Study On The Synthesis Process Of 1,3,7,9-tetramethyluric Acid

The major purine alkaloids in tea include caffeine,theobromine,theophylline,1,3,7,9-tetramethyluric acid(Theacrine).The basic structure of the four purine alkaloids is the purine ring,but the position of methylation or oxidation in the purine ring is different.The biological activity of purine alkaloids in tea is very abundant.The study on biological activity and mechanism of caffeine,theobromine and theophylline was more and all widely used in clinical therapy.1,3,7,9-tetramethyluric acid also has good biological activity,such as: anti-inflammatory and analgesic,anti-depressant and sedative and hypnosis.However,the study on the biological activity and mechanism of 1,3,7,9-tetramethyluric acid is relatively few,and the research is mainly by the domestic scholars.1,3,7,9-tetramethyluric acid mainly exist in Camellia assamica var.kucha.The method of obtaining 1,3,7,9-tetramethyluric acid mainly depends on extracting from Camellia assamica var.kucha.but the resources of Camellia assamica var.kucha are limited,the extraction process is complicated and the cost is high.Finding a method to synthesize 1,3,7,9-tetramethyluric acid is very important for the study of its biological activity and mechanism.In this paper,The main research work is:(1)1,3-dimethylbarbituric acid were synthesized by dimethyl malonate and 1,3-dimethylurea as raw materials,and the ratio of raw materials and reaction temperature were optimized.The optimum reaction conditions were as follows: the ratio of raw materials of dimethyl malonate and 1,3-dimethylurea was 1:1.1.The reaction temperature was reflux temperature.The structure was characterized by IR,1H-NMR and 13C-NMR.(2)The 6-chloro-1,3-dimethyl pyrimidine-2,4-diketone was synthesized by the 1,3-dimethylbarbituric acid and phosphorus oxychloride as raw materials.The optimum reaction conditions were optimized as follows: the halogenated reagents was phosphorus oxychloride,the ratio of raw materials of 1,3-dimethylbarbituric acid and phosphorus oxychloride was 1:13,the temperature is the reflux temperature.The structure of compound 2 was characterized by IR,1H-NMR and 13C-NMR.(3)The 1,3-dimethyl-6-methylaminopyrimidine-2,4-diketone was synthesized by the reaction of 6-chloro-1,3-dimethyl pyrimidine-2,4-diketone and methylamine.The reaction temperature and the ratio of raw materials were optimized.The optimum reaction conditions were as follows: the ratio of raw materials of 6-chloro-1,3-dimethyl pyrimidine-2,4-diketone and methylamine was 1:2,And the reaction temperature was room temperature.The structure was characterized by IR,1H-NMR and 13C-NMR.(4)1,3-dimethyl-5,6-dimethylaminopyrimidine-2,4-diketone was synthesized in two steps by the synthesis of 1,3-dimethyl-6-Methylaminopyrimidine-2,4-diketone as starting material.The halogenated reagent was optimized for the reaction,and the selected halogenating agent was N-bromosuccinimide.(5)The target product 1,3,7,9-tetramethyluric acid was synthesized by the reaction of 1,3-dimethyl-5,6-dimethylaminopyrimidine-2,4-diketone and triphosgene.The reaction temperature and the ratio of raw materials were optimized.The optimum reaction conditions were as follows: The reaction temperature was 30 ?,the ratio of raw materials of 1,3-dimethyl-5,6-dimethylaminopyrimidine-2,4-diketone and triphosgene was 1:1.2.The structure was characterized by IR,1H-NMR,13C-NMR and LC-MS.1,3,7,9-tetramethyluric acid was successfully synthesized by the the above steps.the reaction yield was 38.33%.The cost of drugs was about 56.48 yuan/g.The reaction yield is high,the separation and purification is simple,the raw material is cheap and easy to obtain.The successful synthesis of 1,3,7,9-tetramethyluric acid solves the difficult problem of its extraction,which is great significance for its in-depth study.