Under nitrogen protection, 2-bromo-5-hydroxybenzaldehyde (100 g, 497 mmol) and 4-fluorobenzonitrile (301.2 g, 2487 mmol) were dissolved in a mixed solvent of N,N-dimethylformamide (DMF, 250 mL) and toluene (500 mL). Potassium carbonate (206.2 g, 1492 mmol) was added to this dark solution and the reaction mixture was stirred at 115 °C for 8 hours. Upon completion of the reaction, the reaction endpoint was confirmed by thin layer chromatography (TLC) monitoring. Insoluble material was removed by filtration followed by removal of solvent and excess 4-fluorobenzonitrile by distillation under reduced pressure. Ethyl acetate (800 mL), water (500 mL) and brine (40 mL) were added to the residue and phase separation was carried out at 65-70 °C. The aqueous phase was extracted with ethyl acetate (150 mL) at the same temperature and the combined organic phases were washed sequentially with mixed water (225 mL) and brine (180 mL) at 65-70 °C. The organic phase was concentrated under reduced pressure to give a brown solid product. The solid was purified by twice recrystallization in a mixture of hot ethyl acetate and toluene solvents to give 4-(4-bromo-3-formylphenoxy) benzyl cyanide (Compound A) (107.5 g) in 71% yield. High performance liquid chromatography (HPLC) analysis showed purity greater than 99%. Nuclear magnetic resonance hydrogen spectrum (1H-NMR, 200 MHz, CDCl3, δ ppm): 10.32 (1H, s); 7.62-7.72 (3H, m); 7.57-7.59 (1H, dd; J = 3 Hz, J = 1 Hz); 7.18-7.23 (1H, dd, J = 8 Hz, J = 3 Hz), 7.01-7.08 ( 2H, m). Nuclear magnetic resonance carbon spectrum (13C-NMR, 50 MHz, CDCl3, δ ppm): 190.69; 160.08; 155.13; 135.59; 134.89; 134.39; 126.86; 121.81; 120.28; 118.68; 118.33; 107.32. differential scanning calorimetry (DSC) Showed a heat absorption peak at 11.19°C.
