反应详情

温度

160 °C

A ˜1:1 mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide) and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (850 mg, 2.61 mmol, 5A), N-(4-methoxybenzyl)cyclopropanamine (508 mg, 2.87 mmol) and N,N-diisopropylethylamine (0.683 mL, 3.91 mmol) were heated in DMF (10 mL) at 80° C. After 1 hr, the reaction mixture was concentrated to dryness under reduced pressure, suspended in methanol (20 mL), and the solid was isolated via Buchner filtration. The solid was combined with 4.8 g of trans-cyclohexane)-1,4-diamine and heated at 160° C. After 2.5 hrs, the reaction was cooled to room temperature, suspended in water (20 mL), and the isolated solid was purified with silica gel chromatography (10% methanol to 20% methanol/chloroform). The desired fractions were concentrated, and the solid suspended in water (25 mL), and filtered to isolate 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (834 mg, 1.531 mmol, 58.8% yield) as an off-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=1.69 minutes. [M+H]=545.35.

1. concentrationthe reaction mixture was concentrated to dryness under reduced pressure
2. customthe solid was isolated via Buchner filtration
3. waitAfter 2.5 hrs
4. temperaturethe reaction was cooled to room temperature
5. customthe isolated solid was purified with silica gel chromatography (10% methanol to 20% methanol/chloroform)
6. concentrationThe desired fractions were concentrated
7. filtrationfiltered