NEW SYNTHESIS OF THE 4-PYRIDONES AND 6-PYRIDONES OF 1-METHYLNICOTINAMIDE AND 1-METHYLNICOTINIC ACID (TRIGONELLINE)

New routes are described for preparation of the 4- and 6-pyridones of 1-methylnicotinamide and 1-methylnicotinic acid (trigonelline). For the 4-pyridone series, a carboxyl group is introduced into 4-hydroxypyridine at C-3 by high-pressure carbonation and the resulting 4-hydroxynicotinic acid converted to the amide through ammonolysis of the methyl ester. Both the acid and the amide are then N1-alkylated with methyl iodide. For the 6-pyridone series, commercially available 6-hydroxynicotinic acid is N1-alkylated with methyl iodide and the resulting 6-pyridone of 1-methylnicotinic acid converted to the 6-pyridone of 1-methylnicotinamide by ammonolysis of the acid chloride. The above alkylations do not occur under neutral conditions but do proceed smoothly in the presence of alkali. Spectrophotometric data are given for the compounds of major interest and a chromatographic separation is described for the naturally occurring pyridones and other urinary metabolites of nicotinamide and nicotinic acid.