The Study On The Synthesis Of Oseltamivir Phosphate And Its Chiral Isomer Impurities

Oseltamivir(Tamiflu^?),the first oral neuraminidase inhibitor developed by Gilead and Roche,was approved for influenza A and B viruses by FDA in 1999.In view of its superior clinical usage,it is of great significance to develop a suitable synthetic route to Oseltamivir with high efficiency and selectivity,simple operation,low cost,mild reaction conditions,and large-scale feasibility.In addition,the oseltamivir contains three chiral centers and the chiral impurites were complex,therefore,the research on the preparation of its chiral isomers and provide a suitable analytical methods to ensure product chiral quality are of significant meaning for pharmaceutical research and commerilization.This thesis are mainly focus on above two targets and the research contents includes three chapters.The first chapter introduces the advances of anti-influenza drugs,and comprehensively summarizes and analyzes the synthetic methods of oseltamivir phosphate.The second chapter forcus on the synthesis of oseltamivir phosphate and its chiral imputity.In the first part,the industrial process of oseltamivir phosphate was studied.Shikimic acid was chosen as the starting material,followed by ethyl esterification,ketal reaction,mesylation,selective ketal reduction ring opening,and basic epoxidation led to an key intermediate epoxide derivative,which was then nucleophilic attacked by tert-butylamine,followed by mesylation,intra-nucleophilic substitution to afford intermediate aziridine.Then,the aziridine was selectively nucleophilic atacked by diallylamine,and followed by acetylation and deprotection of tert-butyl group and diallyl group to get oseltamivir.Finally,the target oseltamivir phosphate was achieved in the form of phosphate.Based on the reported synthetic route of Roche,the telescoping approach supplemented by efficient purification methods was creatively used for the the synthesis of Oseltamivir.This synthetic route simplified the industrial post-processing operation with reduced production cost,and the total yield was improved more than 15%in comparison with the literature.At the same time,a unique crystallization process was developed to make a uniform particle size distribution and a stable crystal form of Oseltamivir,and the HPLC purity of Oseltamivir was 99.8%.The chemical structure and crystal form of Oseltamivir Phosphate API were confirmed by IR,¹H NMR,¹³C NMR,MS,DSC,TGA,and XPRD.In the second part,the study of synthetic route to four chiral isomers of oseltamivir phosphate（（S,S,R）、（R,R,R）、（R,S,S）、（R,S,S））was performed to provide control for the quality study of oseltamivir phosphate.The preparation of the above isomer impurities were completed for the first time in this thesis.Similarly,shikimic acid was also chosen as the starting material.A series of problems such as high steric hindrance of the structure and complex purification were solved during the reaction process,which by designing ingenious route and screening suitable substituent groups.The final target isomers were all confirmed by ¹H NMR,NOSEY and MS.In the third chapter,three HPLC analytical methods are developed to evaluate the chiral quality of oseltamivir phosphate.The enantiomeric isomer of oseltamivir phosphate was detected by a normal phase HPLC method,while the diastereoisomers of oseltamivir phosphate were detected by a reverse phase HPLC method.Based on above methods,the quality control system of oseltamivir phosphate were optimized and validated to meet the commercial use.