Improved Synthesis Of Gemifloxacin

Gemifloxacin,7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-1,8-naphthyridine-3-carboxylic acid,is one of the new fluoroquinolones,which had been synthesized by LG Pharmaceutical company of Korea.This product has not been marketed and produced domestically in this time.On the bases of available data,the synthesis of gemifloxacin were deeply studied in this paper.7-branched-chain is the most important part of the quinolones,and it has the decisive influence to the pharmacology activity.This paper importantly researched synthesis of 7-branched-chain,and synthedized gemifloxacin by means of the borate chelate.(1)According to the known synthestic methods of gemifloxacin,a synthesis route was established.7-branched-chain was synthesized from starting material acrylnitrile and glycine ethyl ester hydrochloride.After nucleophilic addition,amino protection,condensation and reduction,then amino protection,oxidation,oximation and deaminate,7-branched-chain was synthesized.In the end,gemifloxacin was synthedized by means of the borate chelate. (2)Intermediates including N-(2-cyano-1-ethyl)ethyl ester, 3-eyano-1(N-Boc)-pyrrolidin-4-ketone,3-(N-Boc)aminomethyl-1-(N-Boo) pyrrolidine-4-alcohol,3-(N-boc)aminomethyl-1-(N-boc)pyrrolidine-4-ketone, 3-aminomethyl-4-methoxy imino pyrrolidine and the end product Gemifloxacin were prepared,meanwhile,each product were characterized.(3)Reduction stage of synthesis was improved.Using KBH₄ as reducer and ZnCl₂ as Catalyst,yields of the reaction was increased, compared with using LiAlH₄ as reducer.And production cost was reduced.(4)On the basis of investigating effects of catalyst amount,solvent volume,reaction time and temperature,reaction conditions of intramolecular Claisen condensation were optimized by uniform experiment.Under the optimum conditions,the yield of 3-cyano-1(N-Boc)-pyrrolidin-4-ketone was 89.4%.(5)In the oxidation stage,reaction rate is controlled by the feeding rate of Jones reagent.Reaction yield achieved 81.6%,adding acetone to reaction system.(6)The extensive literature and information search indicated that we use dried HCl as deprotection,which overcame harsh reaction condition in the patent.(7)Gemifloxacin was synthedized by means of the borate chelate. Meanwhile,main linked factors in last step were studied.Under the condition of optimum technological parameters,the yield is about 80.5%.