Continuous-flow Process For The Synthesis Of P-Cresol And Deoxyarbutin

This dissertation mainly focused on the application of continuous-flow methodology in the synthesis of p-cresol and deoxyarbutin,which could be divided into three chapters:In first chapter,continuous-flow technology and its recent applications in the drug synthesis were introduced initially.Moreover,synthetic routes of p-cresol and deoxyarbutin were summarized systematically.Then,two appropriate routes were selected upon the comprehensive consideration.Our major objective aimed to develop continuous-flow processes to improve and strengthen the reaction processes,besides,to solve various problems effectively in the reactions,thereby developing novel approaches for the efficient and facile synthesis of p-cresol and deoxyarbutin.In chapter two,the process optimizations of diazotiazation and hydrolysis reaction in flow were described.Base on kinetic analysis,the formation mechanisms of three main byproducts of nitrification,sulfonation and coupling were determined,and a 5-inlet fully continuous-flow diazotization-hydrolysis process was finally established.The process of fully continuous-flow diazotization-hydrolysis was then optimized.The optimal process conditions of diazotization section were sumerized as followed:T₁=20?,?₁=20 s,F_NaNO2:F_p-toluidine=1.02;the optimal process conditions of quenching section were depicted as followed:T₂=20?,?₂=15 s,F_urea:F_p-toluidine=0.05;the optimal process conditions of hydrolysis section were described as followed:T₃=130?,?₃=30 s.The final optimized yield was 91%.This study was firstly reported on the preparation of phenolic compound from aromatic amine via diazotization and hydrolysis in a fully continuous-flow reactor.The third chapter introduced the optimization of continuous-flow process for the synthesis of deoxyarbutin in detail.A reversible equilibrium was found in the process for preparing deoxyarbutin via monoetherification.In order to improve the restricted conversion of material and inhibit the consecutive side reaction,a continuous-flow monoetherication process was developed.Then,an envisagement of catalyst-free continuous-flow etherification was proposed and successfully realized accordingly.In addition,a programmed cooling crystallization method was developed,through which the recovering of raw material and the stable separation of product could be achieved.Ultimately,the process of continuous-flow monoetherification was optimized.The optimal process conditions was indicated as followed:T=100?,?=8 min,F_hydroquinone:F_DHP=9.Under the optimum conditions,excellent chemo-selectivity and yield were obtained.