反应详情

Boron tribromide (1.24 mL of 1 M in dichloromethane) was added dropwise to a chilled (ice bath) suspension of N-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamide (500 mg, 1.18 mmol) in dichloromethane (15 mL). The reaction mixture was allowed to slowly warm to ambient temperature and then stirred over the weekend. Additional boron tribromide (1 mL) was added and the reaction mixture was stirred for 24 hours. The reaction was quenched with methanol (10 mL) and then concentrated under reduced pressure. The residue was combined with hydrochloric acid (15 mL of 6 M), heated to 50° C., and stirred for 2 hours. The resulting solution was cooled to ambient temperature and then neutralized (pH 7) with 10% sodium hydroxide. The resulting gummy precipitate was extracted with chloroform (3×15 mL). The combined extracts were washed with brine (15 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide an off white solid. This material was purified by prep HPLC (HORIZON HPFC system, eluting with a gradient of 10-50% CMA in chloroform) to provide a white solid. The solid was triturated with hot acetonitrile, allowed to cool, isolated by filtration, and dried under vacuum to provide 233 mg of N-[2-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamide as a fine white solid, mp 230-232° C.; 1H NMR (300 MHz, DMSO-d6, 350 K) δ 8.53 (dd, J=4.3, 1.6 Hz, 1H), 7.95 (dd, J=8.4, 1.5 Hz, 1H), 7.87 (s, 1H), 7.47 (dd, J=8.4, 4.4 Hz, 1H), 6.55 (s, 2H), 5.31 (s, 1H), 5.15 (s, 2H), 4.79 (d, J=5.4 Hz, 2H), 1.90-1.80 (m, 1H), 1.67-1.43 (m, 5H), 1.31 (s, 6H), 1.24-1.02 (m, 5H); 13C NMR (75 MHz, DMSO-d6) δ 175.9, 154.6, 152.8, 142.8, 140.8, 134.2, 133.5, 133.3, 129.3, 122.5, 56.4, 55.0, 52.3, 44.9, 29.4, 25.7, 25.6, 24.9; MS (ESI) m/z 397 (M+H)+; Anal, Calcd for C21H28N6O2: C, 63.62; H, 7.12; N, 21.20. Found: C, 63.77; H, 7.34; N, 21.50.

1. temperaturea chilled
2. stirringthe reaction mixture was stirred for 24 hours
3. customThe reaction was quenched with methanol (10 mL)
4. concentrationconcentrated under reduced pressure
5. temperatureheated to 50° C.
6. stirringstirred for 2 hours
7. temperatureThe resulting solution was cooled to ambient temperature
8. extractionThe resulting gummy precipitate was extracted with chloroform (3×15 mL)
9. washThe combined extracts were washed with brine (15 mL)
10. dry with materialdried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure
13. customto provide an off white solid
14. customThis material was purified by prep HPLC (HORIZON HPFC system
15. washeluting with a gradient of 10-50% CMA in chloroform)
16. customto provide a white solid
17. customThe solid was triturated with hot acetonitrile
18. temperatureto cool
19. customisolated by filtration
20. customdried under vacuum