Studies On The Synthesis Of Cefepime Dihydrochloride

The fourth-generation cephalosporins are currently available or under development for clinical use. They have a broader spectrum of antibacterial activity than the third generation cephalosporins and they are more active in vitro against Gram-positive aerobic bacteria. In addition, the fact that the fourth-generation cephalosporins are stable to β-lactamases mediated by many of the common plasmid and chromosome, and that they are poor inducer of β-lactamases, and that they are faster drug penetration through the mebrane of Gram-negative bacilli because of having an extra positive charge on the cephem molecule indicates the fourth-generation cephalosporins are useful for treatment of infections resistant to earlier cephalosporins. Cefepime is a fourth-generation paranteral oximine-type cephalosporin that has excellent activitity against both Gram-positive and Gram-negative aerobic bacteria.In this paper, cefepime dihydrochloride was synthesized from 7-aminocephalosporins (7-ACA) in one pot with a new synthesis method. In this method, the amido and carboxyol of the 7-ACA was protected by reaction with 1,1,1,3,3,3-hexamethyldisilazane (HMDS), then the protected 7-ACA reacted with TMSI and N-methylpyrrolidine (NMP) gained compond(IV). Then removed the protected groupand reacted with hydrogen chlorine, then gained compond(V). Whereafter the compond (V) reacted with compond (VI) in one pot yielded Cefepime( I). The crude sample was recrystaled with acetone. The content of the Cefepime dihydrochloride was higher than 99% detected by high performance liquid chromatography (HPLC). So the method we used was easy and the material can get easily. In this method, the condition of the reaction was soft and the yield of the Cefepime dihydrochloride was higher than in other methods.In the literatures, the solvent is 1,1,2-trichlorotrifluoroethane (Freon TF) in the course of sythesis of compond(V). Considering 1,1,2-Freon destroyed the ozone in the aerosphere we researched a series of solvents. Then we confirmed dichloromethane (CH2Cl2) and Cyclohxane and deeply studied the reaction in CH2Cl2 and Cyclohxane. The yield of the Cefepime dihydrochloride in Freon TF, CH2Cl2 and Cyclohxane was24.4%, 17.5% and 15,8% respectively. Whereas the yield was lower both in CH2Cl2 and Cyclohxane than in Freon TF, we prefer CH2Cl2 and Cyclohxane to Freon TF as the reaction solvents. Then we studied the process of the reaction and confirmed the best condition in CH2Cl2 and Cyclohxane. And the conditions of the reaction had been extensively explored.In the last, the structure of the title compound-cefepimedihydrochlorid was confirmed with element analysis (EA), infrared spectrophotometry(IR) N urtraviolet spectrophotometry (UV), nuclear magnetic resonance spectrophotometry (NMR) including 1H-NMR and 13C-NMR and mass spectrophotometry (MS). Then we demonstrated that the title compound we obtained was Cefepime dihydrochloride for sure.