反应详情

温度

65 °C

To a solution of 2-(2-(4-Bromo-2-fluorophenyl)-4-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-1H-imidazol-1-yl)ethanol (7.55 mmol) 14 in N-methylimidazole(12 L) at 35° C. was added methyl tributylammonium chloride (115 g, 0.453 mol), toluene (27.5 L) and 35% potassium hydroxide solution (10.6 kg, 25 mol in 22 L of water). The biphasic solution was stirred vigorously at 65° C. for 18 h when it was judged complete by HPLC. Stirring was stopped but heating was continued and the bottom aqueous layer was removed. Added isopropyl acetate (13.8 L) and the organic phase was washed twice with water (13.8 L and 27.5 L). The solvent was removed via vacuum distillation and after 30 L had been removed, isopropanol (67.6 L) was added. Vacuum distillation was resumed until an additional 30 L of solvent had been removed. Added additional isopropanol (28.8 L) and continued vacuum distillation until the volume was reduced by 42 L. Added isopropanol (4 L) and the temperature was increased to >50° C. Added water (28 L) such that the internal temperature was maintained above 50° C., then heated to 75° C. to obtain a clear solution. The mixture was allowed to cool slowly and the product crystallized out of solution. The resulting suspension was cooled to 0° C., held for 1 h then filtered and the cake was washed with water (5.5 L). The cake was dried at 45° C. under a nitrogen sweep to give III as a tan solid (3.30 kg, 71.6 wt %, 80.6% yield).

1. stirringStirring
2. temperatureheating
3. customthe bottom aqueous layer was removed
4. washAdded isopropyl acetate (13.8 L) and the organic phase was washed twice with water (13.8 L and 27.5 L)
5. customThe solvent was removed via vacuum distillation
6. customafter 30 L had been removed
7. additionisopropanol (67.6 L) was added
8. distillationVacuum distillation
9. customhad been removed
10. additionAdded additional isopropanol (28.8 L)
11. distillationvacuum distillation until the volume
12. temperatureAdded isopropanol (4 L) and the temperature was increased to >50° C
13. temperatureAdded water (28 L) such that the internal temperature was maintained above 50° C.
14. temperatureheated to 75° C.
15. customto obtain a clear solution
16. temperatureto cool slowly
17. customthe product crystallized out of solution
18. temperatureThe resulting suspension was cooled to 0° C.
19. waitheld for 1 h
20. filtrationthen filtered
21. washthe cake was washed with water (5.5 L)
22. customThe cake was dried at 45° C. under a nitrogen sweep