Synthesis of Pyrazolo[1,5-α]pyrimidinone Regioisomers

Abstract

This work describes two distinct routes to prepare pyrazolo[1,5-alpha]pyrimidin-7-ones and two distinct routes to prepare pyrazolo[1,5-alpha]pyrimidin-5-ones. Use of 1,3-dimethyluracil as the electrophile in the preparation of the pyrimidin-5-one regioisomer represents a correction of previously reported results. Also, a novel reaction to prepare this isomer was identified and the reaction mechanism elucidated. This work provides the experimentalist with complimentary synthetic pathways that afford either the pyrimidin-7-one or the pyrimidin-5-one regioisomer.

Synthesis and Biological Evaluation of Pyrazolo[1,5-a]pyrimidine Compounds as Potent and Selective Pim-1 Inhibitors

“…14 The cyclization of 4-phenyl-1H-pyrazol-5-amine with N-methyl uracil as a masked Michael acceptor in ethanol in the presence of sodium ethoxide provided the key building block 3-phenylpyrazolo[1,5-a]-pyrimidinone 5 in good yield. 15 Chlorination of the pyrimidone 5 using POCl 3 without solvent gave penult compound 5-chloro-3-phenylpyrazolo[1,5-a]pyrimidine, which was used for synthesis of final compounds with different amino groups on the 5-position of 3-phenylpyrazolo[1,5-a]pyrimidine. The final amination reaction of trans-4-aminocyclohexanol with the 5-position chloride on 5-chloropyrazolo[1,5-a]pyrimidine 6 proceeded selectively with good yield under basic conditions.…”

Concise and Efficient Access to 5,7‐Disubstituted Pyrazolo[1,5‐a]pyrimidines by Pd‐Catalyzed Sequential Arylation, Alkynylation and SNAr Reaction

“…Pyrazolo[1,5‐ a ]pyrimidin‐5‐ones were subsequently used as key intermediates to lead directly to the fused pyrazolo[1,5‐ a ]pyrimidines. Although many synthetic approaches have been described in the case of pyrazolo[1,5‐ a ]pyrimidin‐7‐ones 3′ , very few syntheses have been reported for pyrazolo[1,5‐ a ]pyrimidin‐5‐one regioisomers 3 (Figure ) . These syntheses are essentially based on the condensation of aminopyrazole with 1,3‐dimethyluracil or with ethyl 3‐ethoxyacrylate.…”

A Facile and Chemoselective Synthesis of Novel Pyrimido[5,4‐b][1,4]thiazines by exo‐dig Iodocyclization Reactions

“…Bicyclic pyrimidinones have been tested as HCV NS3 protease inhibitors . Pyrazolo[1,5‐ α ]pyrimidinones have promising antiproliferative activity. Imidazo[1,2‐ a ]pyrimidinones and pyrimido[1,2‐ a ]pyrimidinones have antiherpetic activities, anesthetic, anti‐allergic properties, PDE inhibitors, and antihypertensive activities .…”