反应详情

温度

103.5 °C

Phosphorus oxychloride (3 vol) is charged to the reactor at 30±5° C. followed by 1,6-naphthyridin-5,7(6H,8H)-dione (1 eq), tetramethylammonium chloride (1.05 eq) and a rinse of phosphorus oxychloride (0.5 vol). The mixture is heated to 103.5±3.5° C. and stirred for a minimum of 36 h. The reaction is then cooled to 60±5° C. and sampled. On receipt of a successful sample, toluene (4 vol) is added and the mixture concentrated to 2-3 volumes by distillation under vacuum (NLT 650 mm of Hg) and temperature<60° C. Additional toluene (2 vol) is added and again the mixture distilled under vacuum to 2-3 vols. This toluene addition/distillation cycle is repeated once more then the mixture is cooled to 47.5±2.5° C. and treated with tetrahydrofuran (8 vol) and ethyl acetate (8 vol). The mixture is cooled to 30±5° C. and poured into 15% aq. sodium carbonate (15 vol) which has been pre-cooled to 5.0±5.0° C. Additional tetrahydrofuran (3 vol) is added along with ethyl acetate (3 vol) in order to rinse out the initial reaction vessel. Whilst still at 5±5° C. the mixture is slowly treated with further 15% aqueous sodium carbonate solution (5 vol) and stirred for 15-30 min. The temperature is increased to 22.5±2.5° C. and the pH adjusted to 7-8 by addition of either 15% aqueous sodium carbonate solution or dilute HCl. Ethyl acetate (5 vol) is added followed by celite. The mixture is stirred then filtered. The celite bed is washed with ethyl acetate (2×2 vol). The filtrate is distilled at <55° C. under vacuum (NLT 650 mm of Hg) down to 30±5 volumes. Water (2 vol) is added and the distilled again down to ˜30 vols. This water addition/distillation cycle is repeated until the tetrahydrofuran, toluene and ethyl acetate content are each NMT 3.0% by GC (% w/w). At that point, water (10 vol) is added and the mixture heated to 42.5±2.5° C. and stirred for 30-60 min. The product is isolated by filtration at 42.5±2.5° C. and washed with water (2×3 vol). The cake is sucked dry then offloaded and charged to a separate reactor. Water (20 vol) is added and the suspension heated to 42.5±2.5° C. and stirred for 30-60 min 42.5±2.5° C. The product is filtered and washed with water (2×3 vol), sucked dry then transferred to a vacuum oven and further dried at 52.5±2.5° C. under vacuum (NLT 650 mm of Hg) for 8±2 h.

1. washa rinse of phosphorus oxychloride (0.5 vol)
2. temperatureThe reaction is then cooled to 60±5° C.
3. aliquotsampled
4. additionOn receipt of a successful sample, toluene (4 vol) is added
5. concentrationthe mixture concentrated to 2-3 volumes by distillation under vacuum (NLT 650 mm of Hg) and temperature<60° C
6. additionAdditional toluene (2 vol) is added
7. distillationagain the mixture distilled under vacuum to 2-3 vols
8. distillationThis toluene addition/distillation cycle
9. temperaturethe mixture is cooled to 47.5±2.5° C.
10. additiontreated with tetrahydrofuran (8 vol) and ethyl acetate (8 vol)
11. temperatureThe mixture is cooled to 30±5° C.
12. additionpoured into 15% aq. sodium carbonate (15 vol) which
13. temperaturehas been pre-cooled to 5.0±5.0° C
14. additionAdditional tetrahydrofuran (3 vol) is added along with ethyl acetate (3 vol) in order
15. washto rinse out the initial
16. customreaction vessel
17. stirringstirred for 15-30 min
18. temperatureThe temperature is increased to 22.5±2.5° C.
19. stirringThe mixture is stirred
20. filtrationthen filtered
21. washThe celite bed is washed with ethyl acetate (2×2 vol)
22. distillationThe filtrate is distilled at <55° C. under vacuum (NLT 650 mm of Hg) down to 30±5 volumes
23. additionWater (2 vol) is added
24. distillationthe distilled again down to ˜30 vols
25. distillationThis water addition/distillation cycle
26. additionAt that point, water (10 vol) is added
27. temperaturethe mixture heated to 42.5±2.5° C.
28. stirringstirred for 30-60 min
29. customThe product is isolated by filtration at 42.5±2.5° C.
30. washwashed with water (2×3 vol)
31. customThe cake is sucked dry
32. additioncharged to a separate reactor
33. additionWater (20 vol) is added
34. temperaturethe suspension heated to 42.5±2.5° C.
35. stirringstirred for 30-60 min 42.5±2.5° C
36. filtrationThe product is filtered
37. washwashed with water (2×3 vol)
38. customsucked dry
39. customfurther dried at 52.5±2.5° C. under vacuum (NLT 650 mm of Hg) for 8±2 h.