Synthesis of 3-bromo-5-fluoro-4-hydroxybenzaldehyde (26): 3-fluoro-4-hydroxybenzaldehyde (2 g, 14.3 mmol, 1 eq.) was dissolved in acetic acid (60 mL) and bromine (2.7 g, 17.0 mmol, 1.2 eq.) was added slowly to a solution of acetic acid (10 mL). The reaction mixture was stirred at 45°C for 26 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure and saturated saline (50 mL) was added to the residue and extracted with ethyl acetate (3 x 80 mL). The organic layers were combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by reversed-phase semi-preparative high-performance liquid chromatography (HPLC) to afford the target product 3-bromo-5-fluoro-4-hydroxybenzaldehyde (26) 1.5 g in 48% yield.
