Process Development of Febuxostat Using Palladium- and Copper-Catalyzed C-H Arylation

There is significant interest in the development of process routes for active pharmaceutical ingredients using C-H arylation methodology. An efficient and practical synthetic route for febuxostat (1), which is the first non-purine-type xanthine oxidase inhibitor, was established via palladium- and copper-catalyzed C-H arylation of thiazole with aryl bromide. The catalyst loading was reduced to 0.1 mol % for the intermolecular C-H arylation, and a three-step synthesis produced febuxostat in 89% overall yield with excellent selectivity.