Study on the Stereoselective Synthesis of Anti-Mdd Drugs with Chiral α-Substituted Secondary Alcohol as Key Intermediate
|Keywords||Fluoxetine Duloxetine Allylic secondary alcohols Lipase PS-30 Kinetic Resolution Dynamic Kinetic Resolution|
With the rapid social development to the enormous pressure of work, life , depression has become one of the more common types of mental illness in modern society . Therefore, the study effective drugs for treatment resistant depression suppression disorders become a very important and meaningful work . This study to explore the two types of high yield , highly selective synthetic antidepressants suppressing disease drug (S) - fluoxetine and duloxetine hydrochloride , a new route , mainly to carry out the work of the following three aspects : First, the design exploration to determine fluoxetine and duloxetine hydrochloride the synthetic route refer to the synthetic methods reported in the literature in the past , programs the desired key intermediates to the stereoselective synthesis of these two types of drugs - the chiral secondary alcohol is pointcut , establishing a three-dimensional specific preparation of chiral secondary alcohols dynamic kinetic reaction system , as the basis of design , exploring the stereoselective synthesis of fluoxetine and duloxetine process . Second, the the allyl the secondary alcohols compound biological enzymatic method Kinetic Resolution biological enzyme PS-30 as the catalyst, the use of asymmetric acetylation reaction , kinetic resolution to obtain a series of allyl secondary alcohols . The highest reaction conversion rate close to 50% of the theoretical maximum enantioselectivity ratio (E) values ??as high as 968 . Optimized by controlling the reaction time, temperature , solvent, etc. , the optimum reaction conditions . Explore the impact of the different structure of the substrate and stereo , electronic effects of substituents and substitution position split effect . Third, the α-position containing attempts a preliminary study of the kinetic resolution of secondary alcohols substituted groups and dynamic kinetic resolution Resolution System ethyl mandelate , cyanohydrin propargyl class splits the effect of the secondary alcohol . Metal organic the racemization catalyst biological enzyme selective reaction , try to co - catalyzed allylic secondary alcohols , cyanohydrins ethyl mandelate class dynamic kinetic resolution of the substrate .