Study On Synthesis Of Hypolipidemic Drug Ezetimibe Derivatives

Objective:This study aims at using organic synthetic method to modify the structure of ezetimibe,and to preliminarily study in vitro antibacterial activity of these derivatives.Methods:In this thesis,three types of ezetimibe derivatives are obtained by three methods;First,structural modification of ezetimibeβ-lactam ring;Second,structural modification of the carbonyl alpha position of ezetimibe by total synthesis;Third,the hydroxyl group of ezetimibe is subjected to hydroxyl protection,acylation,and the like,thereby obtaining an ezetimibe-hydroxy acylated derivative.The structure of these derivatives were characterized by ESI-MS,¹H-NMR and ¹³C-NMR.Finally,the antibacterial activity of ezetimibe hydroxy acylated derivatives was preliminarily determined by two fold dilution method.Results:Fiveβ-lactam ring structurally modified derivatives were obtained by modifying theβ-lactam ring of ezetimibe;One intermediate derivativewasobtained through the four total synthetic methods;Forty fine hydroxy acylated derivatives of ezetimibe were obtained by hydroxyl protection and acylation of ezetimibe hydroxy groups.And hydroxyl derivative derivatives of ezetimibe had no antibacterial activity in vitro.Conclusion:Method one:If a reagent or base with a large steric hindrance is used,no structural modification product of theβ-lactam ring can be obtained,andonly the structure of the beta lactam ring is modified by the formatted reagent or alkali with a small space hindrance;Method Two:Through four total synthetic routes,a structurally modified derivative of ezetimibe carbonyl alpha is not yet obtained,and only one derivative of ezetimibe intermediate is obtained;Through method three,45ezetimibe hydroxy acylated derivatives were obtained.A total of 51 ezetimibe derivatives were obtained.When the phenolic hydroxyl group was modified,the attachment of electron-withdrawing and electron donating group had no effect on its yield.However,when there is a substituent on the benzene ring of sulfonyl chloride or acyl chloride,it is difficult to obtain the adjacent substitution product,and the para-substituted product has a higher yield than the meta-substituted product.