Study On Synthesis Of Marbofloxacin And The Process Improvement

Marbofloxacin is the third generation of fluoroquinolone antibacterial agent with good absorption,low toxic and side effect,broad antibacterial specturm and strong antibacterial activity.Now marbofloxacin is primarly used for treatment of infectious diseases in veterinary clinical and has extensive propest.In the present article,marbofloxacin was synthesized by starting from tetrafluoro benzoic acid and undergoing Michael addition,chloroformylation,condensation,amine exchange,primary cyclization,nucleophilic substitution with N-methyl piperazine,hydrolysis reaction,secondary cyclization and acid-base neutralization.The product and relative intermediates were characterized by HNMR,HRMS,IR and DSC.The quality of prepared marbofloxacin was detected according to European Pharmauopeia(EP)and the results showed the specifications can meet all the requirements.The intermediates involing in the process of marbofloxacin preparation were studied in detail.3-(Benzyl-methyl-amino)-2-(2,3,4,5-tetrafluoro-benzoyl)-acrylic acid ethyl ester,as the product of condensation,can be provided in the purity of 95～98%,thus,the impurities in the subsequent reaction could be avoided.The effect factors of primary cyclization like solvent,material ratios,temperature and time on the product yield were studied in detail,and the yield was imporved form 47.12% to 76.23%.In the process of substitution with N-methyl piperazine,the material proportion was reduced from 1:8 to1:5(molar ratio)by screening acid-binding agent.One important impurities of marbofloxacin were prepared in the hydrolysis reaction,which laid a soild foundation for the quality research of marbofloxacin.The high performance liquid chromatography(HPLC)analysis method for the relative intermediates including the products of condensation,cyclization,N-methyl piperazine substitution and hydrolysis were established,which provided a reasonable and feasible quality monitoring method for marbofloxacin manufacture.The optimized technology has great benefit in the simple operation with the overall yield of 25.16%(based on tetrafluoro benzoic acid)and to be a potential role in industry.