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【结 构 式】 
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【分子编号】67984 【品名】N-(3-bromophenyl)-6,7-dimethoxyquinazolin-4-amine hydrochloride 【CA登记号】183322-45-4 |
【 分 子 式 】C16H14BrN3O2.HCl 【 分 子 量 】396.67082 【元素组成】C 48.45% H 3.81% Br 20.14% Cl 8.94% N 10.59% O 8.07% |
合成路线1
该中间体在本合成路线中的序号：(XVI)Chlorination of 4,5-dimethoxy-2-nitrobenzoic acid (X) with SOCl2, followed by reaction with aqueous ammonia yields the nitrobenzamide (XI), which is reduced to the corresponding aminobenzamide (XII) by means of NaBH4 in the presence of catalytic amounts of CuSO4. Anthranilamide (XII) is then cyclized to quinazolinone (XIII) by refluxing in formic acid . Alternatively, cyclization of 4,5-dimethoxyanthranilic acid (XIV), either by heating with formamide at 190 °C or with formamidine hydrochloride at 210 °C , gives rise to quinazolinone (XIII) . Subsequent chlorination of compound (XIII) to the corresponding 4-chloroquinazoline (XV) is accomplished by treatment with either POCl3 , SOCl2 or (COCl)2 in the presence of catalytic amounts of DMF. Chloroquinazoline (XV) is then condensed with 3-bromoaniline (VIII) in refluxing EtOH or i-PrOH to produce anilinoquinazoline (XVI) , which is finally demethylated by either treatment with BBr3 in THF or by heating with pyridinium chloride at 205 °C .
| 【1】 Hu, S., Xie, G., Zhang, D.X. et al. Synthesis and biological evaluation of crown ether fused quinazoline analogues as potent EGFR inhibitors. Bioorg Med Chem Lett 2012, 22(19): 6301-5. |
| 【2】 Uckun, F.M., Narla, R.K., Liu, X.-P. (Parker Hughes Institute). Quinazolines for treating brain tumor. EP 1082311, JP 2002516823, US 6316454, WO 1999061428. |
| 【3】 Barker, A.J. (AstraZeneca plc). Quinazoline derivatives. CA 2086968, EP 0566226, JP 1994073025, US 5457105, US 5616582. |
| 【4】 Johnström, P., Fredriksson, A., Thorell, J.-O., Stone-Elander, S. Synthesis of [methoxy-11C]PD153035, a selective EGR receptor tyrosine kinase inhibitor. J Label Compd Radiopharm 1998, 41(7): 623-9. |
| 【5】 Bridges, A.J., Zhou, H., Cody, D.R. et al. Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J Med Chem 1996, 39(1): 267-76. |
| 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) | 67978 | 4-[(3-bromophenyl)amino]-6,7-dihydroxyquinazoline | C14H10BrN3O2 | 详情 | 详情 | |
| (VIII) | 19136 | 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine | 591-19-5 | C6H6BrN | 详情 | 详情 |
| (X) | 31789 | 4,5-dimethoxy-2-nitrobenzoic acid | 4998-07-6 | C9H9NO6 | 详情 | 详情 |
| (XI) | 31791 | 4,5-dimethoxy-2-nitrobenzamide | 4959-60-8 | C9H10N2O5 | 详情 | 详情 |
| (XII) | 31792 | 2-amino-4,5-dimethoxybenzamide | 5004-88-6 | C9H12N2O3 | 详情 | 详情 |
| (XIII) | 18684 | 6,7-dimethoxy-4(3H)-quinazolinone | 13794-72-4 | C10H10N2O3 | 详情 | 详情 |
| (XIV) | 23763 | 2-amino-4,5-dimethoxybenzoic acid | 5653-40-7 | C9H11NO4 | 详情 | 详情 |
| (XV) | 23765 | 4-chloro-6,7-dimethoxyquinazoline; 4-chloro-6-methoxy-7-quinazolinyl methyl ether | C10H9ClN2O2 | 详情 | 详情 | |
| (XVI) | 67984 | N-(3-bromophenyl)-6,7-dimethoxyquinazolin-4-amine hydrochloride | 183322-45-4 | C16H14BrN3O2.HCl | 详情 | 详情 |