The Synthesis Of Anticoccidial Drug Toltrazuril And Synthetic Reactions Of Isoselenocyanates

Coccidiosis is a parasitic disease which is more available at poultry and affects the quality and productivity of meat seriously.Toltrazuril,also named as methyl ketone triazine,is a kind of Triazinone anticoccidial drug which could prevent and treat coccidiosis effectively.Moreover,after taking toltrazuril,coccidiosis immunity of poultry would not be impact and not easy to produce drug resistance.So it was very meaningful to develop the preparation route of toltrazuril.Due to readily available,save easily,low toxicity,isoselenocyanates have been widely used in the synthesis of various nitrogen compounds.We reported to prepare three kinds of compounds such as cyanamides,N-acetylureas and1,2,4-triazoles from isoselenocyanates,which broaden isoselenocyanates application in organic synthesis field.The thesis is divided into two parts,the first part contains two chapters.In the first chapter,we introduced the coccidiostat toltrazuril,then outlined synthetic route of toltrazuril and developed a new one.The second chapter mainly optimized the reaction conditions.Firstly,1-?3-methyl-4-?4-?trifluoromethylthio?phenoxy?phenyl?urea 23 could be prepared from 3-methyl-4-?4-?trifluoromethylthio?phenoxy?aniline 15 and NaOCNunderacid.Then1-?3-methyl-4-?4-?trifluoromethylthio?phenoxy?phenyl?urea 23 reacted with methylcarbamic chloride to form 3-methyl-1-[3-methyl-4-?4-methylthio?phenyl]–biuret 12.Finally,the product toltrazuril could be obtained from the cyclization of 12 under base.We optimized solvents,temperatures,times,raw ratios,recrystallization solvents ect.of each step,then confirmed the best reaction conditions.Under the optimal reaction conditions,the total molar yield of toltrazuril was 64%?calculated based on 15?,the purity of toltrazuril was higher than 99.5%?HPLC?,the purity of each impurity was controlled under 0.1%,the purity of total impurities was also controlled under 1.0%.Meanwhile,we proposed the probable mechanisms of each step,deduced the synthesis routes of all impurities,and confirmed structures by¹H NMR,¹³C NMR and HPLC-HRMS.The second part contains four chapters.The third chapter introduced the common biological activities of selenium compounds,then outlined synthesis reactions of selenium ethers,selenium halides,selenomethionine acylates,isoselenocyanates.The fourth chapter described one-pot synthesis of cyanamides 171 from isoselenocyanates via deselenization promoted by ionic liquid-supported hypervalent iodine?III?reagent1-?4-diacetoxyiodobenzyl?-3-methylimidazolium tetrafluoroborate?[dibmim]⁺[BF₄]^–?.Compared with other routes,this approach provided a simple,mild and environmentally benign way to construct cyanamides in good yeilds.Moreover,[dibmim]⁺[BF₄]^–could be easily recycled.In the fifth chapter,we presented a simple and expedient approach to obtain regioselectively N-acetylureas 202 from isoselenocyanates and zinc acetate as the acylating agent.Compared with other methods,this method used the cheap and low toxicity zinc acetate as the acylating agent to construct various N-acetylureas regioselectively in moderate to good yields.In the last chapter,we innovated a simple,efficient and mild method to prepare 1,2,4-triazoles 224 from isoselenocyanates and hydrazine hydrate,which had broaden the scope of application of isoselenocyanates.