【作者】 段学民；

【导师】 陈立功；

【作者基本信息】 天津大学 ， 应用化学， 2005， 博士

【摘要】 头孢菌素C的3位取代基的改造可以显著影响头孢菌素类抗生素的抗菌活性及药物代谢动力学,因此,C-3位改造一直是头孢菌素类药物研究和开发的重点和热点。头孢匹罗正是C-3位改造的成功范例,它以其优良的性能成为第四代头孢菌素类抗生素的代表。第四代头孢菌素的3’位均与含氮芳香化合物、N-取代哌啶或吡咯烷衍生物的氮原子相连接而成季铵结构,这种结构特点使第四代头孢菌素对细胞膜的穿透能力增强,从而使其具有了优异的抗菌性能。所以,用含氮芳香化合物和N-取代哌啶或吡咯烷衍生物对头孢匹罗的3’位进行修饰,将会成为寻找新的头孢菌素的一个重要研究方向。本文首先合成了头孢匹罗的重要中间体2,3-环戊烯并吡啶,然后合成了头孢匹罗类似物,并对其以GCLE为原料的合成路线进行了深入研究,建立了以GCLE为原料合成头孢匹罗及其类似物的合成路线,进而合成了头孢匹罗。另外,还以3-氯甲基吡啶盐酸盐和仲胺化合物为原料,经N-烷基化反应,合成了一系列吡啶衍生物; 以胺类化合物和丙烯酸甲酯为原料,经Michael加成、Dieckmann环合、酸性条件下脱羧,建立了合成N-取代-4-哌啶酮的合成路线。为对头孢匹罗的3’位进行修饰做了一些准备工作。以环戊酮为原料,经缩合、醚化得到O-烯丙基环戊酮肟,再经热重排反应合成了2,3-环戊烯并吡啶,总收率为21.1%。以邻苯二甲酸酐为原料,经置换、醚化、肼解等得到O-烯丙基环戊酮肟,再经热重排反应合成了2,3-环戊烯并吡啶,总收率23.1%。以苯为溶剂,在氧气环境中对O-烯丙基环戊酮肟进行热重排反应,可以提高其收率。以GCLE为原料,经碘置换、吡啶取代,再经“一锅法”脱酯基保护、酶催化水解和酰化反应,合成了头孢匹罗类似物3-[(1-吡啶鎓)-甲基]-7-[2-顺式甲氧亚胺基-2-(2-氨基噻唑基-4)-乙酰胺基]-头孢-3-烯-4-羧酸硫酸盐,总收率为65.2%。以GCLE为原料合成头孢匹罗类似物的最佳反应条件为:GCLE在避光低温(-5～0℃)条件下经置换反应制得GILE,产物不经分离直接与吡啶进行反应,更多还原

【Abstract】 Because the antibacterial activity and pharmacokinetics of cephalosporin antibiotics are changed greatly with the changes of 3 substituents of cephalosporin C, C-3 modification has been intensively studied in the research and development of cephalosporin antibiotics. A good example of C-3 modification is cefpirome, a representative example of the fourth-generation cephalosporins. Because the highlight antibacterial activity of the fourth-generation cephalosprins benefits from combining a C-3’-quaternary ammonium substituent of nitrogen containing aromatic compounds or nitrogen substituted piperidine or pyrrolidine derivatives, modification 3’ substituent of cefpirome using these compounds and then proceeding to find new cephalosporins will be an important research direction. 2,3-Cyclopentenopyridine, an important intermediate of cefpirom, was synthesized in this paper firstly. Then an analogue of cefpirome was synthesized. After the route employing GCLE as starting material was emphatically examined, a synthetic route of cefpirome and its analogue employing GCLE as starting material was established. According to the route, cefpirome was synthesized. In addition, a series of pyridine derivatives were synthesized by N-substitution of 3-chloromethylpyridine hydrochloride with secondary amines as well as a synthetic route of N-substituted 4-piperidones through Michael addition between amines and methyl acrylate, Dieckmann cyclocondensation and decarboxylation were established. These are preparatory work for modification 3’ substituent of cefpirome. Condensation and dehydrobromination of cyclopentanone gave cyclopentanone oxime O-allyl ether, and then proceeding thermal rearrangement gave 2,3-cyclopentenopyridine in 21.1% yield. And it was also obtained in the yield of 23.1% through replacement, dehydrobromination, hydrazinolysis and thermal rearrangement starting from phthalic anhydride. The yield of thermal rearrangement of cyclopentone oxime O-allyl ether could be improved in oxygen environment when benzene was employed as solvent. After replacement of C-Cl of GCLE with iodide, followed by substitution with pyridine, one-pot procedure including deprotection of carboxyl group, hydrolysis of 7-phenylacetamido and reaction with MAEM, the target molecular 7-[2-(2-aminothiazol-4-yl)-2-(Z)-oxyiminoacetamido]-3-(1-pyridiniomethyl)-ceph-3-em-4-carboxylate was obtained in 65.2% yield. The optimum reaction conditions of synthesis of cefpirome analogue are as follows: GILE is obtained from GCLE at low temperature (-5°C to 0°C) and avoiding of light and can react with pyridine directly without separation. The molar ratio of GCLE, NaI and pyridine is 1 ∶2 ∶4. Using one-pot approach, cefpirome analogue is obtained through deprotection of carboxyl group, hydrolysis of 7-phenylacetamido of compound 3.2, and reaction with MAEM. The molar ratio of compound 3.2 and MAEM is 1∶1.04～1.14. According to the above reaction conditions, cefpirome was synthesized in 37.7% yield from GCLE. The temperature of Michael additions between amines and methyl acrylate should be below 80°C; During Dieckmann cyclocondensation, the molar ratio of sodium methoxide and N,N-di-propionic acid dimethyl ester tertiary amine should over 1.1; Decarboxylation process should be performed in acidic environment The structure of the key intermediates and the target compounds obtained in this paper were determined by nuclear magnetic resonance spectra, mass spectroscopy, etc.更多还原