3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride

3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride is a pharmaceutical intermediate compound used in the preparation of Sitagliptin phosphate. Sitagliptin is an oral hypoglycaemic agent, a dipeptidyl peptidase-4 inhibitor, which is used in the treatment of type 2 diabetes.

White Solid or White to Light yellow powder to crystal

Sitagliptin intermediate.

A suspension of N'-[(2Z)-Piperazin-2-ylidene]trifluoroacetohydrazide (27.3 g, 0.13 mol) in 110 mL of methanol was WARMED TO 55 ℃. 37% Hydrochloric acid (11.2 mL, 0.14 mol) was added over 15 min at this temperature. During the addition, all solids dissolved, resulting in a clear solution. The reaction was aged for 30 min. The solution was cooled to 20 ℃ and aged at this temperature until a seed bed formed (10 min to 1 h). 300 ML of MTBE was charged at 20 ℃ over 1 h. The resulting slurry was cooled to 2 ℃, aged for 30 min and filtered. Solids were washed with 50 mL of ethanol: MTBE (1: 3) and dried under vacuum at 45 ℃. Yield of 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride was 26.7 g (99.5 area wt% pure by HPLC).