A Robust Process for an mGluR5 Negative Allosteric Modulator: Difluoromethylation and Sonogashira Coupling on Large Scale
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- 作者：Jeffrey B. Sperry ; Roger M. Farr ; Mahmut Levent ; Mousumi Ghosh ; Steven M. Hoagland ; Richard J. Varsolona ; Karen Sutherland
- 刊名：Organic Process Research & Development
- 出版年：2012
- 出版时间：November 16, 2012
- 年：2012
- 卷：16
- 期：11
- 页码：1854-1860
- 全文大小：315K
- 年卷期：v.16,no.11(November 16, 2012)
- ISSN：1520-586X
文摘
The development of the potent and selective mGluR5 negative allosteric modulator (NAM) 1 is described. Key features in the process, which has been implemented on a multikilogram scale, include a high-temperature difluoromethylation reaction, a Sonogashira coupling, and careful control of residual Pd and Cu in the final API. Due to the relative nonpolar nature of the intermediates, water-miscible solvents were employed in all four steps to allow for direct crystallizations upon reaction completion. In addition, several crystalline morphologies of the API were discovered, and the isolation of the desired form II will be discussed.