Synthesis
General procedure for the synthesis of methyl 5-bromosalicylate from methanol and 5-bromosalicylic acid:
Step a) Synthesis of methyl 5-bromosalicylate: thionyl chloride (440 g, 3.7 mol) was slowly added to a solution of toluene (2 L) containing 5-bromosalicylic acid (200 g, 0.92 mol) at 0 °C and the reaction was stirred. The reaction mixture was then heated to 70 °C and refluxed for 40 hours. Upon completion of the reaction, the excess solvent was removed by distillation. Ethyl acetate (2 L) was added to the crude product for dissolution, and the organic layer was washed sequentially with 10% cold aqueous sodium bicarbonate (2 x 1 L) and brine, and then dried. Finally, the solvent was removed by vacuum to afford methyl 5-bromosalicylate as a low melting point solid (190 g, 89% yield).
TLC conditions: petroleum ether/ethyl acetate (7:3), Rf value: 0.6.
References
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2621 - 2625
[2] Journal of Materials Chemistry, 1996, vol. 6, # 8, p. 1297 - 1307
[3] Organic Letters, 2014, vol. 16, # 19, p. 5140 - 5143
[4] Patent: WO2005/12280, 2005, A1. Location in patent: Page/Page column 46-47
[5] Patent: WO2005/11685, 2005, A1. Location in patent: Page/Page column 41
