Synthesis And Optimization Of Avibactam

The widespread use of ?-lactam antibiotics results that bacteria are prone to produce ?-lactamase,so bacterial resistance threatens human life and safety.Currently,the development of new antibiotics is difficult,so the development of new ?-lactamase inhibitors combined with ?-lactam antibiotics has become an important means to solve this problem.Avibactam is a ?-lactamase inhibitor,which can effectively inhibit Class A,Class C and some Class D?-lactamase.In 2015,US FDA approved the combination of avibactam and ceftazidime for the treatment what severe infections caused by drug-resistant bacteria,its effect is significantly higher than clavulanic acid,sulbactam and tazobactam.Therefore,avibactam will have broad application prospects.However,it is difficult to synthesize avibactam,which hindered industrial production and wider application.This paper aims to optimize the synthesis process of avibactam.First.the starting material of the route is low-cost and readily available,which used to situ the chiral carbons of avibactam sodium.Second,using sulfur ylide to increase carbon and ring-opening of N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester,which avoid the safety problem of diazomethane.Third,separation of isomers by oxalic acid dihydrate avoided problem of column chromatography separation.Fourth,using methyl tert-butyl ether beating the aminolysis product,which avoided the product loss caused by toluene recrystallization.Fifth,replaced expensive 9-fluorenylmethoxycarbonyl with dichlorodimethylsilane.The synthesis reaction conditions are optimized for each small trial and established the HPLC of control standard.The scale was gradually enlarge from the gram to the kilogram.The three batches of 2.50 kg scale L-pyroglutamic acid was performanced,by the benzyl protection,tert-butoxycarbonyl protection,sulfur ylide ring opening,benzyloxyamino hydrochloride condensation,de-tert-butoxycarbonyl,synthesis of piperidine ring,build 5 chiral carbons,isomer resolution,aminolysis,intramolecular ureaization,debenzylation,sulfonation,quaternary ammonium salt and sodium ion exchange,those 15 steps of reaction to obtain avibactam sodium.The average total yield of three batches of kilogram experiments is 18.1%,and HPLC relative purity of final product more than 99.5%.This route has the advantages that few steps,high yield,easy operation and suitability for industrial production.The current work has laid the foundation for the industrial production of avibactam,and it has certain enlightenment and reference significance for the synthesis of diazabicyclooctane compounds,and it provides a guarantee for the further formulation development,preclinical and clinical research from the combined use of avibactam sodium and other ?-lactam antibiotics.