Teneligliptin Hydrobromide (2:5) is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is used to treat type 2 diabetes. It is eliminated via excretion, and has a half-life of 24.2 hours in the human body.
Clinical Use
Teneligliptin is a DPP-4 inhibitor which was approved in Japan in 2012 for the treatment of type II
diabetes. It was discovered and developed by Mitsubishi Tanabe Pharma under the trade name
Tenelia®. Similar to other marketed DPP-4 inhibitors, teneligliptin was well tolerated in all studies and
QD dosing produced a long-lasting inhibitory action against DPP-4 and an increase in active GLP-1
levels, with very low rates of renal excretion.
Synthesis
The only reported synthesis of teneligliptin is described in the scheme below. Reaction of commercially
available N-Boc-piperazine (158) with diketene (159) in DMF at room temperature gave acetoacetamide
160 in 86% yield, and this material was immediately condensed with phenylhydrazine in
methanesulfonic acid followed by a cyclodehydration with phosphorus oxychloride to give pyrazole 161
in 12% yield. The t-butyl carbamate was then removed with TFA in dichloromethane to give amine 162
in 88% yield. This amine was then subjected to butyrolactam 165 (which was prepared from N-Boctrans-
4-hydroxy-L-proline (163) coupled with thiazolidine (164) under conventional amide-forming
conditions using EDC) in the presence of sodium triacetoxy borohydride (STAB-H) in acetic acid.
This reductive amination reaction afforded the cis-aminopyrrolidine 166 exclusively in 50% yield.
Removal of the t-butyl carbamate group with TFA afforded the teneligliptin free amine in 93% yield,
and this freebase was then subsequently treated with 48% hydrobromic acid in refluxing ethanol to give
teleligliptin hydrobromide hydrate (XXV) in 90% yield.
