Process Development and Scale-Up of BIIB129, a Covalent, Selective and Brain Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis

Abstract Optimization of the original discovery synthesis of the cnsBTK inhibitor BIIB129 from gram to multikilogram scale in support of early phase clinical trials and formulation studies is presented. Highlighted process improvements include (1) a 20% increase in overall yield after process optimization; (2) an 85% decrease in PMI (process mass intensity) for the entire synthetic process including starting materials; (3) a 70% reduction in API cost, and (4) improved API impurity controls. These improvements resulted in the successful preparation of 12 kg of crystalline BIIB129 drug substance to support phase I clinical trials.