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【结 构 式】

【分子编号】23221

【品名】N-(3-bromophenyl)-N-(6-nitro-4-quinazolinyl)amine; N-(3-bromophenyl)-6-nitro-4-quinazolinamine

【CA登记号】

【 分 子 式 】C14H9BrN4O2

【 分 子 量 】345.15522

【元素组成】C 48.72% H 2.63% Br 23.15% N 16.23% O 9.27%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(V)

The reaction of 2-amino-5-nitrobenzoic acid (I) with N,N-dimethylformamide dimethylacetal (II) by heating at 100 C gives the formamidine (III), which is cyclized with 3-bromoaniline (IV) in refluxing acetic acid yielding 4-(3-bromophenyl)-6-nitroquinazoline (V). The reduction of (V) with Fe and acetic acid affords the amine (VI), which is finally acylated with 2-butynoic acid by means of isobutyl chloroformate and N-methylmorpholine in THF.

1 Wissner, A.; Johnson, B.D.; Floyd, M.B. Jr.; Kitchen, D.B. (American Cyanamid Co.); 4-Aminoquinazoline EGFR inhibitors. EP 0787722; US 5760041 .
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) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(III) 23219 N'-(2-cyano-4-nitrophenyl)-N,N-dimethyliminoformamide C10H10N4O2 详情 详情
(IV) 19136 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine 591-19-5 C6H6BrN 详情 详情
(V) 23221 N-(3-bromophenyl)-N-(6-nitro-4-quinazolinyl)amine; N-(3-bromophenyl)-6-nitro-4-quinazolinamine C14H9BrN4O2 详情 详情
(VI) 23222 N(4)-(3-bromophenyl)-4,6-quinazolinediamine; N-(6-amino-4-quinazolinyl)-N-(3-bromophenyl)amine C14H11BrN4 详情 详情
(VII) 10938 2-Butynoic acid 590-93-2 C4H4O2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IV)

Reaction of 2-amino-5-nitrobenzonitrile (I) with N,N-dimethylformamide dimethylacetal at 100 C provided formamidine (II), which was cyclized with 3-bromoaniline (III) in refluxing AcOH yielding quinazoline (IV). The nitro group of (IV) was then reduced to amine (V) with iron powder and AcOH. The resulting amine (V) was finally coupled with either acryloyl chloride (VI) in pyridine or with acrylic acid (VII) in the presence of EDC.

1 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 .
2 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 .
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
(VI) 11577 Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride 814-68-6 C3H3ClO 详情 详情
(VII) 19136 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine 591-19-5 C6H6BrN 详情 详情

合成路线3

该中间体在本合成路线中的序号:(IV)

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
Extended Information