Study On Synthesis And Anti-asthmatic Activity Of 8-nitro Benzyl Pyrazol Substituted Xanthine

ObjectiveOptimize the synthesis conditions of 1,3-alkyl substituted-5,6-diamino uracil(A) and nitro-benzyl-1H-pyrazole-4-carboxylic acid (B).Discuss new reaction conditions of Traube condensation and choose the reaction conditions of the highest yield to Synthesize new 8-nitro-benzyl pyrazole substituted xanthine compounds (C1-C9). The target compounds by elemental analysis, mass spectrometry and nuclear magnetic resonance testing to confirm to the structure, and do preliminary study of anti-asthma activity of target compounds.MethodsChange synthetic routes based on the synthesis of 1,3-alkyl substituted-5,6-diamino uracil and nitro-benzyl-1H-pyrazole-4-carboxylic acid which has been reported by literature. 1,3-dimethyl-urea and cyano-acetic acid were condensation cyclizatio with 10%NaOH to be 1,3-dimethyl-6-amino-uracil in Ac2O, which was electrophilic addition by nitrite to be 1,3-dimethyl-5- nitroso -6-amino-uracil, what was reduced by sodium hydrosulfite to be1,3-dimethyl- 5, 6-diamino-uracil.Filter out the optimum conditions by the single factor experiment of the reaction in the feeding mode, the reaction temperature and reaction time, in order to improve the reaction yield.1H-pyrazole-4-carboxylic acid was synthesized from Ethyl cyanoacetate and Triethyl orthoformate via Claisen condensation, cyclization, deamination and hydrolysis.1H-pyrazole-4- carboxylic acid and nitro-benzyl bromide occurred electrophilic substitution to nitro-benzyl-1H-pyrazole-4-carboxylic acid; improve the reaction yield by changing the reaction of the feed ratio, reaction temperature and reaction time. 1,3-alkyl substituted 5,6-diamino uracil and nitro-benzyl-1H-pyrazole-4- carboxylic acid occurred Traube to the target compounds in the microwave. Improve the yield of target compounds by single factor experiments of the catalyst and reaction mode. The target compounds were confirm by elemental analysis, LiquidChromatography-MassSpectrometry and nuclear magnetic, preliminary study of anti-asthma activity of target compounds were done by Hemetoxylin and Eosin (HE) Staining.ResultsFirst identified the synthesis conditions of 1,3-alkyl substituted 5,6- diamino uracil and nitro-benzyl-1H-pyrazole-4-carboxylic acid and the Traube reaction conditions and improve the yield of each step. The yields of 1,3-alkyl substituted 5,6-diamino uracil were over 90%, the highest has been reported by literature was 75%. The highest yield of the Traube were EDCI as a catalyst in the microwave and Synthesize new 8-nitro-benzyl pyrazole substituted xanthine compounds,the yields were over 80%. Confirmed structure by the analysis LiquidChromatography-MassSpectrometry and nuclear magnetic. Finally, experimental results of asthma rats show that the target compounds with anti-asthma activity.Conclusions8-nitro benzyl pyrazol substituted xanthine were prepared by Traube with 5,6-diamion-1,3-diamethyl uracil and 1-(nitro-benzyl-1H-pyrazol-4-carboxylic acid with EDCI as a catalyst in the microwave,the method had adventage of low cost, safe operation,high yield and suitable for industrial production. The structures were confirmed by 1H-NMR and LC-MS, and have varying anti-asthma activity. 8-(3-nitro-benzyl-1H-pyrazole)-1-methylxanthine was strongest.