【作者】 刘立英；

【导师】 付德才；

【作者基本信息】 河北科技大学 ， 药物化学， 2010， 硕士

【摘要】 头孢克肟是第三代口服头孢菌素类抗生素,它通过抑制细胞分裂时细胞壁的合成,从而起到杀菌作用,其对革兰氏阳性菌及革兰氏阴性菌均有较强的抗菌作用,且对β-内酰胺酶高度稳定,对产生β-内酰胺酶的细菌同样具有强大的杀菌力。目前已广泛应用于临床。本课题主要对头孢克肟的合成工艺进行了研究和改进,包括以下三部分内容:第一部分、对2-(2-氨基-4-噻唑)-2-[[(z)-(叔丁氧羰基)甲氧]亚氨]-乙酸(头孢克肟侧链酸)的合成工艺进行了探索,以一种未见文献报道的方法合成了头孢克肟侧链酸,以去甲氨噻肟乙酯为原料,经皂化、醚化、精制得头孢克肟侧链酸,所得产品收率高、质量好。对头孢克肟侧链酸活性酯的合成工艺进行了改进,以亚磷酸三乙酯为缩合剂,三乙胺为缚酸剂与2,2-二巯基苯并噻唑缩合制得了头孢克肟侧链酸活性硫酯。以7-AVCA与头孢克肟侧链酸活性硫酯为原料经酰胺化反应制得头孢克肟叔丁酯,再以甲酸甲基磺酸水解头孢克肟叔丁酯得头孢克肟甲基磺酸盐,精制得头孢克肟三水合物,总收率75%。第二部分、以2-(2-氨基-4-噻唑)-2-[[(z)-(甲氧基羰基)甲氧]亚氨]-乙酸为原料在三苯基膦、三乙胺存在下与DM缩合制得2-(2-氨基-4-噻唑)-2-[[(z)-(甲氧基羰基)甲氧]亚氨]-乙酸-2-苯并噻唑硫酯酯。7-AVCA与2-(2-氨基噻唑-4-基)-2-[[(Z)-(甲氧基羰基)甲氧]亚胺]-乙酸-2-苯并噻唑硫酯经酰胺化反应制得头孢克肟甲酯,再以氢氧化钠水解头孢克肟甲酯得头孢克肟三水合物,总收率80%。第三部分、对以上两种头孢克肟的制备方法进行对比,确定了一条成本较低、操作简便、易于实现工业化的合成方法。在查阅文献的基础上对现有合成工艺进行了优化和改进,使各步中间体及最终产品均可得到高纯度的结晶及较高的收率,经检验头孢克肟三水合物的质量已达到药典标准。更多还原

【Abstract】 Cefixime is the third generation semisynthetic cephalosporin for oral use which exerts for its antibiotic action by inhibiting the synthsis of the bacterium cell wall, It has great inhibition on both gram positive bacteria and gram negative bacteria,This antibiotic is hig hly stable to beta-lactamases, cefixime is widely used in clinical.. Some improvements of synthetic methods about cefixime are researched,mainly includes the following works.First part: The synthesis of 2-(2-aminothiazol-4-y1)-2-[[(Z)- (tert-butoxy carbonyl) methoxy]imino] acetic acid was studied,It was prepared from ethyl (Z) -2- hydroxyl -imino-2-(2-aminothiazol-4-yl) acetate via saponification, etherification and purification. The synthesis of 2-(2-aminothiazol-4-y1)-2-[[(Z)- (tert-butoxy carbonyl) methoxy]imino] acetic acid-2-S-mercaptobenzo-thiazolylester was researched. Condensate 2-(2- -aminothiazol-4-yl) - 2- [[(Z) (tert. butyoxy) carbonyloxy]imino]acetic acid with DM in presense of triethyl phosphate and triethylamine to get the target compound.cefixime was parapered from 7- amino -3- vinyclepalosperianic acid and 2-(2-aminothiazol-4-y1) -2-[[(Z)- (tert- butoxycarbonyl)methoxy]imino] acetic acid-2-S-mercaptobenzo- thiazolyl ester via amidation and hydrolysis,the total yield was 75 per.Second part:The synthesis of 2-(2-aminothiazol-4-yl)-2-[[(Z)(methoxycarbonyl) -methoxy]imino] acetic acid-2-S-mercaptobenzothiazolylester was researched.Condensate 2-(2-aminothiazol-4-yl)-2-[[(methoxycarbonyl) methoxy]imino]-acetic acid with DM in presnce of tripenylphosphine to form the target conpound. Cefixime was synthesized from 7-amino-3-vinyclepalosperi- anic acid and 2-(2-aminothiazol-4-yl)-2-[[(Z) (methoxy carb -onyl)methoxy] imino]acetic acid -2-S-mercaptobenzo-thiazolylester via amidiation and hydrolysis, the total yield was 80 per.Part three:Comparison of these two synthetic route of cefixime, An easier,lower cost and more prone to industrialization way was identified.On the base of literatures,the synthetic route of cefixime was optimized and improved.The products can be obtained in high purity and good yield in above process.As a result ,this process provides highly pure cefixime trihydrate in good yield and conven–ience for production.更多还原