Synthesis Of Prulifloxacin And Route Optimization

In the recent years,the research on quinolone antibacterial agents is developing very quickly.It has received more and more attention from all over the world and becomes the star of the Anti-infection drugs.The first generation of quinolone antibacterial agents is synthesized in 1962 and the fourth generation has been reported. Some experts foresee that quinolone antibacterial agents would be one of the fastest-growing category of drugs in the global pharmaceutical market.Though the fourth generation appears on the market later,it becomes a popular drug quickly in clinical use due to its excellent property.The annual sale rises obviously.Prulifloxacin is the drug belonging to the fourth generation of quinolone antibacterial agents with the characteristic of broad-spectrum,high-efficiency, low-toxicity and safety,which hasn't cross-resistance with other antibacterial drugs and is high cost-effective.It is one of the good drugs which can be researched and developed at present and not belong to delict.In this thesis,the function mechanism and the structure-activity relationship of the quinolone were reviewed based on the latest progress in this field and synthetic route of prulifloxacin reported in the literatures was summarized.On the basis of reducing costs,simplifying operations,improving yield,energy saving and environmental protection,the following synthetic route is choiced:3,4-Difluoro-aniline as start material reacted with carbon disulfide and ethyl chloroformate,and then 3,4-difluoro-phenyl isothiacyanate(6)was got.In this step, cheaper,less toxic dichloromethane replaceed chloroform as solvent,so that the yield increased to 85.4%from 74%.This ester reacted with ethyl malonate to potassium 1-(3,4-difluorophenylamino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxoprop-1-ene-1-thiolat e(7).In the course of ethylation of(7),the yield increased to 99.2%from 92%by controlling the appropriate temperature,and then reacted with xylene to ethyl 2-(ethylthio)-6,7-difluoro-4-hydroxyquinoline-3-carboxylate(9).Then the compound above was deprotected by hydroxyl,chloridized and cyclized to ethyl 6,7-difluoro-1-methyl-4-oxo-1, 4-dihydro-1,3]thiazeto[3,2-a]quinoline-3-carboxylate;3-hydroxybutan -2-one as material reacted with bis(trichloromethyl)carbonate and in the post-processing methyl tert-butyl ether was used as extractant instead of ehtyl ether. The yield increased to 36.5%from 25%.Then the compound above reacted with N-bromosuccinimide to 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one.Reaction conditions in each step are optimized and the reaction yield is improved. These efforts lay the foundation for industrial production.Structures of these intermediates are confirmed by applying of ¹HNMR,¹⁹FNMR,EI-MS methods.