Development of an Expedient Process for the Multi-Kilogram Synthesis of Chk1 Inhibitor GDC-0425
详细信息 查看全文
- 作者：Andreas Stumpf ; Zhigang Ken Cheng ; Brian Wong ; Mark Reynolds ; Remy Angelaud ; James Girotti ; Alan Deese ; Christine Gu ; Lewis Gazzard
- 刊名：Organic Process Research & Development
- 出版年：2015
- 出版时间：June 19, 2015
- 年：2015
- 卷：19
- 期：6
- 页码：661-672
- 全文大小：487K
- ISSN：1520-586X
文摘
A process leading to the multikilogram GMP synthesis of Chk1 inhibitor GDC-0425 (1) was developed. Highlights of the synthesis include protection of the pyrrole ring of a 1,7-diazacarbazole as propyl ethyl ether, an efficient Pd catalyzed cyanation of an aryl chloride, aryl ether formation by SNAr fluoride displacement, and development of a controlled crystallization providing the API with the required polymorphic form. The process delivered high-quality GDC-0425 with low levels of impurities and residual metals in five steps and 31% overall yield.