General procedure for the synthesis of 1-(2-amino-3-chloro-4-methoxyphenyl)ethanone from acetonitrile:
Step A: A dichloromethane solution of boron trichloride (1.0 M, 138 mL, 138 mmol) was slowly added to a solution of 2-chloro-3-methoxyaniline (20.6 g, 131 mmol) in xylene (225 mL) under nitrogen protection. The temperature was monitored during the addition to ensure that the temperature remained below 10°C. The reaction mixture was stirred at 5 °C for 0.5 hours. Subsequently, anhydrous acetonitrile (9.0 mL, 170 mmol) was added at 5 °C. After 0.5 h, the solution was transferred to a dropping funnel and slowly added to a pre-prepared suspension of aluminum trichloride (18.4 g, 138 mmol) in dichloromethane (80 mL). After reacting at 5°C for 45 min, the reaction mixture was heated to 70°C under a stream of nitrogen. After the dichloromethane evaporated, the temperature of the reaction mixture was raised to 65°C and the reaction was kept at this temperature for 12 hours. After completion of the reaction, the mixture was cooled to 0°C, poured into ice (200 g) and slowly heated to reflux for 7 hours. After standing at room temperature for 2 days, 6N sodium hydroxide solution (25 mL) and dichloromethane (100 mL) were added. The mixture was filtered and the filtrate was washed with dichloromethane. The organic layer was separated and washed sequentially with water, 1N sodium hydroxide solution and brine, dried over anhydrous sodium sulfate and the solvent evaporated. The residue was ground with diisopropyl ether at 0 °C, filtered and washed with diisopropyl ether to give 19.0 g (73% yield) of the target product 1-(2-amino-3-chloro-4-methoxyphenyl)ethanone (50) as a white solid with a mass spectrum showing m/z = 200 (M + H)+.
