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【结 构 式】 
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【药物名称】Xaliproden hydrochloride, SR-57746A, Xaprila 【化学名称】1-[2-(2-Naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine hydrochloride 【CA登记号】90494-79-4, 135354-02-8 (free base) 【 分 子 式 】C24H23ClF3N 【 分 子 量 】417.90581 |
【开发单位】Sanofi-synthélabo (Orphan Drug), Sanofi-synthélabo (Originator) 【药理作用】Alzheimer's Dementia, Treatment of , Amyotrophic Lateral Sclerosis, Agents for, Cognition Disorders, Treatment of, Immunologic Neuromuscular Disorders, Treatment of, Multiple Sclerosis, Agents for, Neurodegenerative Diseases, Treatment of, NEUROLOGIC DRUGS, 5-HT1A Receptor Agonists, Neurotrophic Factor Enhancers |
合成路线1
The condensation of 4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (I) with 2-(2-naphthyl)acetyl chloride (II) by means of triethylamine in dichloromethane gives 1-[2-(2-naphthyl)acetyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6 tetrahydropyridine (III), which is finally reduced with LiAlH4 in ethyl ether.
| 【1】 Castaner, J.; Mucke, H.A.M.; SR-57746A. Drugs Fut 1998, 23, 6, 616. |
| 【2】 Nisato, D.; Frigerio, M.; Miranda, G.F. (Midy SpA; Sanofi-Synthelabo ); Trifluoromethylphenyltetrahydropyridines with anorexigenic activity, a process for their preparation and compsns. EP 0101381 . |
合成路线2
A synthesis of [14C]-labeled SR-57746A has been described: The iodination of [14C6]-benzene (I) with nitric acid/I2 gives iodobenzene (II), which is treated with sodium trifluoroacetate and CuI yielding trifluoromethylbenzene (III). The nitration of (III) with sodium nitrate affords 3-(trifluoromethyl)nitrobenzene (IV), which is reduced with Fe/HCl to the corresponding aniline (V). The reaction of (V) with tert-butyl nitrite and CuBr2 provides 3-(trifluoromethyl)bromobenzene (VI), which is treated with Mg in THF affording the corresponding Grignard reagent (VII). The condensation of (VII) with piperidone (VIII) gives the piperidol (IX), which is finally dehydrated in acidic medium. In order to aviod radioactive contamination during the purification of compounds iodobenzene (II) and trifluoromethylbenzene (III) by liquid chromatography, a safer route using less volatile compounds has been developed: The nitration of [14C6]-benzene (I) with nitric acid gives nitrobenzene (X), which is iodinated with IPy2BF4/CF3SO3H yielding 3-iodonitrobenzene (XI). Finally, this compound is trifluoromethylated with CF3SiMe3, CuI and KF to provide 3-(trifluoromethyl)nitrobenzene (IV) already reported.
| 【1】 Robic, N.; Noel, J.P.; Synthesis of [trifluoromethyl-[C-14(6)]-phenyl] SR 57746A. J Label Compd Radiopharm 1999, 42, 2, 109. |
| 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) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (I) | 45201 | benzene | C6H6 | 详情 | 详情 | |
| (II) | 26344 | 1-Iodobenzene | 591-50-4 | C6H5I | 详情 | 详情 |
| (II) | 45202 | 1-iodobenzene | C6H5I | 详情 | 详情 | |
| (III) | 26345 | 1-(Trifluoromethyl)benzene | 98-08-8 | C7H5F3 | 详情 | 详情 |
| (III) | 45203 | 1-(trifluoromethyl)benzene | C7H5F3 | 详情 | 详情 | |
| (IV) | 26346 | 1-nitro-3-(trifluoromethyl)benzene | 98-46-4 | C7H4F3NO2 | 详情 | 详情 |
| (IV) | 45204 | 1-nitro-3-(trifluoromethyl)benzene | C7H4F3NO2 | 详情 | 详情 | |
| (V) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
| (V) | 45205 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline | C7H6F3N | 详情 | 详情 | |
| (VI) | 26348 | 1-bromo-3-(trifluoromethyl)benzene; 3-Bromobenzotrifluoride | 401-78-5 | C7H4BrF3 | 详情 | 详情 |
| (VI) | 45206 | 1-bromo-3-(trifluoromethyl)benzene | C7H4BrF3 | 详情 | 详情 | |
| (VII) | 12028 | Bromo[3-(trifluoromethyl)phenyl]magnesium | 402-26-6 | C7H4BrF3Mg | 详情 | 详情 |
| (VII) | 45207 | bromo[3-(trifluoromethyl)phenyl]magnesium | C7H4BrF3Mg | 详情 | 详情 | |
| (VIII) | 26349 | 1-[2-(2-naphthyl)ethyl]-4-piperidinone | C17H19NO | 详情 | 详情 | |
| (IX) | 26350 | 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinol | C24H24F3NO | 详情 | 详情 | |
| (IX) | 45208 | 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-4-piperidinol | C24H24F3NO | 详情 | 详情 | |
| (X) | 22523 | 1-nitrobenzene | 28250-14-8 | C6H5NO2 | 详情 | 详情 |
| (X) | 45209 | 1-nitrobenzene | C6H5NO2 | 详情 | 详情 | |
| (XI) | 26352 | 3-Iodonitrobenzene; 1-iodo-3-nitrobenzene | 645-00-1 | C6H4INO2 | 详情 | 详情 |
| (XI) | 45210 | 1-iodo-3-nitrobenzene | C6H4INO2 | 详情 | 详情 |