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【结 构 式】 
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【药物名称】Canertinib dihydrochloride, CI-1033, PD-183805(free base) 【化学名称】N-[4-(3-Chloro-4-fluorophenylamino)-7-[3-(4-morpholinyl)propoxy]quinazolin-6-yl]-2-propenamide dihydrochloride 【CA登记号】289499-45-2, 338796-35-3 (deleted CAS), 267243-28-7 (free base) 【 分 子 式 】C24H27Cl3FN5O3 【 分 子 量 】558.87189 |
【开发单位】Pfizer (Originator) 【药理作用】Oncolytic Drugs, HER (erbB) Inhibitors, Inhibitors of Signal Transduction Pathways, Tyrphostins |
合成路线1
4-Chloro-7-fluoro-6-nitroquinazoline (I) was condensed with 3-chloro-4-fluoroaniline (II) to afford the 4-anilino quinazoline (III). Displacement of the activated fluorine of (III) with the potassium alkoxide of morpholinopropanol (IV) gave the morpholinopropyl ether (V). Subsequent reduction of the nitro group of (V), either using iron dust and acetic acid or catalytic hydrogenation over Raney-Ni, furnished aminoquinazoline (VI). This was finally condensed with acrylic acid (VII), via activation as the mixed anhydride with isobutyl chloroformate or using EDC as the coupling reagent, to provide the title acrylamide.
| 【1】 Loo, J.A.; Rewcastle, G.W.; Smaill, J.B.; et al.; Tyrosine kinase inhibitors.17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(Phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides baring additional solubilizing functions. J Med Chem 2000, 43, 7, 1380. |
| 【2】 Bridges, A.J.; Klohs, W.D.; Driscoll, D. (Pfizer Inc.); N-[4-(3-Chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases. EP 1131304; US 6344455; WO 0031048 . |
| 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) | 19142 | 4-chloro-7-fluoro-6-nitroquinazoline | C8H3ClFN3O2 | 详情 | 详情 | |
| (II) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (III) | 54956 | N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine | 162012-67-1 | C14H7ClF2N4O2 | 详情 | 详情 |
| (IV) | 54957 | 3-(4-morpholinyl)-1-propanol | C7H15NO2 | 详情 | 详情 | |
| (V) | 54958 | N-(3-chloro-4-fluorophenyl)-7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-{7-[3-(4-morpholinyl)propoxy]-6-nitro-4-quinazolinyl}amine | C21H21ClFN5O4 | 详情 | 详情 | |
| (VI) | 54959 | N-{6-amino-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl}-N-(3-chloro-4-fluorophenyl)amine; N~4~-(3-chloro-4-fluorophenyl)-7-[3-(4-morpholinyl)propoxy]-4,6-quinazolinediamine | C21H23ClFN5O2 | 详情 | 详情 | |
| (VII) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |