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

• Published in: ChemistrySelect (Weinheim) 2022-06, Vol.7 (21), p.n/a
• Main Authors: Bozhanov, Vladimir I., Bohdan, Dmytro P., Borysov, Oleksandr V., Silin, Aleksey V., Zaremba, Oleg V., Avramenko, Mykola M., Volochnyuk, Dmitriy M., Ryabukhin, Sergey V., Gavrilenko, Konstantin S.
• Format: Article
• Language: English
• Subjects: building blocks; heterocycles; polycycles; polyfunctional scaffolds; privileged scaffolds
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202104287

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. The production of tetrahydropyrazolo[1,5‐a]pyrazines from the corresponding pyrazole‐5‐carboxylic acids and aminoacetals was discussed. The proposed synthetic scheme contains 5 steps (the first three of which are one‐pot) and allows to obtain compounds in fairly good yields. Additionally, the possibility of further modification of such building blocks in 3rd position by various functional groups was shown.