Synthesis of 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)]acetic acid methyl ester, acetic acid, and acetamide analogs as potential antiarthritic agents

The cuprous iodide catalyzed reaction of 2-methyl-2-[1-(3-benzoyl-4-phenylpyridinium)]acetic acid methyl ester bromide (5), prepared by reaction of 3-benzoylpyridine (4) with racemic methyl 2-bromopropionate, with phenylmagnesium chloride at -23 degrees C afforded the 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)acetic acid methyl ester (6, 74%), which was a mixture of four diastereomers. Recrystallization of this diastereomeric mixture from diethyl ether afforded a solid product (6a-solid, 30%, 4R*, 2R* and 4S*, 2S*) and an oil product (6b-oil, 39%, 4R*, 2S* and 4S*, 2R*), each consisting of a mixture of two diastereomers that differ in relative configuration (R* or S*) at the 1,4-dihydropyridine C-4 position and the -CH(Me)CO2Me moiety. Addition of the Grignard reagent from either of the two diastereotopically different faces of the planar pyridinium salt (5) gives rise to two diastereomeric products 6a-solid and 6b-oil in which the C-4 phenyl substituent is pseudoaxial to the boat-shaped 1,4-dihydropyridine ring. Alkaline hydrolysis, or ammonolysis, of the acetic acid methyl ester (6) afforded the respective acetic acid (7), or acetamide (8), derivative.