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【结 构 式】

【分子编号】51865

【品名】tert-butyl 4-cyano-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate

【CA登记号】

【 分 子 式 】C25H35F3N4O2

【 分 子 量 】480.5738696

【元素组成】C 62.48% H 7.34% F 11.86% N 11.66% O 6.66%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IX)

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:(IX)

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
Extended Information