Uses
N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine is a useful synthetic intermediate in the synthesis of Afatinib (A355300); an aminocrotonylamino-substituted quinazoline derivative used for treating cancer and diseases of the respiratory tract, lungs, gastrointestinal tract, bile duct, and gallbladder.
Synthesis
General procedure: N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (15 g, 44.56 mmol) was dissolved in methanol (150 mL) and 50% aqueous potassium hydroxide solution (5 g, 89 mmol) was added. The reaction mixture was stirred at room temperature and then heated to 70 °C and stirred continuously for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic layers were combined, washed with water and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to afford N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine (20 g, 96.7% yield). The product was characterized by 1H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.21 (s, 1H), 8.67 (s, 1H), 8.15 (dd, J = 2.4,6.8 Hz, 1H), 7.79-7.81 (m, 1H), 7.48 (t, J = 7.2 Hz, 2H), 4.07 (s, 3H ).
References
[1] Patent: CN103987700, 2016, B. Location in patent: Paragraph 0182-0184
[2] Patent: US2014/161801, 2014, A1. Location in patent: Page/Page column 0079-0080
[3] Patent: WO2018/119441, 2018, A1. Location in patent: Paragraph 00618; 0619
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 7, p. 1495 - 1503
[5] Patent: CN106008480, 2016, A. Location in patent: Paragraph 0086; 0087; 0088; 0089
