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【结 构 式】 
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【分子编号】51862 【品名】(1R)-1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate 【CA登记号】 |
【 分 子 式 】C10H11F3O3S 【 分 子 量 】268.2567496 【元素组成】C 44.77% H 4.13% F 21.25% O 17.89% S 11.95% |
合成路线1
该中间体在本合成路线中的序号：(IV)Enantioselective reduction of 4-trifluoromethylacetophenone (I) with borane-methyl sulfide complex in the presence of the chiral oxaborolidine (II) provided the (R)-alcohol (III) in high enantiomeric excess. Treatment of (III) with methanesulfonyl chloride and Et3N yielded the corresponding mesylate (IV). Displacement of the mesylate group of (IV) with the Boc-protected piperazine (V) produced the desired (S,S)-alpha-methylbenzyl piperazine (VI) as the major isomer. Separation from minor amounts of the (R,S)-diastereomer was effected by flash chromatography. After acid cleavage of the Boc protecting group of (VI), the resultant piperazine (VII) was subjected to a modified Strecker reaction with N-Boc-piperidone (VIII) and diethylaluminum cyanide, yielding amino nitrile (IX). A methyl group was then introduced at the 4-position of the piperidine (IX) by displacement of the cyano group with methylmagnesium bromide to yield (X). Subsequent acidic Boc group cleavage in (X) gave piperidine (XI). This was finally coupled with 2,4-dimethylnicotinic acid N-oxide (XII) to furnish the title compound.
| 【1】 Tagat, J.R.; Steensma, R.W.; McCombie, S.W.; Nazareno, D.V.; Lin, S.-I.; Neustadt, B.R.; Cox, K.; Xu, S.; Wojcik, L.; Murray, M.G.; Vantuno, N.; Baroudy, B.M.; Strizki, J.M.; Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4-methyl-4-[3(S)-methyl-4[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]-piperidine N1-oxide (Sch-350634), an orally bioavailable, potent. J Med Chem 2001, 44, 21, 3343. |
| 【2】 Labroli, M.A.; Smith, E.M.; Baroudy, B.M.; Gilbert, E.; Tagat, J.R.; Josien, H.B.; Steensma, R.; Laughlin, M.A.; Miller, M.W.; Clader, J.W.; McKittrick, B.A.; Neustadt, B.R.; Palani, A.; McCombie, S.W.; Vice, S.F. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. EP 1175401; WO 0066558 . |
| 【3】 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 . |
| 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) | 39907 | 1-[4-(trifluoromethyl)phenyl]-1-ethanone | 709-63-7 | C9H7F3O | 详情 | 详情 |
| (II) | 28292 | (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-81-8 | C18H20BNO | 详情 | 详情 |
| (III) | 51861 | (1R)-1-[4-(trifluoromethyl)phenyl]-1-ethanol | C9H9F3O | 详情 | 详情 | |
| (IV) | 51862 | (1R)-1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate | C10H11F3O3S | 详情 | 详情 | |
| (V) | 51868 | tert-butyl (3S)-3-methyl-1-piperazinecarboxylate | C10H20N2O2 | 详情 | 详情 | |
| (VI) | 51863 | tert-butyl (3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinecarboxylate | C19H27F3N2O2 | 详情 | 详情 | |
| (VII) | 51864 | (2S)-2-methyl-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazine | C14H19F3N2 | 详情 | 详情 | |
| (VIII) | 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 |
| (IX) | 51865 | tert-butyl 4-cyano-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate | C25H35F3N4O2 | 详情 | 详情 | |
| (X) | 51866 | tert-butyl 4-methyl-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate | C25H38F3N3O2 | 详情 | 详情 | |
| (XI) | 51867 | (2S)-2-methyl-4-(4-methyl-4-piperidinyl)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazine | C20H30F3N3 | 详情 | 详情 | |
| (XII) | 51857 | 3-carboxy-2,4-dimethyl-1-pyridiniumolate | C8H9NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The enantioselective reduction of 4-(trifluoromethyl)acetophenone (I) with BH3/Me2S in the presence of the chiral borane (II) gives the (R) alcohol (III), which is treated with MsCl and TEA to yield the corresponding mesylate (IV). The displacement of the Ms group of (V) by means of the 1-Boc-3(S)-methylpiperazine (V) produced the protected (S,S)-alpha-methylbenzyl piperazine (VI) as the major isomer, which is purified by flash chromatography. After cleavage of the Boc group of (VI) with TFA in dichloromethane, the resulting piperazine (VII) is subjected to a modified Strecker reaction with 1-Boc-piperidin-4-one (VIII) and diethylaluminum cyanide to yield the aminonitrile (IX). A methyl group is then introduced by displacement of the cyano group of (IX) by means of MeMgBr to afford the protected 4-methylpiperidine derivative (X). Subsequent acidic Boc group cleavage in (X) with TFA provides the piperidine (XI), which is finally condensed with 2,4-dimethylpyridine-3-carboxylic acid (XII) by means of EDC and HOBT to furnish the target amide (1-3).
| 【1】 Tagat, J.R.; Steensma, R.W.; McCombie, S.W.; Nazareno, D.V.; Lin, S.-I.; Neustadt, B.R.; Cox, K.; Xu, S.; Wojcik, L.; Murray, M.G.; Vantuno, N.; Baroudy, B.M.; Strizki, J.M.; Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4-methyl-4-[3(S)-methyl-4[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]-piperidine N1-oxide (Sch-350634), an orally bioavailable, potent. J Med Chem 2001, 44, 21, 3343. |
| 【2】 Labroli, M.A.; Smith, E.M.; Baroudy, B.M.; Gilbert, E.; Tagat, J.R.; Josien, H.B.; Steensma, R.; Laughlin, M.A.; Miller, M.W.; Clader, J.W.; McKittrick, B.A.; Neustadt, B.R.; Palani, A.; McCombie, S.W.; Vice, S.F. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. EP 1175401; WO 0066558 . |
| 【3】 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 . |
| 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) | 17145 | 1-(4-methylphenyl)-1-ethanone; p-methylacetophenone; 4-methylacetophenone; 4-methylphenylethanone | 122-00-9 | C9H10O | 详情 | 详情 |
| (II) | 10624 | (3aS)-1,3,3-Trimethyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | C8H16BNO | 详情 | 详情 | |
| (III) | 51861 | (1R)-1-[4-(trifluoromethyl)phenyl]-1-ethanol | C9H9F3O | 详情 | 详情 | |
| (IV) | 51862 | (1R)-1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate | C10H11F3O3S | 详情 | 详情 | |
| (V) | 51868 | tert-butyl (3S)-3-methyl-1-piperazinecarboxylate | C10H20N2O2 | 详情 | 详情 | |
| (VI) | 51863 | tert-butyl (3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinecarboxylate | C19H27F3N2O2 | 详情 | 详情 | |
| (VII) | 51864 | (2S)-2-methyl-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazine | C14H19F3N2 | 详情 | 详情 | |
| (VIII) | 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 |
| (IX) | 51865 | tert-butyl 4-cyano-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate | C25H35F3N4O2 | 详情 | 详情 | |
| (X) | 51866 | tert-butyl 4-methyl-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate | C25H38F3N3O2 | 详情 | 详情 | |
| (XI) | 51867 | (2S)-2-methyl-4-(4-methyl-4-piperidinyl)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazine | C20H30F3N3 | 详情 | 详情 | |
| (XII) | 64432 | 2,4-dimethylnicotinic acid | C8H9NO2 | 详情 | 详情 |