4-Bromo-3-methylbenzoic acid

4-Bromo-3-methylbenzoic acid serves as a precursor for synthesizing derivatives of 1-isopropyl-3-acyl-5-methyl-benzimidazol-one, which exhibit antifungal activity against B. cinerea [4]. The compound undergoes esterification when refluxed with methanol and concentrated sulfuric acid [5].

A suspension of 4-Amino-3-methylbenzoic acid (73 g, 0.483 mol) in water (411 mL) and 47percent HBr (486 mL) was stirred at 25 ℃ for 1 h and then the reaction mixture was cooled to -2 ℃. A solution of sodium nitrate (32 g, 0.463 mol) in water (100 mL) was added to the reaction mixture over 15 min, maintaining the temperature at -1 ℃ to -2°C. The reaction mixture was stirred at -1 ℃ to -2 ℃ for 1.5h. The reaction mixture was added slowly to a suspension of copper(l)bromide (73 g, 0.508 mol) in water (73 mL) and aqueous HBr (73 mL). The reaction mixture was stirred at 250C for 1 h and then digested at 70 °C for 1 h. The solid was filtered, washed with water till the pH of the filtrate was 7 and dried to obtain 4-Bromo-3-methylbenzoic acid.

[1] Patent: WO2006/51477,  2006,  A2. Location in patent: Page/Page column 54
[2] American Chemical Journal,  1881,  vol. 3,  p. 431
[3] Patent: US5409928,  1995,  A
[4] Xu, N., Yang, C., Gan, X., Wei, S., Ji, Z. (2013). Synthesis of 1-isopropyl-3-acyl-5-methyl-benzimidazolone Derivatives and Their Antimicrobial Activity. International Journal of Molecular Sciences, 14(4), 6790–6804. https://doi.org/10.3390/ijms14046790
[5] Yordanov, A., Garmestani, K., Zhang, M., Zhang, Z., Yao, Z., Phillips, K., Herring, B., Horak, E., Beitzel, M., Schwarz, U., Gansow, O., Plascjak, P., Eckelman, W., Waldmann, T., Brechbiel, M. (2001). Preparation and in vivo evaluation of linkers for 211 At labeling of humanized anti-Tac. Nuclear Medicine and Biology, 28(7), 845–856. https://doi.org/10.1016/s0969-8051(01)00257-8