2-Amino-6-bromobenzoic acid serves as a precursor to 5-bromo-2H-3,1-benzoxazine-2,4(1H)-dione (6-bromoisatoic anhydride), formed by treatment with sodium hydroxide and phosgene at 0 °C[1]. The compound condenses with 2-fluorobenzaldehyde to give 5-bromo-2-(2-fluorophenyl)-1,2-dihydro-4H-benzo[d][1,3]oxazin-4-one in 88% yield, and with methylamine in the presence of EDCI and HOBt to afford an amide intermediate that undergoes self-condensation en route to anthranilic diamide analogues. Its hydrochloride is reacted with N,O-dimethylhydroxylamine hydrochloride in DMF under nitrogen to synthesize 2-amino-X-bromo-N-methoxy-N-methylbenzamides[2].
General procedure for the synthesis of 2-amino-6-bromobenzoic acid from 4-bromoindoline-2,3-dione: Commercially available 4-bromoindigo (2.50 g, 11.1 mmol) was dissolved in 1.5 mol/L aqueous sodium hydroxide solution (20 mL), and 33% aqueous hydrogen peroxide solution (1 mL) was added slowly and dropwise at 55 °C. The reaction mixture was stirred continuously at 55 °C for 30 min and then cooled to room temperature. Subsequently, the reaction solution was neutralized with 2.0 mol/L hydrochloric acid solution and finally purified by HP-20 resin column to obtain the target product 2-amino-6-bromobenzoic acid (1.60 g, 67% yield).
[1] Patent: EP2708540, 2014, A1. Location in patent: Paragraph 0092
[2] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1958, vol. 148, p. 481,488
[3] Patent: WO2011/28741, 2011, A1. Location in patent: Page/Page column 202
[4] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 9, p. 831 - 834
[1] McPhee, M. E., Katsifis, A. G., Mattner, F., & Ridley, D. D. (2000). Synthesis of 123 I-Labelled Analogues of Imidazobenzodiazepine Receptor Ligands. Australian Journal of Chemistry, 52(11), 1061–1070. https://doi.org/10.1071/ch99135
[2] Ligon, E. S., Nawyn, J., Jones, L. V., Allred, B. M., Reinhardt, D. V., & France, S. (2019). Synthesis of Flubromazepam Positional Isomers for Forensic Analysis. The Journal of Organic Chemistry, 84(16), 10280–10291. https://doi.org/10.1021/acs.joc.9b01433
