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【结 构 式】 
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【分子编号】10624 【品名】(3aS)-1,3,3-Trimethyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole 【CA登记号】 |
【 分 子 式 】C8H16BNO 【 分 子 量 】153.03218 【元素组成】C 62.79% H 10.54% B 7.06% N 9.15% O 10.45% |
合成路线1
该中间体在本合成路线中的序号：(VII)1) The reaction of the known ketoketal (I) with N-phenyltrifluoromethanesulfonimide and KHMDS in THF gives the enol triflate (II), which is condensed with VIBuSn using tetrakis(triphenylphosphine)palladium(0) as catalyst in THF, yielding the diene (III). The reaction of (III) with 9-BBN in THF affords the alcohol (IV) and, after protection with TBDMS-Cl in dichloromethane, the silyl ether (V), which is oxidized with CrO3 and DMP in dichloromethane to the enone (VI). The stereoselective reduction of (VI) with BH3/THF catalyzed with the chiral borane (VII) yields the alcohol (VIII), which is protected with TBDMS-Cl as before to give (IX). Selective deprotection of (IX) affords the primary alcohol (X), which is oxidized with oxalyl chloride in DMSO to the aldehyde (XI). The condensation of (XI) with the vinyl iodide (XII) catalyzed by NiCl2 and CrCl2 gives the allyl alcohol (XIII), which is oxidized with oxalyl chloride as before to the enone (XIV). The oxidation of (XIV) with 3-phenyl-2-(phenylsulfonyl)oxaziridine and KHMDS yields the hydroxy ketone (XV), which is further oxidized with oxalyl chloride as before to afford the unsaturated dione (XVI). The Diels-Alder condensation between (XVI) and the diene (XVII) gives compound (XVIII) or (XIX), depending on the reaction conditions. The oxidation of the primary alcohol of (XIX) with oxalyl chloride as usual yields the aldehyde (XX), which by elimination of the ketal group in acidic medium affords the tetraketonic aldehyde (XXI).
| 【1】 Danishefsky, S.J.; Bornmann, W.G.; Queneau, Y.; Magee, T.V.; Krol, W.J. (Sloan-Kettering Institute); Total synthesis of taxol. US 5416225 . |
| 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) | 10618 | 6,6,8-Trimethyl-1,4-dioxaspiro[4.5]decan-7-one | C11H18O3 | 详情 | 详情 | |
| (II) | 10619 | 6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl trifluoromethanesulfonate | C12H17F3O5S | 详情 | 详情 | |
| (III) | 10620 | 6,6,8-Trimethyl-7-vinyl-1,4-dioxaspiro[4.5]dec-7-ene | C13H20O2 | 详情 | 详情 | |
| (IV) | 10621 | 6,6,8-Trimethyl-7-vinyl-1,4-dioxaspiro[4.5]dec-7-ene | C13H20O2 | 详情 | 详情 | |
| (V) | 10622 | 2-(6,6,8-Trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)-1-ethanol | C13H22O3 | 详情 | 详情 | |
| (VI) | 10623 | tert-Butyl(dimethyl)[2-(6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)ethoxy]silane; tert-Butyl(dimethyl)silyl 2-(6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)ethyl ether | C19H36O3Si | 详情 | 详情 | |
| (VII) | 10624 | (3aS)-1,3,3-Trimethyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | C8H16BNO | 详情 | 详情 | |
| (VIII) | 10625 | (7S)-9-(2-[[tert-Butyl(dimethyl)silyl]oxy]ethyl)-8,10,10-trimethyl-1,4-dioxaspiro[4.5]dec-8-en-7-ol | C19H36O4Si | 详情 | 详情 | |
| (IX) | 10626 | tert-Butyl(dimethyl)silyl (7S)-9-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-8,10,10-trimethyl-1,4-dioxaspiro[4.5]dec-8-en-7-yl ether; tert-Butyl[2-((9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)ethoxy]dimethylsilane | C25H50O4Si2 | 详情 | 详情 | |
| (X) | 10627 | 2-((9S)-9-[[tert-Butyl(dimethyl)silyl]oxy]-6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)-1-ethanol | C19H36O4Si | 详情 | 详情 | |
| (XI) | 10628 | 2-((9S)-9-[[tert-Butyl(dimethyl)silyl]oxy]-6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)acetaldehyde | C19H34O4Si | 详情 | 详情 | |
| (XII) | 10629 | tert-Butyl[[(E)-3-iodo-2-butenyl]oxy]dimethylsilane; tert-Butyl(dimethyl)silyl (E)-3-iodo-2-butenyl ether | C10H21IOSi | 详情 | 详情 | |
| (XIII) | 10630 | (E)-4-[[tert-Butyl(dimethyl)silyl]oxy]-1-((9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)-3-methyl-3-buten-2-ol | C28H54O5Si2 | 详情 | 详情 | |
| (XIV) | 10631 | (E)-5-[[tert-Butyl(dimethyl)silyl]oxy]-1-((9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)-3-methyl-3-penten-2-one | C29H54O5Si2 | 详情 | 详情 | |
| (XV) | 10632 | (E)-5-[[tert-Butyl(dimethyl)silyl]oxy]-1-((9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)-1-hydroxy-3-methyl-3-penten-2-one | C29H54O6Si2 | 详情 | 详情 | |
| (XVI) | 10633 | (E)-5-[[tert-Butyl(dimethyl)silyl]oxy]-1-((9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)-3-methyl-3-pentene-1,2-dione | C29H52O6Si2 | 详情 | 详情 | |
| (XVII) | 10634 | [(Z)-2-[(E)-2-(Benzyloxy)ethenyl]-4-(phenylsulfanyl)-2-butenyl](trimethyl)silane; Benzyl (1E,3Z)-5-(phenylsulfanyl)-3-[(trimethylsilyl)methyl]-1,3-pentadienyl ether | C22H28OSSi | 详情 | 详情 | |
| (XVIII) | 10635 | 1-[(1S,2R,3S,6S)-6-(Benzyloxy)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-methyl-4-oxo-3-[(phenylsulfanyl)methyl]cyclohexyl]-2-((9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)-1,2-ethanedione | C47H70O8SSi2 | 详情 | 详情 | |
| (XIX) | 10636 | 1-[(1S,2R,3S,6S)-6-(Benzyloxy)-2-(hydroxymethyl)-1-methyl-4-oxo-3-[(phenylsulfanyl)methyl]cyclohexyl]-2-((9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)-1,2-ethanedione | C41H56O8SSi | 详情 | 详情 | |
| (XX) | 10637 | (1R,2S,3S,6S)-3-(Benzyloxy)-2-[2-((9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6,6,8-trimethyl-1,4-dioxaspiro[4.5]dec-7-en-7-yl)-2-oxoacetyl]-2-methyl-5-oxo-6-[(phenylsulfanyl)methyl]cyclohexanecarbaldehyde | C41H54O8SSi | 详情 | 详情 | |
| (XXI) | 10638 | (1R,2S,3S,6S)-3-(Benzyloxy)-2-[2-[(3S)-3-hydroxy-2,6,6-trimethyl-5-oxo-1-cyclohexen-1-yl]-2-oxoacetyl]-2-methyl-5-oxo-6-[(phenylsulfanyl)methyl]cyclohexanecarbaldehyde | C33H36O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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 |