Synthesis
Acrylic acid (12.7 mmol, 0.87 mL) was added to an anhydrous N,N-dimethylformamide (DMF, 20 mL) solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (2.0 g, 6.35 mmol) under nitrogen protection. The reaction mixture was cooled to 0 °C, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI-HCl, 7.62 mmol, 1.46 g). The reaction was stirred at 0 °C for 15 min and then gradually warmed up to room temperature and continued stirring for 2 h. The reaction was carried out at 0 °C for 1 h. The reaction was then stirred for 2 h. After that, acrylic acid (0.30 mL) and EDCI-HCl (0.30 g) were added supplementally. The reaction continued to stir for 2 h. After the reaction was continued, the completion of the reaction was confirmed by thin layer chromatography (TLC). The solvent was removed under reduced pressure and the residue was diluted with saturated sodium bicarbonate (NaHCO3) solution and extracted several times with ethyl acetate (EtOAc). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude product was purified by chromatography on a class III alumina column using ethyl acetate/methanol (95:5, v/v) as eluent, followed by recrystallization with ethyl acetate/hexane to give a spongy white solid. After drying in high vacuum for several hours, N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]acrylamide (1.06 g, 45% yield) was obtained as a cream-colored powder with a melting point of 258-261 °C. 1H NMR ((CD3)2SO, 200 MHz): δ 10.51 (s, 1H, CONH), 9.93 (s, 1H, NH), and 8.83 (br s, 1H, H-5), 8.59 (s, 1H, H-2), 8.18 (br s, 1H, H-2'), 7.94-7.78 (m, 3H, H-6', 8,5'), 7.40-7.27 (m, 2H, H-7,4'), 6.54 (dd, J = 9.8 Hz, J = 17.0 Hz, 1H CH2CHCO), 6.36 (dd, J = 2.1 Hz, J = 16.9 Hz, 1H, CH2CHCO), 5.85 (dd, J = 2.0 Hz, J = 9.7 Hz, 1H, CH2CHCO). Mass spectrum (CI): m/z 371 (95, 81BrMH+), 370 (53, 81BrM+), 369 (100, 79BrMH+), 368 (33, 79BrM+). Elemental analysis (C17H13BrN4O) Calculated values: C, 55.30; H, 3.55; N, 15.17%. Measured values: C, 55.19; H, 3.34; N, 14.88%.
References
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 10, p. 1803 - 1815
[2] Patent: US6344459, 2002, B1. Location in patent: Page column 48
