Synthesis and biological activity of 5-(4-chlorobenzoyl)-4-(hydroxymethyl)-1-methyl-1H-pyrrole-2-acetic acid, a major metabolite of zomepirac sodium.

5-(4-Chlorobenzoyl)-4-(hydroxymethyl)-1-methyl-1H-pyrrole-2-acetic acid (2), the major oxidative metabolite of zomepirac (1), was synthesized starting with ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate (3), the ethyl ester of 1. Compound 3 was oxidized with selenium dioxide to afford the alpha-oxoester, 5. Bromination of 5 with N-bromosuccinimide produced bromomethylpyrrole 7, and reaction of 7 with acetate produced by corresponding acetoxymethylpyrrole 8. Hydrogen sulfide effected the selective reduction of the side-chain carbonyl group if 8 to give 9. Saponification of 9 gave the title compound, 2. Synthetic 2 was identical with the isolated metabolite of zomepirac (1). Biological testing revealed that the metabolite was essentially devoid of the biological activity associated with zomepirac.