Decoration of an α-Resorcylate Nucleus as Part of the Manufacture of a Glucokinase Activator

The need to define a set of processes for the manufacture of a glucokinase activator called for an evaluation of different strategies to differentiate the hydroxyls of an alpha-resorcylic acid derivative. While direct functionalization proved possible, it did not allow access to crystalline intermediates that offered control over the rejection of process impurities. The strategy taken forward involved the installation of a benzoyl protecting group using careful control of pH in order to achieve useful levels of selectivity. This allowed the remaining alpha-resorcylate hydroxyl to be functionalized using a Mitsunobu reaction, with liquid-liquid partitioning being used to separate downstream intermediates of interest away from the redox byproducts of this reaction. Downstream challenges that were overcome in order to deliver a commercially viable means of manufacturing the API included developing an amidation reaction with a poorly reactive aminopyrazine coupling partner.