A Practical and Scalable Synthesis of a Glucokinase Activator via Diastereomeric Resolution and Palladium-Catalyzed C–N Coupling Reaction

Abstract

Here we describe the research and development of a process for the practical synthesis of glucokinase activator ( R )-1 as a potential drug for treating type-2 diabetes. The key intermediate, chiral α-arylpropionic acid ( R )-2, was synthesized in high diastereomeric excess through the diasteromeric resolution of 7 without the need for a chiral resolving agent. The counterpart 2-aminopyrazine derivative 3 was synthesized using a palladium-catalyzed C–N coupling reaction. This efficient process was demonstrated at the pilot scale and yielded 19.0 kg of ( R )-1 . Moreover, an epimerization process to obtain ( R )-7 from the undesired ( S )-7 was developed.