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【结 构 式】 
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【分子编号】69100 【品名】N-(3-fluoro-4-hydroxyphenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 【CA登记号】 |
【 分 子 式 】C17H14F2N2O3 【 分 子 量 】332.30665 【元素组成】C 61.45% H 4.25% F 11.43% N 8.43% O 14.44% |
合成路线1
该中间体在本合成路线中的序号：(I)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】 Gilmer, T.M., Greger, J.G. Jr., Liu, L., Shi, H. (GlaxoSmithKline Inc.). Method of treating cancer using a cMET and AXL inhibitor and an erbB inhibitor. US 2009274693, WO 2009137429. |
| 【3】 Deschamps, N.M., Martin, M.T., Monteith, M.J., Zhou, X. (GlaxoSmithKline Inc.). Preparation of a quinolinyloxydiphenylcyclopropanedicarboxamide. US 2010081805, WO 010036831. |
| 【4】 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 | |
| (II) | 69103 | 7-(benzyloxy)-6-methoxyquinolin-4-yl trifluoromethanesulfonate | C18H14F3NO5S | 详情 | 详情 | |
| (III) | 69101 | N-(4-((7-(benzyloxy)-6- methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide | C34H27F2N3O5 | 详情 | 详情 | |
| (IV) | 69102 | N-(3-fluoro-4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide | C27H21F2N3O5 | 详情 | 详情 | |
| (V) | 69104 | N-(3-chloropropyl)morpholine hydrochloride;3-(Morpholino)propyl chloridehydrochloride;4-(3-Chloropropyl)morpholine hydrochloride;Morpholinopropylchloride hydrochloride | 57616-74-7 | C7H14ClNO.HCl | 详情 | 详情 |
| (VI) | 69105 | 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline;4-(3-((4-chloro-6-methoxyquinolin-7-yl)oxy)propyl)morpholine | C17H21ClN2O3 | 详情 | 详情 | |
| (VII) | 69106 | 3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinolin-4-yl)oxy)aniline | C23H26FN3O4 | 详情 | 详情 | |
| (VIII) | 69107 | 1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl chloride | C11H9ClFNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |