Study On Reaction Of Natural Isoflavones And Their Derivatives With Hydrazine Hydrate

As one of important heterocyclic compound, the chemistry of pyrazole and its derivatives have extensive biological activities, such as in medicinal chemistry as analgesic, anti-inflammatory, antitumor, antimicrobial and therapeutic agents and in agriculture as potent insecticides, herbicides. Due to many promising pharmacological, agrochemical and analytical applications of them, especially, 3, 4-diarylpyrazoles was studied as the inhibitors of heat shock protein 90 (HSP90) and therapeutic of cancer in recently, however, scarcely found in nature. So it becomes much more important to search for the synthetic methods for preparation of them. Intermolecular [2+3] cycloadditions of 1, 3-dipoles (like diazoalkanes) to alkynes and the addition of hydrazines to 1, 3-dicarbonyl compounds are frequently used methods for preparation of pyrazole and its derivatives. Although very frequently used, those routes can give mixtures and lower yields described in most cases. The first section is a summary on the biological activity and previous synthetic methods of pyrazoles.It is an effective method to synthesize of 3, 4-diarylpyrazoles based on isoflavones and hydrazine hydrate. In order to study on the reaction of natural isoflavones with hydrazine hydrate, 21 kinds of 3, 4-diarylpyrazoles and their derivatives were synthesized in high yields; 6 kinds of single crystals of 3, 4-diarylpyrazole were determined by single crystal X-ray diffraction.Firstly, five kind natural isoflavones, namely ipriflavone, daidzein, formononetin, genistein, irisolidone and theirs derivatives reacting with hydrazine hydrate to give 3, 4-diarylpyrazoles were studied. Compounds 3-(2-hydroxy-4-isopropoxyphenyl)-4-phenylpyrazole(1), 3-(3-bromo-2-hydroxy-4-isopropoxyphenyl)-4-phenylpyrazole(2), 3-(2, 4-dihydroxyphenyl)-4-(4-hydroxylphenyl)pyrazole(3), 3-(4-ethoxy-2-hydroxyl phenyl)-4-(4-hydroxyphenyl)pyrazole(4), 3-(4-ethoxy-2-hydroxyphenyl)-4-(4-ethoxy phenyl)pyrazole(5), 3-(2-hydroxyl-4-methoxyphenyl)-4-(4-hydroxyphenyl)pyrazole(6), 3-(2-hydroxy-4-methoxyphenyl)-4-(4-methoxyphenyl)pyrazole(7), 3-(2, 4-dihydroxy phenyl)-4-(4-hydroxy-3, 5-diisopropylphenyl)pyrazole(8), 3-(2, 6-dihydroxy-4-methoxy phenyl)-4-(4-methoxyphenyl)pyrazole(9), 3-(6-hydroxy-2, 4-dimethoxyphenyl)-4-(4-methoxyphenyl)pyrazole(10), 3-(2, 4-dihydroxyphenyl)-4-(4-methoxyphenyl)pyrazole (11), 3-(2-hydroxy-4-methoxyphenyl)-4-(4-methoxyphenyl)pyrazole(12), 3-(2, 6-dihydroxy-4-ethoxyphenyl)-4-(4-hydroxyphenyl)pyrazole(13), 3-(2, 6-dihydroxy-4- ethoxyphenyl)-4-(4-ethoxyphenyl)pyrazole(14), 3-(2, 4-diethoxy-6-hydroxylphenyl)-4-(4-ethoxyphenyl)pyrazole(15) and 3-(6-hydroxy-2, 3, 4-trimethoxyphenyl)-4-(4-methoxyphenyl)pyrazole(16) were synthesized and characterized by IR, ¹H NMR, ¹³C NMR and HRMS. Compounds 3, 5, 7, 9 and 15 were also determined by X-ray single-crystal diffraction analysis. The crystal structure of 3, 4-diarylpyrazole and its derivatives were studied. In the crystal structures of 3 and 9, C—H…πinteractions are found along with hydrogen bonds and aromaticπ…πstacking interactions. Hydrogen bonds and C—H…πinteractions are also existed in other crystal structures. Proposed reaction mechanism and the factors such as temperature and solvents influencing yields were discussed.Secondly, two kind nitroisoflavones reacting with hydrazine hydrate under catalyst or without catalyst were studied. 3'-nitro-4', 7-dihydroxyisoflavone and 3'-nitro-4', 7-dimethoxyisoflavone directly reacted with hydrazine to give 3-(2, 4-dihydroxyphenyl)-4-(3-nitro-4-hydroxyphenyl)pyrazole(17) and 3-(2-hydroxy-4-methoxyphenyl)-4-(3-nitro-4-methoxyphenyl)pyrazole(18). But this reaction catalysed by FeCl₃. 6H₂O/C, 3-(2, 4-dihydroxyphenyl)-4-(3-amino-4-hydroxyphenyl)pyrazole(19) and 3-(2-hydroxyl-4-methoxyphenyl)-4-(3-amino-4-methoxyphenyl)pyrazole(20) were obtained. To further determine the structure of the compound 19, its acetylation derivative 21 was synthesized and characterized by single crystal X-ray diffraction. They were determined by IR, ¹H NMR, ¹³C NMR and HRMS. The dose of catalyst, reaction temperature and the concentration of hydrazine were discussed and obtained the optimal conditions. Therefore, this reaction is a facile and high yields synthetic method to obtain 3, 4-diarylpyrazole.Last, the antioxidation experiment using the synthesized compounds 3, 6, 9, 13 and 19 were studied. It is clear from the experimental results, the synthesized compounds can potent prolong the rats death time. The function results have prominently relation of dose and effection. It indicated that 3-(2, 4-dihydroxyphenyl)-4-(4-hydroxylphenyl) pyrazole and its derivatives possess the effect of antioxidation.The species of 3, 4-diarylpyrazoles were enriched by the reaction between natural isofiavones and hydrazine hydrate. And the new compounds were synthesized. The approach of this paper to synthesize 3, 4-diarylpyrazole in high-throughput would be a powerful advance in helping to speed up drug discovery.