反应详情

TFA (3.66 mL, 47.5 mmol) was added to a stirred mixture of tert-butyl 1-(3,5-dibromopyrazin-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (1.04 g, 2.374 mmol) in dichloromethane (20 mL). The resulting clear yellow solution was stirred at room temperature for 3 h. All volatiles were removed under reduced pressure and the residue dried under high vacuum to give a yellow semi-solid. MS (ESI) m/z 339.1 [M+1]+. Sodium sulfate (1.686 g, 11.87 mmol) was added followed by 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.396 g, 3.09 mmol) and 1,2-dichloroethane (20 mL). The resulting mixture was stirred vigorously and heated at 80° C. under a reflux condenser under nitrogen for 2.5 h. More 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.100 g, 0.780 mmol) and sodium sulfate (1.00 g, 7.04 mmol) were added and heating at 80° C. continued for another 2 h. The resulting yellow solution was removed by pipette from the solid sodium sulfate into a dry 250 mL round bottom flask equipped with a stirbar. The resulting mixture was stirred vigorously and cooled to 0° C. under nitrogen. Sodium triacetoxyborohydride (0.553 g, 2.61 mmol) was added slowly. The resulting mixture was stirred vigorously at 0° C. under nitrogen for 30 min. The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 2 h. The mixture was cooled to 0° C. and more sodium triacetoxyborohydride (0.250 g, 1.180 mmol) was added. The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 1.5 h. More sodium triacetoxyborohydride (0.055 g, 0.260 mmol) was added. The resulting mixture was stirred vigorously at room temperature under nitrogen for 1 h and then stirred overnight at 0° C. The resulting mixture was diluted with methanol and the volatiles removed under reduced pressure. The residue was taken up in methanol, filtered and purified using reverse-phase preparatory HPLC (10-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined and the solvent removed under reduced pressure. The residue was dried under vacuum to give the desired product (0.890 g, 1.978 mmol, 67% yield) as a slightly yellow foam-solid. MS (ESI) m/z 451.3 [M+1]+.

1. customAll volatiles were removed under reduced pressure
2. customthe residue dried under high vacuum
3. customto give a yellow semi-solid
4. stirringThe resulting mixture was stirred vigorously
5. temperatureheated at 80° C. under a reflux condenser under nitrogen for 2.5 h
6. temperatureheating at 80° C.
7. waitcontinued for another 2 h
8. customThe resulting yellow solution was removed by pipette from the solid sodium sulfate into a dry 250 mL round bottom flask
9. customequipped with a stirbar
10. stirringThe resulting mixture was stirred vigorously
11. temperaturecooled to 0° C. under nitrogen
12. stirringThe resulting mixture was stirred vigorously at 0° C. under nitrogen for 30 min
13. customThe cold bath was removed
14. stirringthe resulting mixture stirred at room temperature under nitrogen for 2 h
15. temperatureThe mixture was cooled to 0° C.
16. customThe cold bath was removed
17. stirringthe resulting mixture stirred at room temperature under nitrogen for 1.5 h
18. stirringThe resulting mixture was stirred vigorously at room temperature under nitrogen for 1 h
19. stirringstirred overnight at 0° C
20. customthe volatiles removed under reduced pressure
21. filtrationfiltered
22. custompurified
23. customreverse-phase preparatory HPLC (10-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min)
24. additionFractions containing the desired product
25. customthe solvent removed under reduced pressure
26. customThe residue was dried under vacuum