反应详情

Methyl carbonochloridate (7.81 mg, 0.083 mmol) was added 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 (30 mg, 0.055 mmol) and DIEA (0.00617 mL, 0.035 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred at room temperature for 2 hrs, concentrated and treated with TFA (0.127 mL, 1.653 mmol) at 65° C. for 1 h. The reaction mixture was concentrated and 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)). The title compound, methyl (trans-4-((8-(cyclopropylamino)-3-((3-fluoro-4-pyridinyl)carbamoyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)carbamate, was isolated as a white solid (15 mg, 56.4%). 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=1.63 (M+H=483.24). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (1H, s), 8.74 (1H, d, J=2.27 Hz), 8.51 (1H, t, J=6.17 Hz), 8.44 (1H, d, J=5.54 Hz), 8.01 (1H, s), 7.61 (1H, s), 7.18 (1H, d, J=8.06 Hz), 6.94 (1H, d, J=8.31 Hz), 5.98 (1H, s), 3.79 (1H, br. s.), 3.42-3.64 (4H, m), 3.30 (1H, br. s.), 2.02 (2H, d, J=9.57 Hz), 1.79 (2H, br. s.), 1.17-1.45 (4H, m), 0.70-0.82 (2H, m), 0.54-0.68 (2H, m).

1. concentrationconcentrated
2. concentrationThe reaction mixture was concentrated
3. custompurified 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))