反应详情

To a 20-L flask containing tert-butyl ({[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]amino}sulfonyl)carbamate (1200 g, 2.126 mol) was added ethanol (12 L) at 20° C. The resulting mixture was stirred at room temperature and charged with hydrogen chloride gas (472 g, 12.9 mol, 6.07 equiv.). The batch was heated to 50° C. and the temperature was maintained for 3 h until reaction completion. Solvent was removed by vacuum distillation at 33-39° C. and 6 Kg of distillate was collected. Ethyl acetate (6.8 L, 6.1 Kg) was added to the batch and distilled to collect 5.1 Kg of distillate. Ethyl acetate (7.2 L, 6.48 Kg) was added to the batch and distilled to collect 5.1 Kg of distillate. Ethyl acetate (2.4 L, 2.14 Kg) was added to the batch to adjust the solvents ratio. 1H NMR indicated the mole ratio of ethyl acetate to ethanol was 1.0:0.1. The solution was heated to 65° C. n-Heptane (4.1 kg) was added to the solution at 60-65° C. over 43 min. The resulting slurry was stirred at 65° C. for 1 h. The slurry was cooled to 20° C. over 2.5 h and stirred at that temperature for 15 h. The product was collected by filtration and washed with n-heptane (2.42 L). The product was dried under reduced pressure at 45° C. for 65 h to afford the desired product (906 g, 91.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (dd, J=6.2) 7.72 (m, 1 H), 7.59 (t, J=8.7 Hz, 1 H), 6.67 (t, J=5.9 Hz, 1H), 6.55 (s, 2H) 6.52 (t, J=6.0 Hz, 1 H), 3.38 (dd, J=12.7, 6.3 Hz, 2 H), 3.11 (dd, J=12.3, 6.3 Hz, 2H); C12H11BrFN7O5S (MW 464.23), LCMS (EI) m/e 485.8/487.8 (M+-C5H8O2+Na).

1. temperatureThe batch was heated to 50° C.
2. temperaturethe temperature was maintained for 3 h until reaction completion
3. customSolvent was removed by vacuum distillation at 33-39° C.
4. distillation6 Kg of distillate was collected
5. additionEthyl acetate (6.8 L, 6.1 Kg) was added to the batch
6. distillationdistilled
7. distillationto collect 5.1 Kg of distillate
8. additionEthyl acetate (7.2 L, 6.48 Kg) was added to the batch
9. distillationdistilled
10. distillationto collect 5.1 Kg of distillate
11. additionEthyl acetate (2.4 L, 2.14 Kg) was added to the batch
12. temperatureThe solution was heated to 65° C. n-Heptane (4.1 kg)
13. additionwas added to the solution at 60-65° C. over 43 min
14. stirringThe resulting slurry was stirred at 65° C. for 1 h
15. temperatureThe slurry was cooled to 20° C. over 2.5 h
16. stirringstirred at that temperature for 15 h
17. filtrationThe product was collected by filtration
18. washwashed with n-heptane (2.42 L)
19. customThe product was dried under reduced pressure at 45° C. for 65 h