反应详情

温度

20 °C

To a 20-L glass reactor was added N-[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]sulfamide (799.4 g, 1.72 mol) and THF (3.2 L). The resulting solution was stirred at 20° C. for 7 min. and then charged with water (1.6 L). The batch was cooled to 2° C. and was charged with 30 wt % sodium hydroxide solution (475 mL, 666.4 g, 4.99 mol, 2.9 equiv.) over 8 minutes. The batch was warmed to 20° C. and the temperature was maintained for 16 h. The batch was then charged with methyl tert-butyl ether (8.0 L) over 23 minutes. Water (2.7 L) was added and the batch was cooled to about 0° C. The batch was then charged with 85 wt % phosphoric acid (370.7 g, 3.22 mol, 1.9 equiv.) over 9 minutes. The batch was warmed to 20° C. and stirred for 1 h. The batch was allowed to settle and phases were separated. The organic layer was retained in the reactor and charged with water (2.9 L) and 85 wt % phosphoric acid (370.7 g, 3.22 mol) and stirred at 20° C. for 1 h. The batch was allowed to settle and phases were separated. The organic layer was retained in the reactor and charged with water (3.2 L) and stirred at 20° C. for 1 h. The batch was allowed to settle and phases were separated. The organic solution was retained in the reactor and distilled under reduced pressure at 20° C. to remove 3.4 Kg of distillate. Ethanol (4.8 L) was charged to the batch and the batch was distilled to a volume of 3.2 L. This distillation process was repeated one more time. Ethanol (0.6 L) was added to the batch to adjust the batch volume to 4 L. The batch was stirred at 20° C. for 16 h and then charged with water (6.39 L). The resultant slurry was stirred at 20° C. for 5 h. The product was collected by filtration and was washed twice with a mixture of ethanol (529 mL) and water (1059 mL). The product was dried under reduced pressure at 45° C. for 65 h to afford the desired product (719.6 g, 95.4%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.51 (s, 1 H), 8.90 (s, 1 H), 7.17 (t, J=8.8 Hz, 1 H), 7.11 (dd, J=6.1, 2.7 Hz, 1 H), 6.76 (m, 1 H), 6.71 (t, J=6.0 Hz, 1 H), 6.59 (s, 2 H), 6.23 (t, J=6.1 Hz, 1 H), 3.35 (dd, J=10.9, 7.0 Hz, 2 H), 3.10 (dd, J=12.1, 6.2 Hz, 2 H); C11H13BrFN7O4S (MW 438.23), LCMS (EI) m/e 437.9/439.9 (M++H).

1. temperatureThe batch was cooled to 2° C.
2. temperatureThe batch was warmed to 20° C.
3. temperaturethe temperature was maintained for 16 h
4. temperaturethe batch was cooled to about 0° C
5. temperatureThe batch was warmed to 20° C.
6. stirringstirred for 1 h
7. customphases were separated
8. stirringstirred at 20° C. for 1 h
9. customphases were separated
10. additioncharged with water (3.2 L)
11. stirringstirred at 20° C. for 1 h
12. customphases were separated
13. distillationdistilled under reduced pressure at 20° C.
14. customto remove 3.4 Kg of distillate
15. additionEthanol (4.8 L) was charged to the batch
16. distillationthe batch was distilled to a volume of 3.2 L
17. additionEthanol (0.6 L) was added to the batch
18. stirringThe batch was stirred at 20° C. for 16 h
19. additioncharged with water (6.39 L)
20. stirringThe resultant slurry was stirred at 20° C. for 5 h
21. filtrationThe product was collected by filtration
22. washwas washed twice with a mixture of ethanol (529 mL) and water (1059 mL)
23. customThe product was dried under reduced pressure at 45° C. for 65 h