The general procedure for the synthesis of 2-bromo-5-hydroxy-4-methoxybenzoic acid (B13) from 2-bromo-5-hydroxy-4-methoxybenzaldehyde (B2) is as follows:
1. 1 kg of 2-bromo-5-hydroxy-4-methoxybenzaldehyde (B2) and 1.255 kg of sulfamic acid were added to a solvent mixture containing 4.473 kg of EtOAc and 8 L of water under stirring conditions. Stirring was continued until all solids were completely dissolved.
2. Cool the reaction mixture to -10 to 0 °C.
3. In a separate vessel, an aqueous sodium chlorite solution was prepared by dissolving 505 g of sodium chlorite in 3 L of water.
4. Slowly add the sodium chlorite solution dropwise to the pre-cooled B2 solution while keeping the reaction temperature below 5 °C.
5. After the dropwise addition was completed, the reaction mixture was continued to be stirred at 0 °C for 1 hour, followed by natural warming to room temperature.
6. The reaction was monitored by thin layer chromatography (TLC).
7. After completion of the reaction, the aqueous layer was separated. The aqueous layer was extracted with 1.789 kg EtOAc, the organic phases were combined and transferred to another flask.
8. EtOAc was removed by vacuum distillation at 40 °C. 9.
9. 6.92 kg of toluene was added at 30 to 40 °C, the slurry was cooled to -10 to 0 °C, and the precipitate was collected by filtration to give about 950 g (89% yield) of 2-bromo-5-hydroxy-4-methoxybenzoic acid (B13).
Product characterization: 1H NMR (CDCl3) δ 3.95 (3H, s, OCH3), 7.22 (1H, s, Ar-H), 7.46 (1H, s, Ar-H).
