Kato M, Nishino S, Ito K, Takasugi H
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 1995 Aug;43(8):1346-50. doi: 10.1248/cpb.43.1346.
(+)-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%.
（+）-8,9-二氢-10-甲基-7-[(5-甲基-1H-咪唑-4-基)甲基]吡啶并[1,2-a]吲哚-6(7H)-酮盐酸盐（FK 1052，1）是一种高效的5-HT3（5-羟色胺-3）受体拮抗剂。为了研究FK 1052（1）的代谢和处置情况，我们以10-去甲基FK 1052（8）为原料，通过三步合成了碳-14标记的FK 1052。曼尼希反应以及随后二甲基氨基甲基的氢解反应使得能够在吡啶并[1,2-a]吲哚-6,(7H)-酮环的10位高效引入一个碳原子。（+）-8,9-二氢-7-[(5-甲基-1H-咪唑-4-基)甲基]吡啶并[1,2- ]吲哚-6(7H)-酮（8）与[14C]多聚甲醛和盐酸二甲胺发生曼尼希反应，得到[14C]-10-二甲基氨基甲基化合物（20）。随后用钯-炭和甲酸铵对20进行氢解，接着用（+）-二对甲苯甲酰-D-酒石酸对盐进行重结晶，得到放射化学纯度为99.4%且对映体过量超过97%的[14C]FK 1052。
