Synthesis And Study Of Novel1,2,3-triazole Bridge-connected Phosphonates Compounds

The compound of coumarin is a constituent of many bioactive naturalproducts that are of wide interest because of their diverse biological and clinical applications. coumarin derivatives have varied biological activities including antimicrobial, anticancer,anti-HIV, anti-inflammatory, anticoagulation, anti-hypertensionproperties. According to reported papers, the reason of different performance is the influence of substituentgroups which on coumarin parent.Phosphate ester as an organophosphorus compound which play an important role in life process, Many endogenous active substances containing phosphate ester structure unit. For example,phosphodiester is an important component of DNA and RNA, tripolyphosphate is the component of ATP, phosphate ester structure unit also the components of coenzymecell and cell membrane.These endogenous active substances are participate almost all the lifeprocesses such as Energy conversion, material metabolism, genetic expression and so on. From the chemical level, the essence is phosphorus group’s transfer. Sometimes, insert a phosphate ester group in can significantly change the physical and chemical properties of parent molecule, bring fundamental changes in the intermolecular forces and molecular polarity. Terefore, the phosphate ester groups have been widely applied to drug development and modifications to improve the function of drug activity and bionic function, as in modern pharmaceutical industry often insert phosphate groups into prodrug molecule to increase the solubility and body’s biological access ability.1,2,3-triazole compounds are a class of azacycles that have highly active biologically. This class of compounds showed high anti-microbial, anti-HIV activity and effective in treating arthritis, neurological disorder and tumor prevention. With respect to introducing1,2,3-Triazole groups into organic molecules, one of the most popular reactions within the click chemistry concept, copper(I)-catalyzed azide-alkyne cycloaddition (Huisgen-Click reaction), discovered by the groups of Sharpless and Meldal is a classicalapproach leading to1,4-substituted products with high regioselectivity.Inrecentyears,1,2,3-triazole moiety has been attracted great attentions by medicinal chemists, as an important pharmacophore, was widely introduced into DNA, RNA, peptides and carbohydrates and so on. The modifications showed good results. Moreover,1,2,3-Triazoles as attractive linker units which could connect two pharmacophores to give an innovative bifunctional drugs, have become increasingly useful and important in constructing bioactive molecules and functional molecules.However, little attention has been paid to the introduction of1,2,3-Triazole and phosphonate scaffolds onto coumarin derivatives and to the best of our knowledge only one thesis reported the synthesis of triazoloacyclonucleotide phosphonates as potential HCV inhibitors and showed good results. In order to search new compounds with higher biological activity and lower toxicity, and integrate the advantages of coumarin,1,2,3-Triazole and phosphate ester, this paper plan to design asimpleand high efficientmethod to introduced1,2,3-triazole and phosphate groups into coumarin. In chapter1of the work, the recently development and applications of Huisgen-Click reaction, the structure modifications of coumarin were reviewed. In the following chapter, based on the prodrug principle of drug molecules design introduced a high Efficient and rapid way of synthesis a seriesof1,2,3-triazole and Phosphate ester contained new compounds. The reaction between4-ethynyltoluene and2-azide ethyl diethyl phosphate ester was selected as a model reaction for investigating the optimized reaction condition and twenty one1,4-disubstituted triazole phosphate compounds were synthesized, all of which are new compounds. Their structures were confirmed by IR, ESI MS and NMR.In chapter3,uesd the optimized reaction condition which have been identified in chapter2, eight novel1,2,3-triazole bridge connect phosphate coumarin derivatives were synthesized.Their structures were validated by ESI-MS, IR and NMR. Complete assignments of1H and13C-NMR spectroscopic data, The structure of1,4-disubstituted triazole derivative was confirmed by2D NMR such as COSY,HSQC, HMBC.In chapter4, a shake flask-ultraviolet spectrophotometry method was established to determine n-octanol/water partition coefficient of target compound3-2-1and2-3-8in different pH values. The results shown:Coumarin compounds if not contain aminomethyl on position8’have a similar oil/water partition coefficient. Otherwise, The oil/water partition coefficient in pH10.0-2.0range decreases with the pH value decrease. So we can through adjusting the pH value to control coumarin derivatives’ solubility in organic phase and water phase.