Hydrochloric Acid → 6-(4-Bromo-3-fluorophenyl)-1,2,4-triazin-3-amine

Temperature

75 °C

A 22 L flask was charged with 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (6, 1240 g, 4.07 mol), ethanol (11 L), water (1.4 L), potassium hydroxide (KOH, 910 g, 16.3 mol, 4.0 equiv), and aminoguanidine bicarbonate (1105 g, 8.13 mol, 2.0 equiv) at room temperature. The resulting reaction mixture was then heated to 75° C. for 14 h. When HPLC showed the condensation reaction was deemed complete, the reaction mixture was cooled down to room temperature before being filtered. The filtrate was then concentrated under the reduced pressure to remove the most of the solvents. The residual aqueous solution was extracted with ethyl acetate (EtOAc, 3×6 L). The organic layers were combined and concentrated under the reduced pressure to give a dark brown solid. This solid was dissolved in ethanol (4 L) and the resulting solution was treated with a solution of 0.2 M aqueous hydrochloric acid solution (4 L). The resulting slurry was subsequently heated to 50° C. for 6 h before being allowed to cool down to room temperature. A solution of saturated aqueous sodium bicarbonate solution (NaHCO3, 2 L) was slowly added to the slurry and the resulting mixture was then concentrated under the reduced pressure to remove most of the solvents. The aqueous residue was then treated with ethyl acetate (20 L) to dissolve the solids. The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×2 L). The combined organic layers were concentrated under the reduced pressure. The dark brown solids were treated with methyl tert-butyl ether (MTBE, 4 L) and the resulting slurry was heated to 30° C. and stirred at 30° C. for 30 min. The mixture was filtered and the solids (green to orange in color) were collected (save the filtrate) and washed with methyl tert-butyl ether (MTBE, 2 L) to give the first crop of the crude desired product (7). The filtrate was evaporated under the reduced pressure, and the resulting dark brown solids were treated with methyl tert-butyl ether (MTBE, 2 L). The resulting slurry was heated to 30° C. and stirred at 30° C. for 30 min. The mixture was filtered to give the second crop of the crude desired product (7) which was washed with MTBE (1 L). The combined solids were dried in vacuum at 40-45° C. to afford 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (7, 585 g, 1095.1 g theoretical, 53.4% yield) which was used in the subsequent reaction without further purification. For 7: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.86 (s, 1H), 7.97 (d, 1H, J=10.79 Hz), 7.81 (m, 2H), 7.52 (br s, 2H); C9H6BrFN4 (MW 269.07), LCMS (EI) m/e 269.0/271.1 (M30 +H).

1. customThe resulting reaction mixture
2. customthe condensation reaction
3. temperaturethe reaction mixture was cooled down to room temperature
4. filtrationbefore being filtered
5. concentrationThe filtrate was then concentrated under the reduced pressure
6. customto remove the most of the solvents
7. extractionThe residual aqueous solution was extracted with ethyl acetate (EtOAc, 3×6 L)
8. concentrationconcentrated under the reduced pressure
9. customto give a dark brown solid
10. temperatureThe resulting slurry was subsequently heated to 50° C. for 6 h
11. temperatureto cool down to room temperature
12. concentrationthe resulting mixture was then concentrated under the reduced pressure
13. customto remove most of the solvents
14. additionThe aqueous residue was then treated with ethyl acetate (20 L)
15. dissolutionto dissolve the solids
16. customThe two layers were separated
17. extractionthe aqueous layer was extracted with ethyl acetate (2×2 L)
18. concentrationThe combined organic layers were concentrated under the reduced pressure
19. additionThe dark brown solids were treated with methyl tert-butyl ether (MTBE, 4 L)
20. temperaturethe resulting slurry was heated to 30° C.
21. filtrationThe mixture was filtered
22. customthe solids (green to orange in color) were collected (save the filtrate) and
23. washwashed with methyl tert-butyl ether (MTBE, 2 L)
24. customto give the first crop of the crude desired product (7)
25. customThe filtrate was evaporated under the reduced pressure
26. additionthe resulting dark brown solids were treated with methyl tert-butyl ether (MTBE, 2 L)
27. temperatureThe resulting slurry was heated to 30° C.
28. stirringstirred at 30° C. for 30 min
29. filtrationThe mixture was filtered
30. customto give the second crop of the crude desired product (7) which
31. washwas washed with MTBE (1 L)
32. customThe combined solids were dried in vacuum at 40-45° C.

ORD record

ord-7acbb8aefcf840a08220e137208440d3

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08420645B2