359424-44-5

359424-42-3

359424-44-5

Step B. Synthesis of 3-(3,5-difluorophenyl)-5-chloroisoxazole Ethyl 3,5-difluorobenzoylacetate (1.87 g, 8.19 mmol) and hydroxylamine hydrochloride (626 mg, 9.01 mmol) were dissolved in acetic acid (24 mL) and stirred at reflux for 1 hour. Upon completion of the reaction, the crude reaction mixture was concentrated under vacuum and azeotropized with toluene twice to remove residual water. Subsequently, the crude product was suspended in phosphoryl chloride (37 mL) and triethylamine (2.37 mL, 17.1 mmol) was slowly added. The reaction mixture was stirred at reflux for 2 days, after which it was concentrated under vacuum and azeotropized with toluene three times to completely remove the phosphoryl chloride. The residue was dissolved in dichloromethane and initially purified by passing through a silica gel column (eluting with dichloromethane). After vacuum concentration, the crude product was further purified by fast chromatography (silica gel, dry on sample, eluent 5% hexane solution of ether) to give 3-(3,5-difluorophenyl)-5-chloroisoxazole (600 mg, 35% yield) as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ 7.34-7.24 (m, 2H); 6.98-6.88 (m, 1H); 6.46 (s, 1H).