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【结 构 式】 
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【分子编号】13312 【品名】N-Methyl-1-ethylenesulfonamide 【CA登记号】 |
【 分 子 式 】C3H7NO2S 【 分 子 量 】121.16012 【元素组成】C 29.74% H 5.82% N 11.56% O 26.41% S 26.47% |
合成路线1
该中间体在本合成路线中的序号：(IV)Naratriptan can be obtained by several related ways: 1) The reaction of 5-bromoindole (I) with 1-methylpiperidin-4-one (II) by means of KOH in methylated spirit (or methanol) at room temperature gives 5-bromo-3-(4-(hydroxy-1-methylpiperidin-4-yl)-1H-indole (III) (1, 2), which is condensed with N-methylvinylsulfonamide (IV) by means of palladium acetate and tri-p-tolyl phosphine in hot (110 C) DMF to afford (E)-N-methyl-2-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]vinylsulfonamide (V). Finally, this compound is hydrogenated with H2 over Pd/C in DMF/water/HCl, DMF/water/methanol/HCl, or water/methanesulfonic acid. 2) The reaction of indole (I) with piperidone (II) or with 4-hydroxy-1-methylpiperidine (VI) by means of KOH in refluxing methylated spirit or 1-propanol gives 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (VII), which is then condensed with N-methylvinylsufonamide (IV) as before, yielding the substituted sulfonamide (V), already obtained. 3) The hydrogenation of the tetrahydropyridine (VII) with H2 over PtO2 in methanol/HCl gives 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole (VIII), which is finally condensed with N-methylvinylsulfonamide (IV) as before yielding N-methyl-2-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]vinylsulfonamide (XI). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol/DMF/HCl. 4) The reaction of 5-bromoindole (I) with sulfonamide (IV) by means of palladium acetate as before gives 2-(1H-indol-3-yl)-N-methylvinylsulfonamide (IX), which is condensed with piperidone (II) by means of refluxing KOH as before, yielding the substituted tetrahydropyridine (V), already obtained. 5) The condensation of sulfonamide (IX) with piperidone (II), by means of KOH at room temperature as before gives N-methyl-2-[3-(4-hydroxy-1-methylpiperidin-4-yl)-1H-indol-3-yl] vinylsulfonamide (X), which is dehydrated to tetrahydropyridine (V) with KOH in refluxing methylated spirit. 6) The cyclization of 2-(4-hydrazinophenyl)-N-methylethanesulfonamide (XII) with 2-(1-methylpiperidin-4-yl)acetaldehyde (XIII) by means of HCl in water. 7) The reaction of 2-(1H-indol-5-yl)-N-methylethanesulfonamide (XIV) with piperidone (II) by means of KOH in refluxing methanol, yielding N-methyl-2-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl] ethylsulfonamide (XV), which is finally hydrogenated with H2 over Pd/C in ethanol/DMF.
| 【1】 Mealy, N.; Castaner, J.; Naratriptan. Drugs Fut 1996, 21, 5, 476. |
| 【2】 Oxford, A.W.; Butina, D.; Owen, M.R. (Glaxo Wellcome plc); Indole derivs. AU 8820692; EP 0303507; GB 2208646; JP 1989207288; US 4997841 . |
| 【3】 Blatcher, P.; Carter, M.; Hornby, R.; Owen, M.R. (Glaxo Wellcome plc); Process for the preparation of N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide. WO 9509166 . |
| 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) | 13309 | 5-Bromo-1H-indole; 5-Bromoindole | 10075-50-0 | C8H6BrN | 详情 | 详情 |
| (II) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (III) | 13311 | 4-(5-Bromo-1H-indol-3-yl)-1-methyl-4-piperidinol | 66306-26-9 | C14H17BrN2O | 详情 | 详情 |
| (IV) | 13312 | N-Methyl-1-ethylenesulfonamide | C3H7NO2S | 详情 | 详情 | |
| (V) | 13313 | (E)-N-Methyl-2-[3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indol-5-yl]-1-ethenesulfonamide | 166306-28-1 | C17H21N3O2S | 详情 | 详情 |
| (VI) | 13314 | 4-Hydroxy-1-methylpiperidine; 1-Methyl-4-piperidinol; 4-Hydroxy-N-methylpiperidine; N-Methyl-4-hydroxypiperidine | 106-52-5 | C6H13NO | 详情 | 详情 |
| (VII) | 13315 | 5-Bromo-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole | 116480-53-6 | C14H15BrN2 | 详情 | 详情 |
| (VIII) | 13316 | 5-Bromo-3-(1-methyl-4-piperidinyl)-1H-indole | 66306-26-9 | C14H17BrN2 | 详情 | 详情 |
| (IX) | 13317 | (E)-2-(1H-Indol-5-yl)-N-methyl-1-ethenesulfonamide | C11H12N2O2S | 详情 | 详情 | |
| (X) | 13318 | (E)-2-[3-(4-Hydroxy-1-methyl-4-piperidinyl)-1H-indol-5-yl]-N-methyl-1-ethenesulfonamide | C17H23N3O3S | 详情 | 详情 | |
| (XI) | 13319 | (E)-N-Methyl-2-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]-1-ethenesulfonamide | C17H23N3O2S | 详情 | 详情 | |
| (XII) | 13320 | 2-(4-Hydrazinophenyl)-N-methyl-1-ethanesulfonamide | C9H15N3O2S | 详情 | 详情 | |
| (XIII) | 13321 | 2-(1-Methyl-4-piperidinyl)acetaldehyde | C8H15NO | 详情 | 详情 | |
| (XIV) | 13322 | 2-(1H-Indol-5-yl)-N-methyl-1-ethanesulfonamide | C11H14N2O2S | 详情 | 详情 | |
| (XV) | 13323 | N-Methyl-2-[3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indol-5-yl]-1-ethanesulfonamide | C17H23N3O2S | 详情 | 详情 |