Synthesis, Characterization And Antibacterial Activities Of C2-Ferrocenyl Penem Antibiotics

Both Penem and Ferrocene Derivatives have strong antibacterial activities.At present, they have been used widely in the field of medicine and clinical treatment. This thesis is mainly about the work of synthesis of C2-ferrocenyl penem antibiotics and test of their antibacterial activities. The structure-activity relationships of these compounds are also discussed.Three parts are contained in this thesis as follows:1. The research of new synthetic process of 4-acetoxyazetidione(4-AA).4-AA is mainly used for the synthesis of penems. It is the key chirality intermediate to synthesize all kinds of penems antibiotics. Furthermore,4-AA could be used in the research and development of new drugs with good activities such as antibacterial agents and antihyperlipidemic drugs. With the increasing market demand of penems, the market share of 4-AA increases substantially and its chemical synthesis subjects to growing concern. Through analysing the synthesis route, we improve some reaction conditions and develop a new synthetic process of 4-AA from methyl 6,6-dibromopenicillanate via oxidation, Grignard reaction, reduction, hydroxyl protection, ring opening reaction, methylation, deprotection and acetylation. This process avoids the separation of chiral isomers and the use of heavy metallic salt with an excellent stereoselectivity. The overall yield is 28%.2. The synthesis of new C2-ferrocenyl penem antibiotics. Penem antibiotics have a wide market prospect because of its wide antibacterial spectrum, good antibacterial activities and low toxic side effects. Ferrocene and its derivatives have many characteristics such as lipophilicity, aromaticity, stability and low toxicity. And it shows great value in the field of bio-medicine. Due to the properties of penem antibiotics and ferrocene derivatives, a series of new compounds that the C-2 position of penems modified by ferrocene groups are designed and synthesized with 4-AA as raw material to enhance their antibacterial activities. We improve on the previous methods for the preparation of penems.This thesis provides a convenient and effective route for the synthesis of penems compounds because of it has mild reaction conditions, simple orparations and good repeatabilities.3. The minimal inhibitory concentration(MIC) of C2-ferrocenyl penem antibiotics synthesized previously and faropenem against Staphylococcus aureus etc is determined by the agar dilution method. The structure-activity relationships of these compounds are also discussed. Results show that penems of which the C-2 position modified by ferrocene groups exhibited superior or equivalent antibacterial activities compared with faropenem. In particular, the compound 22h which having a ferrocene heterocyclic group shows the most potent antibacterial activities.