Syntheses Of Cefpirome And Its Analogue And Intermediates

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.