Enzymatic Resolution Of 2-Arylpropionic Acids And Preparation Of Optically-active Polymeric Prodrug

Enzymatic methods play an important role in the resolution of racemic compounds due to their high selectivity, rapid reaction rate, the simplicity of process and mild reaction conditions. 2-Arylpropionic acids (i.e. profens), such as ketoprofen, naproxen and ibuprofen, are an important class of non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for alleviation of pain and inflammation associated with tissue injury. Since the bioactivity of profens is mainly due to the (S)-enantiomer, the preparation of optically active 2-arylpropionic acids has become an important subject of increasing interest over the past decades.In this thesis, an irreversible enzymatic resolution of 2-arylpropionic acids using their vinyl esters as activated substrates by hydrolysis as well as transesterification was investigated. Each optically active monomer was subjected to free radical polymerization and obtained a series of polymeric drugs, which is anticipated to improve curative effects and control drug release.An irreversible enzymatic resolution method is developed to prepare polymerizable and optically active ketoprofen prodrug in high E-value and good yield. The effect of enzyme source, solvent, water amount in the reaction medium and reaction temperature on enantioselectivity and reaction conversion of the enzymatic resolution was systematically studied. Polymerizable, optically active ketoprofen prodrug can be obtained with excellent enantioselectivity (ee >99%, E ~ 400) in a mixture of dioxane/water (97.5/2.5, v/v) at 25 ℃ catalyzed by Lipozyme(?) immobilized from Mucor miehei.Lipase-catalyzed synthesis of optically active naproxen vinyl ester and ibuprofen vinyl ester was developed. The effect of enzyme sources and solvents on the hydrolysis resolution was investigated. For naproxen vinyl ester, Lipase from Candida antarctica showed moderately high catalytic activity and selectivity. For ibuprofen vinyl ester, Lipozyme(?) immobilized from Mucor miehei showed moderate catalytic activity and selectivity. Two kinds of vinyl esters containing hydroxyl groupwere chosen to react with ketoprofen, naproxen and ibuprofen vinyl esters. Results showed that only J?-vinyl esters could be obtained.The chemo-enzymatic method for preparing optically active polymeric prodrug containing ketoprofen, naproxen and ibuprofen residue was developed. (iS)-naproxen, (5)-ketoprofen and (5)-ibuprofen derivatives were obtained by enzymatic resolution. Each optically active monomer was subjected to free radical polymerization and the products were characterized by IR, NMR and GPC.