Study On Synthesis Of Oxacephem Intermediate And Route Optimization

With its high growth and good clinical performance,cephalosporins gain more and more share in the global anti-infective medicine market.After the subtantial development since last 80′s,cephalosporin industry has been developed more rapidly in China,the demand of each cephalosporin intermediate increases quickly.However, there are many problems existing in the intermediate production in China,such as defective process,serious pollution and high cost.So there should be a broad market prospect for the research of cephalosporin intermediates.The fundamental structure characteristics and function mechanism ofβ-Lactam antibiotics are described briefly in the paper,and also the structure-activity relationship of semi-synthetic cephalosporin antibiotics is introduced.The synthesis process and synthesis conditions of oxacehem nuclear parent are researched particularly.Four parts are included as follows:First,Synthesis of penicillin sulfoxide ester:penicillin sulfoxide ester that includes different protecting groups synthesized by 6-Aminopenicillanic acid and penicillin G potassium salt respectively.Second,Isomerization of penicillin sulfoxide ester:Isomerization of diverse penicillin benzhydryl sulfoxide ester catalyzed by alkali is studied.The effect of alkali, reaction temperature,and reaction time of isomerization is investigated.Under the optimum conditions,conversion rate of 6-β-benzoylamino-penicillin benzhydryl sulfoxide ester could reach 77.50%.Third,Synthesis of isopropenylepioxazoline:Isopropenylepioxazoline is synthesized by 6-α-benzoylamino-penicillin benzhydryl sulfoxide ester or 6-α-phenylacetamino-penicillin benzhydryl sulfoxide ester,with the consideration of the effects of various desulfidation reagent,reaction temperature,catalyst,solvent and crystallization,finally confirmed 6-α-benzoylamino-penicillin benzhydryl sulfoxide ester as reactant.Fourth,Chlorination of isopropenylepioxazoline:The solubility of chlorine in different solvent and equivalent of chlorine takes part in reaction was investigated. Flowmeter was applied to control the equivalent of chlorine.It's determined the best route and each step of the synthesis posesses the goal of cutting cost,simplifying operation procedure and improving yield by experiment research.The products are characterized by applying of ~1H-NMR,IR,Ms.And the molecular formula has been confirmed.Meanwhile,the melting points of them are estimated.