反应详情

温度

45 °C

2-Methyltetrahydrofuran (1 vol) was charged into a 30 L jacketed reactor vessel followed by the addition of the hydrochloride salt of 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (11B) (1.2 eq) and 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (7) (573 g, 2.228 mol). An additional 2-methyltetrahydrofuran (9 vol) was charged into the vessel and stirring commenced. T3P in 2-methyltetrahydrofuran (2 eq) was added to the reaction mixture over a period of 15 min. Pyridine (3 eq) was added rapidly in a dropwise fashion using an addition funnel. Under stirring, the mixture was then heated to 45° C. over a period of about 30 min and this temperature was maintained for about 5 h. The mixture was cooled to room temperature. 2-Methyltetrahydrofuran (4 vol) was added, followed by the slow addition of water (6.9 vol), and the temperature of the reaction was kept below 30° C. The water layer was removed and the organic layer was washed twice with NaHCO3 saturated aqueous solution. The organic layer was then carefully washed with 10% w/w citric acid (5 vol) and water (7 vol), polished filtered, and then transferred into another dry vessel. 2-Methyltetrahydrofuran (10 vol) was added and stirring commenced. Heptane (10 vol) was rapidly added in a dropwise fashion with stirring. The mixture was stirred for a period of about 12 h, and then was vacuum filtered. The solid filter cake was introduced into another vessel. Water (15 vol) was charged into the vessel and the suspension was stirred vigorously for 48 h, and then filtered. The solid cake was washed with water (5 vol) and dried at 45° C. to constant weight to give Compound I, Form B.

1. stirringUnder stirring
2. temperaturethis temperature was maintained for about 5 h
3. temperatureThe mixture was cooled to room temperature
4. customwas kept below 30° C
5. customThe water layer was removed
6. washthe organic layer was washed twice with NaHCO3 saturated aqueous solution
7. washThe organic layer was then carefully washed with 10% w/w citric acid (5 vol) and water (7 vol), polished filtered
8. customtransferred into another dry vessel
9. addition2-Methyltetrahydrofuran (10 vol) was added
10. stirringstirring commenced
11. additionHeptane (10 vol) was rapidly added in a dropwise fashion
12. stirringwith stirring
13. stirringThe mixture was stirred for a period of about 12 h
14. filtrationfiltered
15. filtrationThe solid filter cake
16. additionwas introduced into another vessel
17. additionWater (15 vol) was charged into the vessel
18. stirringthe suspension was stirred vigorously for 48 h
19. filtrationfiltered
20. washThe solid cake was washed with water (5 vol)
21. customdried at 45° C. to constant weight