Synthesis And Quality Evaluation Of Entecavir

Entecavir is a kind of 2’-e ring deoxidization guanine nucleoside analogues, which was developed by Bristol-Myers Squibb company in the 1990’s. Its original purpose was used to treat herpes simplex virus. Later it was found that it was with low toxicity relatively and was resistant to HBV strongly, so it is in the market as a treatment for chronic hepatitis b drug.The purpose of this study is to seek new synthetic conditions suitable for industrialized production on the basis of existing synthesis method of entecavir. It can get low cost and high stability of entecavir for the next step of entecavir preparation research. It will create favorable conditions to produce cheaper and effective drugs to benefit the patient for the treatment of chronic hepatitis b.Firstly, the existing synthetic approaches of entecavir were summarized on the basis of existing literature reports. For the purpose of industrial production, the starting material is simple and easy environmentally friendly low-toxic products to the human body. The mild reaction conditions is easy to industrial production, a-pinene, borane dimethyl sulfide complex and cyclopentadiene sodium as the starting material, (1s-trans)-2-[(phenylmethoxy)methyl]-3-cyclopenten-l-olwas synthesized by condensation reaction. (1s-trans)-2-[(phenylmethoxy)methyl]-oxabicyclo[3.1.0]-Cyclopentane-1-ol was synthesized under the epoxidation of (ls-trans)-2-[(phenylmethoxy)methyl]-3-cyclopenten-l-ol in acetylacetone oxygen vanadium and tert-butyl hydrogen peroxide. It was coupled with 6-benzyl guanine after benzyl protecting hydroxyl. Entecavir was synthesized by oxidation, the methylation and deprotection. The molecular structure of entecavir was confirmed by the elemental analysis, ultraviolet spectrum, infrared spectrum and nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, differential thermal analysis and thermogravimetric analysis.Secondly, the quality standards of this product was established by reference to Bristol-Myers Squibb company’s entecavir import registration standard (JX20050113) and the requirements of Chinese pharmacopoeia. The samples were identified by high performance liquid chromatography (HPLC) and infrared absorption spectrometry. The character of the sample, specific rotation, moisture were determined. Combined with production process, the residual solvents were determined by gas chromatography. The content of sample and the possible relevant material were measured by HPLC method.Finally, according to "the technical requirements of the physical and chemical of the new drug (chemicals) and quality standard research "and" Chinese pharmacopoeia "appendix XI X C" drug stability test guidelines-preparation stability test", The light, high temperature, high humidity factors, accelerated stability test for a long time of the product were completed. The results show that the product has essentially the same stability to the original entecavir.