Study On The New Synthesis Process Of Tazobactam

Tazobactam is the strongest enzyme inhibitor and the weakest enzyme inducer in clinic so far.It is aβ-lactamase inhibitor with low toxicity,high product stability and high antibacterial activity.The most important thing is that it can be combined with a variety of antibiotics,which can achieve extremely effective synergistic effect.The effect of medical performance is many times stronger than that of all kinds of antibiotics alone.Because of the unique advantages of tazobactam,it is called the most worthy of study.However,there are still many factors that are not suitable for industrial production in the existing synthesis route of tazobactam,such as:the synthesis route is lengthy and complex,the materials used in the reaction intermediate system are expensive,more dangerous and explosive substances are used,the environment is seriously polluted and the final product yield is low.In view of the above shortcomings,the synthesis process of tazobactam was optimized and improved.In this paper,a new synthetic route of tazobactam suitable for industrial production is established,and the synthetic process of its important intermediate is systematically optimized.The overall synthetic process is divided into two parts for in-depth study and the purpose of high efficiency and high quality synthetic route of tazobactam is achieved.The first part:starting from 6-aminopenicillanic acid,the important intermediate diphenyl methyl sulfoxide of penicillanic acid with high yield was obtained through four steps of bromination,single oxidation,esterification and debromination.Potassium iodide sodium tungstate binary composite catalyst system was used to shorten the reaction time and improve the yield of monooxidation products.The second part:the following reactions were carried out with the purified high yield diphenyl methyl penicillic acid sulfoxide was used as the raw material:1)Diphenyl methyl penicillic acid sulfoxideadding and 2-Mercaptobenzothiazole to generate the thermal cracking ring opening reaction to obtain the thermal cracking ring opening product.In this reaction,the mixed solvent with low boiling point is used as the reaction solvent to effectively reduce the reaction temperature and improve the purity of the thermal cracking ring opening product,and the yield is more than 95%.2)2β-triadimethylcyclopenicillanic acid diphenyl methyl ester was obtained by the reaction of the ring with hydrochloric acid,sodium nitrite and 1H-1,2,3-triazole,respectively.3)2β-triazolylcyclopenicillin diphenyl methyl ester and the dual oxidant potassium permanganate undergo a double oxidation reaction,In the process of the reaction,the optimization of the reaction solvent accelerated the reaction rate and increased the yield of the product,and explored the influence of different oxidants on the yield of the product.4)Finally,the product tazobactam was obtained by decarboxylation of the product of double oxidation and the deprotection reagent m-cresol.In this reaction,the optimal p H value was explored to acidify the reaction solution,so as to achieve the best effect of the product separation and obtain the final product tazobactam with high purity and yield.The overall synthesis process is beneficial to industrial production and meets the production requirements of green chemistry.The total yield is 13.4%,and the purity is94.12%.The products of tazobactam and its key intermediates were characterized by melting point determination,IR,~1HNMR and so on.It was confirmed that tazobactam,an important intermediate and its target product,had been successfully synthesized.