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【结 构 式】 
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【分子编号】67563 【品名】1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-amine 【CA登记号】 |
【 分 子 式 】C11H12ClFN2 【 分 子 量 】226.681 【元素组成】C 58.28% H 5.33% Cl 15.64% F 8.38% N 12.36% |
合成路线1
该中间体在本合成路线中的序号：(XVII)Vilsmeier-Haack formylation of 6-chloro-5-fluoroindole (I) with dimethylformamide (XIII) by means of POCl3 gives 6-chloro-5-fluoroindole-3-carbaldehyde (XIV), which by Henry reaction with nitroethane (XV) in the presence of NH4OAc yields 6-chloro-5-fluoro-3-(2-nitroprop-1-enyl)indole (XVI). Reduction of the unsaturated nitro compound (XVI) by means of LiAlH4 in refluxing THF provides the trypt amine derivative (XVII), which is then subjected to Pictet-Spengler cyclization with 5-chloroisatin (XII) by means of p-TsOH in EtOH at 110 °C to afford spiro racemate (XVIII). Finally, chiral chromatography of racemate (XVIII) affords the desired (1R,3S)-enantiomer .
| 【1】 Ang, S.H., Krastel, P., Leong, S.Y., Tan, L.J., Wong, W.L.J., Yeung, B.K.S., Zou, B. (Novartis AG). Spiro-indole derivatives for the treatment of parasitic diseases. CN 102015711; EP 2722333; KR 2010135320; EP 2285808;JP 2011518852; US 8399453; US 2011275613; WO 2009132921; US 2009275560; US 8053442. |
| 【2】 Yeung, B.K., Zou, B., Rottmann, M. et al. Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria. J Med Chem 2010, 53(14): 5155-64. |
| 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) | 30025 | 6-Chloro-5-fluoroindole; 6-Chloro-5-fluoro-1H-indole | 122509-72-2 | C8H5ClFN | 详情 | 详情 |
| (XII) | 14099 | 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin | 17630-76-1 | C8H4ClNO2 | 详情 | 详情 |
| (XIII) | 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 |
| (XIV) | 67561 | 6-chloro-5-fluoroindole-3-carbaldehyde | C9H5ClFNO | 详情 | 详情 | |
| (XV) | 12117 | Nitroethane; 1-Nitroethane | 79-24-3 | C2H5NO2 | 详情 | 详情 |
| (XVI) | 67562 | (Z)-6-chloro-5-fluoro-3-(2-nitroprop-1-en-1-yl)-1H-indole | C11H8ClFN2O2 | 详情 | 详情 | |
| (XVII) | 67563 | 1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-amine | C11H12ClFN2 | 详情 | 详情 | |
| (XVIII) | 67564 | 5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one | C19H14Cl2FN3O | 详情 | 详情 |