反应详情

Under a nitrogen atmosphere boron tribromide (6.15 mL of 1M in dichloromethane) was added dropwise over a period of 10 minutes to a chilled (0° C.) solution of 1-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanol (0.67 g, 2.0 mmol) in dichloromethane (20 mL). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was cooled to 0° C. and then more boron tribromide (1.0 mL) was added. The reaction mixture was stirred at ambient temperature for 4 hours. Methanol (10 mL) and hydrochloric acid (10 mL of 6N) were added and the reaction mixture was heated at reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature and was then made basic with 6N sodium hydroxide. A portion of the solvent was removed under vacuum, water (10 mL) was added, and the mixture was sonicated. A solid was isolated by filtration and rinsed with water. The aqueous filtrate was extracted with chloroform (3×80 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was combined with the isolated solid and then purified by HPFC eluting with a gradient of 0-30% CMA in chloroform, triturated with acetonitrile, and dried. The resulting material was suspended in water (70 mL) and heated to 90° C. Concentrated hydrochloric acid (about 0.8 mL) was added until a solution was obtained. The hot solution was made basic with solid sodium bicarbonate and then allowed to cool. A precipitate was isolated by filtration, washed well with water, and then dried to provide 1-[(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclobutanol as a white powder, mp 244.0-246.0° C. Anal. Calcd for C15H17N5O2 C, 60.19; H, 5.72; N, 23.40. Found: C, 59.97; H, 5.81; N, 23.31.

1. temperatureThe reaction mixture was cooled to 0° C.
2. stirringThe reaction mixture was stirred at ambient temperature for 4 hours
3. temperaturethe reaction mixture was heated
4. temperatureat reflux for 1 hour
5. temperatureto cool to ambient temperature
6. customA portion of the solvent was removed under vacuum, water (10 mL)
7. additionwas added
8. customthe mixture was sonicated
9. customA solid was isolated by filtration
10. washrinsed with water
11. extractionThe aqueous filtrate was extracted with chloroform (3×80 mL)
12. washThe combined organics were washed with brine (20 mL)
13. dry with materialdried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated under reduced pressure
16. custompurified by HPFC
17. washeluting with a gradient of 0-30% CMA in chloroform
18. customtriturated with acetonitrile
19. customdried
20. temperatureheated to 90° C
21. additionConcentrated hydrochloric acid (about 0.8 mL) was added until a solution
22. customwas obtained
23. temperatureto cool
24. customA precipitate was isolated by filtration
25. washwashed well with water
26. customdried