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【结 构 式】 
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【药物名称】 【化学名称】N-[4-(3-Bromophenylamino)quinazolin-6-yl]-4-(dimethylamino)-2(E)-butenamide 【CA登记号】220699-51-4 【 分 子 式 】C20H20BrN5O 【 分 子 量 】426.3193 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】ONCOLYTIC DRUGS, EGFR (erbB1) Inhibitors, HER2 (erbB2) Inhibitors, Inhibitors of Signal Transduction Pathways |
合成路线1
5-Nitroanthranilonitrile (I) was converted into the corresponding formamidine (II) using dimethylformamide dimethyl acetal. Heating a solution of formamidine (II) and 3-bromoaniline (III) in HOAc gave the nitro quinazoline (IV). The nitro group of (IV) was then reduced with iron in HOAc to yield the intermediate amino quinazoline (V).
| 【1】 Tsou, H.-R.; et al.; 6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity. J Med Chem 2001, 44, 17, 2719. |
| 【2】 Wissner, A.; Johnson, B.D.; Zhang, N.; Tsou, H.-R.; Hamann, P.R. (American Cyanamid Co.); Substd. quinazoline derivs. and their use as tyrosine kinase inhibitors. EP 1000039; JP 2001515071; WO 9909016 . |
| 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) | 23218 | 2-amino-5-nitrobenzonitrile | 17420-30-3 | C7H5N3O2 | 详情 | 详情 |
| (II) | 23219 | N'-(2-cyano-4-nitrophenyl)-N,N-dimethyliminoformamide | C10H10N4O2 | 详情 | 详情 | |
| (III) | 19136 | 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine | 591-19-5 | C6H6BrN | 详情 | 详情 |
| (IV) | 23221 | N-(3-bromophenyl)-N-(6-nitro-4-quinazolinyl)amine; N-(3-bromophenyl)-6-nitro-4-quinazolinamine | C14H9BrN4O2 | 详情 | 详情 | |
| (V) | 23222 | N(4)-(3-bromophenyl)-4,6-quinazolinediamine; N-(6-amino-4-quinazolinyl)-N-(3-bromophenyl)amine | C14H11BrN4 | 详情 | 详情 |
合成路线2
Methyl 4-bromocrotonate (VI) was hydrolyzed with barium hydroxide under controlled conditions and the resulting bromocrotonic acid (VII) was converted to the corresponding acid chloride (VIII) by treatment with oxalyl chloride. Condensation of acid chloride (VIII) with amino quinazoline (V) produced the bromocrotonamide (IX). Finally, nucleophilic displacement of the allylic bromine with dimethylamine provided the title compound.
| 【1】 Tsou, H.-R.; et al.; 6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity. J Med Chem 2001, 44, 17, 2719. |
| 【2】 Wissner, A.; Johnson, B.D.; Zhang, N.; Tsou, H.-R.; Hamann, P.R. (American Cyanamid Co.); Substd. quinazoline derivs. and their use as tyrosine kinase inhibitors. EP 1000039; JP 2001515071; WO 9909016 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 23222 | N(4)-(3-bromophenyl)-4,6-quinazolinediamine; N-(6-amino-4-quinazolinyl)-N-(3-bromophenyl)amine | C14H11BrN4 | 详情 | 详情 | |
| (VI) | 26358 | methyl (E)-4-bromo-2-butenoate | 1117-71-1 | C5H7BrO2 | 详情 | 详情 |
| (VII) | 50563 | (E)-4-bromo-2-butenoic acid | 13991-36-1 | C4H5BrO2 | 详情 | 详情 |
| (VIII) | 50564 | (E)-4-bromo-2-butenoyl chloride | C4H4BrClO | 详情 | 详情 | |
| (IX) | 50565 | (E)-4-bromo-N-[4-(3-bromoanilino)-6-quinazolinyl]-2-butenamide | C18H14Br2N4O | 详情 | 详情 |