Study On The Stereoselective Synthesis Of Anti-Mdd Drugs With Chiral α-Substituted Secondary Alcohol As Key Intermediate

With the rapid development of society, much stress has been posed on people during their work and daily life. The MDD(Mental Disorder Disease) has became one of the common types of mental disorder disease, therefore doing research on the anti-MDD drug becomes necessary from the people's healthy point of view. In our work, we explored the way of stereoselective synthesis of anti-MDD drugs Fluxetine and Duloxetine through the a-substituted secondary alcohol intermediates. This work can be divided into three parts:(1) Design and explore the synthesis route of Fluxetine and DuloxetineBased on our full understanding of optical secondary alcohols, we decide to prepare several kinds of chiral secondary alcohols as key intermediates through the kinetic resolution and dynamic kinetic resolution. We design the process with the secondary alcohols as the intermediates and try to figure out the convenient and high efficient way to the synthesis of Fluxetine and Duloxetine.(2) Kinetic resolution of allylic alcohols via stereoselective acylation catalyzed by lipase PS-30By using lipase PS-30 as catalyst, the kinetic resolution of a series of racemic allylic alcohols has been achieved via stereoselective acylation. The conversion of the reaction has reached close to the maximum of theoretic conversion 50% and the value of kinetic enantiomeric ratio (E) reached up to 968. There we briefly discussed the substituent effect and electronic effect of various substrates, which indicated that has much to do with the results of the resolution.(3) Kinetic and dynamic kinetic resolution of otherα-substituted secondary alcoholsAfter the successful kinetic resolution of allylic alcohols, we continue to explore some other secondary alcohols as our substrates, such as racemic vinyl alcohols, cyanohydrins andα-hydroxy acid esters.