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【结 构 式】 
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【药物名称】SB-243213 【化学名称】5-Methyl-N-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl]-6-(trifluoromethyl)indoline-1-carboxamide 【CA登记号】200940-22-3 【 分 子 式 】C22H19F3N4O2 【 分 子 量 】428.41753 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2C (5-HT1C) Antagonists |
合成路线1
Treatment of 1-methoxy-4-nitro-2-(trifluoromethyl)benzene (I) with 4-chlorophenoxyacetonitrile (II) in the presence of potassium tert-butoxide afforded the arylacetonitrile (III). Reductive cyclization of (III) upon treatment with H2 and Pd/C produced indole (IV), which was further reduced to indoline (V) with NaBH3CN and AcOH. Methyl ether cleavage in (V) using ISiMe3 yielded phenol (VI). After protection of the amino group of (VI) as the acetamide (VII), sulfonylation at the phenol group with trifluoromethanesulfonic anhydride and pyridine gave triflate (VIII). The triflate group was then displaced with tetramethyltin in the presence of palladium catalyst to furnish, after hydrolysis of the acetamide, the 5-methyl-6-(trifluoromethyl)indoline (IX).
| 【1】 Blackburn, T.P. (SmithKline Beecham plc); Pharmaceutical compsn. containing a 5HT2C antagonist and a D2 antagonist. WO 9804289 . |
| 【2】 Bromidge, S.M.; Forbes, I.T. (SmithKline Beecham plc); Indoline derivs. useful as 5-HT-2C receptor antagonists. EP 0912554; WO 9748699 . |
| 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) | 29600 | methyl 4-nitro-2-(trifluoromethyl)phenyl ether; 1-methoxy-4-nitro-2-(trifluoromethyl)benzene | 654-76-2 | C8H6F3NO3 | 详情 | 详情 |
| (II) | 29601 | 2-(4-chlorophenoxy)acetonitrile | 3598-13-8 | C8H6ClNO | 详情 | 详情 |
| (III) | 29602 | 2-[5-methoxy-2-nitro-4-(trifluoromethyl)phenyl]acetonitrile | C10H7F3N2O3 | 详情 | 详情 | |
| (IV) | 29603 | methyl 6-(trifluoromethyl)-1H-indol-5-yl ether; 5-methoxy-6-(trifluoromethyl)-1H-indole | C10H8F3NO | 详情 | 详情 | |
| (V) | 29604 | methyl 6-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl ether; 5-methoxy-6-(trifluoromethyl)indoline | C10H10F3NO | 详情 | 详情 | |
| (VI) | 29605 | 6-(trifluoromethyl)-5-indolinol | C9H8F3NO | 详情 | 详情 | |
| (VII) | 29606 | 1-[5-hydroxy-6-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C11H10F3NO2 | 详情 | 详情 | |
| (VIII) | 29607 | 1-acetyl-6-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl trifluoromethanesulfonate | C12H9F6NO4S | 详情 | 详情 | |
| (IX) | 29608 | 5-methyl-6-(trifluoromethyl)indoline | C10H10F3N | 详情 | 详情 |
合成路线2
Coupling of 3-hydroxypyridine (X) with 2-chloropyridine (XI) afforded the corresponding dipyridyl ether (XII). After reduction of the nitro group of (XII) with SnCl2, the resulting aminopyridine (XIII) was treated with phenyl chloroformate to give the phenyl carbamate (XIV). Finally, condensation of carbamate (XIV) with indoline (IX) produced the title carboxamide.
| 【1】 Bromidge, S.M.; Forbes, I.T. (SmithKline Beecham plc); Indoline derivs. useful as 5-HT-2C receptor antagonists. EP 0912554; WO 9748699 . |
| 【2】 Blackburn, T.P. (SmithKline Beecham plc); Pharmaceutical compsn. containing a 5HT2C antagonist and a D2 antagonist. WO 9804289 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 29608 | 5-methyl-6-(trifluoromethyl)indoline | C10H10F3N | 详情 | 详情 | |
| (X) | 29609 | 2-methyl-3-pyridinol | 1121-25-1 | C6H7NO | 详情 | 详情 |
| (XI) | 29610 | 2-chloro-5-nitropyridine | 4548-45-2 | C5H3ClN2O2 | 详情 | 详情 |
| (XII) | 29611 | 2-methyl-3-[(5-nitro-2-pyridinyl)oxy]pyridine; 2-methyl-3-pyridinyl 5-nitro-2-pyridinyl ether | C11H9N3O3 | 详情 | 详情 | |
| (XIII) | 29612 | 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinamine; 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinylamine | C11H11N3O | 详情 | 详情 | |
| (XIV) | 29613 | phenyl 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinylcarbamate | C18H15N3O3 | 详情 | 详情 |