Synthesis Of Anticancer Drug Nolatrexed

Hepatocellular carcinoma is the third commonest cancer wordwide. One million new cases diagnosed annually. At present there is no gold standard therapy. Nolatrexed dihydrochloride is in the final stage of clinical trials for improvments in hepatocellular carcinoma treatment. The molecular design was carried out by a repetitive crystallographic analysis of protein-ligand structures.Thymidylate synthase plays an essential role in the synthesis of DNA. The enzyme catalyzes the reaction of deoxyuridine monophosphate (dUMP) to deoxythymidylate (dTMP) by a reductive methylation. This rate-limiting step is the exclusive de novo source of dTMP for DNA biosynthesis. Without providing an exogenous supply of thymidine, halting TS activity would lead to a "thymineless cell death". Nolatrexed dihydrochloride occupies the the folate binding site of thymidylate synthase to halt synthesis of DNA.Nolatrexed was synthesized by nitrification, bromination, reduction, condensation, oxidation by concentrated sulfuric acid, oxidation by hydrogen peroxide, acylation, cyclization, esterification, Ullmann reaction successfully in 2% total yields starting from toluene. And furthermore research the technics of intermediates of nolatrexed was carried out. A new synthesis route of 4-mercaptopyridine was introduced. 4-mercaptopyridine was prepared from 4-pyridylpyridinium dichloride and phosphorus pentasulfide using hexamethyldisiloxane (HMDO) as catalyst,in the yield of 68.5%. Influence of reaction conditions, such as reaction times, solvent, equivalent and catalyst on yield of reaction was considered. Without using hydrogen sulfide this method was suitable for industrialization.The structures of key intermediates and target product were confirmed by the analysis of 1H-NMR data.