Efficient and Scalable Synthesis of Glucokinase Activator with a Chiral Thiophenyl-Pyrrolidine Scaffold

Abstract

Herein we describe the practical synthesis of a potent glucokinase activator (1) that has a chiral thiophenyl-pyrrolidine scaffold. The key to the successful synthesis was the application of a telescoped chiral-pool synthesis from a commercially available l-proline methyl ester derivative to introduce the chirality of the thiophenyl-pyrrolidine moiety. This second-generation synthesis of 1 provided several advantages over the previous method including an operational simplicity and avoidance of purification by column chromatography. The industrial relevance of this synthetic method in large-scale preparation was demonstrated by the production of 54.6 kg of 1 with an excellent chemical and optical purity.