RESUMEN
An operably simple microwave-assisted BF3-mediated acetylation reaction of pyrazolo[1,5-a]pyrimidines and a plausible mechanism based on density functional theory (DFT) theoretical calculations for this transformation are reported. Remarkably, and to the best of our knowledge, this is the first example of the direct acetylation for the functional pyrazolo[1,5-a]pyrimidine (PP) core. The synthesis of this essential building block is reported in high yields using mild reaction conditions, inexpensive reagents, and even substrates with electron-deficient or highly hindered groups. In addition, one of the new methyl ketones was successfully used as a substrate for producing novel and valuable bis-electrophilic compounds with yields of up to 90%. Notably, the discovered acetylation method was successfully applied in other π-excedent (N-hetero)aromatic substrates.
Asunto(s)
Pirazoles , Pirimidinas , Acetilación , Pirazoles/química , Pirimidinas/químicaRESUMEN
Pyrazolo[1,5-a]pyrimidine (PP) derivatives are an enormous family of N-heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015-2021) in the synthesis and functionalization of diverse pyrazolo[1,5-a]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-a]pyrimidine core.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Antineoplásicos/química , Catálisis , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Pirazoles/química , Pirimidinas/químicaRESUMEN
Reversan, a multidrug resistance-associated protein (MRP1) inhibitor described more than a decade ago, is a commercial drug (CAS: 313397-13-6) that has a high price and is six to eight times more potent than known drug transporter inhibitors. However, to date, a complete route for synthesizing pyrazolo[1,5-a]pyrimidine-based Reversan is yet to be published. Herein, the silica gel-mediated synthesis of Reversan and a novel family of its structural analogues (amides) via the microwave-assisted amidation reaction of 3-carboethoxy-5,7-diphenylpyrazolo[1,5-a]pyrimidine (ester) with primary amines is reported. Moreover, a set of this ester-type precursor was obtained using the NaF/alumina-mediated reaction of 5-amino-3-carboethoxy-1H-pyrazole with chalcones, implying a final removal of H2 using Na2S2O8. Both esters and amides were obtained in high yields using heterogeneous catalyst and solvent-free, highly efficient, and scalable synthetic protocols.