Synithesis Of The Methoxy Cephalosporins Intermediate And Exploration Of Cefotetan Precursors

In this paper,the development of antibiotics agengts ofβ-lactam antibiotics was described.The synthetic routes of Cefotetan and its precursors was introduced and put the emphasis on the key intermediate 7α-Methoxy-7β-Amino-3-[(1-methyl-1H-tetrazo-5-yl)thiomethyl]-3-Cep hem-4-carboxylic acid diphenylmethyl ester(7-MAC),other intermediates, the key raw materials diphenyldiazomethane(DPM)and 4-tolysulfenyl chloride(TSC).During the course of exploration about the synthetic technics,the methods of synthesized DPM by using the different sorts of oxidants had been systematically studied and it concluded hydrogen peroxide as the oxidant was an efficient,clean innovation technology.By orthogonal optimizing experiments,7-AMCA was synthesized by using 7-Amino cephalosporanic acid(7-ACA)and 5-mercapto-1-methyl-1,2,3,4-tetrazole (5-MMT)as the materials in the solvent and the intermediate 7-DAMC was synthesized through the carboxyl protection by using DPM as esterification reagent.On the basis of 7-DAMC as raw material,three different routes of preparing 7-MAC were studied and compared.The experimental results showed:1)a Clean production process of synthesis DPM with the H₂O₂ as oxidant was successfully explored,and the optimized experimental conditions were obtained through orthogonal experiments.The yield of DPM was 90.83%based on benzophenone hydrazone and the purity was 94.25%;2)7-AMCA was synthesized by using 7-Aminocephalosporanic acid(7-ACA)and 5-mercapto-1-methyl-1,2,3,4-tetrazole (5-MMT)as the materials,the acetic acid used as the solvent,the methylsulfonic acid used as the catalyst.The yield of 7-AMCA was 73.93%based on 7-ACA and the purity was 97.15%.By using 7-AMCA as material,7-DAMC was synthesized by using DPM as carboxyl protection reagent.The yield of 7-DAMC was 48.72%based on 7-AMCA and the purity was 97.93%;3)It was benefit to choose TSC and aromatic aldehydes as amino protection reagents.7-DTMC was synthesized by using 7-DAMC and TSC,and the optimized experimental conditions were obtained through orthogonal regression experiments.The yield of 7-DTMC was 77.62%and the purity was 97.101%;4)The key intermidiate 7-MAC was synthesized by using 7-ACA as original material and the yield was 17.7%based on 7-ACA;5)The synthetic route of Cefotetan precursors should choose 7-MAC and BrCH₂COBr as raw materials through condensation and hydrolysis process and it was well worth to further in-depth study.Through the experimental research,7-MAC was successfully synthesized and the experimental reaction conditions of key materials and some important intermediates were optimized,especially for the heavier pollution steps having made an improvement on them.Through this research projects,it had provided possibility for the industrial production.