4,4'-Difluorobenzhydrylpiperazine

110-85-0

27064-94-4

27469-60-9

GENERAL METHODS: NaBH4 (0.6 mol) was added batchwise to a stirred solution of benzophenone (1.0 mol) in methanol (2 vol) for 45 min at room temperature. The reaction mixture was stirred at ambient temperature for 2-3 h (the progress of the reaction was monitored by TLC), followed by dilution with water (750 mL) and adjusting the pH with acetic acid to 4. Extraction was carried out with dichloromethane (2 x 400 mL), the organic layer was washed with water (200 mL), dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to afford the pure benzophenol derivative as a white to off-white solid The yield was 93-97%. To a solution of diphenylmethanol derivative (1.0 mol) in toluene (370 mL) at room temperature, concentrated HCl (35% aqueous solution, 370 mL) and tetrabutylammonium bromide (0.01 mol) were added while stirring. The mixture was stirred continuously at 40-45 °C for 6-7 hours. After completion of the reaction (confirmed by TLC), it was cooled to room temperature. The organic layer was separated and concentrated under vacuum to give the crude diphenylmethyl chloride derivative as a light brown liquid in 95-97% yield. To a solution of diphenylmethyl chloride derivative (0.96 mol) in toluene (380 mL) at 60-70°C, anhydrous piperazine (5.0 mol) was slowly added over 45-60 minutes. The resulting mixture was heated at 90-100°C for 8-10 hours with stirring. After completion of the reaction, the mixture was cooled, water (380 mL) was added and the organic layer was separated. The organic layer was washed with a mixture of concentrated HCl and water (1:1, 2 x 350 mL) and neutralized with 20% NaOH solution (750 mL). The aqueous layer was again extracted with toluene (2 × 300 mL), and the organic layer was dried with anhydrous sodium sulfate and concentrated in vacuum to give pure 1-(bis(p-fluorophenyl)methyl)piperazine as a white to off-white solid in 88% yield.