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【结 构 式】 
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【药物名称】 【化学名称】cis-3-[4-[6-Methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl]cyclohexyl]-1H-indole-5-carbonitrile 【CA登记号】302916-76-3, 302916-77-4 (hydrochloride) 【 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
Condensation of 3-methoxyphenethylamine (I) with methyl chloroformate in the presence of Et3N gave carbamate (II). This was cyclized to the isoquinolinone (III) by treatment with polyphosphoric acid at 140 C. Reduction of lactam (III) with LiAlH4 provided the tetrahydroisoquinoline (IV). Reductive condensation of (IV) with 4-(5-cyano-3-indolyl)cyclohexanone (V) employing sodium triacetoxyborohydride furnished the corresponding 1,4-disubstituted cyclohexane as a cis/trans mixture from which the desired cis-isomer was isolated by column chromatography.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (I) | 37185 | 2-(3-methoxyphenyl)-1-ethanamine; 3-methoxyphenethylamine | 2039-67-0 | C9H13NO | 详情 | 详情 |
| (II) | 47076 | methyl 3-methoxyphenethylcarbamate | C11H15NO3 | 详情 | 详情 | |
| (III) | 47077 | 6-methoxy-3,4-dihydro-1(2H)-isoquinolinone | C10H11NO2 | 详情 | 详情 | |
| (IV) | 47078 | methyl 1,2,3,4-tetrahydro-6-isoquinolinyl ether; 6-methoxy-1,2,3,4-tetrahydroisoquinoline | C10H13NO | 详情 | 详情 | |
| (V) | 47079 | 3-(4-oxocyclohexyl)-1H-indole-5-carbonitrile | C15H14N2O | 详情 | 详情 |
合成路线2
The intermediate 4-(5-cyano-1H-indol-3-yl)cyclohexanone (V) has been obtained as follows: The condensation of 1H-indole-5-carbonitrile (VI) with cyclohexanone monoethyleneketal (VII) by means of KOH in refluxing methanol gives the cyclohexenone ethyleneketal (VIII), which is reduced with H2 over Pd/C in ethanol to yield 4-(5-cyano-1H-indol-3-yl)cyclohexanone ethyleneketal (IX). Finally, this compound is hydrolyzed to the target intermediate (V) with HCl in THF.
| 【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.; Smith, D.L.; Scerni, R.; Shi, X.; Albuthawa, S.; Andree, T.H.; Mewshaw, R.E.; Schechter, L.E.; Evrard, D.A.; Indolylcyclohexylamines as potent serotonin reuptake inhibitors. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 108. |
| 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) | 31341 | 5-Cyanoindole; Indole-5-carbonitrile; 1H-Indole-5-carbonitrile | 15861-24-2 | C9H6N2 | 详情 | 详情 |
| (VII) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (VIII) | 52018 | 3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-indole-5-carbonitrile | C17H16N2O2 | 详情 | 详情 | |
| (IX) | 52019 | 3-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-indole-5-carbonitrile | C17H18N2O2 | 详情 | 详情 |