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【结 构 式】 
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【分子编号】61518 【品名】4-(3-chloro-4-fluoroanilino)-7-ethoxy-6-nitro-3-quinolinecarbonitrile 【CA登记号】 |
【 分 子 式 】C18H12ClFN4O3 【 分 子 量 】386.7695432 【元素组成】C 55.9% H 3.13% Cl 9.17% F 4.91% N 14.49% O 12.41% |
合成路线1
该中间体在本合成路线中的序号：(VII)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 |