Synthesis Optimization, Scale-Up, and Catalyst Screening Efforts toward the MGAT2 Clinical Candidate, BMS-963272

This paper describes the efficient scale-up synthesis of 1 (BMS-963272) which relies upon a highly selective Mannich-type alkylation strategy to stereospecifically install a quaternary carbon center. An intramolecular cyclization reaction is also used to form the aryl dihydropyridone (ADHP) core. The optimized route has been demonstrated to provide more than 100 g of active pharmaceutical ingredient for preclinical toxicology evaluation. A catalyst screening effort is also discussed as part of a complimentary convergent approach which will facilitate a more expedient assessment of back-up molecules bearing aryl diversity at the C4-position of the ADHP core.