Optimized Synthesis Of Telbivudine

Telbivudine is a specific drug for the treatment of hepatitis B.It has an excellent therapeutic effect and high safety for hepatitis B.Long-term use can improve renal function.Telbivudine is composed of two parts:glycosyl and thymine.The coupling process of these two parts is the key to the synthesis of this drug.There are currently two main ways to synthesize telbivudine.The first method is the glycosylation method.Telbivudine is synthesized by coupling thymine to activated deoxyribose.In this method,the glycosylation product is a mixture ofαandβtypes,which is difficult to separate and not only affects the substitution.The yield of Bivudine also affects its purity.The second method is the base construction method.Telbivudine is synthesized by constructing a thymine group on the glycosyloxazoline,which can effectively avoid the generation of anomers and ensure the purity of the product.The reported routes have problems such as expensive raw materials,serious pollution,low total yield,complex post-processing,and lengthy routes,which are not conducive to large-scale industrial production.It is of great significance to further research and optimize the synthesis process of telbivudine.Through in-depth research on the conjugate addition-elimination reaction of1,2-oxazoline and allyl acid derivatives,which is a key step affecting product yield,a new acrylic acid derivative was discovered and prepared.The new acrylic acid derivative constructs the base,and combines the Michael addition-elimination reaction,cyclization reaction,isomerization reaction to synthesize O^2,2-anhydro-β-L-thymidine in a one-pot method.The various reactions involved in the method reaction are optimized.In the Michael addition-elimination reaction,the influence of solvent,base and the amount of 2-acetoxymethyl methacrylate on the reaction was explored.It is found that with methanol:water=1:9 as the solvent,the molar ratio of 2-acetoxymethyl methacrylate to the raw material is 1.7:1,and the reaction yield can reach the highest when alkali-catalyzed reaction is not required.In the cyclization reaction and the isomerization reaction,the effects of the base,the amount of the catalyst and the temperature on the reaction were explored respectively.By exploring the reaction conditions of the steps involved in the synthesis of O^2,2-dehydration-β-L-thymidine by the 1,2-oxazoline one-pot method and the optimization of the entire process,the one-pot method yield was significantly improved,reaching 44.5%.Through the addition cyclization reaction of L-arabinose and cyanamide,the halogenation reaction of diacetyl-2-anhydrothymidine,the reduction reaction of2-bromothymidine,and the reaction of diacetyl-2-deoxythymidine The hydrolysis reaction was optimized in detail,and the optimal reaction conditions for each step of the reaction were determined.In the addition cyclization reaction of L-arabinose and cyanamide,the influence of reaction time,alkali and the amount of cyanamide on the reaction was explored,the optimal reaction conditions were determined,and the yield was increased to 100.0%.In the halogenation reaction of diacetyl-2-anhydrothymidine,in view of the defects in the methods reported in the literature,a new method of halogenation was explored,which used hydrobromic acid and acetic acid solution for ring-opening and bromination.The method is optimized.By exploring the influence of solvent,temperature and the amount of hydrobromic acid acetic acid solution on the reaction,the optimal reaction conditions were obtained,and the yield of the halogenation reaction reached 80.0%.In the dehalogenation of 2-bromothymidine,a new dehalogenation method was used in this paper,using Ranney Ni to catalytic hydrogenation method to explore the influence of solvent and temperature on the reaction.The optimal reaction conditions were determined.The mixed solution of ethyl acetate and water volume ratio of 7:3 was used as the solvent,and the temperature was room temperature.The yield reached 89.4%.In the hydrolysis reaction of diacetyl-thymidine,the reaction yield of the hydrolysis reaction was improved by investigating the influence of solvent and temperature on the hydrolysis reaction.By optimizing the designed synthetic route of telbivudine,this paper successfully developed a cheap and easy-to-obtain raw material,low production cost,low solvent toxicity,green environmental protection,high yield,high product purity,and simple post-processing,A simple synthetic route for telbivudine.