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【结 构 式】 
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【分子编号】69208 【品名】4-(cyanoacetyl)morpholine;Cyanoacetic acid morpholide;N-(Cyanoacetyl)morpholine;3-Morpholin-4-yl-3-oxopropionitrile;3-(4-Morpholinyl)-3-oxopropanenitrile;(Morpholinocarbonyl)acetonitrile;(Morpholin-4-ylcarbonyl)acetonitrile 【CA登记号】15029-32-0 |
【 分 子 式 】C7H10N2O2 【 分 子 量 】154.16868 【元素组成】C 54.54% H 6.54% N 18.17% O 20.76% |
合成路线1
该中间体在本合成路线中的序号：(XXVIII)N-Protection of 2-amino-5-nitrophenol (XVII) with Ac2O in the presence of AcOH gives N-(2-hydroxy-4-nitrophenyl)acetamide (XXI), which upon O-alkylation with ethyl bromide (XX) in the presence of K2CO3 in DMF at 60 °C affords N-(2-ethoxy-4-nitrophenyl) acetamide (XXII). Reduction of the nitro derivative (XXII) with H2 over Pd/C in THF furnishes the corresponding aniline (XXIII), which by condensation with ethyl 2-cyano-3-ethoxy-2-propenoate (XXIV) at reflux produces enamine (XXV). Thermal cyclization of enamino ester (XXV) in Dowtherm at 250 °C then yields 4-hydroxyquinoline derivative (XXVI) , which upon chlorination with POCl3 in 1,2-diethoxyethane at 80-85 °C affords N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (VII) . Alternatively, condensation of ethyl cyanoacetate (II) with morpholine (XXVII) at 100-110 °C gives 4-(cyanoacetyl)morpholine (XXVIII), which after coupling with 4-acetamido-3-ethoxyaniline (XXIII) in the presence of triethyl orthoformate in i-PrOH at 50-60 °C produces the arylamino propenamide (XXIX). Finally, cyclization of (XXIX) in the presence of POCl3 in acetonitrile at 60-65 °C then leads to the target intermediate (VII) .
| 【1】 Wissner, A., Rabindran, S.K., Tsou, H.-R. (Wyeth). Substituted quinolines as protein tyrosine kinase enzyme inhibitors. EP 1670473, WO 2005034955. |
| 【2】 Rabindran, S.K., Tsou, H.-R., Wissner, A. (Wyeth). Protein tyrosine kinase enzyme inhibitors. US 2005059678, US 7399865, WO 2005028443. |
| 【3】 Bernier, C., Shaw, C.-C. (Wyeth). Method of preparing 4-halogenated quinoline intermediates. WO 2009139797. |
| 【4】 Wang, Y., Warren, C. Papamichelakis, M. (Wyeth). Quinoline intermediates of receptor tyrosine kinase inhibitors and the synthesis thereof. WO 2005070890. |
| 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) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 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 |
| (XVII) | 33067 | 2-amino-5-nitrophenol | 121-88-0 | C6H6N2O3 | 详情 | 详情 |
| (XX) | 30344 | 1-bromoethane；ethyl bromide | 74-96-4 | C2H5Br | 详情 | 详情 |
| (XXI) | 69203 | N-(2-hydroxy-4-nitrophenyl)acetamide | C8H8N2O4 | 详情 | 详情 | |
| (XXII) | 69204 | N-(2-ethoxy-4-nitrophenyl)acetamide | C10H12N2O4 | 详情 | 详情 | |
| (XXIII) | 69205 | N-(4-amino-2-ethoxyphenyl)acetamide | C10H14N2O2 | 详情 | 详情 | |
| (XXIV) | 43563 | ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (XXV) | 69206 | (E)-ethyl 3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyanoacrylate | C16H19N3O4 | 详情 | 详情 | |
| (XXVI) | 69207 | N-(3-cyano-7-ethoxy-4-hydroxyquinolin-6-yl)acetamide | C14H13N3O3 | 详情 | 详情 | |
| (XXVII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XXVIII) | 69208 | 4-(cyanoacetyl)morpholine;Cyanoacetic acid morpholide;N-(Cyanoacetyl)morpholine;3-Morpholin-4-yl-3-oxopropionitrile;3-(4-Morpholinyl)-3-oxopropanenitrile;(Morpholinocarbonyl)acetonitrile;(Morpholin-4-ylcarbonyl)acetonitrile | 15029-32-0 | C7H10N2O2 | 详情 | 详情 |
| (XXIX) | 69209 | (E)-N-(4-((2-cyano-3-morpholino-3-oxoprop-1-en-1-yl)amino)-2-ethoxyphenyl)acetamide | C18H22N4O4 | 详情 | 详情 |