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【结 构 式】 
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【分子编号】29600 【品名】methyl 4-nitro-2-(trifluoromethyl)phenyl ether; 1-methoxy-4-nitro-2-(trifluoromethyl)benzene 【CA登记号】654-76-2 |
【 分 子 式 】C8H6F3NO3 【 分 子 量 】221.1357896 【元素组成】C 43.45% H 2.73% F 25.77% N 6.33% O 21.71% |
合成路线1
该中间体在本合成路线中的序号：(I)Reaction between 1-methoxy-4-nitro-2-trifluoromethylbenzene (I) and 4-chlorophenoxyacetonitrile (II) in the presence of potassium tert-butoxide produced aryl acetonitrile (III). Catalytic hydrogenation of (III) gave rise to indole (IV), which was further reduced to indoline (V) employing sodium cyanoborohydride and AcOH.
| 【1】 Gaster, L.M.; Wyman, P.A.; Mulholland, K.R.; Davies, D.T.; Duckworth, D.M.; Forbes, I.T.; Jones, G.E. (SmithKline Beecham plc); Indole derivs. as 5-HT receptor antagonist. EP 0808312; JP 1998513442; US 5990133; WO 9623783 . |
| 【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 |
|---|---|---|---|---|---|---|
| (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 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |