The general procedure for the synthesis of 5-methoxybenzofuran-2-carboxylic acid from ethyl 5-methoxybenzofuran-2-carboxylate is as follows:
1. 2-Hydroxy-5-methoxybenzaldehyde (3.0 g, 20 mmol) and anhydrous K2CO3 (3.3 g, 23.4 mmol) were dissolved in DMF (50 ml) under the cooling condition in an ice bath, and ethyl bromoacetate (3.3 g, 20 mmol) was added slowly dropwise. After the dropwise addition was completed, the reaction was stirred at 0 °C for 30 min, and then transferred to a 60 °C oil bath and stirred for 12 hours.
2. The reaction solution was poured into ice water and the solid was collected by filtration. The solid was dissolved in chloroform, dried with anhydrous Na2SO4, filtered and purified by silica gel column chromatography, and the solvent was removed by rotary evaporation to give 3.24 g of yellow solid (75% yield).
3. The above product was dissolved in dioxane (30 ml), 1N sodium hydroxide solution (15 ml) was added and stirred at room temperature for 2 hours. The dioxane was removed by evaporation and the residue was poured into ice water, washed sequentially with diethyl ether and dichloromethane and the pH was adjusted to 2. The solid was collected by filtration to give 2.68 g of product (92% yield).
4. The resulting solid was dissolved in methylene dioxane (50 ml), DIC (1.51 g, 11.98 mmol) was added, and after stirring at room temperature for 1 h, DMAP (0.24 g, 1.96 mmol) and dimethyl hydroxyethyl phosphonate (1.84 g, 10.95 mmol) were added. After heating and refluxing for 6 hours, the reaction solution was washed by adding water and saturated brine, dried with anhydrous magnesium sulfate, filtered and evaporated to dryness, and recrystallized by an ethyl acetate-petroleum ether system to give (dimethoxyphosphono)ethyl 5-methoxybenzofuran-2-carboxylate 3.67 g (77% yield).
5. The above ester was dissolved in dichloromethane (50 ml), trimethylmethylsilyl bromide (9.85 g, 64.8 mmol) was added, and stirred at room temperature for 3 hours. After completion of the reaction, the reaction was quenched with methanol and the solvent was removed by evaporation to give a final ethyl phosphine 5-methoxybenzofuran-2-carboxylate 2.38 g (74% yield).
