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【结 构 式】 
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【药物名称】Foretinib;1363089;EXEL-2880;GSK-089;GSK-1363089;XL-880 【化学名称】N-[3-Fluoro-4-[6-methoxy-7-[3-(4-morpholinyl)propoxy]quinolin-4-yloxy]phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 【CA登记号】849217-64-7 【 分 子 式 】C34H34F2N4O6 【 分 子 量 】632.6538 |
【开发单位】Exelixis, Inc. (US); licensed to GlaxoSmithKline (GB) 【药理作用】c-Met and VEGFR-2 Inhibitor;Oncolytic |
合成路线1
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
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3
Treatment of cyclopropane-1,1-dicarboxylic acid (IX) with one equivalent of SOCl2 in the presence of Et3N in THF at 0 °C, followed by condensation of the activated intermediate with 4-fluoroaniline (X), provides the monoamide (XI) , which is optionally chlorinated to (VIII) by treatment with oxalyl chloride in cold THF .
Reaction of 3,4-difluoronitrobenzene (XII) with sodium benzylate prepared from benzyl alcohol and NaH in dimethylacetamide gives 1-benzyloxy-2-fluoro-4-nitrobenzene (XIII) as the main product. Subsequent reduction of compound (XIII) by means of iron and ammonium formate in refluxing toluene leads to the corresponding aniline (XIV), which is subsequently coupled with carboxylic acid (XI) using EDC in CH2Cl2 to afford the diamide (XV). Finally, debenzylation of diamide (XV) by transfer hydrogenation with 1,4-cyclohexadiene and Pd/C in boiling EtOH provides the target intermediate (I) . Scheme 2. Alternatively, acid chloride (VIII) can be directly condensed with 4-amino-2-fluorophenol (XVI) in the presence of 2,6-lutidine in cold THF to give diamide (I) .
| 【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】 Forsyth, T.P., Mac, M.B., Leahy, J.W., Nuss, J.M., Xu, W.(Exelixis, Inc.). c-Met modulators and methods of use. EP 1874759, JP 2008537748, US 2008161305, WO 2006108059. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 69103 | 7-(benzyloxy)-6-methoxyquinolin-4-yl trifluoromethanesulfonate | C18H14F3NO5S | 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 |
| (XVIII) | 69112 | 1-(4-(benzyloxy)-3-methoxyphenyl)ethanone;3'-Methoxy-4'-(benzyloxy)acetophenone;4'-(Benzyloxy)-3'-methoxyacetophenone;Acetovanillone benzyl ether;1-(3-Methoxy-4-phenylmethoxyphenyl)ethanone | 1835-11-6 | C16H16O3 | 详情 | 详情 |
| (XIX) | 69113 | 1-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)ethanone;4’-benzyloxy-5’-methoxy-2’-nitroacetophenone | C16H15NO5 | 详情 | 详情 | |
| (XX) | 69114 | 1-(2-amino-4-(benzyloxy)-5-methoxyphenyl)ethanone | C16H17NO3 | 详情 | 详情 | |
| (XXI) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (XXII) | 67631 | 7-(benzyloxy)-6-methoxyquinolin-4-ol | C17H15NO3 | 详情 | 详情 |
合成路线4
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5
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 |