Optimal Process For Producing Pazufloxacin, A New Quinolone Antibacterial Agent

Pazufloxacin is a structurally unique new fluoroquinolone antibacterial agent,which has just been sold in the international market, belongs to the second newmedicine in civil and will occupy the great civil market with the professional survey.So it will be worth of optimizing the process for synthesis of pazufloxacin. In thiswork, we mainly carried out the following aspects of research works :1. Pazufloxacin was synthesized , based on the commercial available(5)-9 ,10-difluoro-3-methyl-7-oxo-2 ,3-dihydro -7H - pyrido [1 ,2 ,3-de ][1 ,4 ]benzoxazine-6-carboxylic acid ester with mucleophilic substitution,decarboxylation, cyclopropylation , hydrolysis and Hoffman reaction. Byoptimizing the process, the total yield has been 35.9%. The intermediates andthe pazufloxacin was characterized by IR, Mass Spectrum and 1H-NMR.2. HPTLC (high-performance thin layer chromatography) was used as the method for monitoring the course of mucleophilic substitution. The high-performance silica gel plate was used as the chromatography carrier, the developing agent was prepared by methyl alcohol, trichloromethane, acetic ester, stronger ammonia water with the scale of 3:7:0.5:0.5, the sample was composed of reactive liquid (3 drops) and methyl alcohol (10 drops),and the optical checking was used to identify the character of the product. The Rf (ratio to front) of raw material is 0.905, and that of product is 0.604.3. The research emphasis was placed on the synthesis of (S)-10-(cyanoethoxy carbonylinethyl)-9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1 ,2 ,3-de ] [1,4]benzoxazine-6-carboxylic acid ester. The reaction mechanism of mucleophilic substitution was analysized and the key factors influencing the mucleophilic substitution in this reaction system were studied .Finally,the optimal process condition was detailed as: reaction temperature 55℃, feed temperature 55℃, reaction time 6.25 hours, M(raw material) : M(ethyl cyanoacetate) :M(catalyst K) =1:6.94:5.94, solvent of DMF 14ml (based on 0.005mol of raw material) .4. The result of two parallel experiments was similar .Compared with other papers' yield, that has been enlarged under the optimum condition by about 5%.The research showed that the process of synthesis of pazufloxacin can be realized with the more simple operation and the better yield can be gained, which builds the base of commercial process of pazufloxacin.