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【结 构 式】 
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【分子编号】61517 【品名】4-chloro-7-ethoxy-6-nitro-3-quinolinecarbonitrile 【CA登记号】 |
【 分 子 式 】C12H8ClN3O3 【 分 子 量 】277.66664 【元素组成】C 51.91% H 2.9% Cl 12.77% N 15.13% O 17.29% |
合成路线1
该中间体在本合成路线中的序号：(V)The condensation of 3-ethoxy-4-nitroaniline (I) with 2-(ethoxymethylene)cyanacetic acid ethyl ester (II) in refluxing toluene gives the adduct (III), which is further cyclized in Dowtherm at 258 C to yield 7-ethoxy-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile (IV). The reaction of (IV) with refluxing POCl3 affords the 4-chloroquinoline (V), which is condensed with 3-chloro-4-fluoroaniline (VI) in refluxing isopropanol to provide the secondary amine (VII). The reduction of the nitro group of (VII) with Fe and NH4Cl in refluxing methanol/water gives the corresponding amino derivative (VIII), which is condensed with the acid chloride (IX) by means of t-BuOCOCl and NMM in THF to yield the amide (X). Finally, this compound is treated with dimethylamine in THF to afford the target quinoline-3-carbonitrile.
| 【1】 Wissner, A.; Overbeek, E.; Reich, M.F.; Floyd, B.; Johnson, B.D.; Mamuya, N.; Rosfjord, E.C.; Discafani, C.; Davis, R.; Shi, X.; Rabindran, S.K.; Gruber, B.C.; Ye, F.; Hallett, W.A.; Nilakantan, R.; Shen, R.; Wang, Y.-F.; Greenberger, L.M.; Tsou, H.-R.; Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epi. J Med Chem 2003, 46, 1, 49. |
| 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) | 61513 | 3-ethoxy-4-nitroaniline; 3-ethoxy-4-nitrophenylamine | C8H10N2O3 | 详情 | 详情 | |
| (II) | 61514 | ethyl (Z)-2-cyano-3-propoxy-2-propenoate | C9H13NO3 | 详情 | 详情 | |
| (III) | 61515 | ethyl (E)-2-cyano-3-(3-ethoxy-4-nitroanilino)-2-propenoate | C14H15N3O5 | 详情 | 详情 | |
| (IV) | 61516 | 7-ethoxy-6-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile | C12H9N3O4 | 详情 | 详情 | |
| (V) | 61517 | 4-chloro-7-ethoxy-6-nitro-3-quinolinecarbonitrile | C12H8ClN3O3 | 详情 | 详情 | |
| (VI) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (VII) | 61518 | 4-(3-chloro-4-fluoroanilino)-7-ethoxy-6-nitro-3-quinolinecarbonitrile | C18H12ClFN4O3 | 详情 | 详情 | |
| (VIII) | 61519 | 6-amino-4-(3-chloro-4-fluoroanilino)-7-ethoxy-3-quinolinecarbonitrile | C18H14ClFN4O | 详情 | 详情 | |
| (IX) | 50564 | (E)-4-bromo-2-butenoyl chloride | C4H4BrClO | 详情 | 详情 | |
| (X) | 61520 | (E)-4-bromo-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxy-6-quinolinyl]-2-butenamide | C22H17BrClFN4O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)3-Chloro-4-(2-pyridylmethoxy)aniline (I) is condensed with ethyl cyanoacetate (II) at 100-115 °C to give the N-aryl 2-cyanoacetamide (III). Reduction of 3-ethoxy-4-phthalimido-1-nitrobenzene (IV) with H2 over Pd/C in THF at 50 °C followed by coupling of the resulting aniline with the cyano amide (III) by means of triethyl orthoformate in refluxing propanol affords the 3-amino-2-cyanopropenamide derivative (V). After intramolecular cyclization of propenamide (V) by means of POCl3 in acetonitrile at 60-70 °C, the obtained 6-phthalimidoquinoline derivative is hydrolyzed by means of NH4OH in EtOH at 62-68 °C to give the 6-aminoquinoline (VI) (1). Alternatively, the aminoquinoline (VI) can be obtained by condensation of the aniline derivative (I) with 6-acetamido-4-chloro-7-ethoxyquinoline-3-carbonitrile (VII) in the presence of methanesulfonic acid at 70-75 °C, affording the diarylamine (VIII), which is then deacetylated to the aminoquinoline (VI) by hydrolysis with HCl . Finally, compound (VI) is acylated with 4-(dimethylamino)-2-butenoyl chloride (IX) , obtained by chlorination of the corresponding free acid (X) or its hydrochloride salt with either (COCl)2 by means of DMF in THF or DMF/i-PrOAc , POCl3 in DMAc, or SOCl2 in DMAc , in the presence of NMP .
In a related strategy, 4-chloro-7-ethoxy-6-nitroquinoline-3-carbonitrile (XI) is reduced to the corresponding amine (XII) by means of Fe and acetic acid in refluxing methanol. Subsequent acylation of (XII) with 4-(dimethylamino)-2-butenoyl chloride (IX) in the presence of NMP in acetonitrile or DMF yields carboxamide (XIII), which is finally coupled with 3-chloro-4-(2-pyridylmethoxy)aniline (I) by means of pyridinium chloride in refluxing isopropanol or 2-methoxyethanol .
| 【1】 Chew, W., Papamichelakis, M. (Wyeth). Methods of preparing 3-cyanoquinolines and intermediates made thereby. WO 2006127205. |
| 【2】 Wissner, A., Rabindran, S.K., Tsou, H.-R. (Wyeth). Substituted quinolines as protein tyrosine kinase enzyme inhibitors. EP 1670473, WO 2005034955. |
| 【3】 Rabindran, S.K., Tsou, H.-R., Wissner, A. (Wyeth). Protein tyrosine kinase enzyme inhibitors. US 2005059678, US 7399865, WO 2005028443. |
| 【4】 Chew, W., Cheal, G.K., Lunetta, J.F. (Wyeth). Methods of synthesizing substituted 3-cyanoquinolines and intermediates thereof. EP 1883631, JP 2008545688, US 2006270668, WO 2006127207. |
| 【5】 Chew, W., Rabindran, S.K., Discafani-Marro, C., McGinnis, J.P. III, Wissner, A., Wang, Y. (Wyeth). Methods of synthesizing 6-alkylaminoquinoline derivatives. WO 2006127203. |
| 【6】 Lu, Q., Ku, M.S., Chew, W., Cheal, G.K., Hadfield, A.F., Mirmehrabi, M. (Wyeth). Maleate salts of (E)-N-[4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide and crystalline forms thereof. EP 2212311, WO 2009052264. |
| 【7】 Gontcharov, A., Eng, K.K., Sutherland, K., Sebastian, A., Yu, Q., Place, D.W. (Wyeth). Improved process for preparation of coupled products from 4-amino-3-cyanoquinolines using stabilized intermediates. WO 2010048477. |
| 【8】 Tsou, R.H., Overbeck-Klumpers, E.G., Hallett, W.A. et al. Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem 2005, 48(4): 1107-31. |
| 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) | 69190 | 3-Chloro-4-(2-pyridylmethoxy)aniline | C12H11ClN2O | 详情 | 详情 | |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 69191 | N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-2-cyanoacetamide | C15H12ClN3O2 | 详情 | 详情 | |
| (IV) | 69192 | 2-(2-ethoxy-4-nitrophenyl)isoindoline-1,3-dione | C16H12N2O5 | 详情 | 详情 | |
| (V) | 69193 | (Z)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-2-cyano-3-((4-(1,3-dioxoisoindolin-2-yl)-3-ethoxyphenyl)amino)acrylamide | C32H24ClN5O5 | 详情 | 详情 | |
| (VI) | 69194 | 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile | C24H20ClN5O2 | 详情 | 详情 | |
| (VII) | 69196 | 6-acetamido-4-chloro-7-ethoxyquinoline-3-carbonitrile;4-Chloro-3-cyano-7-ethoxy-6-(acetylamino)quinoline | 848133-76-6 | C14H12ClN3O2 | 详情 | 详情 |
| (VIII) | 69195 | N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide | C26H22ClN5O3 | 详情 | 详情 | |
| (IX) | 69197 | 4-(dimethylamino)-2-butenoyl chloride;(E)-4-(dimethylamino)but-2-enoyl chloride | C6H10ClNO | 详情 | 详情 | |
| (X) | 69198 | (E)-4-(dimethylamino)but-2-enoic acid | 149586-32-3 | C6H11NO2 | 详情 | 详情 |
| (XI) | 61517 | 4-chloro-7-ethoxy-6-nitro-3-quinolinecarbonitrile | C12H8ClN3O3 | 详情 | 详情 | |
| (XII) | 69199 | 6-amino-4-chloro-7-ethoxyquinoline-3-carbonitrile | C12H10ClN3O | 详情 | 详情 | |
| (XIII) | 69200 | (E)-4-chloro-6-((5-(dimethylamino)penta-1,3-dien-2-yl)amino)-7-ethoxyquinoline-3-carbonitrile | C19H21ClN4O | 详情 | 详情 |