Development of an Enantioselective Hydrogenation Based Synthesis of a Glucokinase Activator

This article describes the development and optimization of chemical reactions and subsequent multi-kilogram preparation of the glucokinase activator (R)-1 to fund clinical evaluation as a potential therapeutic for type II diabetes. The major process developments presented here are a Wittig olefination isomerization based synthesis of an E-acrylic acid, an optimized enantioselective hydrogenation of the E-acrylic acid, and a challenging final amide coupling.