Multikilogram Synthesis of a Hepatoselective Glucokinase Activator

• DOI: 10.1021/op300194c
• Publication Date: 2012-08-31T01:35:57Z
• Authors: 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 Martínez
• Keywords: Glucokinase; Racemization; Amide

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