反应详情

Boron tribromide (2.5 equivalents, 15.6 mL of 1 M solution in dichloromethane) was added dropwise to a cooled (ice bath) suspension of N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isobutyramide (2.4 g, 6.2 mmol) in dichloromethane (25 mL). The reaction mixture was allowed to slowly warm to ambient temperature and then stirred for 1 day. Additional boron tribromide (5 equivalents, 31 mmol, 31 mL) was added to the mixture. The reaction was quenched slowly with methanol (100 mL) and then concentrated under reduced pressure. The residue was combined with 6 M hydrochloric acid (100 mL), heated to 5° C., and stirred for 2 hours. The resulting solution was cooled (ice bath) and then free-based (pH 9) with the addition of 6 M sodium hydroxide. A brown gummy solid formed in the basic aqueous solution. The resulting solid was extracted with dichloromethane (6×50 mL). The combined extracts were washed with brine (100 mL), dried with magnesium sulfate, filtered, and then concentrated under reduced pressure. This material was purified by prep HPLC (Analogix Separation System, Biotage Si 40+M column, eluted with a gradient of 0-20% methanol in dichloromethane with 1% ammonium hydroxide) to provide a light brown solid. The solid was triturated with hot acetonitrile, allowed to cool, isolated by filtration, washed with ether, and dried under vacuum to provide N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]isobutyramide (0.049 g) as a white solid, mp 222-224° C.; MS (ESI) m/z 356 (M+H)+; Anal. Calcd for C19H25N5O2.0.25HBr.0.10H2O: C, 60.46; H, 6.80; N, 18.55. Found C, 60.26; H, 6.64; N, 18.43.

1. temperaturea cooled
2. customThe reaction was quenched slowly with methanol (100 mL)
3. concentrationconcentrated under reduced pressure
4. temperatureheated to 5° C.
5. stirringstirred for 2 hours
6. temperatureThe resulting solution was cooled (ice bath)
7. additionfree-based (pH 9) with the addition of 6 M sodium hydroxide
8. customA brown gummy solid formed in the basic aqueous solution
9. extractionThe resulting solid was extracted with dichloromethane (6×50 mL)
10. washThe combined extracts were washed with brine (100 mL)
11. dry with materialdried with magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customThis material was purified by prep HPLC (
15. customAnalogix Separation System, Biotage Si 40+M column
16. washeluted with a gradient of 0-20% methanol in dichloromethane with 1% ammonium hydroxide)
17. customto provide a light brown solid
18. customThe solid was triturated with hot acetonitrile
19. temperatureto cool
20. customisolated by filtration
21. washwashed with ether
22. customdried under vacuum