Development of a Scalable Synthesis of a Bruton’s Tyrosine Kinase Inhibitor via C–N and C–C Bond Couplings as an End Game Strategy

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• 作者：Jun-Bae Hong ; James P. Davidson ; Qingwu Jin ; Gary R. Lee ; Michael Matchett ; Erin O’Brien ; Michael Welch ; Bill Bingenheimer ; Keshab Sarma
• 刊名：Organic Process Research & Development
• 出版年：2014
• 出版时间：January 17, 2014
• 年：2014
• 卷：18
• 期：1
• 页码：228-238
• 全文大小：502K
• ISSN：1520-586X

文摘

A scalable and convergent synthesis of a BTK (Bruton鈥檚 tyrosine kinase) inhibitor has been developed. Synthetic routes to key intermediates were explored for the scale-up campaign, especially the process for 6-dimethylaminodihydroisoquinolinone, which was prepared via a regioselective cyclization of an isocyanate, mediated by AlCl₃. Improved routes to key building blocks were demonstrated by expedient multikilogram productions. The target compound was assembled through a Pd-catalyzed amidation reaction followed by a Suzuki鈥揗iyaura cross-coupling reaction.