Synthesis Of Cephalpsporins Intermediates Side Chain Acid

Cephalosporins is the most widely applied and the largest used antibiotics in theword. In our country, Cephalosporins has a great market, it is the focus of competitionin the drug market.2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid and (Z)-2-(methoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl) acetic acid are the importantintermediates of many third and forth Cephalosporins. Their researches have great economic and practical value. This paper explores the new technology of2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid and (Z)-2-(Methoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl) acetic acid on the basic of literature. Thepaper is divided into the following parts to discuss.1. Ethyl acetoacetate is used as raw material, though the Oximation, Methylation, Halogenation, Cyclocondensation and Hydrolyzation,2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid is successfully synthesized. Each steps isoptimized. The results are shown as followed.Oximation.sodium and sulfuric acid is used as Oxination agent. The ratio ofEthyl acetoacetate and Oxination agent is1:1.1, the reaction time is3h and thereaction temperature is10-15degree.Methylation. Dimethyl sulfate is used as Methylation agent and sodiumcarbonate is used as Acid blinding agent. Without the use of phase-transfer catalyst,Methyl and Water were used as component solvent. The reaction time is3h and thereaction temperature is40degree.Halogenation. Sulfuryl chloride and Bromine are used as Halogenation agent. In thereaction of chlorination, the solvent is dichloromethane. The ratio of Ethyl acetoacetateand Sulfuryl chloride is1:0.9. The reaction time is4h and the reaction temperature is50degree. In the reaction of Bromination, hydrogen peroxide is used to oxidize thebromine hydride, the generated bromine can take part in reaction again. By this way,the dosage of bromine is saved. The best ratio of Ethyl acetoacetate, bromine and hydrogen peroxide is1:0.8:0.5.Cyclocondensation. Chlorinated product and Brominated product are used as rawmaterial of Cyclocondensation, and compare the finial product. Calculate by Ethylacetoacetate, the final yield of Chlorinated product is46.8%, and the final yield ofBrominated product is55.4%.2.(Z)-2-(Methoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl) acetic acidAcetic Acid is synthesis from tert-Butyl acetoacetate by the steps of Oximation,Etherification, Chlorination, Cyclocondensation and Hydrolyzation. On the basic of2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid, some brief exploration havedone to its conditions. In the Oximation, the Oxination agent is sodium nitrite andethylic acid. In the Etherification reaction, potassium carbonate is used to insteadsodium catbonate. DMF and dichloromethane is used as reaction solvent. Compare withsodium catbonate. It has higher conversion. Sulfuryl chloride is used as Chlorinationagent. Then, the Cyclocondensation happens in the solvent of DMF and ethanol.Calculate by tert-Butyl acetoacetate, the final yield is35.5%. In the reaction ofHydrolyzation, the influence of temperature is explored. The reaction temperature is10degree, and the yield is91.3%.