反应详情

BOP (62.5 mg, 0.141 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 8B (20 mg, 0.047 mmol), DIEA (0.0062 mL, 0.035 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (17.83 mg, 0.094 mmol) in DMF (1 mL). The clear reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated down, dissolved in CH2Cl2 (0.50 mL) and TFA (0.545 mL, 7.07 mmol) and stirred at rt for 30 min. The reaction mixture was concentrated and purified with 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 isolate the title compound, 6-((trans-4-(L-alanylamino)cyclohexyl)amino)-8-(cyclopropylamino)-N-(3-fluoro-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide (10 mg, 42.8%), as a white solid. 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=1.41 (M+H=496.3). 1H NMR (400 MHz, MeOD) δ ppm 8.85 (1H, t, J=6.55 Hz), 8.69 (1H, d, J=3.53 Hz), 8.48 (1H, d, J=6.04 Hz), 8.13 (1H, s), 6.11 (1H, s), 3.97 (1H, d, J=4.28 Hz), 3.87 (1H, q, J=7.13 Hz), 3.72 (1H, br. s.), 2.59 (1H, td, J=6.80, 3.53 Hz), 2.21 (2H, br. s.), 1.99 (2H, br. s.), 1.32-1.62 (7H, m), 0.78-0.96 (2H, m), 0.55-0.76 (2H, m).

1. concentrationThe reaction mixture was concentrated down
2. dissolutiondissolved in CH2Cl2 (0.50 mL)
3. concentrationThe reaction mixture was concentrated
4. custompurified with 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))