Study On The Synthesis Of α,α-Difluoro-β-Hydroxyketone

The α,α-difluoro-β-hydroxyketone skeleton is an important pharmacodynamic structure in the research of drug molecules.This structure exists in a variety of active molecules such as HMG-Co A inhibitors,analgesics,protease inhibitors,and GABAB modulators.And attracted much attention.The Reformatsky reaction is the earliest and most extensive method for preparing α,α-difluoro-β-hydroxyketone skeleton molecules,and it provides a practical and efficient solution,so it has also attracted extensive attention and research.At present,there have been many studies on the preparation of α,α-difluoro-β-hydroxyketone skeletons using the Reformatsky reaction mediated by metals(Zn,Cu,In,etc.).The main mechanism is the process of metal-to-carbon-halogen bond insertion.However,These methods still have corresponding limitations,which are mainly manifested in the insufficient adaptability of the substrate,the reduction of halogenated(Cl,Br)difluoroketones and the self-condensation by-products,etc.,which limit the Reformatsky reaction in preparation to a certain extent.The development and application of α,α-difluoro-β-hydroxyketone skeleton compounds.Therefore,the development of more effective Reformatsky reaction conditions for preparingα,α-difluoro-β-hydroxyketone skeletons and overcoming the existing limitations has important theoretical significance and practical application value.In view of this,this article starts from the economical and easily available iododifluoroketone,through the free radical process initiated by indium,and the new strategy of reformatsky reaction with various aldehydes in pure water to synthesize various corresponding α,α-difluoro-β-hydroxy ketone skeleton compound,and the method was applied to synthesize GABAB regulator,active aldehyde fluorine derivative and paeonol fluorine derivative.In the first part,we realized the Reformatsky reaction of indium-mediated halogenated difluoroketones and various aldehydes in pure water to prepare correspondingα,α-difluoro-β-hydroxy ketone compounds and apply them to GABAB Modifiers and synthesis of fluorine-containing derivatives of reactive aldehydes.Mechanism studies indicate that the reaction may undergo a free radical process initiated by the single electron transfer(SET)of indium.In the second part,we introduced difluoride into the α-position of the carbonyl group of paeonol(2-hydroxy-4-methoxyacetophenone)and prepared it into a building block with an iododifluoride structure,using indium A series of paeonol derivatives withα,α-difluoro-β-hydroxy ketone skeleton were prepared by the mediated Reformatsky reaction.In addition,the 2-position hydroxyl,4-position methoxy group and the 4-position methoxy group of paeonol were also synthesized by a simple method.The 5-position of the benzene ring was modified to obtain the corresponding paeonol difluoro derivative,and the inhibitory activity of the Hep G2 cell line in vitro was carried out together with the paeonol derivative with α,α-difluoro-β-hydroxyketone skeleton The measurement results show that the inhibitory effect of several derivatives are better than paeonol.In the third part,we utilized the trifluoromethyl-containing gem-diol structure intermediates in the previous step for the preparation of iododifluoroketones.Under the treatment of the inorganic weak alkali sodium bicarbonate aqueous solution,we achieved the compatibility with isatin and various types of Aldol reaction of aldehydes to prepare corresponding isatin derivatives and α,α-difluoro-β-hydroxy ketone compounds.This work is a more efficient method for preparing α,α-difluoro-β-hydroxy ketone compounds,which uses the removal of trifluoroacetic acid to achieve carbon-carbon bond cleavage and produce α,α-difluoroenol anions.The Aldol reaction is carried out in a pure water environment,which opens up new ideas for the preparation of α,α-difluoro-β-hydroxy ketone compounds and isatin derivatives.