Study On The Process Of Preparing Cefepime Hydrochloride

Cefepime hydrochloride is the fouth-generation cephalosporin drugs developed by BMS company in the 1990s.Its synthetic method was first reported in 1983. It is first listed on the market in Sweden in 1993 as the first fouth-generation cephalosporin.At present it has been used in the clinical treatment of bacterial infections diseases. Cefepime hydrochloride is a very promising treatment infected medicine with wide external antimicrobial activity covering spectrum of gram-positive and gram-negative bacterium.At present the literature's methods still have some shortcomings such as long reaction time,high reaction temperature, rigorous reaction condtions,poor product quality and so on.So the target of this paper is to improve the prosess route of synthesizing Cefepime hydrochloride. 1,l,l,3,3,3-Hexamethyldisilazane(HMDS) is replaced by trimethylchlorosilane(TMSCl) so as to shorten the reaction time and lower reation temperature.Freon TF and cyclopentane mentioned in the literature are displaced by low-cost dichloromethane as the solvent of silylanization and iodine displacement in order to reduce reaction time. The traditional single solvent of N-phenylpyrrolidine displacement is replaced by dichloromethane mixed with cyclopentane.The new mixed solvent improve product quality and avoid a lot of△2 isomers.In this paper,key intermediates 7-amino-3-[(1-methyl-1-pyrrolidino)methyl]ceph -3-em-4-carboxylate hydrochloride(7-MPCA) is synthsized from 7-ACA by one-pot procedure:protected by silane, replaced by iodine, N-phenylpyrrolidine displacement, romove the protected group, form salt.Whereafter the copound 7-MPCA reacts with AE active ester yielding Cefepime hydrochloride. The content of the Cefepime hydrochloride is higher than 99% detected by High performance liquid chromatography after recrystallization.It is prepared in overall yieled of 63% from 7-ACA.In this paper, the best reaction conditions were selected by analyzing the experiment conclusion.Reactant ratio: the reactant dosage of trimethylchlorosilane, trimethyliodosilane and N-phenylpyrrolidine is respectively is 2.8, 1.8 and 1.6 refer to 7-ACA.The reaction temperature and time: the optimal silicon alkylation reaction temperature is 45℃, the optimal reaction time is 2.5 h; the optimal iodine displacement reaction temperature is 0℃, the optimal reaction time is 2.5 h; the optimal NMP replacement reaction temperature is - 10℃, the optimal reaction time is 1 h;The condensation conditions of 7-MPCA with AE active ester: the reactant ratio of 7-MPCA with AE active ester is 0.9; Solvent ratio of acetone mixed with water is 4.0.In the last,the structure of the title compound of Cefepime hydrochloride is confirmed with element analysis (EA),infrared spectrophotometry(IR),urtraviolet spectrophotometry(UV),nuclear magnetic resonance spectrophotometry(NMR) including 1HNMR and13CNMR,mass spectronhotometry(MS) and so on.Then we demonstrate that the title compound we obtained is Cefepime hydrochloride.