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【结 构 式】 
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【药物名称】Mefloquine hydrochloride, WR-142490, Mephaquin, Lariam, Fansimef 【化学名称】(R*,S*)-(±)-alpha-(2-Piperidinyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol hydrochloride 【CA登记号】53230-10-7 【 分 子 式 】C17H17ClF6N2O 【 分 子 量 】414.78124 |
【开发单位】Chugai (Originator), Roche (Originator), Walter Reed Army Institute (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Antimalarials, Treatment of Protozoal Diseases |
合成路线1
The PPA condensation of 2-trifluoromethylaniline (I) with ethyl 4,4,4-trifluoroacetoacetate (II) yields 2,8-bis(trifluoromethyl)-4-quinolone (III), which is converted into 2,8-bistrifluoromethyl-4-bromoquinoline (IV) with POBr3. The carboxylation of the quinoline (IV) with butyllithium and CO2 gives 2,8-bistrifluoromethylquinoline-4-carboxylic acid (V); this product is condensed with 2-pyridyllithium (A) giving 2,8-bis(trifluoromethyl)-4-quinolinyl-2-pyridyl ketone (VI). The last step is the reduction of ketone (VI) with H2 over Pt in ethanol.
| 【1】 Blackwell, J.T.; Carrol, F.I.; Optical isomers of aryl-2-piperidylmethanol antimalarial agents. Preparation, opticol purity and absolute stereochemistry. J Med Chem 1974, 17, 2, 210-219. |
| 【2】 Lutz, R.; et al.; Antimalarials 7-Bis-(trifluoromethyl)-(2-piperidyl)-4-quinoline methanols. J Med Chem 1971, 14, 10, 926-928. |
| 【3】 Castaner, J.; Playle, A.C.; Mefloquine. Drugs Fut 1976, 1, 6, 296. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 34016 | 2-pyridinyllithium | C5H4LiN | 详情 | 详情 | |
| (I) | 34012 | 2-(trifluoromethyl)-2,4-cyclohexadien-1-ylamine; 2-(trifluoromethyl)-2,4-cyclohexadien-1-amine | C7H8F3N | 详情 | 详情 | |
| (II) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
| (III) | 34013 | 2,8-bis(trifluoromethyl)-4(1H)-quinolinone | C11H5F6NO | 详情 | 详情 | |
| (IV) | 34014 | 4-bromo-2,8-bis(trifluoromethyl)quinoline | 35853-45-3 | C11H4BrF6N | 详情 | 详情 |
| (V) | 34015 | 2,8-bis(trifluoromethyl)-4-quinolinecarboxylic acid | C12H5F6NO2 | 详情 | 详情 | |
| (VI) | 34017 | [2,8-bis(trifluoromethyl)-4-quinolinyl](2-pyridinyl)methanone | C17H8F6N2O | 详情 | 详情 |