反应详情

温度

80 °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 8A (3 g, 8.6 mmol), N-(4-methoxybenzyl)cyclopropanamine (1.79 g, 10.12 mmol) and N,N-diisopropylethylamine (2.41 mL, 13.80 mmol) were suspended in DMF (30 mL) and heated at 80° C. for 1 hr. The reaction mixture was concentrated, dried under reduced pressure for 16 hrs, suspended in methanol (20 mL) and an off-white solid collected via Buchner filtration (2×10 mL methanol rinse) and taken to the next step without further purification. The reaction mixture was combined with trans-1,4-diaminocyclohexane (16.28 g, 143 mmol) and heated at 160° C. for 2.5 hours. The reaction was cooled to room temperature, and water (40 mL) was added, and the solid collected via Buchner filtration. The crude product was purified with silica gel chromatography using a stepwise gradient of 10% methanol/chloroform to 25% methanol/chloroform/1% triethylamine to isolated a foamy solid. The solid was suspended in water (50 mL) and collected with Buchner filtration (2×25 mL water wash) and dried for 16 hrs under reduced pressure to isolate 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (3.2 g, 5.58 mmol, 63% yield) as a 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=1.68 (M+H=545.22).

1. concentrationThe reaction mixture was concentrated
2. customdried under reduced pressure for 16 hrs
3. filtrationan off-white solid collected via Buchner filtration (2×10 mL methanol rinse)
4. customtaken to the next step without further purification
5. temperatureheated at 160° C. for 2.5 hours
6. temperatureThe reaction was cooled to room temperature
7. filtrationthe solid collected via Buchner filtration
8. customThe crude product was purified with silica gel chromatography
9. customto isolated a foamy solid
10. filtrationcollected with Buchner filtration (2×25 mL water wash)
11. customdried for 16 hrs under reduced pressure