Synthesis Of Trelagliptin Succinate And The Related Substances

Trelagliptin succinate,the first approved long-acting dipeptidyl peptidase-4 inhibitor,is a novel hypoglycemic agent for type 2 diabetes mellitus.In phase ? clinical studies,once-weekly oral trelagliptin was proved to be noninferior to its analogue alogliptin used once daily,and the safty of trelagliptin was higher.The improved synthesis of trelagliptin succinate based on the original company route was reported in this paper,the bromination of 4-fluoro-2-methylbenzonitrile gave benzyl bromide 5 and dibromide 5',5' was then converted into 5 in the presence of diethyl phosphite.Then 5 reacted with 3-methyl-6-chlorouracil gave the key intermediate 6,which was substituted by(R)-3-aminopiperdine to give trelagliptin.Trelagliptin succinate was formed by mixing crude trelagliptin and succinic acid directly and then recrystallized in a mixture of isopropyl alcohol and water with a total yield of 61%,based on 4-fluoro-2-methylbenzonitrile.The purity(above 99.9%)of the product was measured by HPLC,without detection of the enantiomer.Before the synthesis of trelagliptin,the possible related substances A~G were prepared,and HPLC methods that can efficiently separate trelagliptin and related substaces were established,which were used for screening reaction condition.The screening outcomes indicated that alcohol,especially with high steric hindrance,is a better solvent than aprotic solvent for this reaction,and sodium bicarbonate as a base was better than potassium carbonate or diisopropylethylamine.The best condition for this reaction is isopropyl alcohol as solvent and sodium bicarbonate as a base.Since the crude trelagliptin synthesized by the optimized method had a purity of more than 94%,it was mixed with succinic acid directly,eliminating the purification via the hydrochloride salt in the literature.In the conversion of 5' into 5,the feed ratio of diethyl phosphate and diisopropylethylamine was decreased to 1/4 and 1/5,respectively,compared with the literature.Besides,seven kinds of organic solvents were used in the original company patent,including class one solvent 1,2-dichloroethane.In our study,1,2-dichloroethane was removed and only three kinds of solvent were utilized: dichloromethane,tetrahydrofuran and isopropyl alcohol.Ten related substances of trelagliptin succinate were synthesized and two have not been found in literatures.All these related substances were confirmed by 1H-NMR and MS,and the HPLC methods that can efficiently separate them from trelagliptin was established.