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【结 构 式】 
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【分子编号】67754 【品名】1-benzyloxy-2-fluoro-4-nitrobenzene;1-(benzyloxy)-2-fluoro-4-nitrobenzene 【CA登记号】 |
【 分 子 式 】C13H10FNO3 【 分 子 量 】247.226 【元素组成】C 63.16% H 4.08% F 7.68% N 5.67% O 19.41% |
合成路线1
该中间体在本合成路线中的序号：(XIII)a) Condensation of the phenolic compound (I) with 7-benzyloxy-6-methoxyquinolinyl triflate (II) in refluxing 2,6-lutidine affords the quinolinyl ether (III), which is O-debenzylated by transfer hydrogenation with 1,4-cyclohexadiene and Pd/C in EtOH at 65 °C, producing the 7-hydroxyquinoline derivative (IV). Finally, the hydroxyquinoline (IV) is alkylated with N-(3-chloropropyl)morpholine hydrochloride (V) by means of K2CO3 in DMF at 90 °C .
b) Direct coupling of the phenol derivative (I) with 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline (VI) in the presence of Pd(OAc)2, 2-(di-tert-butylphosphino)-1,1’-binaphthyl (DTBPB) and K3PO4 in anisole at 110 °C or NMP/toluene at 95 °C .
c) Acylation of the quinolinyloxyaniline intermediate (VII) with 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride (VIII) by means of K2CO3 in THF/H2O .
| 【1】 Bannen, L.C., Chan, D.S.-M., Chen, J. (Exelixis, Inc.). c-Met modulators and methods of use. EP 1673085, EP 2210607, EP 2213661, JP 2007506777, JP 2010235631, JP 2010235632, WO 2005030140. |
| 【2】 Deschamps, N.M., Martin, M.T., Monteith, M.J., Zhou, X. (GlaxoSmithKline Inc.). Preparation of a quinolinyloxydiphenylcyclopropanedicarboxamide. US 2010081805, WO 010036831. |
| 【3】 Wilson, J., Zuberi, S., Naganathan, S., Goldman, E., Kanter, J. (Exelixis, Inc.). Methods of preparing quinoline derivatives. WO 2010056960. |
| 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) | 69100 | N-(3-fluoro-4-hydroxyphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide | C17H14F2N2O3 | 详情 | 详情 | |
| (VIII) | 69107 | 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride | C11H9ClFNO2 | 详情 | 详情 | |
| (IX) | 69108 | cyclopropane-1,1-dicarboxylic acid | C5H6O4 | 详情 | 详情 | |
| (X) | 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 |
| (XI) | 69109 | 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid | C11H10FNO3 | 详情 | 详情 | |
| (XII) | 17013 | 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene | 369-34-6 | C6H3F2NO2 | 详情 | 详情 |
| (XIII) | 67754 | 1-benzyloxy-2-fluoro-4-nitrobenzene;1-(benzyloxy)-2-fluoro-4-nitrobenzene | C13H10FNO3 | 详情 | 详情 | |
| (XIV) | 67755 | 4-benzyloxy-3-fluoroaniline | C13H12FNO | 详情 | 详情 | |
| (XV) | 69110 | N-(4-(benzyloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide | C24H20F2N2O3 | 详情 | 详情 | |
| (XVI) | 69111 | 4-amino-2-fluorophenol;2-Fluoro-4-aminophenol | 399-96-2 | C6H6FNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Substitution of 1,2-difluoro-4-nitrobenzene (I) with benzyl alcohol in the presence of KOH in CH2Cl2 gives 1-benzyloxy-2-fluoro-4-nitrobenzene (II), which is reduced to 4-benzyloxy-3-fluoroaniline (III) by means of H2 and Pt/C in EtOAc. Condensation of aniline (III) with benzyl chloroformate (IV) in the presence of NaHCO3 in acetone/H2O affords carbamate (V), which is cyclized with (R)-glycidyl butyrate (VI) using BuLi in THF at –60 °C to provide the oxazolidinone derivative (VII) . Debenzylation of compound (VII) with H2 over Pd/C in THF/MeOH produces alcohol (VIII), which is condensed with epoxide (IX) in the presence of Na2CO3 in DMF at 100 °C to obtain the corresponding ether (X). N-Deprotection of intermediate (X) by means of H2 over Pd/C in EtOAc/MeOH gives the piperidine derivative (XI), which is finally condensed with the quinolone boron chelate (XII) —prepared by reaction of the quinolone ester (XIII) with B(OH)3 and AcOH in the presence of ZnCl2 at 110 °C — using DIEA in NMP at 85 °C .
| 【1】 Hermecz, I., Kereszturi, g., Vasvari, L. et al. (Chinoin Zrt). Quinoline carboxylic acid boric acid anhydrides and process for the preparation thereof. CN 88101941, EP 0310647, JP 1989003300, US 4940794, WO 1988007998. |
| 【2】 Hubschwerlen, C., Panchaud, P., Specklin, J.-L. (Actelion Pharmaceuticals, Ltd.). 5-Hydroxymethyl-oxazolidin-2-one derivatives. CN 102014903, EP 2086968, JP 2010509314, JP 2010132677, KR 2010137569, US 2009247578, US 8124623, WO 2008056335. |
| 【3】 Hubschwerlen, C., Locher, H. (Actelion Pharmaceuticals, Ltd.). 5-Hydroxymethyl-oxazolidin-2-one derivatives for treating bacterial intestinal diseases. EP 2296651, JP 2011519914, WO 2009136379. |
| 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) | 17013 | 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene | 369-34-6 | C6H3F2NO2 | 详情 | 详情 |
| (II) | 67754 | 1-benzyloxy-2-fluoro-4-nitrobenzene;1-(benzyloxy)-2-fluoro-4-nitrobenzene | C13H10FNO3 | 详情 | 详情 | |
| (III) | 67755 | 4-benzyloxy-3-fluoroaniline | C13H12FNO | 详情 | 详情 | |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 67756 | benzyl (4-(benzyloxy)-3-fluorophenyl)carbamate | C21H18FNO3 | 详情 | 详情 | |
| (VI) | 18385 | (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate | 60456-26-0 | C7H12O3 | 详情 | 详情 |
| (VII) | 67757 | (R)-3-(4-(benzyloxy)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one | C17H16FNO4 | 详情 | 详情 | |
| (VIII) | 67758 | (R)-3-(3-fluoro-4-hydroxyphenyl)-5-(hydroxymethyl)oxazolidin-2-one | C10H10FNO4 | 详情 | 详情 | |
| (IX) | 67759 | benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (X) | 67760 | (R)-benzyl 4-((2-fluoro-4-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenoxy)methyl)-4-hydroxypiperidine-1-carboxylate | C24H27FN2O7 | 详情 | 详情 | |
| (XI) | 67761 | (R)-3-(3-fluoro-4-((4-hydroxypiperidin-4-yl)methoxy)phenyl)-5-(hydroxymethyl)oxazolidin-2-one | C16H21FN2O5 | 详情 | 详情 | |
| (XII) | 67762 | C17H14BClFNO7 | 详情 | 详情 | ||
| (XIII) | 30340 | ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | 86483-54-7 | C15H13ClFNO3 | 详情 | 详情 |