Research On Optimization Of Synthesis Process Of GSK-A1

Hepatitis C virus(HCV)is a blood-borne disease.At present,about 130～180million people worldwide are infected with hepatitis C,and about 700000 people die of hepatitis C and its complications each year.Phosphatidylinositol 4-kinase IIIα(PI4KIIIα)is a lipid kinase mainly responsible for the production of lipid phosphatidylinositol 4-phosphate(PI4P)on the plasma membrane and is often involved in the replication of pathogenic RNA viruses,the most commonly studied role of PI4KIIIαis the replication of hepatitis C virus.It is currently found that NS5A can activate PI4KIIIαfurther increase PI4P.The prospect of the synthesis of selective PI4KIIIαinhibitors is that these inhibitors can be used to combat HCV infection.Thestarting point for the synthesis of selective PI4KIIIαinhibitors is that these inhibitorscan be used to combat HCV infection.GSK-A1 is a potent and selective PI4KIIIα-type inhibitor,which interferes with the supply of PI4P by inhibiting PI4KIIIαand thus inhibits the replication of hepatitis C virus.after consulting the literature,it was found that the existing synthetic route is protected by patents,the yield is low and the post-processing is complicated,so it is not suitable for pilot scale-up production.Therefore,it was commissioned by a cooperative company to optimize the experimental synthesis of GSK-A1 and its intermediates.At the same time as the target compound is synthesized,the laboratory preparation process is improved,and preparations are made for the next pilot study and the preparation of GSK-A1 derivatives.This project designed and investigated two synthetic routes.Through experimental investigations,the synthetic routes suitable for pilot scale-up experiments were determined,using 5-bromo-2-chloro-3-nitropyridine,4-morpholinoaniline and 4-bromo-2-fluoronitrobenzene as raw materials,and the target compound is synthesized through reactions such as nitro reduction,sulfonylation,borate esterification,cyclization and Suzuki-Miyaura.Compared with the reported literature route,the raw material of the design route after the experimental optimization of this subject is relatively cheap and easy to obtain,and it has advantages of feasible reaction operation,suitable conditions,simple post-treatment and high yield,so it is suitable for subsequent pilot scale-up production and it laid a good foundation for the next amplification experiment.The structure of the target compound is characterized by ~1H NMR、MS and IR.It’s total yield was 22.45%.