Synthetic Research Of Doripenem

This thesis deals with the process research of the new β -methylcarbapenem antibiotic doripenem.Doripenem, now available on the Japanese market, exhibits broad and well-balanced antibacterial activity. It has more potent activity against Pseudomonas aeruginosa than any other launched carbapenems.We designed and accompolished a novel synthetic route of doripenem, and synthesized three novel intermediate compounds. We also adopted one-pot methods in many reaction steps to reduce tedious work-up operations. In the last step, we developed two methods of deprotection employing zinc dust and catalytic hydrogenolysis respectively to give the final product, and improved the work-up as well.In the study of synthetic process referred to the literature route, we adjusted the ratio of the reactants in the preparation of (25,45)-1-p-nitrobenzylcarbonyl-2-[(sulfamoyl)(tert-butoxy carbonyl)amino] methyl-4-acetylthiol-pyrrolidine(17) and (4R,5S,6S)-6-[(1R)-l-Hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-1 -[[(4-nitrophenyl)methoxy]carbonyl]-3-pyrrolidinyl]thio]-1 -azabicyclo[3.2.0]hept-2-ene-2- (4-nitrobenzyl) carboxylate(16), and improved the work-up. Thus, we developed a process with satisfied yield and amenable for industrial production.Due to the configuration inversions of chiral carbon in the synthesis of side chain, we synthesized the corresponding optical isomer of doripenem for quality control.