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【结 构 式】 
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【分子编号】69105 【品名】4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline;4-(3-((4-chloro-6-methoxyquinolin-7-yl)oxy)propyl)morpholine 【CA登记号】 |
【 分 子 式 】C17H21ClN2O3 【 分 子 量 】336.81812 【元素组成】C 60.62% H 6.28% Cl 10.53% N 8.32% O 14.25% |
合成路线1
该中间体在本合成路线中的序号：(VI)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：(VI)Alkylation of 4’-hydroxy-3’-methoxyacetophenone (XVII) with benzyl bromide by means of K2CO3 in DMF gives benzyl ether (XVIII), which is reacted with fuming HNO3 and concentrated H2SO4 in cold CH2Cl2 to afford 4’-benzyloxy-5’-methoxy-2’-nitroacetophenone (XIX). After reduction of the nitro group of compound (XIX) using iron powder and ammonium formate in refluxing H2O/toluene, the resulting 2-aminoacetophenone derivative (XX) cyclizes with ethyl formate (XXI) in the presence of NaOEt in DME, providing 7-benzyloxy-6-methoxy-4-quinolinol (XXII). Finally, quinolinol (XXII) is treated with trifluoromethanesulfonyl chloride in the presence of DMAP and 2,6-lutidine in cold CH2Cl2 .
| 【1】 Deschamps, N.M., Martin, M.T., Monteith, M.J., Zhou, X. (GlaxoSmithKline Inc.). Preparation of a quinolinyloxydiphenylcyclopropanedicarboxamide. US 2010081805, WO 010036831. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (XXIVa) | 22605 | 4-(3-Chloropropoxy)-3-Methoxyacetophenone;3-(4-Acetyl-2-methoxyphenoxy)propyl chloride;1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone;1-[4-(3-chloropropoxy)-3-methoxyphenyl]-1-ethanone | 58113-30-7 | C12H15ClO3 | 详情 | 详情 |
| (XXIVb) | 69115 | 1-(4-(3-bromopropoxy)-3-methoxyphenyl)ethanone | C12H15BrO3 | 详情 | 详情 | |
| (XXVa) | 69117 | 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone | C12H14ClNO5 | 详情 | 详情 | |
| (XXVb) | 69116 | 1-(4-(3-bromopropoxy)-5-methoxy-2-nitrophenyl)ethanone | C12H14BrNO5 | 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 | |
| (XVII) | 22604 | 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone | 498-02-2 | C9H10O3 | 详情 | 详情 |
| (XXI) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (XXIII) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (XXVI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XXVII) | 69118 | 1-(5-methoxy-4-(3-morpholinopropoxy)-2-nitrophenyl)ethanone | C16H22N2O6 | 详情 | 详情 | |
| (XXVIII) | 56891 | 1,3-propanediol cyclic sulfate;1,3,2-dioxathiane 2,2-dioxide;1,3-Propylene sulfate | 1073-05-8 | C3H6O4S | 详情 | 详情 |
| (XXIX) | 69119 | 4’-(morpholinopropoxy)acetophenone;1-(3-methoxy-4-(3-morpholinopropoxy)phenyl)ethanone | C16H23NO4 | 详情 | 详情 | |
| (XXX) | 69120 | 1-(2-amino-5-methoxy-4-(3-morpholinopropoxy)phenyl)ethanone | C16H24N2O4 | 详情 | 详情 | |
| (XXXI) | 69121 | 6-methoxy-7-(3-morpholinopropoxy)quinolin-4-ol | C17H22N2O4 | 详情 | 详情 | |
| (XXXII) | 20360 | methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline | 93-61-8 | C8H9NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The 4-(aminophenoxy)quinoline precursor (VII) can be obtained from chloroquinoline (VI) by two related methods. Condensation of chloride (VI) with 2-fluoro-4-nitrophenol (XXXIII) in 2,6-lutidine at 140-145 °C affords the 2-fluoro-4-nitrophenyl ether (XXXIV), which is then reduced by catalytic hydrogenation over Pd/C in the presence of HCl in H2O/EtOH .
Alternatively, by direct coupling of chloroquinoline (VI) with 2-fluoro-4-aminophenol (XVI) by means of sodium tert-butoxide in DMAc at 100 °C .
| 【1】 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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XVI) | 69111 | 4-amino-2-fluorophenol;2-Fluoro-4-aminophenol | 399-96-2 | C6H6FNO | 详情 | 详情 |
| (XXXIII) | 54801 | 2-Fluoro-4-nitrophenol; 4-Nitro-2-fluorophenol | 403-19-0 | C6H4FNO3 | 详情 | 详情 |
| (XXXIV) | 69122 | 4-(3-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)propyl)morpholine | C23H24FN3O6 | 详情 | 详情 |