反应详情

温度

40 °C

To a 50 liter jacketed glass reactor fitted with an N2 inlet and a mechanical stirrer was added 1-methyl-2-pyrrolidinone (NMP) (3.75 liters). The solution was stirred, 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide hydrobromide salt (1500.2 g, 3.94 moles, 1.0 eq) was added and chased with NMP (1 liter), and the jacket temperature was adjusted to 35° C. Potassium carbonate (1631.9 g, 11.8 moles, 3.0 eq, 325 mesh) was then added portionwise over 10 minutes, during which time the reaction temperature increased to 40° C. The resulting suspension was treated with a solution of 4-fluoro-2-methylphenol (5, 546.1 g, 4.33 moles, 1.1 eq, AK Scientific) in NMP (2.25 liters) with stirring, and the addition funnel was then rinsed with NMP (0.75 liters) to give an orange suspension. The jacket temperature was raised to 61° C. over 30 minutes and the suspension was stirred overnight under nitrogen, at which time the reaction was judged to be complete by HPLC analysis. To the reaction mixture was added 2-methyltetrahydrofuran (15 liters) and water (15 liters) and the mixture stirred until all solids dissolved. Stirring was stopped, the orange aqueous layer drained off, and the organic layer washed with water (7.5 liters) while stirring and a jacket temperature of ˜52° C.). The aqueous wash procedure was repeated 4 times (3×7.5 liter water washes, then 1×4.5 liter water wash). The resulting organic slurry was stirred at a jacket temperature of 50.8° C., and isopropyl acetate (6 liters, Sigma Aldrich) was added. The jacket temperature was ramped down to 20° C. over 30 minutes, and the slurry was stirred overnight before collecting the precipitated solid by filtration. The collected solid was returned to the reactor, slurried in isopropyl acetate with stirring for about 2 hours, then filtered, rinsed with isopropyl acetate (1.5 liters) and dried in vacuo at 65° C. to give 1253.1 g (78%) of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a) as an off-white solid.

1. customfitted with an N2 inlet and a mechanical stirrer
2. customwas adjusted to 35° C
3. stirringwith stirring
4. washthe addition funnel was then rinsed with NMP (0.75 liters)
5. customto give an orange suspension
6. temperatureThe jacket temperature was raised to 61° C. over 30 minutes
7. stirringthe suspension was stirred overnight under nitrogen, at which time the reaction
8. stirringthe mixture stirred until all solids
9. dissolutiondissolved
10. stirringStirring
11. washthe organic layer washed with water (7.5 liters)
12. stirringwhile stirring
13. customa jacket temperature of ˜52° C.
14. washThe aqueous wash procedure
15. wash1×4.5 liter water wash)
16. stirringThe resulting organic slurry was stirred at a jacket temperature of 50.8° C., and isopropyl acetate (6 liters, Sigma Aldrich)
17. additionwas added
18. stirringthe slurry was stirred overnight
19. custombefore collecting the precipitated solid
20. filtrationby filtration
21. stirringwith stirring for about 2 hours
22. filtrationfiltered
23. washrinsed with isopropyl acetate (1.5 liters)
24. customdried in vacuo at 65° C.