反应详情

温度

27.5 °C

Into a reactor at room temperature was added methyl 4-amino-2-methoxybenzoate (4, 38 kg, 210 mol) and methanol (224 L). The mixture was stirred at 25 to 30° C. for 30 min. Aqueous cyanamide (50% w/w, 43 kg, 512 mol) was added over a minimum of 30min at 20 to 25° C. The reaction mixture was heated to reflux using a maximum jacket temperature of 75° C. Concentrated nitric acid (45 kg, 499 mol) was added over a minimum of 60 min. The resulting mixture was heated at reflux for 2 h. A suspension of seed crystals (16 g in 600 mL methanol) was added and the mixture was stirred using a 75° C. jacket temperature for 60 to 90 min. The mixture was cooled to 20 to 25° C. over at least 2 h and stirred for an additional 2 h. The mixture was filtered and washed with methanol (180 L) while stirring for 1 h. The wet cake was washed a second time with methanol (180 L) while stirring for 1 h. The resulting wet cake was dried under vacuum at 25° C. to provide 30.0 kg (50% yield) of 5. 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.57 (s, 4H), 6.97 (d, J=2.3 Hz, 1H), 6.84 (dd, J=2.3, 8.2 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H); MS (ESI) m/z 224.4 (M+, 100%).

1. temperatureThe reaction mixture was heated
2. temperatureto reflux
3. customa maximum jacket temperature of 75° C
4. temperatureThe resulting mixture was heated
5. temperatureat reflux for 2 h
6. additionwas added
7. stirringthe mixture was stirred
8. customusing a 75° C.
9. customfor 60 to 90 min
10. temperatureThe mixture was cooled to 20 to 25° C. over at least 2 h
11. stirringstirred for an additional 2 h
12. filtrationThe mixture was filtered
13. washwashed with methanol (180 L)
14. stirringwhile stirring for 1 h
15. washThe wet cake was washed a second time with methanol (180 L)
16. stirringwhile stirring for 1 h
17. customThe resulting wet cake was dried under vacuum at 25° C.