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【结 构 式】 
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【分子编号】29604 【品名】methyl 6-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl ether; 5-methoxy-6-(trifluoromethyl)indoline 【CA登记号】 |
【 分 子 式 】C10H10F3NO 【 分 子 量 】217.1907496 【元素组成】C 55.3% H 4.64% F 26.24% N 6.45% O 7.37% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(V)3-Fluoro-5-(3-pyridyl)aniline (IX) was prepared by palladium coupling of 3-fluoro-5-iodonitrobenzene (VI) and 3-pyridylboronic acid (VII), followed by reduction of the resultant nitro derivative (VIII) using stannous chloride in aqueous HCl (3). Treatment of aniline (IX) with phenyl chloroformate in the presence of triethylamine gave rise to carbamate (X). This was then coupled with indoline (V) to furnish the title amide.
| 【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】 Dabbs, S.; Davies, D.T.; Bromidge, S.M.; et al.; Biarylcarbamoylindolines are novel and selective 5-HT2C receptor inverse agonists: Identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent. J Med Chem 2000, 43, 6, 1123. |
| 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) | 29604 | methyl 6-(trifluoromethyl)-2,3-dihydro-1H-indol-5-yl ether; 5-methoxy-6-(trifluoromethyl)indoline | C10H10F3NO | 详情 | 详情 | |
| (VI) | 38824 | 1-fluoro-3-iodo-5-nitrobenzene | C6H3FINO2 | 详情 | 详情 | |
| (VII) | 38825 | 3-pyridinylboronic acid | 1692-25-7 | C5H6BNO2 | 详情 | 详情 |
| (VIII) | 38826 | 3-(3-fluoro-5-nitrophenyl)pyridine | C11H7FN2O2 | 详情 | 详情 | |
| (IX) | 38827 | 3-fluoro-5-(3-pyridinyl)phenylamine; 3-fluoro-5-(3-pyridinyl)aniline | C11H9FN2 | 详情 | 详情 | |
| (X) | 38828 | phenyl 3-fluoro-5-(3-pyridinyl)phenylcarbamate | C18H13FN2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)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 |