O. G. Khudina

Synthesis, analgesic and antipyretic activity of 2-(antipyrin-4-yl)hydrazones of 1,2,3-triketones and their derivatives

Abstract1,2,3-Triketone 2-(antipyrin-4-yl)hydrazones were synthesized via the azo-coupling reactions of 1,3-diketones with 2-(antipyrin-4-yl)diazonium chloride. The fluoroalkyl-containing hetarylhydrazone enters into cyclocondensation with hydrazines at the 1,3-dicarbonyl fragment to yield 3-tetrafluoroethyl derivatives of pyrazole. It was found that 1,2,3-triketone 2-(antipyrin-4-yl)hydrazones and N-(2-hydroxyethyl)-substituted pyrazole exhibit analgesic activity comparable with that of their structural analog analgin (metamizole sodium), but do not possess antipyretic properties. In contrast, N-phenyl-substituted pyrazole did not exhibit analgesic properties but produced a certain antipyretic effect four hours after pyrogenic administration. Fluoroalkyl-containing compounds are less toxic substances than nonfluorinated 2-(antipyrin-4-yl)hydrazone and analgin.

One-step solvent-free synthesis of fluoroalkyl-substituted 4-hydroxy-2-oxo(thioxo)hexahydropyrimidines in the presence of 1-butyl-3-methylimidazolium tetrafluoroborate

A convenient procedure has been developed for the synthesis of fluoroalkyl-substituted 6-aryl-4-hydroxy-2-oxo-(thioxo)hexahydropyrimidine derivatives by three-component condensation of fluorinated β-dicarbonyl compounds with aromatic aldehydes and urea or thiourea in the absence of a solvent using 6 mol % of 1-butyl-3-methylimidazolium tetrafluoroborate as catalyst.

Synthesis of fluoroalkyl-containing 1,2,3-triketone 2-hetarylhydrazones and their reactions with hydrazines

Fluoroalkyl-containing 1,2,3-triketone 2-(2,3-dimethyl-5-oxo-1-phenyl-1,2-dihydropyrazol-4-yl)-, 2-(4-ethoxycarbonylpyrazol-3-yl)-, and 2-(1,2,4-triazol-3-yl)hydrazones were synthesized by the azo coupling reactions of fluorinated 1,3-diketones with the corresponding hetaryldiazonium chlorides. The hetarylhydrazones thus synthesized were subjected to cyclocondensation with hydrazines at the 1,3-dicarbonyl fragment to give 3-fluoroalkyl-4-hetarylazopyrazoles.

Synthesis, structure, and complexing ability of fluoroalkyl-containing 2,2′-(biphenyl-4,4′-diyldihydrazono)bis(1,3-dicarbonyl) compounds

New fluoroalkyl-containing 2,2′-(biphenyl-4,4′-diyldihydrazono)bis(1,3-diketones) and 2,2′-(biphenyl-4,4′-diyldihydrazono)bis(3-oxopropionates) were synthesized by azo coupling of the corresponding 1,3-dicarbonyl compounds with biphenyl-4,4′-bis(diazonium) dichloride. Complexing ability of the obtained bis-hydrazones was studied, and new coordination compounds of the general formula M2L2 [where M = Ni(II), Cu(II); L = fluoroalkyl-containing 2,2′-(biphenyl-4,4′-diyldihydrazono)bis(1,3-diketone)] were obtained.

Geometric isomerism in the series of fluoroalkyl-containing 1,2,3-trione 2-arylhydrazones

According to the 1H, 13C, and 19F NMR data, fluoroalkyl-containing 1,2,3-trione 2-arylhydrazones in CDCl3 exist exclusively, while in (CD3)2CO preferentially, as isomers in which the acyl or aroyl group is involved in intramolecular hydrogen bond. The isomer structure was assigned on the basis of the chemical shifts of the carbonyl carbon atoms and fluorine atoms and carbon-fluorine spin-spin coupling constants JC-F. X-Ray diffraction data showed that 1,2,3-trione 2-arylhydrazones in crystal have the same structure as in CDCl3 solution. Quantum-chemical calculations were performed to rationalize predominant formation of 1,2,3-trione 2-arylhydrazone isomers with a free polyfluoroacyl group.

Synthesis and Tuberculostatic Activity of Some 1,2,4-Triazines

The antituberculosis activity of dihydrotriazolo[5,1-c][1,2,4]triazines, dihydropyrazolo[5,1-c][1,2,4]triazines, dihydroimidazolo[5,1-c][1,2,4]triazines, and dihydrotetrazolo[5,1-c][1,2,4]triazines was studied. A synthetic method for convenient synthons, 3-amino-1,2,4-triazines, was proposed. Their tuberculostatic activity was investigated.

Synthesis of Pyrimido[2,1-b][1,3,5]Thiadiazines Containing Polyfluoroalkyl- and Amino Acid Fragments

8-Polyfluoroalkylpyrimido[2,1-b][1,3,5]thiadiazine-6-ones containing a structural fragment of amino acid or its ester were synthesized by a multicomponent cyclization of 6-polyfluoroalkyl-2-thiouracils with formaldehyde and amines. The use of diamino acids allowed the preparation of bis(pyrimido-[2,1-b][1,3,5]thiadiazin-6-ones), containing an aliphatic linker with a carboxy group. Two of the synthesized compounds exhibited weak antituberculosis activity in vitro.

Synthesis, structure, tuberculostatic activity, and toxicity of fluoroalkyl-containing 3-hydroxyimino-1,5-benzodiazepines

An improved method for the synthesis of fluoroalkyl-containing 3-hydroxyimino-1,5-benzodiazepines is proposed. For this, 3-hydroxyimines were obtained via nitrosation of 1,3-diketones and 3-oxoesters by tert-butylnitrite in diethylether under acid catalysis conditions and were reacted without isolation and further purification with ortho-phenylenediamine. It was found that polyfluoroalkyl-containing 3-hydroxyimino-1,5-benzodiazepin-2-ones and 2-hydroxy-3-hydroxyimino-2-trifluoromethyl-4-phenyl-1H-1,5-benzodiazepine possess high tuberculostatic activity comparable with that of isoniazide. Tests for acute toxicity of the trifluoromethylated heterocycles showed that they are less toxic than isoniazide.

Steric structure of alkyl 2-aryl(hetaryl)hydrazono-3-fluoroalkyl-3-oxopropionates

Steric structure of fluorinated 2-arylhydrazono-3-oxo esters was studied by 1H, 19F, and 13C NMR spectroscopy and X-ray analysis. It was found that these compounds in the crystalline state and in solutions in acetone-d6, DMSO-d6, and CDCl3 exist as Z isomers with the ester fragment involved in intramolecular hydrogen bond with the hydrazone NH proton. Exceptions are alkyl 2-arylhydrazono-4,4-difluoro-3-oxobutanoates which exist in acetone-d6 as mixtures of Z and E isomers, the former prevailing. Unlike fluorinated analogs, ethyl 2-(4-methylphenyl)hydrazono-3-oxobutanoate in crystal has the structure of E isomer in which intramolecular hydrogen bond is formed between the NH proton and acetyl carbonyl group. The same compound in acetone-d6, DMSO-d6, and CDCl3 gives rise to a mixture of Z and E isomers, the latter prevailing.

2-Methylsulfanyl-6-Polyfluoroalkyl-Pyrimidin-4-Ones: Synthesis and Nucleophilic Substitution Reactions

We have optimized the reaction conditions for the synthesis of 2-methylsulfanyl-6-polyfluoro-alkylpyrimidin-4-ones. In particular the yield of trifluoromethyl-substituted heterocycle was increased to 96%, and new polyfluoroalkyl-substituted analogs were prepared. The interaction of these heterocycles with morpholine or hydrazine was shown to result in nucleophilic substitution of the methylsulfanyl group, leading to 2-morpholino- and 2-hydrazino-6-polyfluoroalkylpyrimidin-4-ones. The reaction of 2-(2-phenylhydrazino)-6-trifluoromethylpyrimidin-4-one with paraform produced 5-oxo-2-phenyl-7-tri-fluoromethyl-5H-1,2,4-triazolo[4,3-а]pyrimidin-1-id-2-ium. The lactam structure of the synthesized heterocycles was established by X-ray structural analysis, as well as by IR and NMR spectroscopy.