Synthesis
The general procedure for the synthesis of 2-bromo-4-methoxybenzoic acid from 4-methoxybenzoic acid was as follows: 152.3 g (1.0 mol) of 4-methoxybenzoic acid was added to a 2,000 mL four-necked flask fitted with a stirrer, a thermometer, and a reflux condenser tube, followed by the addition of 800 g of water and stirring until the 4-methoxybenzoic acid was completely dispersed. Then, 273.3 g (2.05 mol) of 30% aqueous sodium hydroxide was added. The temperature of the reaction solution was lowered to 0 °C and 167.8 g (1.05 mol) of bromine was slowly added dropwise over the temperature range of 0 to 5 °C. After the dropwise addition was completed, the reaction was continued with stirring for 1 hour by keeping the temperature at 0 to 5 °C. Upon completion of the reaction, 1.28 g (0.01 mol) of sodium sulfite was added to quench the reaction, followed by the addition of 100 g of toluene and raising the temperature of the reaction solution to 70 °C. The organic phase was removed by a liquid-liquid separation operation. To the aqueous phase obtained by separation 104.2 g (1.0 mol) of 35% hydrochloric acid was slowly added dropwise and stirred at room temperature for 1 hour. The precipitated solid product was collected by filtration and dried under reduced pressure to give 238.9 g (99.9% purity, 91.4% yield) of 2-bromo-4-methoxybenzoic acid.
