General procedure for the synthesis of 4-bromo-2,5-difluoronitrobenzene from 2,5-difluorobromobenzene: Referring to Example-50, a mixture of acids was prepared by cooling concentrated sulfuric acid (57 mL) in an ice bath, followed by the slow dropwise addition of 69% nitric acid (25.5 g, 279 mmol) over a period of 25 minutes. A dichloroethane (125 mL) solution of 2-bromo-1,4-difluorobenzene (50 g, 254 mmol) was added slowly dropwise over 1.5 h to the above mixed acid under ice bath cooling conditions. After the dropwise addition, the reaction mixture was continued to be stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction solution was slowly poured into ice water (500 g) and extracted with ether (300 mL x 2). The organic phases were combined and washed sequentially with water (300 mL), saturated aqueous sodium bicarbonate solution (300 mL) and saturated saline (300 mL). The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. The resulting crude product was purified by silica gel column chromatography (eluent: hexane/chloroform=4:1) to afford 1-bromo-2,5-difluoro-4-nitrobenzene (56 g, yield: 93%) as a pale yellow solid.1H-NMR (400 MHz, CDCl3): δ 7.59 (dd, J=9.5 and 5.5 Hz, 1H), 7.89 (dd, J=7.3 and 6.5 Hz, 1H).19F-NMR (376 MHz, CDCl3): δ -120.1 (d, J=15.2 Hz, 1F), -107.9 (d, J=15.2 Hz, 1F).
