반응 #711812

반응 방정식

2-(2-(4-Bromo-2-fluorophenyl)-4-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-1H-imidazol-1-yl)ethanol

toluene

potassium hydroxide

→

III

9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

용매

N-methylimidazole

반응 조건

후처리

1. 1
   workup.STIRRINGStirring
2. 2
   온도heating
3. 3
   기타the bottom aqueous layer was removed
4. 4
   세척Added isopropyl acetate (13.8 L) and the organic phase was washed twice with water (13.8 L and 27.5 L)
5. 5
   기타The solvent was removed via vacuum distillation
6. 6
   기타after 30 L had been removed
7. 7
   workup.ADDITIONisopropanol (67.6 L) was added
8. 8
   workup.DISTILLATIONVacuum distillation
9. 9
   기타had been removed
10. 10
    workup.ADDITIONAdded additional isopropanol (28.8 L)
11. 11
    workup.DISTILLATIONvacuum distillation until the volume
12. 12
    온도Added isopropanol (4 L) and the temperature was increased to >50° C
13. 13
    온도Added water (28 L) such that the internal temperature was maintained above 50° C.
14. 14
    온도heated to 75° C.
15. 15
    기타to obtain a clear solution
16. 16
    온도to cool slowly
17. 17
    기타the product crystallized out of solution
18. 18
    온도The resulting suspension was cooled to 0° C.
19. 19
    workup.WAITheld for 1 h
20. 20
    여과then filtered
21. 21
    세척the cake was washed with water (5.5 L)
22. 22
    기타The cake was dried at 45° C. under a nitrogen sweep

실험 절차

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).

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