Multikilogram Synthesis of a Hepatoselective Glucokinase Activator

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• 作者：Joshua R. Dunetz ; Martin A. Berliner ; Yanqiao Xiang ; Timothy L. Houck ; Fabrice H. Salingue ; Wang Chao ; Chen Yuandong ; Wang Shenghua ; Yun Huang ; Douglas Farrand ; Steven J. Boucher ; David B. Damon ; Teresa W. Makowski ; Mark T. Barrila ; Raymond Chen ; Isamir Mart铆nez
• 刊名：Organic Process Research & Development
• 出版年：2012
• 出版时间：October 19, 2012
• 年：2012
• 卷：16
• 期：10
• 页码：1635-1645
• 全文大小：554K
• 年卷期：v.16,no.10(October 19, 2012)
• ISSN：1520-586X

文摘

This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone 伪-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively non-nucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator.