Synthesis Of New Anti-influenza Virus Drug Baloxavir Marboxil And Its Intermediate Analogues

This paper consists of two parts: the synthesis of the new anti-influenza drug Baloxavir marboxil and the synthesis of its intermediate analogues.Part 1: Synthesis of the new anti-influenza drug Baloxavir marboxil.Baloxavir marboxil is an anti-influenza drug with the latest mechanism of action in the past two decades.It acts against influenza A and B viruses by selectively inhibiting the cap structure-dependent endonuclease of influenza viruses.The drug was approved in Japan in February 2018 and is mainly used to treat influenza A and B virus in patients 12 years and older,and approved in the United States in October2018.Based on literature research of Baloxavir marboxil,the drug was mainly involved in the synthesis of three fragments,such as 3-(benzy-loxy)-4-oxo-4H-pyran-2-carboxylic acid,7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione,and intermediate 11.In this study,3-(benzy-loxy)-4-oxo-4H-pyran-2-carboxy-lic acid was synthesized from methylmaltol by benzyl protection,bro-mination,hydrolysis and oxidation.Then methylateon,Boc-protection,amidation and deprotection,and cyclization with chloroacetaldehyde to obtain 7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione.Finally,through chiral resolution,coupli-ng,deprotection,and esterification,Baloxavir marboxil is obtained.C-ompared with the literature,thismethod has greatly shortened the syn-thetic route,simple operation,relatively mild reaction conditions,hig-h yield,and has a good industryal application prospect.Part 2: Synthesis of polycyclic carbamyl pyridone analogues,an intermediate of Baloxavir marboxil.Polycyclic carbamoyl pyridone analogues are widely used in medicine.In this study,polycyclic carbamoyl pyridone analogs were prepared by reacting chloroacetaldehyde with o-aminoamide derivatives under alkaline conditions.This method does not require other catalysts,has a short synthetic route,good substrate universality,and high yield.It has successfully synthesized 10 new compounds that have not been reported in the literature,laying a theoretical foundation for the synthesis of new drugs for epimerization.