反应详情

To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8B (40.0 mg, 0.073 mmol) in CH2Cl2 (1 mL) was added 2-isocyanatopropane (0.0072 mL, 0.073 mmol). The reaction solution was stirred at room temperature for 30 min. The reaction mixture was concentrated and treated with TFA (1.132 mL, 14.69 mmol) at 70° C. for 1 hr. The reaction mixture was purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to obtain the title compound, 8-(cyclopropylamino)-N-(3-fluoro-4-pyridinyl)-6-((trans-4-((isopropylcarbamoyl)amino)cyclohexyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide, as a white solid (16.9 mg, 45.2%). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.73 (M+H=510.32). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.38 (1H, s), 8.68 (1H, d, J=2.75 Hz), 8.51 (1H, t, J=6.05 Hz), 8.44 (1H, d, J=5.50 Hz), 8.01 (1H, s), 7.59 (1H, s), 6.92 (1H, br. s.), 5.99 (1H, s), 5.61 (2H, br. s.), 3.79 (2H, br. s.), 3.52-3.74 (2H, m), 2.00 (2H, d, J=9.90 Hz), 1.83 (2H, d, J=10.45 Hz), 1.12-1.41 (4H, m), 1.02 (6H, d, J=6.60 Hz), 0.71-0.83 (2H, m), 0.54-0.69 (2H, m).

1. concentrationThe reaction mixture was concentrated
2. customThe reaction mixture was purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA))