The general procedure for the synthesis of tert-butyl 4-cyano-4-(2-fluoro-4-methylphenyl)piperidine-1-carboxylate from 2-fluoro-4-methylphenylacetonitrile and tert-butyl N,N-bis(2-chloroethyl)carbamate is as follows:
A: In a 1L round-bottomed flask assembled with a mechanical overhead stirrer, sodium hydride (11.70 g, 293 mmol) and DMSO (200 mL) were added to form a suspension. Subsequently, 2-fluoro-4-methylphenylacetonitrile (11.49 g, 77 mmol) was gradually added to the above suspension. The reaction mixture was stirred for about 5 hours and then cooled in an ice bath. Next, tert-butyl N,N-bis(2-chloroethyl)carbamate (20.38 g, 84 mmol) dissolved in 30 mL of DMSO was slowly added. The resulting mixture was gradually warmed to ambient temperature and stirred overnight. Upon completion of the reaction, water was slowly added and the organic phase was extracted with dichloromethane (3 x 300 mL). The combined dichloromethane extracts were washed with water (2 x 400 mL), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on 330 g silica gel, using a dichloromethane solution of 70-100% hexane as eluent. The final target product, tert-butyl 4-cyano-4-(2-fluoro-4-methylphenyl)piperidine-1-carboxylate, was obtained as a yellow oil (8.2 g, 33% yield). Mass spectrum (electrospray ionization) m/e 219.1 [M + H]+.
