Steps for the synthesis of 3-bromo-5-pyridineboronic acid (2b): 3-bromo-5-fluoropyridine (2a) (25 kg, 142 moles, 1.0 eq.), THF (222.5 kg), and isopropyl borate (28 kg, 149.3 moles, 1.05 eq.) were added to a 700 L cryoreactor. The mixture was cooled to -90°C to -80°C and stirred. Subsequently, n-BuLi (40.2 kg, 2.5 M, 142 mol, 1.0 eq.) was added dropwise at a rate of 2 kg/h while ensuring that the temperature was below -87°C. After the dropwise addition, stirring of the reaction mixture was continued for 2.5 h at -88 °C to -83 °C. After confirming the completion of the reaction by HPLC analysis, the reaction was quenched by the addition of 9% HCl aqueous solution (7.7 kg). The mixture was transferred to a 1000 L glass-lined reactor and warmed to -20°C to -10°C. Next, additional HCl solution (122.3 kg) was added to adjust the pH to 1-2, during which the temperature was maintained at 0-10°C. It was allowed to stand for 0.5 h to stratify, the organic layer was separated and washed with saturated brine (38 kg). After stirring again for 0.5 h, the mixture was left to stratify for 0.5 h. The aqueous layer was separated. The aqueous layer was separated and the combined aqueous layers were extracted twice with EtOAc (51kg and 25kg). The organic phases were combined and the pH was adjusted to 6 with 30% NaOH aqueous solution (27.4 kg), at which point solids precipitated. The slurry was filtered by centrifugation and the solids were dried in a disk drier at 40-45 °C to give 3-bromo-5-pyridineboronic acid (2b) as a white solid (17.5 kg, 87.4% yield, 98.6% purity AUC, method of use B).
