Synthesis And Studying Of Adefovir Dipivoxil

Hepatitis B virus(HBV) infection is the major reason which cause cirrhosis and hepatocellular carcinoma, and leads to death in the end. Adefovir dipivoxil(AD) is a novel nucleoside antiviral drug of hepatitis B, which, in the sdudies conducted to date, reduces viral load in all types of patients with chronic hepatitis B, and improves lamivudine-risistant HBV infection especially. No evidence of HBV resistance to AD has been detected so far. Therefore, the successful research of this agent will improve the present situation that many patients can not get the effective therapy, and it possesses tremendous social and economic benefit. To this artic, the author designed a new synthetic route of AD and performed it after refered the prior route of synthesis. As a result, the yield of intermediats were improved, and their purification operative procedure were simplified. At the same time, the cost was cut down, and environmental pollution were diminished. The main contents of this paper are as follows:(1) Diisopropy Phosphite is directly synthesized from phosphorus trichoride and isopropanol by using solevent method. The effects of base, solvent and reaction temperature on the ester yield are studied.In the presence of base, the content of product can exceed 99% and the yield can reach 87%.(2) With the promotion of triethylamine, diisopropyl(hydroxymethyl)phosphonate is synthesized from diisopropy phosphite and paraformaldehyde, the content of product can exceed 99% and the yield can reach 83%.(3) p-Toluenesulfonyl chloride is added to the reaction system of (2) in dry Et2O. Both of the preparation and purification operative procedure were simplified, and the content of product can exceed 99% and the yield can reach 84%.(4) We designed a new synthetic route of 9-(2-hydroxyethyl)adenine, used chlorohydrin instead of ethylene carbonate, and replaced potassium carbonate for sodium hydroxide. In this way, the cost is lowed and the content of product can exceed 99% and the yield can reach 92%.(5) We use sodium instead of sodium hydride or sodium alkoxide to react with 9-(2-hydroxyethyl)adenine in dry DMF, and the effects of base and solvent on the yield are studied.In conclusion, through the new synthetic route of AD , the yields of intermediats were improved, and the purification operative procedure was simplified. At the same time, the cost was cut down, and environmental pollution was diminished. All of these provide the theoretical and experimental evidence for industrialization production of AD.