反应详情

温度

35 °C

A 50 liter jacketed glass reactor was fitted with an N2 inlet, a mechanical stirrer, and a condenser. With the stirrer set to 150 rpm and the jacket temperature set at 40° C., 2-Me-THF (6.000 L, 3.0 vol), 2-fluoro-4-(trifluoromethyl)benzoic acid (2000 g, 9.610 mol), 2-methoxypyridin-4-amine (1.278 kg, 10.09 mol), and TEA (2.917 kg, 4.018 L, 28.83 mol) were added to the reactor, which resulted in a slightly hazy, light amber solution. The reactor was switched to reaction control and heated to 35° C. To the solution was added T3P in 2-Me-THF (9.176 kg, 9.176 L of 50% w/w, 14.42 mol) over 30-45 min, which resulted in a light amber solution. After 2 hours, the reaction was judged to be complete by HPLC analysis (<2% of 1 remaining). The reaction was quenched with water (1.000 L, 0.5 vol), which was added via addition funnel over a period of 10 minutes in order to control the exothermic quenching reaction. The mixture was then diluted with 2-Me-THF (8.000 L, 4.0 vol) and water (8.000 L, 4.0 vol) and stirred for 30 minutes at 30-40° C. After stirring was stopped, the layers were allowed to separate, and the aqueous layer was removed. The organic layer was washed with 10% aqueous NaOH (6.000 L, 3.0 vol), stirring resulted in an emulsion. Brine (500.0 mL, 0.25 vol) was added, and the mixture was stirred for about 5 minutes. The layers were separated, and the aqueous layer removed. The organic layer was washed again with brine (10.00 L, 5.0 vol), and the aqueous layer was drained. The organic layer was dried over Na2SO4, and filtered through diatomaceous earth (Celite). The filter cake was washed with 2-Me-THF (4.000 L, 2.0 vol) and pulled dry. The filtrate was transferred to a rotovap, and partial distillation of solvent was begun at a bath temperature of 40° C. and a pressure of 150 mbar, resulting in the formation of solids in the mixture. Cyclohexane (10.00 L, 5.0 vol) was added portionwise during the partial distillation. Distillation was stopped, the reaction mixture (˜8 liter) was slurried on the rotovap, and the bath temperature was reduced to room temperature. The mixture was filtered, and the filter cake was washed with cyclohexane (2.000 L, 1.0 vol) and pulled dry under a nitrogen blanket to afford a light yellow solid. The solid was scooped out of the funnel and dried in vacuo (40° C., <30 mbar, rotovap) to afford 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide (2,501 g, 7.959 mol, 83%) as a fine, off-white solid.

1. customwas fitted with an N2 inlet, a mechanical stirrer, and a condenser
2. customset at 40° C.
3. customresulted in a slightly hazy, light amber solution
4. customThe reactor was switched to reaction control
5. customwhich resulted in a light amber solution
6. customThe reaction was quenched with water (1.000 L, 0.5 vol), which
7. additionwas added via addition funnel over a period of 10 minutes in order
8. customexothermic quenching
9. customreaction
10. stirringAfter stirring
11. customto separate
12. customthe aqueous layer was removed
13. washThe organic layer was washed with 10% aqueous NaOH (6.000 L, 3.0 vol)
14. stirringstirring
15. customresulted in an emulsion
16. stirringthe mixture was stirred for about 5 minutes
17. customThe layers were separated
18. customthe aqueous layer removed
19. washThe organic layer was washed again with brine (10.00 L, 5.0 vol)
20. dry with materialThe organic layer was dried over Na2SO4
21. filtrationfiltered through diatomaceous earth (Celite)
22. washThe filter cake was washed with 2-Me-THF (4.000 L, 2.0 vol)
23. custompulled dry
24. distillationThe filtrate was transferred to a rotovap, and partial distillation of solvent
25. customwas begun at a bath
26. customtemperature of 40° C. and a pressure of 150 mbar, resulting in the formation of solids in the mixture
27. distillationDistillation
28. customwas reduced to room temperature
29. filtrationThe mixture was filtered
30. washthe filter cake was washed with cyclohexane (2.000 L, 1.0 vol)
31. custompulled dry under a nitrogen blanket
32. customto afford a light yellow solid
33. customdried in vacuo (40° C., <30 mbar, rotovap)