Synthesis
To a round bottom flask was added 4-bromo-3,5-dimethoxybenzoic acid (Compound 8, 4 g, 15.3 mmol) and anhydrous methanol (100 mL). The reaction mixture was cooled to 0 °C and thionyl chloride (11.1 mL, 153 mmol) was added slowly and dropwise with stirring. After the dropwise addition was completed, the reaction system was heated to 80 °C and the reaction was stirred at this temperature for 2 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate (100 mL) and the organic layer was washed sequentially with water (50 mL x 2) and saturated saline (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford methyl 4-bromo-3,5-dimethoxybenzoate as a white crystalline solid (Compound 12, 4.24 g, quantitative yield).Results of LC-MS analysis: retention time (TR) = 2.3 min; [M+H]+ = 274.9, 277.0 (bromine isotope peak).
References
[1] Chemistry - A European Journal, 2013, vol. 19, # 15, p. 4786 - 4797
[2] Patent: WO2018/85552, 2018, A1. Location in patent: Page/Page column 59
[3] European Journal of Medicinal Chemistry, 2016, vol. 107, p. 255 - 274
[4] RSC Advances, 2016, vol. 6, # 2, p. 947 - 952
