New 5-HT_3 (Serotonin-3) Receptor Antagonists. III. 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)

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(+)-8,9-Dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one hydrochloride (FK 1052,1) is a highly poten 5-HT_3 (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-a]indol-6(7H)-one ring. The Mannich reaction of (+)-8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (8) with [^<14>C]paraformaldehyde and dimethylamine hydrochloride gave the [^<14>C]-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[^<14>C]FK 1052 with a radiochemical purity of 99.4% and an enantiomeric excess of more than 97%.
社団法人日本薬学会の論文
1995-08-15