Synthesis Of Anti-HCV Drugs Sofosbuvir And Its Analogues

Hepatitis C is a continuous and infectious disease caused by the hepatitis C virus(HCV),not only has a high prevalence,but also has caused potentially serious complications by persistent infection.This chronic disease is closely related to cirrhosis,liver cancer and other advanced liver disease.Once infected with hepatitis C virus,only 20 percent of those infected can achieve viral clearance,the vast majority of infected people carry HCV lifetime.For those initially infected with HCV approximately 80 percent progress to become chronic liver disease,20 percent of these ultimately progress to liver cirrhosis in 10 to 20 years,and 1-4%of these eventually become hepatocellular carcinoma.HCV infection is becoming a global problem of public health.Currently,owing to the lack of effective vaccines and drugs against HCV,a method,injections of pegylated a-interferon(PEG-IFNa)with daily oral administration of ribavirin(RBV),is used as the current therapy for treating HCV infection.But this treatment has many disadvantages.In attempts to improve on the overall HCV cure rate and reduce or eliminate the serious side effects associated with PEG-IFN/RBV therapy,the search for direct acting antivirals(DAAs)that are new,safe and effective has become an urgent endeavor.In recent years,targeting NS5B RNA-dependent RNA polymerase(RdRp)has been playing an increasingly important role in the field of discovering novel anti-HCV drugs.NS5B RdRp is encoded by the non-structural genes NS5B.NS5B RdRp not only is the key enzyme of hepatitis C virus replication,but also is the necessary enzyme to synthesize double-stranded RNA from single-stranded RNA.On the other hand,human cells do not express the enzyme of which its function is in the same or similar to NS5B RdRp.Thus the NS5B RdRp inhibitors would have a particularly good selectivity,and NS5B RdRp is one of the best antiviral drug targets.Lots of NS5B RdRp inhibitors have entered clinical studies.PSI-6130 is a prominent candidate among of these inhibitors.But the result of animal models showed that it has a low oral bioavailability(24%).Its absorption is also very slow and incomplete.To improve its absorption and drug exposure in plasma,it is a useful strategy to design and synthesize prodrugs of PSI-6130.Sofosbuvir(GS-7977)is a prodrug of which its core structure is similar to PSI-6130.The FDA approved sofosbuvir for the treatment of chronic hepatitis C on December 6,2013.Sofosbuvir is the world’s first orally drugs and without co-administration with interferon to treat chronic hepatitis C.This study consists of two parts:(1)Synthesis of Sofosbuvir;(2)Based on previous work of our research group,PSI-6130 was selected as the original drug to design and synthesize Sofosbuvir analogues.By analyzing the reported method in the literature,the synthetic strategy of Sofosbuvir was selected.Sofosbuvir was successfully synthesized through a multi-steps route of more than 20 steps in this research.The reaction conditions of every step in the synthesis,were investigated in detail.Especially,the synthetic methods of intermediates h and q were improved to compare with literature.This improvement ensured the synthesis of Sofosbuvir ongoing stably and smoothly.Based on the literature and our group previous work,Sofosbuvir analogues were designed and synthesized.By maintaining the structure of NZ-510,a prodrug of PSI-6130,and employing a similar 5’-OH phosphorylation strategy of Sofosbuvir,the following Sofosbuvir analogues were designed:NZ-510(R=pentyl,cyclohexyl,isopropyl)One(R=isopropyl)of the designed Sofosbuvir analogues was successfully synthesized in this research.The synthesized Sofosbuvir analogue has not been reported so far in the literatures.Structures of all intermediates were confirmed by 1H-NMR.Also the structures of some key intermediates were confirmed by 31P-NMR,LC-MS and optical rotation.This research will give a foundation for further design and synthesis of Sofosbuvir analogues.