Design And Synthesis Of The Catalyst For Asymmetry Henry Reaction And Its Application In Pharmaceutical Intermediates

Optical pure chiral compound are all very improtant in the chemistry and medicine andwere obtained by lot of methods, such as chiral separation or extracted from the natural worldor asymmetric synthesis. But the catalytic asymmetric synthesis is the one of most atomeconomy and challengeable method from the point of view of industrial. Henry reaction isimportant method of construction of carbon-carbon bonds, and the products can easily beconverted into corresponding chiral aldehyde, ketone,α-carboxylic acid, α-amino alcohol, andother a series of improtant pharmaceutical intermediates. So, further in-depth study ofasymmetric henry reaction has improtant theoretical significance and application prospects.Based on the literature, we found that three types of catalysts were used in asymmetricHenry reaction. Such as, metal complexes, organocatalyst, quaternary ammounium saltcatalysts. So, according to the predecessors’ work, we designed and synthesized a series ofnew catalysts with tryptophan and take it to appliction of asymmetric henry reaction. Themain works that we have done were shown in the following list:Prepared the axially chiral and hexamethyleneamides ligand form L-tryptophan, thencoupled with CuCl2.H2O to get the Cu(II) complexs. The complexs were used as catalystss inasymmetric Henry reacrion a variety of aldehydes (inclued heterocyclic aldehyde, aromaticaldehydes, aliphatic aldehydes) with nitromethane. As the result shown, under the optimisedconditions(-30oC, IPA as solvent,100%DIPEA as additives,5%CuCl2.2H2O as metal salt),Cu(II)/4a complex can catalyze the reaction with high performance for a variety of aldehydes.For the Henry adducts up to98%ee and99%yield. So, under the encouragement above, weaslo studied the Henry reaction of aldehydes with nitroethane by Cu(II)/4a complex catalyst.The results show that catalytic activity is as high as99%, but the stereoselectivity is notideal(r=1：4.4, ee=30、23%). At the same time, Cu(II)/4a complex also was appied to synthesisof (-)-denopamine intermediates with98%ee and90%yield.To sum up, we have succefully developed a new catalyst systems for the Henry reactionwith high enantioselectivity and yield, respectively. The feature of catalyst is that loading of catalyst were low, and the preparations was simple, especially catalyst was considerednon-toxic and the process of reaction was exposed to air. So, the catalyst system has improtantapplication prospects on the industrial.