Synthesis
Step 1: To a mixed solution of 4-bromo-2-methylbenzoic acid (15.1 g, 0.070 mol) in tetrahydrofuran (180 mL) and methanol (45 mL) was slowly added dropwise (trimethylsilyl) diazomethane in 2.0 M hexane solution (42 mL, 0.084 mol) at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred continuously for 1 hour. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure to afford methyl 4-bromo-2-methylbenzoate (16 g, 100% yield) as a yellow oil. The crude product could be used in the subsequent reaction without further purification. The product was characterized as follows: 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 1H), 7.42 (s, 1H), 7.38 (d, 1H), 3.88 (s, 3H), 2.58 (s, 3H). Mass spectrum (EI): m/z 230 ([M+H]+, C9H9BrO2).
References
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 999 - 1004
[2] Patent: WO2009/55077, 2009, A1. Location in patent: Page/Page column 430
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2334 - 2356
[4] Patent: US2009/69370, 2009, A1. Location in patent: Page/Page column 17-18
[5] Patent: WO2009/158369, 2009, A1. Location in patent: Page/Page column 38; 39
