反应详情

温度

90 °C

To a solution of NaOH (27 Kg, 675 mol) in water (617 L) was added 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (XXI) (9.8 Kg, 46.2 mol). The solution was heated at 90° C. for 3 hours under nitrogen before adding a solution of KMnO4 (53.6 Kg, 339 mol) in water (870 L) slowly over 2 hours. The reaction was heated at 95° C. for 5 hours under nitrogen. The solution was cooled to 75° C. and filtered through diatomaceous earth (11 Kg) followed by washing the diatomaceous earth with water (150 L) heated at 75° C. The solution was cooled to 0° C. under nitrogen before the pH was adjusted to 1 with aqueous 35% HCl (˜75 L). The solution was warmed to room temperature before adding n-BuOH (473 L) which was stirred for 25 min and then the organic layer was separated. n-BuOH (473 L) was again added to the aqueous layer, stirred for 25 min and separated. The combined organic phases were concentrated under vacuum to a volume of ˜54 L. The n-BuOH was removed by adding to the solution 9×n-heptane (78 L) dropwise over 1 hour and then concentrating the volume to ˜54 L after each addition of n-heptane. The solid was filtered and washed 3×n-heptane (17 L). The solid was dried under vacuum at 45° C. to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) (3.2 Kg, 13.2 mol, 64.4% purity, 29.0% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.57 (d, J=2.4 Hz, 1H), 8.71 (d, J=2 Hz, 1H), 13.45 (brs, 1H), 14.65 (s, 1H); ESIMS found C7H4BrN3O2 m/z 243.8 (M+H).

1. temperatureThe reaction was heated at 95° C. for 5 hours under nitrogen
2. temperatureThe solution was cooled to 75° C.
3. filtrationfiltered through diatomaceous earth (11 Kg)
4. washby washing the diatomaceous earth with water (150 L)
5. temperatureheated at 75° C
6. temperatureThe solution was cooled to 0° C. under nitrogen before the pH
7. temperatureThe solution was warmed to room temperature
8. additionbefore adding n-BuOH (473 L) which
9. customthe organic layer was separated
10. additionn-BuOH (473 L) was again added to the aqueous layer
11. stirringstirred for 25 min
12. customseparated
13. concentrationThe combined organic phases were concentrated under vacuum to a volume of ˜54 L
14. customThe n-BuOH was removed
15. additionby adding to the solution 9×n-heptane (78 L) dropwise over 1 hour
16. concentrationconcentrating the volume to ˜54 L
17. additionafter each addition of n-heptane
18. filtrationThe solid was filtered
19. washwashed 3×n-heptane (17 L)
20. customThe solid was dried under vacuum at 45° C.