3-Bromo-5-fluoropyridine → (5-Fluoropyridin-3-yl)boronic acid

3-bromo-5-fluoropyridine (2a) (25 kg, 142 moles, 1.0 equiv.), THF (222.5 kg) and isopropyl borate (28 kg, 149.3 moles, 1.05 equiv.) were added to a 700 L low temperature reactor. The resulting mixture was cooled to −90° C.˜−80° C. while stirred. Then n-BuLi (40.2 kg, 2.5 M, 142 moles, 1.0 equiv.) was added dropwise (2 kg/h) maintaining the temperature below −87° C. After the addition was complete, the mixture was maintained at −88˜−83° C. for 2.5 h. When the reaction was deemed complete by HPLC analysis, it was quenched by addition of 9% aqueous HCl (7.7 kg). The mixture was transferred to a 1000 L glass-lined reactor and the temperature returned to −20˜−10° C. Additional HCl solution (122.3 kg) was then added until pH was adjusted to 1˜2 maintaining the temperature at 0˜10° C. The mixture was then held for 0.5 h in order to allow layers to separate. The organic layer was separated and washed with saturated brine (38 kg). It was stirred for 0.5 h and then held again for 0.5 h to allow layer separation. The aqueous layer was separated and the combined aqueous layers were extracted with EtOAc twice (51+25 kg). The organic phase was separated and pH was adjusted to a value of 6 by using 30% aqueous NaOH solution (27.4 kg). At this pH a solid precipitated out. The slurry was filtered by centrifuge and allowed to dry in a tray dryer at 40˜45° C. Title compound (2b) was obtained as a white solid (17.5 kg, 87.4%, purity: 98.6% AUC using method B).

1. temperatureThe resulting mixture was cooled to −90° C.˜−80° C.
2. temperaturemaintaining the temperature below −87° C
3. additionAfter the addition
4. temperaturethe mixture was maintained at −88˜−83° C. for 2.5 h
5. customwas quenched by addition of 9% aqueous HCl (7.7 kg)
6. customThe mixture was transferred to a 1000 L glass-lined reactor
7. customreturned to −20˜−10° C
8. additionAdditional HCl solution (122.3 kg) was then added until pH
9. temperaturemaintaining the temperature at 0˜10° C
10. customto separate
11. customThe organic layer was separated
12. washwashed with saturated brine (38 kg)
13. stirringIt was stirred for 0.5 h
14. waitheld again for 0.5 h
15. customlayer separation
16. customThe aqueous layer was separated
17. extractionthe combined aqueous layers were extracted with EtOAc twice (51+25 kg)
18. customThe organic phase was separated
19. customAt this pH a solid precipitated out
20. filtrationThe slurry was filtered by centrifuge
21. customto dry in a tray dryer at 40˜45° C

ORD record

ord-82928dbce2e14e9fbbbd7d0b447ab11d

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08217172B2