Rapid Enabling of Negishi Couplings for a Pair of mGluR5 Negative Allosteric Modulators

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• 作者：Alexander Gontcharov ; Joshua R. Dunetz
• 刊名：Organic Process Research & Development
• 出版年：2014
• 出版时间：September 19, 2014
• 年：2014
• 卷：18
• 期：9
• 页码：1145-1152
• 全文大小：440K
• ISSN：1520-586X

文摘

A pair of end game Negishi reactions was developed for the large-scale synthesis of two mGluR5 negative allosteric modulators from a common template. Key developmental aspects include the preparation of the core iodide and organozinc reagents, the management of an exotherm during cross-coupling by switching from a batch process to a semibatch process, and the removal of metals (Pd, Zn, Mg) from the Negishi products. Various aqueous workups, carbon treatments, and Si-Thiol were screened for the purging of heavy metals to regulatory limits, a task made more challenging by the metal coordinating abilities of both drug substances. In the case of one API, a series of crystallizations was required to provide the drug substance with the desired purity and solid form. Both of these Negishi couplings were implemented on hectogram to kilogram scale under the aggressive timelines of early process development.