4-Bromo-5-fluoro-2-nitrotoluene

pale yellow powder

4-Bromo-5-fluoro-2-nitrotoluene can be used as a raw material to synthesis a kind of dihydropyridinone P2X7 receptor antagonists.^[6]

2-Fluoro-4-methyl-5-nitro-aniline (1.85 g, 10.90 mmol) was suspended in concentrated hydrobromic acid (22 ml_) and cooled to 0 ℃. Solution of sodium nitrite (0.83 g, 12.00 mmol) in water (3.6 ml_) was added dropwise while maintaining the temperature at 0-5 °C. After stirring for 15 min, the mixture was filtered through a cotton pad and slowly poured into a solution of cuprous oxide (2.60 g, 17.5 mmol) and concentrated hydrobromic acid (20 ml) at 0 °C. After stirring overnight, the reaction mixture was diluted with EtOAc, washed with 10 % aq NaOH and 5percent aq Na2S2Os successively, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate: hexane; 2:98) to afford 1-Bromo-2-fluoro-4- methyl-5-nitro-benzene as a colorless oil (2.30 g, 91 %).

[1] Patent: WO2003/99824,  2003,  A1. Location in patent: Page 32
[2] Patent: WO2003/99275,  2003,  A1. Location in patent: Page 65
[3] Bioorganic and Medicinal Chemistry Letters,  2006,  vol. 16,  # 2,  p. 457 - 460
[4] Patent: WO2015/54572,  2015,  A1. Location in patent: Page/Page column 247
[5] Patent: US2004/224973,  2004,  A1. Location in patent: Page 21
[6] Lopez-Tapia, F., Walker, K. A. M., Brotherton-Pleiss, C., Caroon, J., Nitzan, D., Lowrie, L., Gleason, S., Zhao, S.-H., Berger, J., Cockayne, D., Phippard, D., Suttmann, R., Fitch, W. L., Bourdet, D., Rege, P., Huang, X., Broadbent, S., Dvorak, C., Zhu, J., … Alker, A. (2015). Novel Series of Dihydropyridinone P2X7 Receptor Antagonists. Journal of Medicinal Chemistry, 58 21, 8413–8426. https://doi.org/10.1021/acs.jmedchem.5b00365