Acryloyl chloride → N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)-2-propenamide

Participants

Reaction Conditions

Reaction Steps

8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b) (2.17 g, 4.74 mmol) in DCM (30 mL) and THF (30 mL) at 0° C. was treated with DIEA (1.66 mL, 9.49 mmol) and acryloyl chloride (0.46 mL, 5.69 mmol) dropwise over 15 min and stirred at 0° C. After 1.5 h, additional acryloyl chloride (0.20 mL) was added slowly over 10 min then the suspension was stirred at 0° C. for another 20 min. Additional acryloyl chloride (0.1 mL) was added and the reaction mixture stirred another 15 min. The reaction mixture was treated with a saturated solution of NaHCO3, extracted with DCM (5×100 mL), dried over Na2SO4, filtered and concentrated. Purification of the crude residue on a silica gel column (1-20% MeOH in DCM) afforded the desired product as a yellow solid. This material was treated with 20 mL of EtOH and the slurry was filtered through a medium porosity sintered glass frit and washed with additional EtOH (10 mL) and Et2O (3×10 mL) affording N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(71-1)-yl)phenyl)acrylamide (1) (680 mg, 1.33 mmol, 28% yield) as a yellow solid after drying overnight at 36° C. in a vacuum oven. m/z (ESI, +ve ion) 512.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.35 (1H, s), 8.75 (1H, br. s.), 8.17 (1H, br. s.), 7.92 (2H, d, J=9.4 Hz), 7.59 (1H, br. s.), 7.52 (1H, t, 0.1=8.1 Hz), 7.29 (1H, d, J=9.0 Hz), 7.01 (1H, d, J=8.0 Hz), 6.54 (1H, br. s.), 6.37-6.50 (2H, m), 6.20-6.33 (1H, m), 6.03 (1H, br. s.), 5.77 (1H, d, J=10.0 Hz), 3.78 (3H, s), 3.07 (4H, br. s.), 2.43 (3H, s), 2.34 (4H, br. s.).

Provenance & Evidence