NEW 5-HT3 (SEROTONIN-3) RECEPTOR ANTAGONISTS .3. AN EFFICIENT SYNTHESIS OF CARBON 14-LABELED (+)-8,9-DIHYDRO-10-METHYL-7-[(5-METHYL-1H-IMIDAZOL-4-YL)METHYL]PYRIDO[1,2-A]INDOL-6(7H)-ONE HYDROCHLORIDE (FK-1052)

(+)-8,9-Dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-alpha]indol-6(7H)-one hydrochloride (FX 1052, 1) is a highly potent 5-HT3 (serotonin-3) receptor antagonist. For the study of the metabolism and disposition of FK 1052 (1), we synthesized carbon 14-labeled FK 1052 in three steps from 10-demethyl FK 1052 (8). The Mannich reaction and subsequent hydrogenolysis of the dimethylaminomethyl group enabled the efficient introduction of one carbon atom at the 10-position of the pyrido[1,2-alpha]indol-6(7H)-one ring. The Mannich reaction of (+)-8,9-dihydro-7-C(5-methyl-1H-imidazol-4-yl)methyl]pyrido [1,2-alpha]iodol6(7H)-one (8) with [C-14]paraformaldehyde and dimethylamine hydrochloride gave the [C-14]-10-dimethylaminomethyl compound (20). Subsequent hydrogenolysis of 20 with palladium on carbon and ammonium formate, followed by recrystallization of the salt with (+)-di-p-toluoyl-D-tartaric acid, gave [C-14]FK 1052 with a radiochemical purity of 99.4% and an enantiomeric excess of more than 97%.