反应详情

温度

45 °C

2-Methyltetrahydrofuran (0.57 L, 1.0 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) (791 g, 2.67 mol) and 4-oxo-5 -(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (7) (573 g, 2.23 mol) and an additional 5.2 L (9.0 vol) of 2-methyltetrahydrofuran. Stirring commenced, and T3P in 2-methyltetrahydrofuran (2.84 kg, 4.46 mol) was added to the reaction mixture over 15 min. Pyridine (534.0 g, 546.0 mL, 6.68 mol) was then added via an addition funnel dropwise over 30 min. The mixture was warmed to 45° C. over about 30 min and stirred for 12-15 h. The mixture was then cooled to room temperature and 2-Methyltetrahydrofuran (4 vol, 2.29 L) was added followed by water (6.9 vol, 4 L), while the temperature was maintained below 30° C. The water layer was removed and the organic layer was carefully washed twice with NaHCO3 saturated aqueous solution. The organic layer was then washed with 10% w/w citric acid (5 vol) and finally with water (7 vol). The mixture was polished filtered and transferred into another dry vessel. Seed crystals of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide hydrochloride (Form A-HCl) (3.281 g, 5.570 mmol) were added. HCl (g) (10 eq) was bubbled over 2 h and the mixture was stirred overnight. The resulting suspension was filtered, washed with 2-methyltetrahydrofuran (4 vol), suction dried and oven dried at 60° C. provide Compound I as Form A-HCl.

1. stirringstirred for 12-15 h
2. temperatureThe mixture was then cooled to room temperature
3. temperaturewas maintained below 30° C
4. customThe water layer was removed
5. washthe organic layer was carefully washed twice with NaHCO3 saturated aqueous solution
6. washThe organic layer was then washed with 10% w/w citric acid (5 vol) and finally with water (7 vol)
7. filtrationThe mixture was polished filtered
8. customtransferred into another dry vessel
9. additionwere added
10. stirringthe mixture was stirred overnight
11. filtrationThe resulting suspension was filtered
12. washwashed with 2-methyltetrahydrofuran (4 vol), suction
13. customdried
14. customoven dried at 60° C.