Synthesis And Process Optimization Of Entecavir

Viral Hepatitis Type B is a liver infectious disease.According to the statistics of the World Health Organization,in 2005,there were 257 million people infected with chronic hepatitis B,887000 people died of hepatitis B cirrhosis,liver cancer and other related diseases.In 2010,about 2 million people died of hepatitis B related diseases,accounting for 4% of the world’s death toll.There are about 86 million hepatitis B carriers in China,accounting for one third of the world’s total.Hepatitis B drugs mainly include interferon,nucleoside drugs and Chinese herbal medicine,and nucleoside drugs account for 80% of the hepatitis B drug market.Entecavir is a guanine nucleotide derivative developed by Bristol Myers Squibb Company.It was approved by FDA on March 29,2005.Its trade name is Baraclude.In this paper,the mechanism,pharmacological action,research status and development prospect of entecavir are introduced.Because of its strong antiviral effect and low drug resistance rate,it has become one of the first-line drugs in the treatment of hepatitis B.At present,the sales volume of entecavir has accounted for 60% of the market share of hepatitis B drugs,and there is a trend of continuous growth.Therefore,it is necessary to study the synthesis process of its intermediates and APIs.The purpose of this study is to optimize the synthesis of entecavir on the basis of the existing process,and to find better synthesis conditions for industrial production.In this paper,the synthetic routes reported in the existing literature were analyzed and compared,and based on patent US5206244 A,the reactions in this route were optimized.Entecavir was synthesized from compound(1S,2S,3S,5S)-5-(2-amino-6-benzyloxy-9h-purine-9-yl)-3-benzyloxy-2-benzyloxy methyl cyclopentanol as the starting material by condensation,oxidation,methylation,hydrolysis and deprotection.When the key intermediate 1 was prepared in the experimental study,the process of batch adding amino protecting group was used in the synthesis for the first time,which shortened the reaction time and improved the yield and quality of the reaction.The optimized synthesis route has the advantages of simple operation,mild reaction conditions,short total reaction period,good product quality and total yield of 30%.At the same time,a series of effective chemical detection and structure identification of the target product entecavir and its reaction intermediates were carried out,such as liquid chromatography,mass spectrometry,nuclear magnetic resonance.