The competitive N1-, N2-, O- and C-methylation of 3-trifluoromethyl-1H-pyrazol-5-ol for synthesis of analgesic compounds

[Display omitted] •The approach for selective methylation of 3-trifluoromethyl-1H-pyrazol-5-ol was developed.•The quantum-chemical calculations were used to explain methylation direction.•The isomeric and tautomeric structure of the initial pyrazole and its methylated derivatives was studied.•An ana...

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Bibliographic Details
Published in:Journal of fluorine chemistry 2019-02, Vol.218, p.1-10
Main Authors: Burgart, Ya.V., Agafonova, N.A., Shchegolkov, E.V., Borisevich, S.S., Khursan, S.L., Maslova, V.V., Triandafilova, G.A., Solodnikov, S.Yu, Krasnykh, O.P., Saloutin, V.I.
Format: Article
Language:English
Subjects:
Acute toxicity
Analgesic activity
Analgesics
Biocompatibility
Chemoselectivity
Infrared analysis
Infrared spectroscopy
Isomers
Magnetic resonance spectroscopy
Mathematical analysis
Methylation
NMR spectroscopy
Organic chemistry
Pyrazole
Quantum chemistry
Quantum-chemical calculations
Substitutes
Toxicity
Trifluoromethyl-1H-pyrazol-5-ol
X-ray diffraction
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Summary:[Display omitted] •The approach for selective methylation of 3-trifluoromethyl-1H-pyrazol-5-ol was developed.•The quantum-chemical calculations were used to explain methylation direction.•The isomeric and tautomeric structure of the initial pyrazole and its methylated derivatives was studied.•An analgesic activity of the obtained pyrazoles was investigated. We have found selective conditions for methylation of 3-trifluoromethyl-1H-pyrazol-5-ol that allowed us to obtain mono-Me-substituted N1- and O-isomers as well N1,N2-, N1,O- and N2,O-disubstituted isomers. A tautomeric structure of the parent pyrazole and its Me-substituted derivatives was investigated using quantum-chemical calculations, X-ray diffraction analysis, IR and NMR spectroscopy. Besides, the quantum-chemical calculations were used to explain the methylation direction. An analgesic activity and acute toxicity of some synthesized compounds were evaluated in vivo experiments.
ISSN:0022-1139
1873-3328
DOI:10.1016/j.jfluchem.2018.11.009