4,5-dimethoxy-2-nitrobenzamide -Drug Synthesis Database

【结构式】

【分子编号】31791

【品名】4,5-dimethoxy-2-nitrobenzamide

【CA登记号】4959-60-8

【分子式】C₉H₁₀N₂O₅

【分子量】226.18888

【元素组成】C 47.79% H 4.46% N 12.38% O 35.37%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(III)

4,5-Dimethoxy-2-nitrobenzoic acid (I) was treated with thionyl chloride to form acid chloride (II), followed by reaction with ammonia to yield 4,5-dimethoxy-2-nitrobenzamide (III). This was reduced with sodium borohydride in the presence of copper sulfate to give aminobenzamide (IV), which was refluxed with formic acid to afford 6,7-dimethoxyquinazoline-4(3H)-one (V). Subsequent treatment of (V) with phosphoryl chloride gave the chloroquinazoline (VI). The title compound was then prepared by condensation of (VI) with 2-bromo-4-aminophenol (VII) in refluxing ethanol.

参考文献中间体

合成目标

【1】 Liu, X.-P.; Narla, R.K.; Uckun, F.M. (Parker Hughes Institute); Quinazolines for treating brain tumor. WO 9961428 .

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)	31789	4,5-dimethoxy-2-nitrobenzoic acid	4998-07-6	C₉H₉NO₆	详情	详情
(II)	31790	4,5-dimethoxy-2-nitrobenzoyl chloride		C₉H₈ClNO₅	详情	详情
(III)	31791	4,5-dimethoxy-2-nitrobenzamide	4959-60-8	C₉H₁₀N₂O₅	详情	详情
(IV)	31792	2-amino-4,5-dimethoxybenzamide	5004-88-6	C₉H₁₂N₂O₃	详情	详情
(V)	18684	6,7-dimethoxy-4(3H)-quinazolinone	13794-72-4	C₁₀H₁₀N₂O₃	详情	详情
(VI)	23765	4-chloro-6,7-dimethoxyquinazoline; 4-chloro-6-methoxy-7-quinazolinyl methyl ether		C₁₀H₉ClN₂O₂	详情	详情
(VII)	31793	4-amino-2-bromophenol		C₆H₆BrNO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

参考文献中间体

合成目标

【1】 Liu, X.-P.; Narla, R.K.; Uckun, F.M. (Parker Hughes Institute); Quinazolines for treating brain tumor. WO 9961428 .

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)	31789	4,5-dimethoxy-2-nitrobenzoic acid	4998-07-6	C₉H₉NO₆	详情	详情
(II)	31790	4,5-dimethoxy-2-nitrobenzoyl chloride		C₉H₈ClNO₅	详情	详情
(III)	31791	4,5-dimethoxy-2-nitrobenzamide	4959-60-8	C₉H₁₀N₂O₅	详情	详情
(IV)	31792	2-amino-4,5-dimethoxybenzamide	5004-88-6	C₉H₁₂N₂O₃	详情	详情
(V)	18684	6,7-dimethoxy-4(3H)-quinazolinone	13794-72-4	C₁₀H₁₀N₂O₃	详情	详情
(VI)	23765	4-chloro-6,7-dimethoxyquinazoline; 4-chloro-6-methoxy-7-quinazolinyl methyl ether		C₁₀H₉ClN₂O₂	详情	详情
(VII)	15715	4-Aminophenol	123-30-8	C₆H₇NO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

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 .

参考文献中间体

合成目标

【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