反应详情

温度

70 °C

[5-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-N,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-amine (13.01 g, 40.38 mmol) and 2-[4-(difluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.75 g, 50.18 mmol) were combined in ethanol (126 mL), and the resulting slurry was treated with a solution of potassium phosphate (98%, 11.04 g, 50.97 mmol) in water (42 mL) and warmed to 70° C. over 30 minutes while a vigorous nitrogen flow was applied through a bubbler. After addition of tetrakis(triphenyl phosphine) palladium(0) (481 mg, 0.416 mmol), the reaction mixture was heated at reflux for 4 hours, then cooled to room temperature and stirred for an additional 16 hours. The mixture was filtered through a plug of cotton, and the filtrate was concentrated in vacuo, then reconcentrated with 2-methyltetrahydrofuran (2×150 mL). The residue was reconstituted in 2-methyltetrahydrofuran (150 mL) and extracted with aqueous hydrochloric acid (1 M, 70 mL, stirred for 20 minutes). The aqueous layer (pH ˜2-3) was discarded. The organic layer was extracted twice with 1 M aqueous hydrochloric acid: first with 100 mL (stirring for 1 hour), then with 75 mL (stirring for 20 minutes). The 100 mL aqueous layer was back-extracted with 2-methyltetrahydrofuran (75 mL, stirred for 20 minutes) to remove a light yellow color; from this organic layer precipitated a solid, which was collected and rinsed with tert-butyl methyl ether to provide X-ray quality crystals. Single crystal X-ray analysis revealed this material to be the monohydrate of the hydrochloride salt of the product. The two hydrochloric acid layers were combined and treated with aqueous sodium hydroxide solution (5 M, 35.5 mL), which adjusted the pH to 6. The resulting mixture was extracted with 2-methyltetrahydrofuran (150 mL); the organic layer was passed through a plug of sodium sulfate (58 g) and concentrated in vacuo to a volume of roughly 150 mL. This yellow solution was treated with Darco® G-60 activated carbon (5.03 g), and spun on a rotary evaporator in a 50° C. water bath for 1.5 hours. The warm solution was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The resulting light yellow solid was treated with tert-butyl methyl ether (250 mL) and spun on a rotary evaporator in a 55° C. water bath for 1 hour. Roughly 100 mL of solvent was removed using the rotary evaporator, and the resulting mixture was cooled to room temperature with stirring over 1 hour. The slurry was then cooled in an ice bath and stirred for an additional 30 minutes. The solids were collected by filtration and rinsed with chilled tert-butyl methyl ether (cooled in ice—saturated aqueous sodium chloride solution bath; 50 mL) to provide the product as a powdery white solid. Yield: 11.27 g, 30.51 mmol, 76%. LCMS m/z 370.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.65 (br s, 3H), 2.98 (d, J=5.1 Hz, 3H), 3.94 (s, 3H), 5.48-5.55 (m, 1H), 6.65 (t, J=56.3 Hz, 1H), 7.52 (br AB quartet, JAB=8.4 Hz, ΔvAB=17.9 Hz, 4H), 7.73 (s, 1H), 7.90 (br s, 1H).

1. temperaturethe reaction mixture was heated
2. temperatureat reflux for 4 hours
3. temperaturecooled to room temperature
4. filtrationThe mixture was filtered through a plug of cotton
5. concentrationthe filtrate was concentrated in vacuo
6. extractionextracted with aqueous hydrochloric acid (1 M, 70 mL, stirred for 20 minutes)
7. extractionThe organic layer was extracted twice with 1 M aqueous hydrochloric acid
8. stirringfirst with 100 mL (stirring for 1 hour)
9. stirringwith 75 mL (stirring for 20 minutes)
10. extractionThe 100 mL aqueous layer was back-extracted with 2-methyltetrahydrofuran (75 mL, stirred for 20 minutes)
11. customto remove a light yellow color
12. customfrom this organic layer precipitated a solid, which
13. customwas collected
14. washrinsed with tert-butyl methyl ether
15. customto provide X-ray quality crystals
16. extractionThe resulting mixture was extracted with 2-methyltetrahydrofuran (150 mL)
17. concentrationconcentrated in vacuo to a volume of roughly 150 mL
18. additionThis yellow solution was treated with Darco® G-60 activated carbon (5.03 g)
19. customspun on a rotary evaporator in a 50° C. water bath for 1.5 hours
20. filtrationThe warm solution was filtered through a pad of Celite
21. concentrationthe filtrate was concentrated under reduced pressure
22. additionThe resulting light yellow solid was treated with tert-butyl methyl ether (250 mL)
23. customspun on a rotary evaporator in a 55° C. water bath for 1 hour
24. customRoughly 100 mL of solvent was removed
25. customthe rotary evaporator
26. temperaturethe resulting mixture was cooled to room temperature
27. stirringwith stirring over 1 hour
28. temperatureThe slurry was then cooled in an ice bath
29. stirringstirred for an additional 30 minutes
30. filtrationThe solids were collected by filtration
31. washrinsed with chilled tert-butyl methyl ether (cooled in ice—saturated aqueous sodium chloride solution bath; 50 mL)