title: New 5-HT3 (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).
abstract: (+)-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 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-a]indol-6,(7H)-one ring. The Mannich reaction of (+)-8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2- ]indol-6(7H)-one (8) with [14C]paraformaldehyde and dimethylamine hydrochloride gave the [14C]-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 [14C]FK 1052 with a radiochemical purity of 99.4% and an enantiomeric excess of more than 97%.
authors.affiliation: New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.forename: S
authors.initials: S
authors.lastname: Nishino
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Takasugi
mesh_terms: D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D008352:Mannich Bases; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D007093:Imidazoles; D007211:Indoles; D008352:Mannich Bases; D012702:Serotonin Antagonists; C081308:FK 1052