Synthesis Of [1,2,4] Triazolo [4,3-a] Pyrazine And 2-substituted [1,2,4] -triazolo [1,5-c] Pyrimidine Derivatives

As the most outstanding representatives, triazoles and triazolo pyrazines, triazolo piperazines, pyrazolo pyrimidines, triazolo pyrimidines have gained ever increasing synthetic incentive, due to their unique biochemical properties. These compounds have been used in medicine, food, agricultural and technical field, the synthetic methods of which are always an important topic in organic chemistry.The present thesis covers two kinds of work.1. Describe a convenient and efficient way for preparation of [1,2,4]triazolo[4,3-a]pyrazine and their derivatives. Starting materials, synthetic conditions were modified to meet the industrial need.2. A convenient and efficient synthetic method for preparation of novel 2-substituted-[1,2,4]triazolo[1,5-c]pyrimidine and its derivatives has been developed.In the first part, the synthesis of 3-trifluoromethyl-tetrahydro-[1,2,4]triazolo[4,3-a] piperazine 2-9 was investigated. The reaction conditions have been optimized for each of the synthetic steps. The piperazine hydrochloride 2-9 was prepared in 48% overall yield. Moreover, by using different anhydride acylations of 2-17, diverse 3-substituted-tetrahydro-[1,2,4]triazolo[4,3-a]piperazine derivatives can be obtained, with overall yields in 40 to 50%. The intermediate is one of the key synthetic blocks for the synthesis of sitagliptin.In the second part, we found a simple and mild condition, for converting aldehyde (6-chloro-4-yl)hydrazone 3-39 to 2-substituted-8-bromo-[1,2,4]-triazolo[1,5-c] pyrimidine derivatives 3-42 by reaction with bromine. The structure of products was ascertained by X crystal diffraction analysis. The whole process involves bromination, cyclization, and Dimroth rearrangement. The present method carries several advantages, such as simple and mild reaction conditions, easy workup aside products, good to excellent yields. The two halogen atoms in the 7,8 positions of the pyrimidine ring provide the potent for the further manipulation by, for example coupling reaction and nucleophilic substitution reaction.