反应详情

温度

50 °C

To a 12-L, three-neck, round-bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, addition funnel and thermocouple was charged 4-bromo-3-fluoroaniline (800.0 g, 4.21 mol, Matrix lot #Q13H), THF (6.4 L, 8 vol), and solid sodium bicarbonate (530.5 g, 6.32 mol, 1.5 eq). The addition funnel was charged with benzyl chloroformate (861.9 g, 5.05 mol, 1.2 eq), which was added dropwise to the reactor over 70 minutes. The temperature of the reaction was maintained below 20° C. with an ice water bath. The batch was aged 1 hour at room temperature at which point HPLC analysis indicated that the reaction was complete. The reaction mixture was transferred to a 22-L flask and the mixture was diluted with water (6.4 L, 8 vol). The two-phase mixture was warmed to 50° C. and held at temperature for 16 hours to quench the excess benzyl chloroformate. The mixture was transferred hot to a separatory funnel to remove the lower aqueous phase. A rag layer was observed which was taken with the aqueous layer. The THF layer was filtered through Whatman #1 filter paper to remove some particulates, and the mixture was transferred back to a 22-L flask equipped for distillation. Heptane was added in portions and distilled to remove the THF. (Note that it is best to distill some of the THF out first before adding the first amount of heptane.) A total of 26.5 L of heptane was added, and the total distillate collected was 25 L. At this point, the pot temperature had reached 97.7° C. and the distillate coming over contained 0.9% THF by 1H NMR analysis. The mixture was cooled to room temperature and the thick white slurry was filtered. The filter cake was washed with heptane (4 L). The product was dried in a vacuum oven at 40° C. to give 1257.0 g of intermediate 5 (92% yield). The HPLC assay was 98.3% (AUC).

1. additionwas added dropwise to the reactor over 70 minutes
2. temperatureThe temperature of the reaction was maintained below 20° C. with an ice water bath
3. customThe reaction mixture was transferred to a 22-L flask
4. waitheld at temperature for 16 hours
5. customto quench the excess benzyl chloroformate
6. customThe mixture was transferred hot to a separatory funnel
7. customto remove the lower aqueous phase
8. filtrationThe THF layer was filtered through Whatman #1
9. filtrationfilter paper
10. customto remove some particulates
11. customthe mixture was transferred back to a 22-L flask
12. customequipped for distillation
13. additionHeptane was added in portions
14. distillationdistilled
15. customto remove the THF
16. distillationto distill some of the THF out first
17. additionbefore adding the first amount of heptane
18. addition) A total of 26.5 L of heptane was added
19. distillationthe total distillate collected
20. customhad reached 97.7° C.
21. temperatureThe mixture was cooled to room temperature
22. filtrationthe thick white slurry was filtered
23. washThe filter cake was washed with heptane (4 L)
24. customThe product was dried in a vacuum oven at 40° C.