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【结 构 式】

【分子编号】67978

【品名】4-[(3-bromophenyl)amino]-6,7-dihydroxyquinazoline

【CA登记号】 

【 分 子 式 】C14H10BrN3O2

【 分 子 量 】332.156

【元素组成】C 50.62% H 3.03% Br 24.06% N 12.65% O 9.63%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(I)

Cyclization of 4-[(3-bromophenyl)amino]-6,7-dihydroxyquinazoline (I) with ditosylate (II) [prepared by sulfonylation of triethylene glycol (III) with p-TsCl in the presence of NaOH in THF/H2O (1)] by means of K2CO3 in DMF at 80-90 °C yields the tetraoxacyclododecane derivative (IV), which is finally submitted to Sonogashira coupling with (trimethylsilyl)acetylene (V) using Pd(PPh3)4, CuI and K2CO3 in refluxing DMF .
The aryl bromide precursor (IV) can also be prepared by chlorination of the quinazolinone (VI) using POCl3 in the presence of a catalytic amount of DMF at reflux to afford the 4-chloroquinazoline derivative (VII), which is then coupled with 3-bromoaniline (VIII) in i-PrOH/DMF .
Alternatively, condensation of chloroquinazoline (VII) with 3-ethynyl-aniline (IX) in refluxing i-PrOH/DMF directly produces icotinib .

1 Wang, Y., Ding, L., Tan, F. et al. (Zhejiang Beta Pharma, Inc.). Icotinib hydrochloride, synthesis, crystallographic form, medical combination, and uses thereof. CN 10187818, EP 2392576, JP 2011527291, KR 2011031370, US 2011182882, WO 2010003313.
2 Zhang, D., Xie, G., Davis, C., Cheng, Z., Chen, H., Wang, Y., Kamal, M.(Beta Pharma, Inc.). Fused quinazoline derivatives useful as tyrosine kinase inhibitors. US 2004048883, US 7078409, WO 2003082830.
3 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.
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
(II) 67980 (ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate) 19249-03-7 C20H26O8S2 详情 详情
(III) 67979 2,2'-(ethane-1,2-diylbis(oxy))diethanol;Triethylene glycol 112-27-6 C6H14O4 详情 详情
(IV) 67981 N-(3-bromophenyl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4-amine   C20H20BrN3O4 详情 详情
(V) 23897 ethynyl(trimethyl)silane;trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(VI) 67982 7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4(3H)-one   C14H16N2O5 详情 详情
(VII) 67983 4-chloro-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline   C14H15ClN2O4 详情 详情
(VIII) 19136 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine 591-19-5 C6H6BrN 详情 详情
(IX) 56445 3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene 54060-30-9 C8H7N 详情 详情

合成路线2

该中间体在本合成路线中的序号:(I)

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
Extended Information