|
【结 构 式】 
|
【药物名称】 【化学名称】trans-3-[4-[6-Methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]cyclohexyl]-1H-indole- 5-carbonitrile 【CA登记号】302916-78-5 【 分 子 式 】C25H27N3O 【 分 子 量 】385.51344 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT Reuptake Inhibitors, 5-HT1A Antagonists |
合成路线1
Base-catalyzed condensation of 5-cyanoindole (I) with 1,4-cyclohexanedione mono-ethylene ketal (II) furnished the cyclohexenyl indole (III), which was further hydrogenated in the presence of Pd/C to the cyclohexyl analogue (IV). Subsequent hydrolysis of the ethylene ketal function of (IV) gave ketone (V).
| 【1】 Meagher, K.L.; et al.; Studies towards the next generation of antidepressants. Part 1: Indolylcyclohexylamines as potent serotonin reuptake inhibitors. Bioorg Med Chem Lett 2001, 11, 14, 1885. |
| 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) | 31341 | 5-Cyanoindole; Indole-5-carbonitrile; 1H-Indole-5-carbonitrile | 15861-24-2 | C9H6N2 | 详情 | 详情 |
| (II) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (III) | 52018 | 3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indole-5-carbonitrile | C17H16N2O2 | 详情 | 详情 | |
| (IV) | 52019 | 3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-indole-5-carbonitrile | C17H18N2O2 | 详情 | 详情 | |
| (V) | 47079 | 3-(4-oxocyclohexyl)-1H-indole-5-carbonitrile | C15H14N2O | 详情 | 详情 |
合成路线2
Acylation of 3-methoxyphenethyl amine (VI) with methyl chloroformate gave the corresponding carbamate (VII). Intramolecular cyclization of (VII) with hot polyphosphoric acid produced a mixture of isomeric isoquinolinones (VIII) and (IX) from which the desired 6-methoxy isomer (IX) was isolated by column chromatography. Reduction of (IX) with LiAlH4 furnished the tetrahydro isoquinoline (X). Then reductive alkylation of amine (X) with ketone (V) in the presence of NaBH(OAc)3 produced the corresponding cyclohexyl amine as a mixture of cis/trans isomers. The title trans compound was obtained from the reaction mixture by chromatographic separation.
| 【1】 Meagher, K.L.; et al.; Studies towards the next generation of antidepressants. Part 1: Indolylcyclohexylamines as potent serotonin reuptake inhibitors. Bioorg Med Chem Lett 2001, 11, 14, 1885. |
| 【2】 Meagher, K.L.; Mewshaw, R.E. (American Home Products Corp.); Tetrahydroisoquinolinyl-indole derivs. for the treatment of depression. WO 0064886 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 47079 | 3-(4-oxocyclohexyl)-1H-indole-5-carbonitrile | C15H14N2O | 详情 | 详情 | |
| (VI) | 37185 | 2-(3-methoxyphenyl)-1-ethanamine; 3-methoxyphenethylamine | 2039-67-0 | C9H13NO | 详情 | 详情 |
| (VII) | 47076 | methyl 3-methoxyphenethylcarbamate | C11H15NO3 | 详情 | 详情 | |
| (VIII) | 52503 | 8-(methyloxy)-3,4-dihydro-1(2H)-isoquinolinone | C10H11NO2 | 详情 | 详情 | |
| (IX) | 47077 | 6-methoxy-3,4-dihydro-1(2H)-isoquinolinone | C10H11NO2 | 详情 | 详情 | |
| (X) | 47078 | methyl 1,2,3,4-tetrahydro-6-isoquinolinyl ether; 6-methoxy-1,2,3,4-tetrahydroisoquinoline | C10H13NO | 详情 | 详情 |