The general procedure for the synthesis of methyl 3-(benzyloxy)-5-hydroxybenzoate from methyl 3,5-dihydroxybenzoate and benzyl bromide is as follows:
1. potassium carbonate (9 mol) was added to a stirring solution of methyl 3,5-dihydroxybenzoate (5.95 mol) in DMF (6 L) under argon protection to form a suspension.
2. benzyl bromide (8.42 mol) was slowly added to the suspension over a period of 1 h. The reaction was slightly exothermic.
3. The reaction mixture was stirred at room temperature overnight.
4. Upon completion of the reaction, the reaction was carefully quenched with ammonium chloride solution (5 L) followed by addition of water (35 L) for further quenching.
5. The aqueous phase was extracted with dichloromethane (DCM, 1 x 3 L and 2 x 5 L).
6. The organic phases were combined, washed with water (10 L) and dried with anhydrous magnesium sulfate overnight.
7. The solvent was removed by vacuum evaporation to give the crude product.
8. the crude product is purified by column chromatography in batches (fast column, 3 x 2 kg silica gel, elution gradient of 10% to 100% DCM in isohexane solution followed by gradient elution with 50% ethyl acetate in DCM solution) to remove unreacted feedstock.
9. The crude product was further purified by high performance liquid chromatography (HPLC) (Amicon HPLC, 5 kg normal phase silica gel, elution with 20% ethyl acetate in isohexane solution) to afford the target compound in 21% yield.
10. The structure of the product was confirmed by 1H NMR (d6-DMSO): δ 3.8 (s, 3H), 5.1 (s, 2H), 6.65 (m, 1H), 7.0 (m, 1H), 7.05 (m, 1H), 7.3-7.5 (m, 5H), 9.85 (br s, 1H).
