反应详情

温度

2.5 °C

Into a reactor at room temperature was added (2-amino-5-chlorophenyl)(2,6-difluorophenyl)methanone (1, 60.0 kg, 224 mol) and acetic acid (427 L). The mixture was stirred until all solids fully dissolved, filtered and washed with acetic acid (9.47 L). Concentrated HCl (156 L) was added over a minimum of 30 minutes at 20 to 25° C. and the resulting mixture was cooled to 0 to 5° C. A solution of sodium nitrite (18.6 kg, 269 mol) in water (88.0 L) was added while maintaining the reaction temperature between 0 and 5° C. The mixture was stirred for 1 h at 0 to 5° C. Water (270 L) and isopropyl acetate (717 L) were then added at 0 to 5° C. A solution of potassium iodide (50.2 kg, 303 mol) in water (133 L) was added over 1 h at 0 to 5° C. The reaction mixture was stirred for 30 min and warmed to 20 to 25° C. over 1.5 h. The layers were separated and the organic phase was washed with a dilute brine solution (22 kg NaCl in 200 L water) and a sodium carbonate solution (175 kg Na2CO3 in 523 L water). The resulting organic layer was washed twice with a sodium ascorbate solution (15.8 kg in 188 L water for each wash) followed by water (200 L). The organic phase was concentrated using a maximum 50° C. jacket temperature until 430 L of solvent was removed. Heptane (400 L) was added and the mixture was concentrated using a 50° C. jacket temperature until 395 L of solvent were removed. 2-Butanol (398 L) was added and the mixture was concentrated using a maximum 60° C. jacket temperature until 322 L of solvent were removed. An additional portion of 2-butanol (398 L) was added and the mixture was concentrated using a 70° C. jacket temperature until 390 L of solvent were removed. The reaction mixture was cooled to −5 to −8° C., stirred for 2 h, filtered and washed with 2-butanol (2×84.2 L) at −5 to 0° C. The resulting wet cake was dried at 40 to 50° C. under vacuum to provide 67.6 kg (80% yield) of 2. 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=8.2 Hz, 1H), 7.51 (m, 1H), 7.44 (d, J=2.3 Hz, 1H), 7.18 (dd, J=2.3, 8.2 Hz, 1H), 7.00 (m, 2H); Elemental Anal. Calcd. for C13H6ClF2IO: C, 41.25; H, 1.60; Cl, 9.37; F, 10.04; I, 33.52; O, 4.23. Found: C, 41.36; H, 1.65; Cl, 9.51; F, 10.03; I, 33.41; O, 4.04.

1. dissolutionfully dissolved
2. filtrationfiltered
3. washwashed with acetic acid (9.47 L)
4. additionConcentrated HCl (156 L) was added over a minimum of 30 minutes at 20 to 25° C.
5. temperaturewhile maintaining the reaction temperature between 0 and 5° C
6. stirringThe mixture was stirred for 1 h at 0 to 5° C
7. stirringThe reaction mixture was stirred for 30 min
8. temperaturewarmed to 20 to 25° C. over 1.5 h
9. customThe layers were separated
10. washthe organic phase was washed with a dilute brine solution (22 kg NaCl in 200 L water)
11. washThe resulting organic layer was washed twice with a sodium ascorbate solution (15.8 kg in 188 L water for
12. washeach wash)
13. concentrationThe organic phase was concentrated
14. customusing a maximum 50° C.
15. customwas removed
16. additionHeptane (400 L) was added
17. concentrationthe mixture was concentrated
18. customusing a 50° C.
19. customwere removed
20. addition2-Butanol (398 L) was added
21. concentrationthe mixture was concentrated
22. customusing a maximum 60° C.
23. customwere removed
24. additionAn additional portion of 2-butanol (398 L) was added
25. concentrationthe mixture was concentrated
26. customusing a 70° C.
27. customwere removed
28. temperatureThe reaction mixture was cooled to −5 to −8° C.
29. stirringstirred for 2 h
30. filtrationfiltered
31. washwashed with 2-butanol (2×84.2 L) at −5 to 0° C
32. customThe resulting wet cake was dried at 40 to 50° C. under vacuum