Synthesis Process Of Cefuroxime Key Intermediates

Furan ammonium salt is a key intermediate in the synthesis of the second-generation cephalosporin antibiotic cefuroxime.Cefuroxime has the broad antibacterial spectrum,resistance to?-lactamase,and little side effects on the kidneys.Since it was prepared in 1988,it has become one of the best-selling infectious drugs in the world.With the increasing market requirement of cefuroxime at home and abroad in recent years,the market demand for furan ammonium salt is also increased.However,the synthesis of furan ammonium salt in our country still has some diadvantageds such as restrict production,serious pollution of the wastes,low yield,poor reaction selectivity,and high production cost.In this paper,through a comparative analysis of various synthetic routes of furan ammonium salts,a process route suitable for industrial production is determined.Furan ammonium salt was prepared by four steps which is furan acetylation,selective oxidation,oximation and salt formation.The conditions of each step were optimized,and the best reaction conditions were selected finally.In the process of oxidation reaction,the effects of protonic acid catalyst,reaction temperature and reaction time on the acylation reaction were investigated by orthogonal experiments.Finally:phosphoric acid was as the catalyst,the reaction temperature was 60 ~oC,the reaction time was for 6 h,the yield of 2-acetylfuran reached 82%;and the excess acetic acid and acetic anhydride were recovered by vacuum distillation,which solved the problems of high consumption of acetic anhydride,difficult post-treatment and wastewater pollution in the original treatment process.In the study of acetylfuran oxidation,the catalyst,acid medium and temperature were studied through orthogonal experiments.Finaly:copper chloride was the catalyst,hydrochloric acid as the acid medium,and citric acid as the buffer.The reaction temperature was 65 ~oC.Sodium nitrite solution adopts gradient addition for achieve gradient oxidation technology.The yield reached 87.6%,and the product purity was>97%.In the study of the furanone acid oximation process,the effects of pH,temperature,material ratio and other conditions on the reaction were optimized by the single factor variable method.The optimal molar ratio of acetylfuran and methoxyamine was 1.0:1.2.The pH value of the reaction solution was keeping at 3.0-4.0 by dropping methoxyamine aqueous solution and hydrochloric acid.The reaction temperature was 20 ~oC.The reaction time was 4 h.The selectivity of(Z)-2-methoxyimino-2-furylacetic acid was increased to 90%.The extraction agent chosen butyl acetate,and the extraction rate reaches 98.8%.In the research about the synthesis process of furan ammonium salt,the effect of various crystallization conditions was studied,and ideal crystallization conditions were obtained.20%methanol amine was added dropwise.The salt formation temperature was kept at-5 ~oC.The drop time was controlled to 1 h and kept it warm for 1 h.The yield of ammonium furan salt reached to 71.2%.During the oximation reaction,the trans isomer(E)-2-methoxyimino-furyl ammonium acetate was generated.This paper developed a method to convert the trans isomer to the cis product.Using water as a solvent extracted the trans isomer in the solution after salt formation.The pH value of the reaction solution was controled at 3.0-4.0.Reduced graphene oxide/cobalt tetroxide composite material was as the catalyst.The reaction solution was refluxed at100 ~oC for 6 h.The trans isomers was changed to cis products.The yield of furan ammonium salt was increased from 71.2%to 74.6%.The furan ammonium salt and its intermediates were confirmed and characterized by nuclear magnetic,high performance liquid chromatography and liquid chromatography-mass spectrometry.