反应详情

温度

20 °C

1,1-Dimethylethyl (3R)-3-{[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (1 wt), 1-(1,1-dimethylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.76 wt), sodium bicarbonate (0.64 wt) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.00825 wt) are dissolved/suspended in 1,4-dioxane (8 vol) and water (2 vol). The mixture is heated to reflux and stirred for 3 h. The mixture is cooled to 20±3° C. to form a suspension. The solid is filtered off under vacuum. The filtrate is concentrated to 2 vol via vacuum distillation. Toluene (10 vol) is added. The solution is washed with water (5 vol) then stirred with Silicycle Si-Thiol derivatised silica gel (1 wt) at 60-65° C. for 2 h. The mixture is filtered at 60-65° C. and the cake washed with toluene (2 vol). The organic filtrate is then heated to 60-63° C. and 4M hydrogen chloride in 1,4-dioxane (2.9 vol) added over 30 min. The mixture is stirred at 60-63° C. for 5 h. The resulting slurry is cooled to 20±3° C. and aged for 15.5 h. The solid is filtered off under suction and washed with toluene (2×2 vol). The product is dried in vacuo at 40±3° C. to constant probe temperature.

1. temperatureThe mixture is heated
2. temperatureto reflux
3. customto form a suspension
4. filtrationThe solid is filtered off under vacuum
5. concentrationThe filtrate is concentrated to 2 vol via vacuum distillation
6. additionToluene (10 vol) is added
7. washThe solution is washed with water (5 vol)
8. stirringthen stirred with Silicycle Si-Thiol
9. customat 60-65° C.
10. customfor 2 h
11. filtrationThe mixture is filtered at 60-65° C.
12. washthe cake washed with toluene (2 vol)
13. temperatureThe organic filtrate is then heated to 60-63° C.
14. addition4M hydrogen chloride in 1,4-dioxane (2.9 vol) added over 30 min
15. stirringThe mixture is stirred at 60-63° C. for 5 h
16. temperatureThe resulting slurry is cooled to 20±3° C. and aged for 15.5 h
17. filtrationThe solid is filtered off under suction
18. washwashed with toluene (2×2 vol)
19. customThe product is dried in vacuo at 40±3° C. to constant probe temperature