135748-35-5

508203-26-7

135748-35-5

The general procedure for the synthesis of 4-chloro-2,5-difluorobenzonitrile from 4-chloro-2,5-difluorobenzamide was as follows: a mixture of 4-bromo-2,5-difluorobenzoic acid (11a, 53.28 g), thionyl chloride (165 mL), and N,N-dimethylformamide (DMF, 0.87 mL) was stirred for 1.5 hr at 80 °C, and subsequently cooled to room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in chloroform (300 mL). To this solution, 28 wt% ammonia (300 mL) was slowly added dropwise at 5 °C and stirred for 0.5 h at the same temperature. After completion of the reaction, the mixture was extracted with chloroform, the organic layers were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure to give a pale yellow solid. The solid was mixed with phosphoryl chloride (195 mL) and stirred at 80 °C for 2 h. After completion of the reaction it was cooled to room temperature. The reaction mixture was concentrated under reduced pressure and the residue was treated with ether (500 mL) and ice water (300 mL) followed by stirring for 0.5 h at room temperature. The mixture was extracted with ether and the organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine, then dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure to afford the target product 4-chloro-2,5-difluorobenzonitrile (9h, 41.57 g, 85% yield) as a light yellow solid.