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【结 构 式】 
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【药物名称】Ricasetron, BRL-46470 【化学名称】endo-3,3-Dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydroindole-1-carboxamide 【CA登记号】117086-68-7 【 分 子 式 】C19H27N3O 【 分 子 量 】313.44654 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, Anxiolytics, GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, 5-HT3 Antagonists |
合成路线1
The target compound has been obtained by condensation of 3.3-dimethylindoline-1-carbonyl chloride (IV) with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (II) by means of triethylamine followed by salification with HCl. The intermediates (II) and (IV) have been obtained as follows: A) The metthylation of 3-methylindole (III) with methylmagnesium iodid / methyl iodid, followed by hydrogenation with H2/Pt in acetic acid gives 3,3-dimethylindoline (I), which is then treated with phosghene / Et3N to afford intermediate (IV). B) The reductocondensation of 8-methyl-para-bicyclo[3.2.1]octan-3-one (V) with benzylamine and H2/Pt gives the secondary benzylamine (VI), which is finally deprotected by hydrogenation over Pd/C to give intermediate (II).
| 【1】 Archer, S.; Lewis, T.R.; Unser, M.J.; 3alpha-(2-Diethylaminoethyl)-aminotropane and related compounds. J Am Chem Soc 1957, 79, 4194-8. |
| 【2】 Miyasaka, T.; Mutai, M.; Nokata, K.; Sawada, S.; Sugino, E. (Yakult Honsha Co., Ltd.); New camptothecin derivs. and process for preparing same. EP 0137145; JP 1985019790 . |
| 【3】 Joiner, K.A.; King, F.D. (SmithKline Beecham plc); Certain 2,3-dihydro-indole-1-carboxamido-N-[8-azabicyclo(3.2.1)octan-3-yl] derivatives having 5-HT-antagonist activity. EP 0363466; JP 1990503569; US 4871744; US 5049556; WO 8909217 . |
| 【4】 Blackburn, T.; King, F.; BRL46470A. Drugs Fut 1992, 17, 11, 987. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 12411 | 3,3-Dimethylindoline | C10H13N | 详情 | 详情 | |
| (II) | 12412 | (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine | C8H16N2 | 详情 | 详情 | |
| (III) | 63428 | 3-methyl-1H-indole | C9H9N | 详情 | 详情 | |
| (IV) | 12414 | 3,3-Dimethyl-1-indolinecarbonyl chloride | C11H12ClNO | 详情 | 详情 | |
| (V) | 16443 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one | C8H13NO | 详情 | 详情 | |
| (VI) | 12413 | N-Benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amine; (1R,5S)-N-Benzyl-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C15H22N2 | 详情 | 详情 |