【结 构 式】 |
【分子编号】68205 【品名】2,4-di-tert-butylphenol;2,4-Bis(1,1-dimethylethyl)-phenol 【CA登记号】96-76-4 |
【 分 子 式 】C14H22O 【 分 子 量 】206.32808 【元素组成】C 81.5% H 10.75% O 7.75% |
合成路线1
该中间体在本合成路线中的序号:(I)O-Protection of 2,4-di-tert-butylphenol (I) with methyl chloroformate (II) in the presence of Et3N and DMAP in CH2Cl2 gives 2,4-ditert-butylphenyl methyl carbonate (III), which by nitration with HNO3 and H2SO4 provides a mixture of the 5- and 6-nitrophenyl carbonates (IVa) and (IVb), respectively. Hydrolysis of the mixture of carbonates (IVa) and (IVb) by means of KOH in MeOH followed by chromatographic separation of the resulting mixture of nitrophenols affords 2,4-di-tert-butyl-5-nitrophenol (V), which is reduced by transfer hydrogenation with HCOONH4 in the presence of Pd/C in refluxing EtOH to the amine (VI). Finally, amine (VI) is condensed with 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (VII) by means of HBTU and Et3N in DMF or CH2Cl2 .
4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (VII) is prepared by coupling of diethyl 2-(ethoxymethylene)malonate (VIII) with aniline (IX) by heating at 140-150 °C to afford diethyl 2-(anilinomethylene) malonate (X), which by cyclization by means of PPA and POCl3 at 70 °C yields ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (XI). Finally, ethyl ester derivative (XI) is saponified with NaOH at reflux, followed by acidification with HCl .
【1】 Hadida Ruah, S.S., Hazlewood, A.R., Grootenhuis, P.D.J., Van Goor, F.F., Singh, A.K., Zhou, J., McCartney, J. (Vertex Pharmaceuticals, Inc.).Modulators of ATP-binding cassette transporters. CN 10193301, EP 1773816, JP 2008504291, US 2006074075, US 7495013, US 8101767, WO 2006002421. |
【2】 Hurter, P. (Vertex Pharmaceuticals, Inc.). Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. EP 1993360, JP 200952278, US 011064811, WO 2007079139. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IVa) | 68207 | 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate | 873055-55-1 | C16H23NO5 | 详情 | 详情 |
(IVb) | 68208 | 2,4-di-tert-butyl-6-nitrophenyl methyl carbonate | 详情 | 详情 | ||
(I) | 68205 | 2,4-di-tert-butylphenol;2,4-Bis(1,1-dimethylethyl)-phenol | 96-76-4 | C14H22O | 详情 | 详情 |
(II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester;[(chlorocarbonyl)oxy]methane;methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
(III) | 68206 | 2,4-ditert-butylphenyl methyl carbonate | C16H24O3 | 详情 | 详情 | |
(V) | 68209 | 2,4-di-tert-butyl-5-nitrophenol | C14H21NO3 | 详情 | 详情 | |
(VI) | 68210 | 5-amino-2,4-di-tert-butylphenol | C14H23NO | 详情 | 详情 | |
(VII) | 68211 | 4-oxo-1,4-dihydroquinoline-3-carboxylic acid | 13721-01-2 | C10H7NO3 | 详情 | 详情 |
(VIII) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
(IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
(X) | 35953 | diethyl 2-(anilinomethylene)malonate | C14H17NO4 | 详情 | 详情 | |
(XI) | 68212 | ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate | C12H11NO3 | 详情 | 详情 |