Straightforward Synthesis of Functionalized 4,5,6,7-Tetrahydro-pyrazolo[1,5-a]pyrazines - Important Building Blocks for Medicinal Chemistry

A set of building blocks based on the 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine scaffold is synthesized in a multigram scale in a cost-efficient manner. The possibility of the introduction of different substituents, neutral or functionalized in different positions of pyrazole and/or piperazine rings, is shown. The efficacy of using NH-pyrazole carbonic acids as a key intermediate of the process is demonstrated. The regioselectivity for direct insertion of the substituent to the 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine core is discussed. The synthetic perspectives for using the functionalized 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine as a bifunctional scaffold is discussed. The utilizing of building blocks obtained for the different region- and/or stereoselective synthesis, including sole transformations or modifications of functional groups, is demonstrated. The advantages of the proposed approach are proven compared with the other known methodologies.