The thesis is devoted to developing efficient preparative of synthesis of novel linearly functionalized and heteroannulated pyrazolo[1,5-a]pyrazines based on 4-halopyrazolo[1,5-a]pyrazines, pyrazolo[1,5-a]pyrazine-4(5H)-thiones, 4-hydrazinylpyrazolo[1,5-a]pyrazines and pyrazolo[1,5-a]pyrazine-4-carboxylic acid derivatives.
Scientific novelty. The efficiency of using pyrazole-5-carboxylic acids as basic building blocks in the improved version of the synthesis of pyrazolo[1,5-a]pyrazin-4(5H)-ones was shown. 4-Chloro(bromo)pyrazolo[1,5-a]pyrazines and pyrazolo[1,5-a]pyrazine-4(5H)-thions were synthesized from pyrazolo[1,5-a]pyrazin-4(5H)-ones using phosphorus oxychloride or phosphorus oxybromide and phosphorus pentasulfide, respectively.
New 4-amino(thio)substituted pyrazoles[1,5-a]pyrazines with satisfactory antibacterial and fungicidal activity were synthesized by the method, based on the reaction of 4-halopyrazolo[1,5-a]pyrazines with alkylamines and thiophenols or the alkylation of pyrazolo[1,5-a]pyrazin-4(5H)-thiones with functionalized alkyl bromides.
The conditions for Pd-catalyzed cross-coupling by Suzuki-Miaura of 4-bromopyrazolo[1,5-a]pyrazines with aryl(hetaryl)boric acids were determined, which allowed to obtain a number of previously unknown 4-aryl(hetaryl)pyrazolo[1,5-a]pyrazines.
Pyrazolo[1,5-a]pyrazin-4-ylacetonitriles were synthesized by condensation of 4-chloropyrazolo[1,5-a]pyrazines with tert-butyl cyanoacetate, via formation of tert-butyl cyano(pyrazolo[1,5-a]pyrazin-4(5H)-ylidene)ethanoates. Synthesized 2-azahetarylacetonitriles were used to obtain derivatives of a new pyrazolo[1,5-a]pyrido[2,1-c]pyrazine system.
Methyl pyrazolo[1,5-a]pyrazine-4-carboxylates were synthesized by Pd-catalyzed carbonylation of 4-chloropyrazolo[1,5-a]pyrazines under increased pressure. These esters were converted into the corresponding amidoximes and amidines through intermediate nitriles. Cyclocondensation of amidoximes with trifluoroacetic anhydride or ethyl chloroformate, and cyclocondensation of amidines with the acetoacetic ester or ethoxymethylenemalonic ester were found to be effective for the synthesis of new 4-(1,2,4-oxadiazolyl)- and 4-pyrimidinyl-substituted pyrazolo[1,5-a]pyrazines.
A convenient method for the synthesis of the first representatives of the new heterocyclic system of pyrazolo[5',1':3,4]pyrazino[2,1-b]quinazoline, based on [2+4]-cyclocondensation of 4-chloropyrazolo[1,5-a]pyrazines with anthranilic acids, were developed.
Ethyl imidazo[1,5-a]pyrazolo[5,1-c]pyrazine-1-carboxylates, obtained by the reaction of [3+2]-dipolar cycloaddition of of 4-chloropyrazolo[1,5-a]pyrazines with ethyl isocyanoacetate, have been successfully used to yield their new derivatives with carboxyl, hydroxymethyl and formyl groups, promising scaffolds for the design of biologically important compounds.
The 4-hydrazinylpyrazolo[1,5-a]pyrazines obtained by selective reaction of 4-chloropyrazolo[1,5-a]pyrazines with hydrazine hydrate were found to undergo a reaction with with monocentric (triethyl orthoformate, acetic anhydride, ethyl chloroformate, phenyl isothiocyanate, nitrous acid) and bicentric (diethyl oxalate) reagents to give corresponding 1,2,4-triazolo-, tetrazolo- and 1,2,4-triazinoannulated derivatives. 4-(1-Pyrazolyl)-substituted pyrazolo[1,5-a]pyrazines were synthesized by reaction with acetylacetone and ethoxymethylene derivatives of malononitrile and ethyl cyanoacetate.
The practical application: developing effective preparative methods for the synthesis of 4-halogeno- and 4-hydrazinylpyrazolo[1,5-a]pyrazines as effective synthetic templates for the construction of a wide range of bioperspective linearly functionalized and heteroannulated derivatives. Bioscreening methods have shown that 4-aminosubstituted pyrazolo[1,5-a]pyrazines demonstrate moderate antimicrobial activity against bacteria S. aureus 209, B. subtilis ATCC6633, M. luteus 4698 and fungi C. ablicans 669/1080 and C. krusei ATCC 6258, and the value of the minimum bacteriostatic and bactericidal (MBC) concentration of N-benzylpyrazolo[1,5-a]pyrazin-4-amine in relation to the strain M. luteus ATCC 4698 indicates its higher activity compared to the drug “Ketodine”. At the same time, promising derivatives with antibacterial activity have been identified among the 4-S-substituted pyrazolo[1,5-a]pyrazines. In particular, 4-[(4-fluorophenyl)thio]pyrazolo[1,5-a]pyrazine was active against S. aureus test cultures, 4-[(4-chlorophenyl)thio]-2-methylpyrazolo[1,5-a]pyrazine showed activity against S. aureus and M. luteum, and 1-(4-fluorophenyl)-2-(pyrazolo[1,5-a]pyrazin-4-ylthio)ethan-1-one has a pronounced antifungal effect against the test culture of the fungus A. niger.
Keywords: pyrazolo[1,5-a]pyrazine-4(5H)-ones(thiones), 4-halo(hydrazinyl)pyrazolo[1,5-a]pyrazines, pyrazolo[1,5-a]pyrazine-4-carboxylic acid derivatives, structural modification, linear functionalization, heteroannulation, biological activity, new heterocyclic system.
