Synthesis
General procedure for the synthesis of 2-bromo-6-methyl-4-nitroaniline from 4-nitro-2-methylaniline: 2-methyl-4-nitroaniline (2.0 g, 13.2 mmol) was dissolved in acetonitrile (40 mL) at 60 °C, followed by the addition of N-bromosuccinimide (2.8 g, 15.8 mmol). The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The reaction mixture was concentrated and diluted with dichloromethane (50 mL). The organic phase was washed sequentially with 2.5 M sodium hydroxide solution and saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate, 4/1, v/v) to afford 2-bromo-6-methyl-4-nitroaniline as a yellow solid (2.75 g, 91% yield). Melting point: 178-179°C. Thin layer chromatography Rf value: 0.40 (unfolding agent: n-hexane/ethyl acetate, 5/1, v/v).1H NMR (DMSO-d6, 400MHz) δ 8.15 (d, J=2.5Hz, 1H), 7.93 (d, J=2.1Hz, 1H), 6.53 (s, 2H), 2.23 (s, 3H). Mass spectrum (ESI) m/z: 228.5 [M-H]-.
References
[1] Patent: WO2016/176460, 2016, A1. Location in patent: Page/Page column 97
[2] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 2, p. 597 - 599
[3] European Journal of Medicinal Chemistry, 2017, vol. 131, p. 1 - 13
[4] Journal of the Chemical Society, 1929, p. 1255
[5] Bulletin de la Societe Chimique de France, 1924, vol. <4>35, p. 1328
