Development of a Process to a 4-Arylated 2-Methylisoquinolin-1 (2H)-one for the Treatment of Solid Tumors: Lessons in Ortho- Bromination, Selective Solubility, Pd Deactivation, and Form Control

We here present an optimized, scalable synthesis of bromodomain and extra-terminal (BET) inhibitor BMS-986378 (CC-90010). The original route and process 1A was 7 steps with 33.8% yield and featured numerous problematic solvents, process safety concerns, difficult to scale unit operations, and challenging to control impurities. Reaction optimization to remove or mitigate these challenges resulted in our first scale-up route and process, 2A. Subsequent challenges encountered on scale-up of route and process 2A warranted the creation and implementation of an enhanced process, which eliminated dichloromethane from a phenol bromination, improved catalyst performance in the penultimate cross-coupling, and finally developed a concomitant solvent charging process for form control in the final API crystallization. The resulting scale-up route and process, 2B, was demonstrated on a > 50 kg scale and afforded the final product in 49% yield over 7 steps in > 99.9% assay and area purity, meeting all ICH requirements for quality.