反应详情

To a solution of 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) (12.7 Kg, 95.4 mol) in HOAc (57 L) was added NaOAc (20.4 Kg, 248 mol), water (13.3 L), and Br2 (40 L, 780 mol). The reaction was stirred at room temperature for 5 hours and then at 115° C. for 6 hours. The reaction was cooled to room temperature and diluted with DCM (686 L). To this solution was added water (508 L) and cooled to 0° C. followed by dropwise addition of aqueous 30% NaOH while maintaining the temperature <20° C. under pH=9. The mixture was filtered through diatomaceous earth (14 Kg) followed by washing the diatomaceous earth with 3×DCM (50 L). The organic layer was separated, washed with aqueous 25% NaCl (200 L) and concentrated under vacuum to a volume of 70 L. The product was crystallized by charging the solution with 3×n-heptane (88 L) while concentrating the volume to 70 L after each addition of n-heptane. The solid was filtered and washed 3×n-heptane (22 L). The solid was dried under vacuum at 45° C. to yield 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (XXI) (9.8 Kg, 46.2 mol, 92.6% purity, 48.4% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 2.48 (s, 3H), 8.50-8.55 (m, 2H), 13.42 (brs, 1H); ESIMS found C7H6BrN3 m/z 213.7 (M+H).

1. waitat 115° C. for 6 hours
2. temperatureThe reaction was cooled to room temperature
3. temperaturecooled to 0° C.
4. temperaturewhile maintaining the temperature <20° C. under pH=9
5. filtrationThe mixture was filtered through diatomaceous earth (14 Kg)
6. washby washing the diatomaceous earth with 3×DCM (50 L)
7. customThe organic layer was separated
8. washwashed with aqueous 25% NaCl (200 L)
9. concentrationconcentrated under vacuum to a volume of 70 L
10. customThe product was crystallized
11. concentrationwhile concentrating the volume to 70 L
12. additionafter each addition of n-heptane
13. filtrationThe solid was filtered
14. washwashed 3×n-heptane (22 L)
15. customThe solid was dried under vacuum at 45° C.