反应详情

温度

60 °C

2,6-Difluoro-4-bromobenzaldehyde (1000 g, 4.39 mol) and 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (57.2 g: 87.76 mmol) were charged to a 20 L vessel. Tetra-n-butylammonium chloride (122 g, 438.97 mmol) was added followed by dimethylacetamide (5 L). The vessel was purged with a stream of nitrogen gas. Diisopropylethylaine (1.5 L, 8.78 mol) was added to the vessel followed by methyl acrylate (0.435 L, 4.82 mol). The mixture was agitated and heated to 60° C. The mixture was held at this temperature for 20 hours. Ethyl acetate (10 L) was added to the mixture and the heating was switched off. Water (5 L) was added to the vessel. The stirred mixture was cooled to 25° C. and stirring was continued for 10 minutes. Agitation was stopped and the layers were allowed to separate. The aqueous layer was removed and discarded. The organic layer was washed sequentially with hydrochloric acid (2.2M, 6 L) and water (5 L). Phosphonics SPM32 Scavenger (1050 g, 1050 mol) was added to the vessel and the mixture was stirred for 3 days at 25° C. The solid material was removed by filtration. The cake was washed with ethanol (5 L) and the combined filtrates were concentrated under reduced pressure to afford a solid. The solid was dissolved in ethanol (9 L) and the solution was agitated in a 20 L vessel. The solution was heated to 50° C. A solution of sodium bisulfite (460 g, 4.42 mol) in water (2.5 L) was added over 30 minutes. A thick slurry resulted which was stirred for 4 hours at 50° C. The slurry was cooled to 20° C. over 2 hours. The solid was isolated by filtration and the vessel and filter cake were washed with MTBE (2×3 L). The resulting solid was dried in vacuo to afford sodium {2,6-difluoro-4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl}(hydroxy)methanesulfonate (1035 g, 71%) as a light brown solid. 1H NMR (500 MHz, DMSO, 27° C.) δ 3.73 (3H, s), 5.32 (1H, d), 5.94 (1H, d), 6.76 (1H, d), 7.40 (2H, d), 7.60 (1H, d).

1. customThe vessel was purged with a stream of nitrogen gas
2. additionDiisopropylethylaine (1.5 L, 8.78 mol) was added to the vessel
3. temperatureThe stirred mixture was cooled to 25° C.
4. stirringstirring
5. waitwas continued for 10 minutes
6. customto separate
7. customThe aqueous layer was removed
8. washThe organic layer was washed sequentially with hydrochloric acid (2.2M, 6 L) and water (5 L)
9. additionPhosphonics SPM32 Scavenger (1050 g, 1050 mol) was added to the vessel
10. stirringthe mixture was stirred for 3 days at 25° C
11. customThe solid material was removed by filtration
12. washThe cake was washed with ethanol (5 L)
13. concentrationthe combined filtrates were concentrated under reduced pressure
14. customto afford a solid
15. stirringthe solution was agitated in a 20 L vessel
16. temperatureThe solution was heated to 50° C
17. customA thick slurry resulted which
18. stirringwas stirred for 4 hours at 50° C
19. temperatureThe slurry was cooled to 20° C. over 2 hours
20. customThe solid was isolated by filtration
21. filtrationthe vessel and filter cake
22. washwere washed with MTBE (2×3 L)
23. customThe resulting solid was dried in vacuo