反应详情

A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.4 g, 3.55 mmol), 3,4-difluorophenylboronic acid (1.12 g, 7.10 mmol), potassium carbonate (1.62 g, 11.7 mmol), 1,2-dimethyoxyethane (DME)(13 mL), and water (7 mL) was stirred under nitrogen. Dichlorobis(triphenylphosphine)palladium(II)(0.025 g, 0.036 mmol) was added, and the suspension was heated at reflux for five hours, allowed to cool to room temperature, diluted with water (20 mL), and extracted with dichloromethane (50 mL). An emulsion formed. Solid sodium chloride was added to saturate the aqueous layer. The organic layer was then removed under reduced pressure. The aqueous layer was extracted with dichloromethane (4×50 mL); the third extraction was allowed to stand overnight. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown solid (2.03 g) was dissolved in dichloromethane (45 mL), purified by automated flash chromatography (40+M silica cartridge, eluting with 3% to 10% methanol in ethyl acetate), and then triturated with acetonitrile. The resulting solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 485 mg of 1-[4-amino-7-(3,4-difluorophenyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 193-195° C.

1. temperaturethe suspension was heated
2. temperatureat reflux for five hours
3. extractionextracted with dichloromethane (50 mL)
4. customAn emulsion formed
5. concentrationto saturate the aqueous layer
6. customThe organic layer was then removed under reduced pressure
7. extractionThe aqueous layer was extracted with dichloromethane (4×50 mL)
8. extractionthe third extraction
9. dry with materialThe combined organic extracts were dried over magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated under reduced pressure
12. dissolutionThe resulting brown solid (2.03 g) was dissolved in dichloromethane (45 mL)
13. custompurified by automated flash chromatography (40+M silica cartridge, eluting with 3% to 10% methanol in ethyl acetate)
14. customtriturated with acetonitrile
15. customThe resulting solid was isolated by filtration
16. washwashed with acetonitrile
17. customdried in a vacuum oven