| Difluoxacin Hydrochloride & Danofloxacin Mesylate are two kinds of newly-designed fluoroquinolone antibacterials for animals.They are remained with the third category of quinolones.This paper is focused around a systematic research on new synthetic process of Difluoxacin Hydrochloride & Danofloxacin Mesylate,and confirm the product through structure and property analysis.During the newly-designed synthetic process of Difluoxacin hydrochloride, dichlorofluorobenzene &acetyl chloride were chose to be the raw materials;and the total recovery rate is 36.2% after all the esterification,ring closing reaction,hydrolysis reaction,condensation reaction and salt forming reaction; the purity of the product has reached 99.08%, with the confirmation of Infrared analysis , Ultraviolet analysis, HPLC and Element analysis on the property and content of the products.Systematic research on the influences of optimum ratio of reactants,optimum temperature ,time and solvent during all the steps of synthetic process of Difluoxacin hydrochloride. The optimum reaction time is 3h for the synthetic reaction process of 2,4-Dichloro-5-fluoro-acetophenone;the optimum ratio between Dimethyl carbonate(volume)and 2,4-Dichloro-5-fluoro-acetophenone ( weight) is 7:1during the synthetic reaction process of Ethyl2-(2,4-dichloro -5-fluorobenzoyl)acetate;during the synthetic reaction process of enamino ketones and esters,the optimum ratio for acetic anhydride as a solvent(volume)and reactant is 5:3;in the ring closing reaction,the optimum ratio between DMF(volume) and enamino ketones and esters(weight)is 5:1,optimum raction time is 30 minutes;In the two-step hydrolysis reaction , the optimum reaction temperature is 90-100℃and 80℃separately;in the synthetic process of difloxacin,DMSO is a better choice as solvent,with a optimum ratio of 5:1 between DMSO(volume)and Difluo-carboxylic acid(weight). When the ratio between difluo-carboxylic acid(weight)and N-Methyl piperazine(volume)reaches 2:3,total recovery rate is maximum.During the newly-designed synthetic process of Danofloxacin Mesylate,4-Hydroxy-L-proline and 4-toluene sulfonyl chloride were chose to be the raw materials,and the total recovery rate is 36% after all the N-sulfonylation,carboxyl reduction,hydroxyl sulfonylation,ring closing and desulfonylation. While the total recovery rate for the five-step intermediates synthesis of (1S,4S)-2,5-Diazabicyclo[2,2,1] heptane dihydrobromide is 50.0%.The product is proved to be Danofloxacin Mesylate after Infrared analysis , Ultraviolet analysis, NMR and MS analysis of product structure.Systematic research on the influences of optimum ratio of reactants,optimum temperature ,time and solvent during all the steps of synthetic process of Danofloxacin Mesylate:in the carboxyl reduction reaction, the optimum mole ratio between NaBH4 and N-toluene sulfonyl-4- hydroxyl-L-proline is 2:1,the optimum reaction temperature is 0-10℃;in the process of hydroxyl sulfonylation,pyridine is chosen to be the binding solvent with all the reaction going under lower temperature, thus (2S,4R)-1-(4-toluene sulfonyl)-2-(chloromethyl)-4- (4-tosyloxy)pyrrolidine is avoided ;the optimum mole ratio between reactants and pyridine is 1:3;in the ring closing reaction,methylamine, methanol are chosen to be the reactants and acid-binding reagents,and the mole ratio between methylamine and (2S,4R)-1-(4-toluenesulfonyl) -2-(4- toluenesulfonyloxymethyl)-4- (4- toluenesulfonyloxy) pyrrolidine is controlled to be a little higher than 3:1;during the synthetic process of Danofloxacin,the mass ratio between (1S,4S)-2-methyl-Diazabicyclo [2,2,1]heptane dihydrobromide and cyclopropane carboxylic acid optimum is 1:1.6.A pilot scale product of Danofloxacin Mesylate's intermediate (1S,4S)-2-methyl-Diazabicyclo[2,2,1] heptane dihydrobromide was carried out, based on the optimized synthetic process, and the total recovery rate is 41.5% with a steady quality。... |
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