Abstract
We reported a novel simplified synthetic procedure for the preparation of monosubstituted piperazine derivatives which can now be easily prepared in a one-pot-one-step way from a protonated piperazine with no need of introduction of a protecting group. Reactions, proceeding either at room or higher temperatures in common solvents, involve heterogeneous catalysis by metal ions supported on commercial polymeric resins. A general synthetic scheme was successfully applied to afford a wide range of monosubstituted piperazines. Furthermore, we picked up a set of piperazine derivatives and studied the possibilities of microwave acceleration of given synthetic reactions to make them even more efficient. Our research proceeded from a simple batch technique to the construction of a flow microwave reactor prototype and resulted in promising findings which are summarized and discussed in the article.
Highlights
Piperazine derivatives are very desirable building blocks for the production of many pharmaceuticals and they have great potential in the field of pharmaceutical research and development [1,2,3,4]
One-step Synthesis of Monosubstituted Piperazine Derivatives. As it was described in patented procedures [46,47,48] and literature [49,50], we discovered and verified a new and simple one-pot-one-step synthetic procedure for the preparation of a large variety of monosubstituted piperazine derivatives which can be obtained in high yields and purity while keeping costs low
The principle of a protonated piperazine was rarely mentioned in literature [26,27,28,32], it was not applied in a broader scale for the synthesis of other monosubstituted piperazines
Summary
Piperazine derivatives are very desirable building blocks for the production of many pharmaceuticals and they have great potential in the field of pharmaceutical research and development [1,2,3,4]. Piperazine itself shows some significant medicinal features such as anthelmintic activity [5], piperazine or substituted piperazine moieties appear in more complex structures of both commercially available (anti-vertigo agents Cyclizine and Meclizine or drugs to treat erectile dysfunction and pulmonary arterial hypertension (PAH) such as Sildenafil or Vardenafil) and potential pharmaceuticals. An introduction of a piperazine structural motive into the drug molecule is usually realized via 1-monosubstituted piperazine and, there is still an unrelenting demand for these kinds of piperazine derivatives in the field of pharmaceutical research and development. Their broader use in the pharmaceutical industry is still limited by their high price, which is a consequence of their problematic preparation. When the direct monosubstitution of a free piperazine is involved, the yields of monosubstituted piperazines are significantly decreased by Molecules 2020, 25, 2168; doi:10.3390/molecules25092168 www.mdpi.com/journal/molecules
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