A Practical Synthesis of a Diazepinylbenzoic Acid, a Retinoid X Receptor Antagonist

An optimized convergent synthetic route for the preparation of retinoid X receptor (RXR) antagonist ( 1 ) in an overall yield of 35% is described. The formation of the benzodiazepine was achieved in 85% yield using POCl 3 in toluene. The drug substance 14 was obtained by treatment of aryl bromide with vinyl butyl ether in the presence of palladium acetate, DPPP, and cesium carbonate This one-pot operation incorporating three chemical transformations (i.e., Heck reaction, hydrolysis of vinyl ether, and hydrolysis of ester) was achieved in 85% yield.