Research On The Synthesis Of Melogliptin

In recent years, with the changes of lifestyles and the improvement of life-quality, the incidence of diabetes has increased annually, more attention has drove to the study of diabetes drugs. Dipeptidyl peptidase-4(DPP-4) inhibitors for the treatment of type 2diabetes has approved to have good effects, Melogliptin is a medicine on clinical trial now, it demonstrated potential to the best-in-class in achieving glycemic control with low incidence of hypoglycemia and neutral effect on body weight.Considering the feasibility in the industrialized production enlargement, the use of expensive reagents and long steps of route in the reported literature could be improved.Through contrastive analysis of the synthesis route of the existing literature, the present study determined to synthesis from(±)-2- aza bicyclo [2,2,1] hept-5-ene-3-one(2),which followed by amino protection, reduction, mesylation and coupled with 1,2,4-triazole to give the cis-3- [(1H-1,2,4- triazol-1-yl) methyl] cyclopentyl-amine(8), and resolute with tosyl- D-phenylglycine, then condension with(2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2- carbonitrile(11) to afford the final product Meloglipin.Effect of reactant ratio, reaction temperature and time on all the reactions was examined in the optimization of each step. Split conditions and resolving agents were mainly investigated in the present study. The improved technological operation needs mild condition, which is easy to operate in high yield of 13 %.Additionally, the target compound and its intermediates were confirmed by IR、1H NMR and 13 C NMR.