The Synthesis Of Benzhydryl 7?-[(pheny Lacetyl)Amino]-3-[4-(1-methyl-4-pyridinio)-2-thiazolythio]-3-Cephem-4-carboxy Late Iodide

Methicillin-resistant Staphylococcus aureus(MRSA)is a variant of Staphylococcus aureus,clinically,it is not only resistant to penicillin,also has a strong resistance to semi-synthetic penicillin methicillin,the infection spread almost all over the world,is a serious threat to human life and health.The current control and treatment of drugs against methicillin-resistant Staphylococcus aureus have some limitations,there is an urgent need for a new effective control and treatment of drugs.In 2010,the US Food and Drug Administration approved a new cephalosporin drug-Ceftaroline fosamil.Ceftaroline fosamil is a fifth-generation cephalosporins,with broad-spectrum antibacterial,is efficient to treat Gram-negative bacteria and most Gram-positive bacteria,especially for methicillin-resistant Staphylococcus aureus.It has important social and economic significance for the synthesis of Ceftaroline fosamil and its intermediates.In this paper,the synthesis of Ceftaroline fosamil intermediate 7?-phenylacetamido-3-[4-(1-methyl-4-pyridinium)-2-thiazolylmercapto]]-3-cephem(BPMPCCI):3-hydroxyl cephalosporin as the starting material,through the C-3 activation,and then connected to the three-side to synthesize BPPCC,and finally through the A And other processes to synthesize the target product BPMPCCI.The main contents are as follows:(1)In the process of synthesizing BPMCC at the C-3 position of 3-hydroxy cephalosporin,methyl sulfonic anhydride was used as the substitution reagent,and the factors such as solvent,acid binding agent,reaction temperature,feed ratio and reaction time were investigated.he optimum conditions were determined.The products were characterized by nuclear magnetic resonance(NMR),and the purity of the product was analyzed by high performance liquid chromatography(HPLC).The yield of product BPMCC was 95.0%.(2)In the process of connecting the 3-side side chain to synthesize BPPCC.We used a two-step method:the first step using PTT to synthesize PTTS,comparing the two synthetic PTTS mehods.In the first scheme,sodium hydroxide was used as the conversion reagent.The effects of solvent,temperature,sodium hydroxide concentration and reation time on the yield of the target product were investigated.The optimum reaction conditions were determined and the yield were 80.1%.In the second solution,sodium ethoxide was used as the conversion reagent.The effects of solvent,temperature,feed ratio and reation time on the yield of PTTS were investigated.The optimum reaction conditions were determined.Under the conditions,the optimum yield was 89.5%.After comparing the two schemes,PTTS was synthesized by ethanol sodium method.The second step was to synthesize BPPCC by using BPMCC to react with PTTS.The factors such as reaction solvent,raw material adding order,reaction temperature,feed ratio and reaction time were investigated.The optimum conditions for the reaction were determined.The product was characterized by NMR and the purity of the product was determined by high performance liquid chromatography.The yield of the target product BPPCC was 84.0%.(3)In the methylation reaction synthesis BPMPCCI process,we use methyl iodide react with BPPCC to synthesize BPMPCCI.The effects of solvent,reaction temperature,feed ratio and reaction time on the yield of BPMPCCI were investigated.The structure was characterized by nuclear magnetic resonance(NMR)and mass spectrometry.The purity of the product was analyzed by high performance liquid chromatography(HPLC).The yield of BPMPCCI was 96.0%,and the total yield was 76.6%.