头孢卡品酯侧链新合成方法的化学原理解析

Resolution on the New Synthesis of Side Chain Material of Cefcapene Pivoxil by Principles of Chemistry

本文对药物头孢卡品酯侧链——顺式噻唑酸的新合成方法进行了详细的化学原理解析。工艺研究中通过Hantzsch噻唑合成机理探索,充分认识在反应条件下顺式噻唑酸发生顺反互变的结构原因,继而提出新工艺路线:以Boc保护的硫脲代替硫脲进行Hantzsch噻唑合成,抑制顺反式互变副反应,实现顺式噻唑酸的高效制备。这样建立在机理研究之上,对反应步骤给予科学的工艺配置,可以实现顺式噻唑酸的高效制备。该药物中间体制备工艺的新案例应用于本科生和研究生教学中,可促进学生科学思维的培养。此外,文中也介绍了以冷冻结冰工艺高效促进Knoevenagel缩合反应的实例。

The synthetic method of side chain material of cefcapene pivoxil,cis-thiazole-acid,has been resolved by principles of chemistry in detail.Through investigations of the mechanism of Hantzsch thiazole synthesis in the process study,a structurally inherent cause,which leads to cis/trans-isomerization of the original cis-thiazole-acidunder the reaction conditions,was fully understood.Accordingly,we put forward a new synthetic route to the material.This efficient preparation of cis-thiazole-acid was accomplished by using Boc-protected thiourea instead of free thiourea as a starting feedstock in the Hantzsch thiazole synthesis,thereby restraining the potential cis/trans-isomerization side reaction.Based on the mechanism researches,we carried out the synthesis with rational processing allocations for each step,thus attaining a highly efficient preparation of cis-thiazole-acid.This new case of preparation technology of pharmaceutical intermediate has been applied in classroom teaching of undergraduate and graduate students,inspiring their scientific thinking.Besides,a living example effectively promoting Knoevenagel condensation with water-freezing process,involved in the synthesis of cis-thiazole-acid,was also presented.