Step-1: Synthesis of tert-butyl 4-cyano-4-(4-fluorobenzyl)-piperidine-1-carboxylate
Diisopropylamine (3.2 mL, 22.8 mmol) and anhydrous THF (30 mL) were added to a dry three-necked flask under nitrogen protection and cooled to 0 °C. The solution of n-butyllithium was added to the flask. A hexane solution of n-butyllithium (1.6 M, 15.8 mL, 26.6 mmol) was slowly added dropwise, keeping the reaction temperature below 0 °C. The reaction was then cooled to 0 °C and the reaction temperature was reduced to 0 °C. After the dropwise addition was completed, the reaction mixture was brought to room temperature and stirred for 1 hour to form a lithium diisopropylamino (LDA) solution. Subsequently, the reaction mixture was cooled to -78 °C.
In another dry vessel, N-Boc-4-cyanopiperidine (4.0 g, 19 mmol) was dissolved in anhydrous THF (20 mL) and slowly added dropwise at -78 °C to the above LDA solution. After the dropwise addition, the reaction mixture was slowly warmed up to -40 °C and kept at this temperature for 1 hour.
The reaction mixture was again cooled to -78°C and a THF solution of 4-fluorobenzyl bromide (pre-prepared) was added slowly dropwise. After the dropwise addition was completed, stirring was continued at -78°C for 4 hours. After completion of the reaction, the reaction mixture was raised to 0 °C and the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL).
The reaction mixture was extracted with ethyl acetate (3 × 30 mL) and the organic layers were combined. The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was recrystallized from hexane to give tert-butyl 4-cyano-4-(4-fluorobenzyl)-piperidine-1-carboxylate (3.0 g, 50% yield) as a white solid.
LC/MS (ESI): m/z [M + H]+ calculated value 319.4, measured value 319.4.
