Study On The Synthesis Of Bicyclic Pyridone And Thalidomide Derivatives

Bicyclic pyridone has a very prominent biological activity,and the parent structural units of many commercially available drugs have such a structure,which is one of the research hotspots in the field of medicinal chemistry today.The development of thalidomide also has a long and bumpy history,This is due to teratogenic effects on infants.But at the same time,There are numerous studies proving its powerful immune-modulating,anti-inflammatory,anti-angiogenic and anti-cancer properties.Many derivatives of thalidomide have been clinically tested and approved by the US FDA.Thalidomide and its derivatives are currently used to treat a variety of diseases such as Crohn’s disease,leprosy,graft-versus-host(GVHD)and other neurological cancers.The recent anti-inflammatory effects of bicyclopyridone and thalidomide derivatives have led pharmacologists to recognize their potential as potential drugs for the treatment of lung damage caused by COVID-19.Therefore,exploring the synthesis of novel bicyclic pyridone derivatives and thalidomide derivatives has a positive effect on the development of pharmaceuticals.The first part of this paper studies the total synthesis of bicyclic pyridone compounds and designs a novel synthetic route,By modifying the synthetic route,the total synthesis was finally completed.During the research,the protecting groups and key conditions were optimized and screened,and a new route suitable for gram-level synthesis was determined,that is,starting from a simple and readily available raw material 2-hydroxy-6-methylnicotinonitrile,through simple addition,Bioactive bicyclic pyridone derivatives were synthesized in 11 steps by hydrolysis,Curtius rearrangement,nucleophilic substitution,selective protection of hydroxyl groups,and intramolecular cyclization.In the second part of this paper,a novel thalidomide derivative was designed and its total synthesis was systematically studied.According to the structural characteristics of the target compound,three synthetic routes were designed and verified.Condensation,deprotection and other six-step reactions are performed to obtain the final product.In addition,the key steps of each line were optimized to improve the yield of the target product and complete the gram-level preparation of the final product.