83190-02-7

888327-32-0

General procedure for the synthesis of 5-bromo-2-(difluoromethoxy)toluene from 4-(difluoromethoxy)-3-methylaniline: to a stirred solution of 4-amino-1-(difluoromethoxy)-2-methylbenzene (5 g, 28.90 mmol) in a mixture of hydrobromic acid (20 mL) and water (20 mL), at 0 °C, sodium nitrite (2.07 g 30.00 mmol) in aqueous solution (10 mL), and the titration process was controlled to be completed within 20 minutes. After the dropwise addition, the reaction mixture was continued to be stirred at 0 °C for 30 min. Subsequently, copper (I) bromide (4 g, 27.87 mmol) was added and the mixture was heated to 60 °C for 30 min of reaction. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate (3 x 50 mL), the organic layers were combined, washed once with water (10 mL), dried over anhydrous sodium sulfate and concentrated to give 2.5 g of 4-bromo-1-(difluoromethoxy)-2-methylbenzene in 37% yield.