Asymmetric Synthesis Of Antiepileptic Drugs Brivaracetam Intermediates

In this thesis,two key intermediates?+?-?R?-4-propyl-4,5-dihydrofuran-2?3H?-one and?R?-4-propylpyrrolidin-2-one of the new chiral antiepileptic drug brivaracetam were used.Study on the asymmetric synthesis of?+?-?R?-4-propyl-4,5-dihydrofuran-2?3H?-one,the cyanation of?,?-unsaturated carbonyl compounds and its application in the synthesis of?R?-4-propylpyrrolidin-2-one mainly includes the following contents:First,the introduction outlines the basic information of the latest definitions,pathogenesis,characteristics and related symptoms of epilepsy.Then it describes the brief development history of antiepileptic drugs,the advantages of various antiepileptic drugs and related toxic and side effects.Finally,it describes the new antiepileptic drug brivaracetam and its related research at home and abroad,including mechanism of action,pharmacological activity and synthesis method.According to the literature,the synthesis of brivaracetam is mainly based on chiral separation and asymmetric synthesis.In this paper,a new asymmetric route to the key intermediate?+?-?R?-4-propyl-4,5-dihydrofuran-2?3H?-one of brivaracetam was developed.Mono-methyl succinate or methyl 4-chloro-4-oxobutyrate was synthesized from succinic anhydride,which was cheap and readily available,and then reacted with the chiral auxiliary?R?-4-benzyl-2-oxazolidinone,and then reacted with propionaldehyde via Evans aldol reaction.The?R?-1-hydroxypropyl group is stereoselectively introduced,and the hydroxyl group is removed by a Barton-McCombie deoxygenation reaction.Alternatively,after the introduction of the chiral auxiliary group,it is reacted with allyl bromide,the?R?-allyl group is introduced by Evans asymmetric alkylation reaction,and the allyl group is reduced to obtain an R-propylated product.The obtained R-propylated product is subjected to removal of a chiral auxiliary group,and the carboxyl group is reduced and lactonized to obtain a brivaracetam intermediate?+?-?R?-4-propyl-4,5-dihydrofuran-2?3H?-one with high optical purity with a total yield of 25%.The cyanidation of?,?-unsaturated carbonyl compounds with TMSCN catalyzed by MgI₂·?OEt₂?_n was also studied.The results showed that MgI₂·?OEt₂?_n had good catalytic activity and good yield under mild conditions,which laid a foundation for the synthesis of?R?-4-propylpyrrolidin-2-one,a key intermediate of brivaracetam.