反应详情

温度

25 °C

To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (60.0 mg, 0.110 mmol), acetaldehyde (14.56 mg, 0.331 mmol) and acetic acid (13.23 mg, 0.220 mmol) in DCM (2 mL) was stirred at room temperature for 5 minutes, then sodium triacetoxyborohydride (46.7 mg, 0.220 mmol) was added and the reaction was stirred at 25° C. for 2 hrs. The reaction mixture was concentrated down and treated with TFA (0.509 mL, 6.61 mmol) at 65° C. for 1 hr, concentrated, diluted in methanol and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% 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 isolate 8-(cyclopropylamino)-6-((trans)-4-(ethylamino)cyclohexylamino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (19.3 mg, 0.043 mmol, 38.7% yield). LC/MS (BEH C18 2.1×50 mm 1.7u, Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2.2 min with 1 min hold time, Flow rate=2 mL/min, detection at 254 nm, Solvent A: 100% water/0.05% TFA; Solvent B: 100% ACN/0.05% TFA). Rt=0.67 minutes [M+H]=453.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, s), 8.21 (1H, d, J=5.52 Hz), 7.96 (1H, s), 7.60 (1H, d, J=1.51 Hz), 7.51 (2H, s), 6.86-7.03 (1H, m), 5.98 (1H, s), 3.57-3.76 (1H, m), 2.56 (2H, d, J=7.03 Hz), 2.33-2.47 (1H, m), 2.02-2.20 (2H, m), 1.80-2.02 (2H, m), 1.18-1.37 (2H, m), 1.04-1.18 (2H, m), 1.01 (3H, t, J=7.03 Hz), 0.69-0.85 (2H, m), 0.53-0.71 (2H, m) and 8-(cyclopropylamino)-6-((trans)-4-(diethylamino)cyclohexylamino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (25.6 mg, 0.053 mmol, 48.4% yield).). LC/MS (BEH C18 2.1×50 mm 1.7u, Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2.2 min with 1 min hold time, Flow rate=2 mL/min, detection at 254 nm, Solvent A: 100% water/0.05% TFA; Solvent B: 100% ACN/0.05% TFA). Rt=0.69 minutes [M+H]=481.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33-11.48 (1H, m), 8.29-8.48 (1H, m), 8.21 (1H, d, J=5.52 Hz), 7.98 (1H, s), 7.64 (1H, d, J=1.25 Hz), 7.53-7.63 (1H, m), 7.51 (1H, s), 6.97-7.11 (1H, m), 6.00 (1H, s), 3.62-3.81 (1H, m), 2.97-3.14 (1H, m), 2.92 (4H, q, J=7.28 Hz), 2.15-2.32 (2H, m), 1.95-2.09 (2H, m), 1.49-1.67 (2H, m), 1.27-1.46 (2H, m), 1.02-1.30 (6H, m), 0.71-0.85 (2H, m), 0.56-0.72 (2H, m)

1. concentrationThe reaction mixture was concentrated down
2. concentrationconcentrated
3. additiondiluted in methanol
4. custompurified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)