The Synthesis Of Meropenem And 1,3,4 - Thiadiazole Carbapenem Compounds Synthesis And Antibacterial Activity Determination

Since the discovery of thienamycin, carbapenem antibiotics have used in clinical treatment of severe bacterial infections caused by multidrug resistant strains. But the susceptibility to renal dehydropeptidase-Ⅰ (DHP-Ⅰ) and the chemical instability of the carbapenem antibiotics have been understood as an impediment in clinical use. Meropenem was developed as the first 1β -methyl carbapenem antibiotic that requires no coadministration drug. The introduction of a 1β -methyl group on the carbapenem skeleton improved not only its stability against DHP-I, but also antibacterial activity against gram-negative bacteria including Pseudomonas aeruginosa. Meropenem reduced side effect and was appreciated to be a potent and safe antibiotic.On the basis of preparation of 1β -methyl carbapenem key intermediate,we synthesized the carbapenem bicyclic nuclus of carboxylic group protected allyl and benzyl group with the intramolecular Dieckmann-type cyclization. We also studied the reaaction mechanism and the factors to affect the intramolecular Dieckmann reaction. And prerared the Meropenem side chain of amino group protected by allyloxycarbonyl and benzyloxycarbonyl group with two routes separately. The side chain of amino group protected by allyloxycarbonyl group was intraduced into the carbapenem bicyclic nuclus of carboxylic group protected allyl group. Removal of protections, we gained Meropenem successfully. The overall yield was increased by 18%.Since the carbapenems on sale such as Imipenem and Meropenem were lack of effective antibacterial activity against methicillin-resistant staphylococcus aureus (MRSA), we focused on the synthesis of anti-MRSA carbapenem derivatives. Activited...