7-yl ester to yield 1-chloro[4,7']bis-isoquinolinyl. This intermediate is transformed to thedesired drug substance in one additional step, by reaction with2-tert-butyl-5-aminopyrimidine in the presence of NaH. Aspecial focus was put on the finally successful removal of tracesof Zn and Pd in the drug substance, which came from theNegishi coupling.