Synthesis
General procedure for the synthesis of methyl 5-bromo-2-hydroxyphenylacetate from methanol and o-hydroxyphenylacetic acid: 2-(2-hydroxyphenyl)acetic acid (484 g, 3.18 mol) was dissolved in methanol to which tetrabutylammonium tribromide (1549 g, 3.18 mol) was subsequently added. The reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was removed by vacuum evaporation and the residue obtained was dissolved in ethyl acetate (EtOAc). The organic phase was washed sequentially with 1N hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by fast column chromatography on silica gel with the eluent of petroleum ether/ethyl acetate (10:1, v/v) to afford pure methyl 5-bromo-2-hydroxyphenylacetate (750 g, 94% yield). The structure of the product was confirmed by 1H NMR (400 MHz, CDCl3): δ 7.48 (br s, 1H), 7.20-7.25 (m, 2H), 6.75-6.78 (m, 1H), 3.74 (s, 3H), 3.62 (s, 2H). Mass spectrometry analysis showed a molecular ion peak (M + H)+ of 245.
References
[1] Patent: WO2011/106986, 2011, A1. Location in patent: Page/Page column 38; 39
[2] Patent: WO2011/106929, 2011, A1. Location in patent: Page/Page column 79
[3] ChemMedChem, 2017, vol. 12, # 17, p. 1436 - 1448
[4] Journal of Medicinal Chemistry, 1999, vol. 42, # 1, p. 164 - 172
[5] Patent: WO2013/134562, 2013, A1. Location in patent: Paragraph 00109
