反应详情

温度

86 °C

A mixture of 6-bromo-1,2,4-triazin-3-amine (17, 100.0 g, 571.47 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (19, 145.43 g, 588.61 mmol, 1.03 equiv) in 1,4-dioxane (1200 mL) was stirred at room temperature for 10 min before potassium carbonate (K2CO3, 355.4 g, 2572 mmol) in water (600 mL) was added to give a deep red solution. The mixture was degassed by bubbling with nitrogen for 10 min before 1,1′-bis(diphenyl phosphino)ferrocene dichloropalladium(II) complex with dichloromethane (1:1) (Pd(dppf)2Cl2, 14.14 g, 17.14 mmol, 0.03 equiv) was added at room temperature. The resulting reaction mixture was degassed by bubbling with nitrogen for 10 min and then heated at 86° C. under nitrogen. After 2 h, HPLC showed that the reaction was deemed complete, and the reaction mixture was cooled to room temperature and then to 0-5° C. with an ice-water bath. 1,4-Dioxane (400 mL) was added to the cooled reaction mixture before a solution of 3.3 M aqueous hydrochloric acid solution (HCl, 1900 mL) was added dropwise with stirring to adjust pH to 0.40-0.93. The mixture was stirred at room temperature for 30 min and filtered. The solid collected was stirred with 1,4-dioxane (260 mL) and then added 1N HCl (400 mL). The mixture was stirred at room temperature for 10 min and filtered. The filtrate was combined with the filtrate obtained earlier and washed with ethyl acetate (EtOAc, 2×2 L). The combined ethyl acetate extracts was extracted with 1 N aqueous hydrochloric acid solution (HCl, 3×200 mL). The combined aqueous solution was then treated with activated charcoal (20 g) and stirred at room temperature for 30 min. The mixture was filtered through a celite bed and the filtrate was cooled to 0-5° C. with an ice-water bath. A solution of 50% of sodium hydroxide in water (NaOH, 240 mL, 4500 mmol) was added dropwise at 5-12° C. to adjust pH to 10.6-11.6. The mixture was stirred at 0-5° C. for 30 min and then filtered. The solids collected were washed with aqueous ammonium hydroxide (1 to 3 of 28% concentrated NH4OH to water, 1900 mL) and dried under vacuum at 40-45° C. to constant weight to afford 4-(3-amino-1,2,4-triazin-6-yl)-2-fluorobenzonitrile (20, 101.2 g, 122.9 g theoretical, 82.3% yield) as a off-white powder. For 20: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94 (s, 1H), 8.12 (d, 1H, J=11.41 Hz), 8.08-8.00 (m, 2H), 7.71 (br s, 2H); C10H6FN5 (MW 215.19), LCMS (EI) m/e 215.9 (M++H).

1. additionwas added
2. customto give a deep red solution
3. customThe mixture was degassed
4. additionwas added at room temperature
5. customThe resulting reaction mixture
6. customwas degassed
7. customby bubbling with nitrogen for 10 min
8. temperaturethe reaction mixture was cooled to room temperature
9. customto 0-5° C.
10. addition1,4-Dioxane (400 mL) was added to the cooled reaction mixture before a solution of 3.3 M aqueous hydrochloric acid solution (HCl, 1900 mL)
11. additionwas added dropwise
12. stirringThe mixture was stirred at room temperature for 30 min
13. filtrationfiltered
14. customThe solid collected
15. stirringwas stirred with 1,4-dioxane (260 mL)
16. additionadded 1N HCl (400 mL)
17. stirringThe mixture was stirred at room temperature for 10 min
18. filtrationfiltered
19. customobtained earlier
20. washwashed with ethyl acetate (EtOAc, 2×2 L)
21. extractionThe combined ethyl acetate extracts was extracted with 1 N aqueous hydrochloric acid solution (HCl, 3×200 mL)
22. additionThe combined aqueous solution was then treated with activated charcoal (20 g)
23. stirringstirred at room temperature for 30 min
24. filtrationThe mixture was filtered through a celite bed
25. temperaturethe filtrate was cooled to 0-5° C. with an ice-water bath
26. stirringThe mixture was stirred at 0-5° C. for 30 min
27. filtrationfiltered
28. customThe solids collected
29. washwere washed with aqueous ammonium hydroxide (1 to 3 of 28% concentrated NH4OH to water, 1900 mL)
30. customdried under vacuum at 40-45° C. to constant weight