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【结 构 式】 
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【药物名称】SB-228357 【化学名称】N-[3-Fluoro-5-(3-pyridyl)phenyl]-5-methoxy-6-(trifluoromethyl)indoline-1-carboxamide 【CA登记号】181629-93-6 【 分 子 式 】C22H17F4N3O2 【 分 子 量 】431.39329 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antidepressants, Antiparkinsonian Drugs, Anxiolytics, Extrapyramidal Disorders, Treatment of, Mood Disorders, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2C (5-HT1C) Antagonists |
合成路线1
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
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 |