Development of a Multigram Preparation of Optically Pure (−)-7-(Bromomethylene)-3-amidobicyclo[2.2.1]heptane-2-carboxamide BMT-395137, a Versatile Scaffold for Divergent Drug Discovery Synthesis

This paper describes the development of a synthetic route for the multigram synthesis of (−)-(1R,2S,3R,4R,Z)-7-(bromomethylene)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2,2,2-trifluoroacetamido)bicyclo[2.2.1]heptane-2-carboxamide ((−)-14, BMT-395173), a versatile scaffold for divergent drug discovery synthesis. This new process begins with readily available commercial starting materials and includes a highly scalable stereoselective Diels–Alder reaction between (Z)-4-(benzyloxy)-4-oxobut-2-enoic acid (21) and ferrocenium hexafluorophosphate (15), resulting in the formation of alcohol rac-20. Additionally, a stereoselective Wittig reaction of ketone rac-10 with (bromomethyl)triphenylphosphonium bromide introduces the bromomethylene group of (−)-14. The process was applied to the preparation of over 100 g of optically pure BMS-395173 via multiple batches for preclinical chemotype optimization.