Study On New Synthetic Technology Of Side Chain Acid Of Ceftazidime

Side chain acid of ceftazidime is an important raw material of ceftazidime. General mainly using acetyl methyl acetate or ethyl acetoacetate as starting material, via bromination and oxim two-step reaction, obtained ethyl-(Z)-2-hydroxyimino-2-(2-aminothiazol-4-yl) acetate(EHATA). EHATA reacted with t-butyl 2-bromo isobutyrate ,then the product of etherification was partial hydrolysised . Side chain acid of ceftazidime can be obtained. But there existed many problems in this reaction routes. For example, serious pollution problems. Due to a large number of hydrogen bromide or hydrogen chloride produced, serious equipment corrosion. Current domestic production only in a small-scale stage, The total production capacity is about 20 tons / year around. According to incomplete statistics, the domestic demand for side chain acid of ceftazidime is 100 tons / year above. The production and supply of side chain acid of ceftazidime has seriously constrained the development of original drug.To make up for the shortcomings of traditional crafts, The subject used the diketene as starting materials, via halogenation and esterification , gived 4 - halogenated ethyl acetoacetate. The side chain ccid of ceftazidime was synthesized from 4 - halogenated ethyl acetoacetate by oxime reaction, cyclic condensation , etherification and hydrolysis. We carried out a lot of experimental studies. To obtain a new optimization technology in the best conditions. the experimental results are discussed in detail.This new process has the following features:1.Diketene used as starting materials of 4 - halogenated ethyl acetoacetate. Avoid Multihalogenation reaction in the Traditional crafts using ethyl(methyl) acetoacetate as starting materials . Fundamentally reduced the formation of by-products. In the process , the purity of EHATA was more than 97%. EHATA is not only the key intermediate of the side chain acid of ceftazidime, but also the important Intermediates of other antibiotic products, such as cefixime.2,Using diketene as the starting material of 4 - halogenated ethyl acetoacetate, no halodrogen chloride or hydrogen bromide be generated in the process, waste less;3,The side chain acid of ceftazidime was synthesized from diketene by chloridation, esterification, oxime reaction, cyclic condensation , etherification and hydrolysis. The total yield was more than 40%. The purity was more than 98. 5%.On the whole, The new process is A very suitable method for industrial production.