反应详情

温度

40 °C

Into a reactor at room temperature was added 2 (67.6 kg, 179 mol) and MTBE (344 L). The mixture was warmed to 40° C. and stirred for 30 min until solids fully dissolved. The mixture was then cooled to 25 to 30° C. Sodium methoxide as a 25% w/w solution in methanol (45.2 kg, 209 mol) was added over a minimum of 90 min at 25 to 30° C. The reaction mixture was stirred for at least 2 h until >99.0% conversion was obtained by HPLC analysis. Water (483 L) was added slowly over 30 min while maintaining the temperature between 20 and 25° C. The layers were separated and the aqueous phase was extracted with MTBE (77 L). The combined organic extracts were washed with a dilute brine solution (38 kg NaCl in 342 L water). The organic layer was filtered, washed with water (242 L) and the organic phase was filtered. The resulting organic phase was concentrated until 360 L of solvent were removed while maintaining the internal temperature below 70° C. Isobutanol (302 L) was added and the mixture was concentrated while maintaining the internal temperature below 70° C. until 307 L of solvent were removed. A second portion of isobutanol (330 L) was added and the mixture was concentrated while maintaining the internal temperature below 70° C. until 210 L of solvent were removed. The mixture was heated to 60 to 85° C. until a clear solution was obtained and cooled to 50° C. A slurry of seed crystals (50 g in 150 mL isobutanol) was added and the mixture was cooled to 40° C. A second slurry of seed crystals (30 g in 60 mL isobutanol) was added and the mixture was cooled to 20 to 25° C. over a minimum of 3 h. The resulting mixture was stirred an additional 2 h. The mixture was filtered and washed with isobutanol (2×65 L). The resulting wet cake was dried at 20 to 35° C. under vacuum to provide 50.9 kg of crude 3. Into a separate reactor was charged crude 3 and isobutanol (69 L). The mixture was heated to 75 to 80° C. until a clear solution was obtained. The reaction mixture was cooled to 55° C. and a slurry of seed crystals (50 g in 500 mL isobutanol) was added. The mixture was stirred for 30 min at 55° C., cooled to 20 to 25° C. over a minimum of 3 h and stirred an additional 2 h. The mixture was filtered and washed with isobutanol (2×31 L). The wet cake was dried under vacuum at 40° C. to provide 46.0 kg (66% yield) of purified 3. 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=8.2 Hz, 1H), 7.42 (m, 2H), 7.13 (dd, J=2.3, 8.2 Hz), 6.76 (m, 2H), 3.73 (s, 3H); MS (ESI) m/z 391.2 (M+H+, 30%).

1. dissolutionfully dissolved
2. temperatureThe mixture was then cooled to 25 to 30° C
3. stirringThe reaction mixture was stirred for at least 2 h until >99.0% conversion
4. customwas obtained by HPLC analysis
5. temperaturewhile maintaining the temperature between 20 and 25° C
6. customThe layers were separated
7. extractionthe aqueous phase was extracted with MTBE (77 L)
8. washThe combined organic extracts were washed with a dilute brine solution (38 kg NaCl in 342 L water)
9. filtrationThe organic layer was filtered
10. washwashed with water (242 L)
11. filtrationthe organic phase was filtered
12. concentrationThe resulting organic phase was concentrated until 360 L of solvent
13. customwere removed
14. temperaturewhile maintaining the internal temperature below 70° C
15. additionIsobutanol (302 L) was added
16. concentrationthe mixture was concentrated
17. temperaturewhile maintaining the internal temperature below 70° C. until 307 L of solvent
18. customwere removed
19. additionA second portion of isobutanol (330 L) was added
20. concentrationthe mixture was concentrated
21. temperaturewhile maintaining the internal temperature below 70° C. until 210 L of solvent
22. customwere removed
23. temperatureThe mixture was heated to 60 to 85° C. until a clear solution
24. customwas obtained
25. temperaturecooled to 50° C
26. temperaturethe mixture was cooled to 40° C
27. temperaturethe mixture was cooled to 20 to 25° C. over a minimum of 3 h
28. stirringThe resulting mixture was stirred an additional 2 h
29. filtrationThe mixture was filtered
30. washwashed with isobutanol (2×65 L)
31. customThe resulting wet cake was dried at 20 to 35° C. under vacuum
32. customto provide 50.9 kg of crude 3
33. temperatureThe mixture was heated to 75 to 80° C. until a clear solution
34. customwas obtained
35. temperatureThe reaction mixture was cooled to 55° C.
36. stirringThe mixture was stirred for 30 min at 55° C.
37. temperaturecooled to 20 to 25° C. over a minimum of 3 h
38. stirringstirred an additional 2 h
39. filtrationThe mixture was filtered
40. washwashed with isobutanol (2×31 L)
41. customThe wet cake was dried under vacuum at 40° C.
42. customto provide 46.0 kg (66% yield)
43. customof purified 3