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【结 构 式】 
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【分子编号】23222 【品名】N(4)-(3-bromophenyl)-4,6-quinazolinediamine; N-(6-amino-4-quinazolinyl)-N-(3-bromophenyl)amine 【CA登记号】 |
【 分 子 式 】C14H11BrN4 【 分 子 量 】315.1723 【元素组成】C 53.35% H 3.52% Br 25.35% N 17.78% |
合成路线1
该中间体在本合成路线中的序号：(VI)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：(V)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：(I)Title compound was obtained by condensation of the 6-aminoquinazoline (I) with acrylic acid in the presence of EDC.
| 【1】 Cushman, M.; Insaf, S.; Paul, G.; Ruell, J.A.; De Clercq, E.; Schols, D.; Pannecouque, C.; Witvrouw, M.; Schaeffer, C.A.; Turpin, J.A.; Williamson, K.; Rice, W.G.; Extension of the polyanionic cosalane pharmacophore as a strategy for increasing anti-HIV potency. J Med Chem 1999, 42, 10, 1767. |
| 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) | 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4
该中间体在本合成路线中的序号：(V)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5
该中间体在本合成路线中的序号：(V)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 |