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【结 构 式】 
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【分子编号】51868 【品名】tert-butyl (3S)-3-methyl-1-piperazinecarboxylate 【CA登记号】 |
【 分 子 式 】C10H20N2O2 【 分 子 量 】200.28108 【元素组成】C 59.97% H 10.07% N 13.99% O 15.98% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(VIII)The reaction of 4-fluoroacetophenone (I) with sodium hydrogensulfide in hot DMF gives 4-sulfanylacetophenone (II), which is condensed with 5-iodo-1,3-benzodioxole (III) by means of CuI and K2CO3 in hot DMF to yield the thioether (IV). The oxidation of (IV) with MCPBA in dichloroethane affords the sulfone (V), which is enantioselectively reduced by means of BH3/SMe2 and Corey's oxoborolidine catalyst in THF to provide the chiral (R)-alcohol (VI). The reaction of (VI) with Ms-Cl in dichloromethane gives the mesylate (VII), which is condensed with the monoprotected 2(R)-methylpiperazine (VIII) by means of tetramethylpiperidine (TMP) in refluxing acetonitrile to yield the expected benzylic (S)-methyl compound (IX). The elimination of the Boc protecting group of (IX) with refluxing 6N HCl affords the piperazine derivative (X), which is reductocondensed with 1-(Boc)piperidin-4-one (XI) by means of NaBH(OAc)3 to provide adduct (XII). Elimination of the Boc protecting group of (XII) as before gives the piperidine derivative (XIII), which is finally sulfonated with ethylsulfonyl chloride and TEA to provide the target ethylsufonyl piperidine.
| 【1】 Kozlowski, J.A.; Zhou, G.; Tagat, J.R.; et al.; Substituted 2-(R)-methyl piperazines as muscarinic M2 selective ligands. Bioorg Med Chem Lett 2002, 12, 5, 791. |
| 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) | 37684 | 1-(4-fluorophenyl)-1-ethanone | 403-42-9 | C8H7FO | 详情 | 详情 |
| (II) | 54059 | 1-(4-sulfanylphenyl)-1-ethanone | n/a | C8H8OS | 详情 | 详情 |
| (III) | 54060 | 1-Iodo-3,4-methylenedioxybenzene | 5876-51-7 | C7H5IO2 | 详情 | 详情 |
| (IV) | 54061 | 1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]-1-ethanone | n/a | C15H12O5S | 详情 | 详情 |
| (V) | 50643 | 1-[4-(1,3-benzodioxol-5-ylsulfanyl)phenyl]-1-ethanone | C15H12O3S | 详情 | 详情 | |
| (VI) | 50645 | (1R)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]-1-ethanol | C15H14O5S | 详情 | 详情 | |
| (VII) | 50646 | (1R)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl methanesulfonate | C16H16O7S2 | 详情 | 详情 | |
| (VIII) | 51868 | tert-butyl (3S)-3-methyl-1-piperazinecarboxylate | C10H20N2O2 | 详情 | 详情 | |
| (IX) | 54062 | tert-butyl (3R)-4-{(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl}-3-methyl-1-piperazinecarboxylate | n/a | C25H32N2O6S | 详情 | 详情 |
| (X) | 50649 | (2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methylpiperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methylpiperazinyl]ethyl]phenyl sulfone | C20H24N2O4S | 详情 | 详情 | |
| (XI) | 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 |
| (XII) | 54063 | tert-butyl 4-((3R)-4-{(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl}-3-methylpiperazinyl)-1-piperidinecarboxylate | n/a | C30H41N3O6S | 详情 | 详情 |
| (XIII) | 54064 | (2R)-1-{(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl}-2-methyl-4-(4-piperidinyl)piperazine; 1,3-benzodioxol-5-yl 4-{(1S)-1-[(2R)-2-methyl-4-(4-piperidinyl)piperazinyl]ethyl}phenyl sulfone | n/a | C25H33N3O4S | 详情 | 详情 |
| (XIV) | 54065 | Ethanesulfonyl chloride; Ethylsulfonyl chloride | 594-44-5 | C2H5ClO2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)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 |
合成路线4
该中间体在本合成路线中的序号：(V)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 |