Study On The Synthetisis Technology Of Avibactam And Tazobactam

This paper focus on the issue of the preparation of avibactam and tazobactam.The main work was detailed as follow:1.We have accomplished the full synthesis of avibactam and the initial design of the synthesis route. Our synthesis route utilized pyroglutamic acid as starting materials and employed approprate protecting groups to protect it. Following, we introduced sulfur ylide to extent the carbon chain.We used O-benzylhydroxylamine hydrochloride as the nucleophilic reagent to give an 95% yield of ketoxime intermediates. We studied the reduction reaction of ketoxime compounds which is the key to the synthesis route. We use lithium tri-tert-butoxyaluminohydride as catalyst to reduce ketoxime compounds to achieve triple of main product than by-product. We also put forword a new synthesis route for settle the chirality problem. We adopted the saturated ammonia-methanol solution to handle aminolysis reaction, which avoid the problem of the product loss in the water phase when ammonia water was introduced in this reaction, then we let the single-step yield as high as 95%; We employed CDI as coupling reagent to give a higher yield of shrinkage urea compounds. We also introduced Palladium-hydrogen system accompany with sulfur trioxide pyridine complex with the method of one-pot reaction to gain a wonderful sulfonation yield, which makes the production cycle of avibactam shut down.2.This paper keeps a watchful eye on the traditional synthesis process of tazobactam, and we utilized 6-APA as raw material to optimize the whole route, winning an overall yield of 16%. In this paper, we improved the total yield of halogenations, sulfoxidation, esterification, dehydrohalogenation as high as 66%. We employed cesium oxide to catalyze oxidation to achieve a higher reaction yield which was more than 90%. Bromine-nitrosyl positive ions was introduced in this paper to promote the cyclization reaction to complete, which have settled the problem of the incompletion of reaction and the introduction of heavy metals catalyzed by copper halide. We also established the liquid phase conditions to the reaction of thermal rearrangement open-loop、halogenated closed loop and azide substitution. At the same time, We adopted the phase transfer catalyst to shut the reaction time of halogenated cyclization down. We employed azide quaternary ammonium salt as the nucleophilic reagent, which was a new method to the preparation of our intermediate.