The general procedure for the synthesis of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride from (2,4-difluorophenyl)-(4-piperidinyl)methanone oxime hydrochloride was as follows: potassium hydroxide (27 g) was dissolved in 600 mL of methanol, followed by addition of (2,4-difluorophenyl)-(4-piperidinyl)methanone oxime hydrochloride (55 g). The reaction mixture was heated to reflux for about 2.5 hours. After completion of the reaction, it was cooled to room temperature, dried by adding an appropriate amount of anhydrous magnesium sulfate and stirred for about 1 hour. The filtrate was concentrated under reduced pressure to remove the solvent. To the concentrate was added 500mL of acetone, stirred at room temperature for about 0.5 hours, and filtered to remove insoluble material. Hydrochloric acid was slowly added to the filtrate and the pH was adjusted to 23, precipitating a white solid. The solid was collected by filtration and dried to give 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (35 g) with 0.4% methanol.
