The Desighn And Synthesis Of Nucleosides Through Green Stratiges

With the contribution to the economy development, chemical industry has been generating the seriousenvironmental pollution. The reaction solvent, the reaction process and the synthetic strategy are not green,being important factors in causing pollution. Thus, the sustainable development of chemical industrydepends on maximizing the utiliztion of green reaction process, the application of green synthetic strategy,the use of green solvents, avoiding of conventional organic solvents or using non-toxic, harmless solvents.Because of its unique green synthetic performance, atom economy reaction and using water as solvent hasbeen attractting more and more attention.Nucleoside drugs are widely used in the treatment of tumor and HIV, with a huge international marketshare and demand. The current producing methods often use organic solvents, heavy metal catalysts, or arenot atom-economic, seriously hampering the development of nucleoside industry. The research ofnucleoside drugs with green chemistry is the international forefront project, not only to solve the pollutionproblem caused by nucleoside production, but also to overcome technical bottlenecks and to promotesustainable development of nucleoside industry.In this paper, with a guide of green chemical strategy, we combine green reaction route withnucleoside production, to develop green reaction and achieve the environment-friendly production ofnucleoside drugs. The main contents are as follows:1. It is for the first time to synthesize an important anti-HBV drug Vidarabine using water as thereaction medium. The desired Vidarabine was produced using water as the solvent, air as the oxidant,replacing organic solvent such dioxane and an excess of heavy metals such as mercury oxide or silver oxiderepectively. Not only for small scale reaction, more importanly, when the reaction scale expanded tokilograms, this method is still very efficient, showing a good prospect. With the evaluation of greenchemistry, this method takes advantages of high atom economy, short reaction time, high yield, simpleoperation and work-up process, avoiding of the huge pollution caused by least3.8times the amount ofmercury oxide, decreasing the E-factor and the environmental quotient dramtically. With the ingeniousdesigned experiments, the mechanism and the nature of green reaction were investageted deeply, laid thetheoretical foundation for the further expansion of the scope of application of the reaction. This method hasa universal substrate scope and also is suitable to prepare drugs with similar structures. This is by far themost green synthetic route of Vidarabine, with originality and intellectual property rights, and has broadapplication prospects.2. It is for the first time to accomplish the green alkylation reaction of purine nucleosides at C6position, using water as the solvent,5%FeSO4as catalyst, using avaible and inexpensive carboxylic acid asthe alkylating agents. The reaction can be conducted at very mild conditions under ambient temperature andstirring. It avoides organic boron, organic magnesium or organic zinc reagents for conventional methods.The toxic heavy metal catalyst such as Pd or Ni and the organic solvents such as tetrahydrofuran or acetonitrile are also avoided. With the evaluation of green chemistry, this method takes advantages of highatom economy, mild reaction conditions, high yield, simple operation and work-up process, avoiding of thehuge pollution caused by tetrahydrofuran and toxic heavy metal catalyst, decreasing the E-factor and theenvironmental quotient dramtically. The mechanism and the nature of green reaction were investageteddeeply by the designed experiments, obtaining the theoretical research results. The method has broadsubstrate scope and is green, mild and efficient, laid the foundation for the application of this reaction.3. It is for the first time to improve the atom economy of purine nucleoside alkylation, utilizing theC-H bond activation which is international forefront of green chemistry concept. This method avoids thetedious steps of the transformation metal halide reagent and metal reagents, using the oxidizing to promotecoupling reaction through double bond C-H activation directly with only one molecule hydrogen asby-product. The green nature of synthetic process was evaluated, finding that this methd has good atomeconomy, high yield and not uses organic solvents with small E-factor and the environmental quotient. Themechanism and the nature of green reaction were also investageted deeply. In the screening the activity ofthe desired compounds, a compound with the good activity of anti-HL-60cells was obtained.4. It is for the first time to improve atom economy and selectivity of the purine dialkylated reaction.The C6alkylation products and C6, C8-dialkylated purine nucleosides were obtained through the controlof substrate ratio and reaction time. The direct double C-H bond activation is accomplished usingcommercialized purine and alkane substrates. With the evaluation of green chemistry, this method takesadvantages of high atom economy, high yield, simple operation and work-up process. The screening theactivity of the desired compounds found a compound with the good activity of anti-HL-60cells.The research results are ingenious with independent intellectual property rights. The study expandedthe range of application of the green chemistry in nucleoside chemistry, providing a theoretical basis for theapplication of green chemistry in nucleoside production, laiding the foundation of wide application of greenchemical strategies in the drug synthesis.