Research On The Synthesis Of ?-thymidine

?-thymidine?Thymidine?,also called 2-deoxy-thymidine,is a natural deoxynucleosides,used as pharmaceutical intermediate for the synthesis of anti-HIV drugs?such as zidovudine?.With the rapid growth of AIDS,the demand of?-thymidine is increasing.At present,2-deoxy-D-ribose route is the mainly synthetic route of?-thymidine,yet this condensation process could produce?and?isomers at the same time.In order to obtain high content of active?configuration,F-C catalyst such as SnCl₄,HgCl₂,etc.are often used.But this process will not only cause post-processing emulsification problem,but also produce much heavy metal waste water.In industry alcoholysis reaction,inorganic alkali catalysts such as sodium hydroxide,potassium carbonate and sodium methoxide are used.Although they have high catalytic activity,they will introduce cations thus cation exchange resins are needed to remove the impurities.The activation of the resins will produce waste acid water and cause certain pollution.So study and improve the synthetic process of?-thymidine have vital significance.In this paper,1-chloro-2-deoxy-3,5-di?-O-p-chlorobenzoyl?-D-ribofuranose was used as a raw material to react with trimethylsilyl protected thymine,thus?-2-deoxy-3,5-di?-O-p-chlorobenzoyl?thymidine was prepared by Silyl-Hilbert-Johnson reaction.Then?-thymidine was synthesized by the alcoholysis reaction.We focused our study on the synthesis process of generating C-N glycosidic bond?Silyl-Hilbert-Johnson reaction?.Reaction factors,such as molar ratio of the reactants,catalyst,reaction temperature and solvents were optimized.In order to remove?-type byproduct,the method of reprocessing has also been optimized.Experiments results showed that high production of?-thymidine could be obtained without F-C catalyst When chloroform was used as a solvent,the reaction temperature was 20?,and trimethylsilyl protected thymine/chlorinated sugar at a molar ratio of1.1/1.0.In order to remove?-type byproduct and other impurities,the optimized preservation temperature was set at 5?,with 30%acetone aqueous.According to the experiments,it was believed that in weaker or nopolar solvents the reaction mainly followed the S_N1 mechanism with 3-position protecting group participated.When to deprotect the acyl group,ammonia,organic base of triethylamine,diethylamine were innovatively used to replace traditional inorganic base such as sodium hydroxide,potassium carbonate,sodium methoxide,etc.thus a cation exchange resin could be avoided,and recycled catalyst could be applied.This process would be green and meaningful.Results showed that the optimized factors are followed:diethylamine amount was 10%to 15%,temperature was controlled at 60⁶5?,reaction time was 4⁶ h,the preservation temperature was 30?,and the quantity of acetone was 100 mL.The two-step total yield was 79.00%.Based on the experiment results,we conducted pilot test.It showed the results were consistent with that of the experiment.Our work provided the theoretical basis for the industrial production of?-thymidine.