Study On New Synthesis Process Of Ceftazidime And Ceftolozane

Cephalosporins have strong antibacterial activity and small side effects.They are broadly used in clinic to treat different kinds of diseases caused by bacterial infection.With the increasing demand for cephalosporins,the development of their synthetic processes has also attracted more and more attention.In this paper,the synthesis process of ceftazidime among the third generation cephalosporins and ceftolozane among the fifth generation cephalosporins were studied and optimized.The first is the synthesis of ceftazidime.Its structure is mainly divided into three parts: the cephalosporin nucleus,the 3-position pyridine group and the 7-position thiazole group.By analyzing its synthetic raw materials of 7-amino cephalosporanic acid(7-ACA)and 7-phenglacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester(GCLE),7-ACA with simple process and high synthesis yield was preferentially selected as the ceftazidime starting material.Ceftazidime was obtained through nucleophilic substitution reaction,amide condensation reaction,hydrolysis reaction and crystallization purification process.While opening the process route,HPLC was used to test the purity of the key intermediates of ceftazidime.Factors such as feed ratio,crystallization solvent and p H value that affected the yield and purity were analyzed.The optimized yield of each step was greater than 70%,the impurity content of the final product was less than 2.0%,and the total yield reached 47%.According to the standard of pharmacopoeia,a preliminary quality study was carried out on the synthesized ceftazidime.Next is the synthesis of ceftolozane.Its structure is similar to ceftazidime,including the cephalosporin nucleus,the 3-position pyrazole group and the 7-position thiadiazole group.In this paper,using GCLE as the starting material,the 7-position amino protecting group was removed,and the activated(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((1-(tertbutoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetic acid(TATD)underwent an amide coupling reaction.By screening different activators,the synthesis yield exceeded 90%.The 3-position of the cephalosporin nucleus underwent C-N coupling reaction with the pyrazole group,and the synthesis yield was increased to 65% by single factor optimization.The amino and carboxyl protecting groups were removed to obtain ceftolozane trifluoroacetate.Through the research on the synthesis of ceftazidime and ceftolozane,the process parameters are optimized,the yield and quality of raw materials are improved.It is beneficial to the development of ceftazidime and ceftolozane in industrial production.