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【结 构 式】 
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【分子编号】39907 【品名】1-[4-(trifluoromethyl)phenyl]-1-ethanone 【CA登记号】709-63-7 |
【 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：(VIII)The cyclization of trifluoroacetylmethylpyridinium bromide (I) with 3-(4-trifluoromethylbenzoyl)acrylic acid (II) by means of ammonium acetate in refluxing methanol gives 2-trifluoromethyl-6-(4-trifluoromethylphenyl)isonicotinic acid (III), which by condensation with 2-bromopyridine (IV) by means of butyllithium in ethyl ether yields 2-trifluoromethyl-6-(4-trifluoromethylphenyl)4-pyridyl-2'-pyridyl ketone (V). Finally, this compound is reduced with H2 over Pt in aqueous concentrated HCl. The starting products are prepared as follows: 1) The acrylic acid (II) is obtained by condensation of maleic anhydride (VI) with 4-trifluoromethylphenylmagnesium bromide (VII) by means of ZnCl2 in refluxing ethyl ether. An alternative method is the condensation of 4-trifluoromethylacetophenone (VIII) with glyoxylic acid (IX) by means of triethylamine at 135 C. 2) The pyridinium salt (I) is prepared by bromination of 1,1,1-trifluoroacetone (X) giving 1,1,1-trifluoro-3-bromoacetone (XI), which is then condensed with pyridine.
| 【1】 La Montagne, M.P.; et al.; Antimalarials. 6. Synthesis, antimalarial activity and configurations of rracemic alpha-(2-piperidyl)-4-pyridinemethanols. J Med Chem 1974, 17, 5, 219-523. |
| 【2】 Ash, A.B.; et al. (Department of the Army); 2-Substituted phenyl-6-trifluoromethyl-4-pyridylcarbinolamines. US 3940404 . |
| 【3】 Ash, A.B.; et al. (Department of the Army); 2-Aryl-6-trifluoromethyl-4-pyridylcarbinolamine antimalarials. US 3953463 . |
| 【4】 Ash, A.B.; et al. (Department of the Army); 2-Aryl-6-trifluoromethyl-4-pyridylcarbinolamine antimalarials. US 3886167 . |
| 【5】 Castaner, J.; Roberts, P.J.; WR-180,409. Drugs Fut 1978, 3, 9, 694. |
| 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) | 39908 | 1-(3,3,3-trifluoro-2-oxopropyl)pyridinium bromide | C8H7BrF3NO | 详情 | 详情 | |
| (II) | 39906 | (E)-4-oxo-4-[4-(trifluoromethyl)phenyl]-2-butenoic acid | C11H7F3O3 | 详情 | 详情 | |
| (III) | 39910 | 2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]isonicotinic acid | C14H7F6NO2 | 详情 | 详情 | |
| (IV) | 29052 | 2-Bromopyridine；α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
| (V) | 39911 | 2-pyridinyl[2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]-4-pyridinyl]methanone | C19H10F6N2O | 详情 | 详情 | |
| (VI) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (VII) | 39311 | bromo[4-(trifluoromethyl)phenyl]magnesium | C7H4BrF3Mg | 详情 | 详情 | |
| (VIII) | 39907 | 1-[4-(trifluoromethyl)phenyl]-1-ethanone | 709-63-7 | C9H7F3O | 详情 | 详情 |
| (IX) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (X) | 35449 | 1,1,1-trifluoroacetone | 421-50-1 | C3H3F3O | 详情 | 详情 |
| (XI) | 39909 | 3-bromo-1,1,1-trifluoroacetone | 431-35-6 | C3H2BrF3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |