Synthesis Of(2S,4S)-Tert-Butyl-2-Cyano-4-Fluoropyrrolidine-1-Carboxylate And The 4-Epimer

In recent years,the incident of diabetes has increased annually with the changes of lifestyle and the improvement of life-quality.According to the estimation of international Diabetes Federation,the total number of people with diabetes has extremely reached to 415 million worldwide.Diabetes has became one of the chronic noninfectious diseases which seriously threaten the health of human.Dipeptidyl peptidase-Ⅳ(DPP-Ⅳ),which has high potential to be a decent is a new target for the treatment of diabetes.Therefore,it has gained increasing attention in developing selectⅣe and sensitⅣe DPP-Ⅳ inhibitors in curing of diabetes.(2S,4S)-tert-butyl-2-cyano-4-fluoropyrrolidine-1-carboxylate is the key intermediate of DPP-Ⅳ inhibitors which contain the structural fragments of 4-fluoropyrrolidine.In the present article,(2S,4S)-tert-butyl-2-cyano-4-fluoropyrrolidine-1-carboxylate was synthesized by starting from(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid and undergoing esterification,Boc-protection,hydroxy activating with trifluoromethanesulfonic anhydride,substitution by tetrabutylammonium bifluoride,hydrolysis of sodium hydroxide,and then reaction with ammonium hydroxide to the amide,finally dehydration to the nitrile group.The product was characterized by 1H NMR and 13C NMR.This technology has great benefit in the simple operation and industrial production with the overall yield of 40.2%.In order to demonstrate that the fluorination step is a stereoselective reaction,the 4-epimer(2S,4R)-2-cyano-4-fluoropyrrolidine-1-carboxylate was synthesized and characterized by 1H NMR and 13C NMR.