Study On The Syntheses Of The Fourth Generation Cephalosporins' Analogues And Their Intermediates

C-3 modification of cephalosporin is an emphasis in the research and development of cephalosporin antibiotics at all times because C-3 modification can greatly improve the antibacterial activity and pharmacokinetics of cephalosporin antibiotics. C-3 quaternary ammonium, which is one of the most important structure characteristics of the fourth-generation cephalosporins, strengthens the ability of the fourth generation cephalosporins to penetrate through the bacterial membrane and improves the antibacterial activities of them. Therefore, C-3 modification of cephalosporin nucleus employing Nitrogen-containing heterocyclic compounds will be one of the most important research direction to find novel cephalosporins.Some novel 3- quaternary ammonium cephalosporins (for example, cephalo- sporins introducing 4,4'-bipyridine, N-pyridylmethyl carbazole and 2,3-cyclopenteno- pyridine derivatives) were designed and synthesized in this thesis in order to obtain novel cephalosporins with higher antibacterial activities, broader antibacterial spectrum, higher stability againstβ-lactamase and lower toxicities.7β-phenylacetamido-3-(1-pyridiniomethyl) -3-cephem-4-carboxylic acid and 7β-phenylacetamido-3-[3-(9H-carbazolylmethyl) 1-pyridiniomethyl]-3-cephem-4- ca- rboxylic acid were synthesized from GCLE through C-3 activation, C-3 nucleophilic substitution and 4-position deprotection in the total yield of 72.4%, 62.5%, respectively.7-[2-(2-aminothiazol-4-yl)-2-(Z)-oxyiminoacetamido]-3-(1-pyridiniomethyl)-ceph-3-em-4-carboxylate and 7-[2-(2-aminothiazol-4-yl)-2-(Z)-oxyiminoacetamido]-3- (2,3-cyclopenteno-1-pyridiniomethyl)-ceph-3-em-4-carboxylate were obtained from 7-ACA through the reaction with AE active ester and the nucleophilic substitution with pyridine and 2,3-cyclopentenopyridine as the nucleophiles in the presence of TMSI in the total yield of 64.8%, 64.0%, respectively.The synthesis of 7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine was studied in the thesis. With dimethyl adipate as the starting material, methyl 3-methyl-1-(2- cyanoethyl)-2-oxocyclopentane carboxylate was synthesized through Dieckmann cyclization, methylation, isomerization and Michael addition, with the total yield of 57.1%.