Study On The Synthesis Of 2-pyrrolidone Derivates

Many natural products and synthetic compounds with clinical value contain the basic structure of 2-pyrrolidone.With the alteration of the substituents in theγ-lactam ring, 2-pyrrolidone derivatives show different biological activities, such as antiinfla-mmatory, anti-tumor, anti-HIV, anti-senile dementia and so on. Clausenamide, a kind of multi-substituted 2-pyrrolidone compound, is isolated from aqueous extract of leaves of Clausenalansium. Based on the pharmacological study, Clausenamide could be used as liver protectant or nootropics, so modification on such compound has good study prospects.As natural multi-substituted 2-pyrrolidone compound, the structure of Clausenamide has multiple sites for modification. QSAR studies show 7- hydroxyl of Clausenamide is a very important active group. According to principle of Bioisosterism, this thesis aimed to the modification of 7- hydroxyl of Clausenamide by the replacement between amino and hydroxyl. Compound 3-hydroxy-4-phenyl-5-(α-amino)benzyl-N-methyl-2-pyrrolidone was designed and synthesized, named F1. Based on the existing research, Clausenamidone as raw material, the synthetic route of compound F1 was got through by the Leuckart reaction . To optimize the reaction conditions, temperature, ratio of raw materials, reaction solvent, catalyst and other factors were investigated. For the sake of the lower ester-water partition coefficient lgP of compound F1, we adopted N-alkylation reaction in the side chain ofγ-lactam ring to improve liposolubility of compound F1. Taking into account the substituent steric and electronic effects ,we selectively synthesized six N-alkylation products with different types of substituent group in the side chain of compound F1.Reaction conditions of Clausenamidone preparing, Leuckart reaction, N-alkylation were investigated, and related mechanisms were also been discussed in this thesis. For the purpose of pharmacological screening, nine new type of 2-pyrrolidone derivates were synthesized totally, and they haven't been reported in any records. All of the target compounds were characterized by means of elemental analysis, IR, ~1H-NMR, MS.