Process Study On The Synthesis Of 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]-tria-zolo-[4,3-a] Pyrazine Hydrochloride

3-Trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]-triazolo-[4,3-a] pyrazine hydrochloride was the main intermedia for the synthesis of the Sitagliptin phosphate. It was prepared in 32.6% yield over four chemical steps using 2-chloropyrazine by hydrazinolysis, acylation, cyclization and hydrogenation. The influences of reaction conditions such as materials'ratios, reaction time and temperature was described.The optimum condition for the synthesis of 2-hydrazinopyrazine was obtained as follows:the mole ratio of 2-chloropyrazine to hydrazine was 1:6.6, reaction 15h under 63℃-65℃, the yield was 76.3%; The optimum condition for the synthesis of (1,2)-Bis-trifluoroacetyl-1-pyrazinylhydrazide was obtained as follows:the mole ratio of 2-hydrazino-pyrazine to trifluoroacetic anhydride was 1:5, reaction 48h under about 0℃, the used solvent could be reused by three times, and the yield was 63.0%; The optimum condition for the synthesis of 3-trifluoromethyl-[1,2,4]-triazolo-[4,3-a] pyrazine was obtained as follows:the mole ratio of (1,2)-Bis-trifluoroacetyl-l-pyrazinylhydrazide to PPA was 1:1.5, reaction 7h under 85℃, the yield was 94.3%; The optimum condition for the synthesis of 3-trifluoro-methyl-5,6,7,8-tetrahydro-[1,2,4]-triazolo-[4,3-a] pyrazine was obtained as follows:the quality ratio of 3-trifluoromethyl-[1,2,4]-triazolo-[4,3-a] pyrazine to 10%Pd/C was 1:0.2, reaction 24h under 30℃, the yield was 90.0%; The yield of the preparation of 3-trifluoro-methyl-5,6,7,8-tetrahydro-[1,2,4]-triazolo-[4,3-a] pyrazine hydrochloride was 80.0%.