Study On The Synthesis Of β-Enamioesters As The Important Intermediates Of Levofloxacin

Quinolones is a kind of important antibacterial medicine. Levofloxacin,as one of the best quinolones,have been widely used in clinic treatment because of its' broad spectrum antimicrobial and low toxicity.Although the demand for levofloxacin was large,the old route of their synthesis have many drawbacks such as more steps,time consuming, more foreign matter and poor yield.So the development of new process of preparation of levofloxacin was needed.The preparation and application of important intermediates,ethylβ-dimethylamino acrylate,in the new process of synthesizing levofloxacin was studied.An efficient synthesis of variousβ-enaminoesters has been achieved via Reformatsky reaction with disubstituted formamides as novel electrophiles in this thesis.A new process of preparing of ethylβ-dimethylamino acrylate was described.To ethyl formate,ethyl acetate,dimethylamino hydrochloride as raw materials,sodium hydride as a catalyst,in one pot synthesize objective product.Inspect some factors detailed,the factors included the solvent,the match of raw materials,the catalyst and so on.Based on a large number of experimental contrasts,the optional experimental conditions are as follows:the solvent is toluene,sodium hydride is the catalyst,ethyl acetate:sodium hydride:ethyl formate:dimethylamino hydrochloride=1:1:1.2:1.2,the reaction temperature is room temperature. The yield is 73 present.The product were identified by IR,GC-MS and HNMR.When dimethylamino hydrochloride was substituted by others amino hydrochloride,various ofβ-enamioesters were prepared. Interestingly,the secondary amine gave the products of E-isomers,while the primary amine gave the mixture of E and Z isomers.The object compound,intermediate of Levofloxacin,was prepared from 2,3,4,5-tetafluorbenzoic chloride,via ethylβ-dimethylamino acrylate coupling,S-(+)-2-aminopropanol displacement,cyclization,the total yield is 65%.This process have shorted the synthetic route,cut down the consumption of the raw material,decurtated the reaction time, increased the yield of reaction and simpled the postprocessing,so this is a kind of economic synthesis method of levofloxacin.β-enaminoesters was synthesized via highly stereoselective Reformatsky reaction with disubstituted formamides as electrophiles.The experimental conditions are as follows:the solvent is toluene, disubstituted formamides:a-haloesters:Zn dust=1:2:4.The yield is 60-72 present.The exclusiveβ-enaminoester E isomers were prepared.