Study On The Novel Process For Synthesis Of Key Intermediates Of Levofloxacin

Levofloxacin, as the forth generation of quinolones, has beenwidely used in clinic treatment because of its‘broad spectrumantimicrobial and low toxicity. Levofloxacin, as the state‘s basic drug, isplaying an increasing important role in reducing the patients‘pain andtreating diseases. Although the demand for levofloxacin was large, theold route of their synthesis have many drawbacks such as more steps,more complicated process, more heavily polluted. So the development ofnew process of preparation of levofloxacin was needed.Based on the references, a novel process parameters of synthesizingthe important intermediates of Levofloxacin,(S)-ethyl-9,10-difluoro-3-methyl-7-oxo-7-dihydro-2H-[1,4]-o-xazino[1,2,3-de]quinoline-6-carboxylate, was studied. To ethyl formate, ethyl acetate, dimethylaminohydrochloride as raw materials, sodium hydride as a catalyst, in one potsynthesize sodium acetoacetate. Then,2,3,4,5-tetafluorbenzoic chlorideadded to sodium acetoacetate, the two materials appeal above viacoupling, S-(+)-2-aminopropanol displacement, cyclization, then obtain the object compound. The process parameters were optimizedexperimentally as follows：n(sodium hydride): n(ethyl acetate): n(ethylformate): n(tetrafluorobenzoyl chloride): n(S-(+)-2-amino-propanol)=1.1:1:1.2:0.95:1.05, the reaction solvent was toluene; theacid-binding agent of cyclization was KF, the match of ethyl acetate andKF is1:2, the reaction solvent was DMF. The total yield of the objectcompound is54%.Two different processes of preparing of ethyl β-dimethylaminoacrylate, the important raw material of Levofloxacin, were described.The first process is ethyl formate route, and the other is CO route. Theparameters were optimized experimentally as follows：the first route,n(sodium hydride): n(ethyl acetate): n(ethyl formate): n(dimethylaminohydrochloride)=1.2︰1︰1.5︰1.5, the reaction temperature is roomtemperature. The yield is44.1present；the other route,means CO route,n(ethyl acetate): n(sodium ethoxide)=1.5︰1, the pressure of carbonmonoxide is2.0MPa, the reaction temperature is50℃, then adddimethylamino hydrochloride to the Reaction system, the mach ofsodium ethoxide and dimethylamino hydrochloride is1︰1, thetemperature is room temperature, the total yield is47.2present.Primary amine react with dicarbonyl compounds to obtain alkenylamine, then the alkenyl amine and azo compound react viaaza-Baylis-Hillman reaction to obtain13compounds via the correspond substituted amine or dicarbonyl compounds in high yield. The yield ofobject componds achieve about90present. The condition of this reactionis moderate to meet the requirements of green chemistry.