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【结 构 式】 
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【分子编号】64941 【品名】2-[4-(trifluoromethyl)phenyl]oxirane 【CA登记号】 |
【 分 子 式 】C9H7F3O 【 分 子 量 】188.1491896 【元素组成】C 57.45% H 3.75% F 30.29% O 8.5% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 4-(trifluoromethyl)styrene (I) with mCPBA in dichloromethane gives the epoxide (II), which is treated with MeONa in methanol to yield the benzyl alcohol (III). The reaction of (III) with MsCl and TEA affords the mesylate (IV), which is condensed with the monoprotected piperazine (V) in refluxing acetonitrile to provide a diastereomeric mixture of compounds (VI) + (VII) that is resolved by flash chromatography. The desired isomer (VII) is deprotected by means of HCl or TFA to give piperazine (VIII), which is condensed with N-Boc-4-piperidone (IX) with simultaneous alkylation by means of Ti(OiPr)4 and Et2Al-CN in refluxing dichloromethane to yield the intermediate (X). The reaction of (X) with MeMgBr in THF affords the methylated compound (XI), which is deprotected by means of TFA to provide the substituted piperidine derivative (XII). Finally, this compound is acylated by means of 4,6-dimethylpyrimidine-5-carbonyl chloride (XIII) and aqueous NaOH in dichloromethane to provide the target compound. (1-3)
| 【1】 Imamura, S.; Baba, M.; Ishihara, Y.; Hashiguchi, S.; Kanzaki, N.; Nishimura, O. (Takeda Chemical Industries, Ltd.); Cyclic amide cpds., process for the preparation of the same and uses thereof. EP 1180513; JP 2001011073; WO 0066551 . |
| 【2】 Neustadt, B.R.; Smith, E.M.; McKittrick, B.A.; McCombie, S.W.; Tagat, J.R.; Clader, J.W.; Vice, S.F.; Baroudy, B.M.; Josien, H.B.; Miller, M.W.; Palani, A.; Steensma, R.; Gilbert, E.; Labroli, M.A. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. US 6391865 . |
| 【3】 Neustadt, B.R.; Smith, E.M.; McKittrick, B.A.; McCombie, S.W.; Tagat, J.R.; Clader, J.W.; Vice, S.F.; Laughlin, M.A.; Baroudy, B.M.; Josien, H.B.; Miller, M.W.; Palani, A.; Steensma, R.; Gilbert, E.; Labroli, M.A. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. US 2003069252; US 6689765 . |
| 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) | 64940 | 1-ethenyl-4-(trifluoromethyl)benzene | C9H7F3 | 详情 | 详情 | |
| (II) | 64941 | 2-[4-(trifluoromethyl)phenyl]oxirane | C9H7F3O | 详情 | 详情 | |
| (III) | 64942 | 2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]-1-ethanol | C10H11F3O2 | 详情 | 详情 | |
| (IV) | 64943 | 2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate | C11H13F3O4S | 详情 | 详情 | |
| (V) | 51868 | tert-butyl (3S)-3-methyl-1-piperazinecarboxylate | C10H20N2O2 | 详情 | 详情 | |
| (VI) | 64944 | 1,1-dimethylethyl 3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinecarboxylate | C20H29F3N2O3 | 详情 | 详情 | |
| (VII) | 64945 | 1,1-dimethylethyl 3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinecarboxylate | C20H29F3N2O3 | 详情 | 详情 | |
| (VIII) | 64946 | 2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}piperazine; methyl 2-(2-methyl-1-piperazinyl)-2-[4-(trifluoromethyl)phenyl]ethyl ether | C15H21F3N2O | 详情 | 详情 | |
| (IX) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (X) | 64947 | 1,1-dimethylethyl 4-cyano-4-(3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinecarboxylate | C26H37F3N4O3 | 详情 | 详情 | |
| (XI) | 64948 | 1,1-dimethylethyl 4-methyl-4-(3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinecarboxylate | C26H40F3N3O3 | 详情 | 详情 | |
| (XII) | 64949 | methyl 2-[2-methyl-4-(4-methyl-4-piperidinyl)-1-piperazinyl]-2-[4-(trifluoromethyl)phenyl]ethyl ether; 2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-4-(4-methyl-4-piperidinyl)piperazine | C21H32F3N3O | 详情 | 详情 | |
| (XIII) | 64950 | 4,6-dimethyl-5-pyrimidinecarbonyl chloride | C7H7ClN2O | 详情 | 详情 |