反应详情

To a solution of 500 g (4.50 mol) of 3-fluoroaniline and 2 L of CH2Cl2 in a 12 L round bottom flask was added a solution of 473 g (3.42 mol, 0.76 equiv.) of K2CO3 in 2 L of water. Isobutylchloroformate (663 g, 4.86 mol, 1.08 equiv.) was added with stirring via an addition funnel over 3 h so as to allow the isotherm to warm and maintain the mixture at gentle reflux. Gas evolves vigorously near the end of the addition. The organic phase was sampled for GC analysis 1 h after completion of the addition; less than 0.5% 3-fluoroaniline remained. The mixture was quenched by addition of 72 mL of conc. NH4OH. After stirring for 15 minutes, the mixture was neutralized to pH by addition of 120 mL of conc. aq. HCl. The layers were separated, and the aqueous layer was extracted with 1.5 L of CH2Cl2. To the combined organic layers was added 987 g (3.45 mol, 0.77 equiv.) of 1,3-dibromo-5,5-dimethylhydantoin and 2.5 L of water. The mixture was allowed to isotherm to 39° C. and held at that temperature by gentle heating for 2 hours. The reaction was judged complete by HPLC analysis of the organic layer. The mixture was cooled to 32° C. by addition of 500 g of ice, and the solids not soluble in either liquid layer (mostly hydantoins and partially brominated hydantoins) were removed by filtration. The filtrate layers were separated, extracting the aqueous layer with 500 mL of CH2Cl2. the combined organic layers were added with rapid stirring to a solution of 410 g of Na2SO3 in 3 L of water. The layers were separated, extracting the aqueous layer with 3400 mL of CH2Cl2. The combined organics were distilled on a rotovap and replaced with heptane, maintaining a constant volume. The resulting thick slurry was cooled to 4° over 2.5 h. The solids were collected by filtration, washed with heptane ( 2×750 mL) and air dried, affording 1097 g (84%) of 2-Methylpropyl (4-bromo-3-fluorophenyl)carbamate as a white crystalline solid.

1. temperatureto warm
2. temperaturemaintain the mixture at gentle reflux
3. additionGas evolves vigorously near the end of the addition
4. aliquotThe organic phase was sampled for GC analysis 1 h
5. additionafter completion of the addition
6. customThe mixture was quenched by addition of 72 mL of conc. NH4OH
7. stirringAfter stirring for 15 minutes
8. additionto pH by addition of 120 mL of conc. aq. HCl
9. customThe layers were separated
10. extractionthe aqueous layer was extracted with 1.5 L of CH2Cl2
11. customto isotherm to 39° C.
12. temperatureby gentle heating for 2 hours
13. customthe solids not soluble in either liquid layer (mostly hydantoins and partially brominated hydantoins) were removed by filtration
14. customThe filtrate layers were separated
15. extractionextracting the aqueous layer with 500 mL of CH2Cl2
16. additionthe combined organic layers were added
17. stirringwith rapid stirring to a solution of 410 g of Na2SO3 in 3 L of water
18. customThe layers were separated
19. extractionextracting the aqueous layer with 3400 mL of CH2Cl2
20. distillationThe combined organics were distilled on a rotovap
21. temperaturemaintaining a constant volume
22. temperatureThe resulting thick slurry was cooled to 4° over 2.5 h
23. filtrationThe solids were collected by filtration
24. washwashed with heptane ( 2×750 mL) and air
25. customdried