[Synthesis]
The general procedure for the synthesis of 1-bromo-5-fluoro-4-methoxy-2-nitrobenzene from 5-fluoro-4-methoxy-2-nitroaniline was as follows: 5-fluoro-4-methoxy-2-nitroaniline (4.1 g) was dissolved in a mixed solvent of water (20 ml) and 1,4-dioxane (10 ml), and 48% hydrobromic acid (12 ml) was added. The above solution was heated and refluxed for 15 minutes under reflux conditions. Subsequently, the reaction mixture was cooled to 0°C, aqueous sodium nitrite solution was slowly added dropwise and stirred at 0°C for 15 minutes. The resulting diazonium salt solution was added dropwise to a mixed solution of copper (I) bromide (3.6 g) dissolved in water (20 ml) and 48% hydrobromic acid (12 ml) while maintaining 0 °C. The reaction mixture was warmed to 60°C and stirred for 15 minutes, then cooled to room temperature and stirring was continued for 1 hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, the organic phase was washed sequentially with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate/hexane=1:8) to afford the target product 1-bromo-5-fluoro-4-methoxy-2-nitrobenzene crystals (5 g, 91% yield).1H-NMR (300 MHz, CDCl3) δ (ppm): 3.96 (3H, s), 7.40 (1H, d, J=9.9 Hz), 7.58 ( 1H, d, J=8.1Hz). |