Triethylamine (Et3N, 4.1 mL, 30 mmol) was added to a solution of N,N-dimethylformamide (DMF, 20 mL) containing 4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzoic acid (1.88 g, 5.0 mmol). Aminoacetonitrile hydrochloride (0.93 g, 10 mmol), N-hydroxybenzotriazole (HOBt, 0.81 g, 6.0 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.1 g, 6.0 mmol) were then added sequentially. The reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was dissolved in dichloromethane (CH2Cl2, 100 mL) and washed with saturated aqueous sodium bicarbonate (NaHCO3). The organic phase was dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) with ethyl acetate (EtOAc) as eluent to afford N-(cyanomethyl)-4-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)benzamide (Momotinib) as a yellow solid with a yield of 1.86 g (90% yield) and a melting point of 232- 234°C (literature value 238-243°C IR (cm-1): 3365, 3282, 1660, 1596, 1576, 1512, 1456, 1232. elemental analysis (C23H22N6O2) calculated: C, 66.65; H, 5.35; N, 20.28; measured: C, 66.78; H, 5.49; N, 20.39. ESI-MS: m/z 415.1 [M + M + N]. z 415.1 [M + H]+, 437.1 [M + Na]+, 413.2 [M - H]-. 1H NMR (300 MHz, DMSO-d6): δ 9.47 (s, 1H), 9.32 (t, J = 5.4 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.27 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H). 8.03 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 5.1 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H), 4.35 (d, J = 5.1 Hz, 2H), 3.74-3.77 (m, 4H), 3.04-3.07 (m, 4H).13C NMR (75 MHz, DMSO-d6): δ 166.1, 162.4, 160.3, 159.2, 146.2, 139.9, 134.5, 132.8, 127.8, 126.9, 120.3, 117.5, 115.6, 107.6, 66.1, 49.2, 27.7.
