Study On The Synthesis Of 2-Aryl-3-oxobutyrate Via Ullmann-type Cross-coupling Reaction

Elagolix,the only oral drug used to treat endometriosis,is obtained through chemical library screening and structural modification.Aiming at the study on the synthesis of 2-aryl-3-oxobutyrate by Ullmann-type cross-coupling reaction,this paper can mainly divided into the following two parts:The first chapter briefly introduces the development history and recent development of the Ullmann-type carbon-carbon coupling reaction,especially the major milestones of the Ullmann-type carbon-carbon coupling reaction in the last two decades,and its application status.We can draw a conclusion that the Ullmann coupling reaction has progressed a lot,but the research on the substrate mainly focuses on the synthesis of monosubstituted or disubstituted aryl compounds are insufficient.The mechanism of the Ullmann coupling reaction is unclear,and the position and nature of the substituents tend to have different effects on the reaction.Therefore,the study of the Ullmann coupling reaction of the polysubstituted halobenzene is very necessary.The second chapter introduces the discovery process of elagolix in detail,then designs a new key intermediate compound 2-14,which are 2-aryl-3-oxobutyrate compounds.As shown in Fig.1,starting from aryl halide compound 2-11,key intermediates 2-14 can be prepared by Ullmann-type coupling reaction,elagolix can be obtained through a series of conventional reactions afterwards.In the study of the synthesis of 2-aryl-3-oxobutyrate compounds by Ullmann-type cross-coupling reaction,solvent effect was investigatied.The discovery of the significant solvent effect of this coupling reaction deserves further in-depth systematic studies.For some less reactive multi-substrate substrates,the interaction of the dipole moment of the mixed solvent with the active catalytic complex are very important.The nature of the impact has a positive reference for the study of other related types of coupling reactions.