【作者】 潘劲松；

【导师】 马淑涛； 冯维春；

【作者基本信息】 山东大学 ， 制药工程， 2008， 硕士

【摘要】 头孢他啶侧链酸是合成头孢他啶的原料药的重要原料。一般主要是以乙酰乙酸甲酯或乙酰乙酸乙酯为起始原料,经肟化和溴代两步反应,制得去甲基氨噻肟酸甲(或乙)酯,将该酯与α溴代异丁酸叔丁酯进行醚化反应,再将所得的醚化产物进行部分水解,就可得到头孢他啶侧链酸。该工艺路线存在副反应多,污染严重等问题。由于有大量卤化氢产生,设备腐蚀严重。目前国内只能处于小规模生产阶段,总生产能力约20吨/年左右。据不完全统计,目前国内对该产品的需求量在100吨/年以上。头孢他啶侧链酸的生产供应已经严重制约了我国头孢他啶原药的发展。为了克服传统工艺的缺点,本课题以双乙烯酮为起始原料,经卤化、酯化制备4-卤代乙酰乙酸乙酯,将4-卤代乙酰乙酸乙酯进行肟化、环合反应制备去甲基氨噻肟酸乙酯,再将去甲基氨噻肟酸乙酯进行醚化和水解反应制备头孢他啶侧链酸。我们对新工艺进行了大量的实验研究,对实验结果进行了详细的讨论,优选出新工艺的最佳反应条件,制定出适合我国工业实际情况生产的工艺方案。新工艺具有以下特点:1、采用双乙烯酮为起始原料,获得4-卤代乙酰乙酸乙酯,避免了直接使用乙酰乙酸乙酯卤化反应中的多卤代的发生,从根本上减少头孢他啶侧链酸现有工艺中副产物的产生,所得去甲基氨噻肟酸乙酯含量可达97%以上,去甲基氨噻肟酸乙酯不仅是生产头孢他啶侧链酸的重要中间体,而且也是头孢克肟侧链酸等其他抗生素产品的关键中间体。2、以双乙烯酮为起始原料,经卤化、酯化制备4-卤代乙酰乙酸乙酯的合成工艺,反应过程中无卤化氢产生,三废少;3、以双乙烯酮为起始原料合成头孢他啶侧链酸,累计收率可达40%以上(以双乙烯酮计),产品质量稳定可靠。总之,该工艺路线具有很强的市场竞争力,是一条非常适合工业化生产的方法。更多还原

【Abstract】 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.更多还原