| (R)-phenylephrine hydrochloride is anα1-adrenergic receptor agonist which can be widely used in clinically effective agent.This paper report a novel method for the synthesis of（R）-phenylephrine using Corey-Bakshi-Shibata（CBS）catalyst.Employing CBS catalyst for the synthesis of（R）-phenylephrine is an efficient synthesis strategy due to its advantages of both short synthetic steps（4 steps）,mild condition and high enantioselectivity.In the first,3’-hydroxyacetophenone as the starting material was reacted with acetic oxide for the purpose of protecting hydroxy group,and then generate 3’-acetoxyacetophenone.Theα-displacement reaction as the so called bromination reaction between bromine and 3’-Acetoxyacetophenone to affordα-bromo-3-acetyloxyla-cetophenone.In the second,according to various of substituent group of boron atom,B-H,B-OMe and B-Me as three different versions of CBS catalyst was prepared.In the presence of CBS catalyst and BH3?THF,α-bromo-3-acetyloxyla-cetophenone was reduced to（1R）-α-bromo-1-（3-hydroxylphenyl）-ethanol in an asymmetric hydrogenation process,the highest enantiomeric excess was 99%.In the last,the Hoffman alkylation reaction between（1R）-α-bromo-1-（3-hydroxylphenyl）-ethanol and excessive methylamine to afford（R）-phenylephrine as the target product.However,considering the price of the catalyst and the required quantity are not negligible,the CBS catalyst need recycle and used repeatedly.In spite of the catalyst can be recycled in the form of its precursor hydrochloride,the application in industry is still a challenging due to catalyst recovery and continuous reaction.Attaching the catalytically active centre to macroporous resin is favorable for the separation from product.Besides,a setup for continuous reaction was built and the catalytic properties were discussed when the polymeric catalysts was used repeatedly.Moreover,a preliminary attempt was made to achieve a continuous reaction.Result show that,when the degree of cross-linking is 8%and the mole ratio of functional monomer is 9.67%,employing polymeric catalysts converted acetophenone into（R）?1?phenylethanol with 89.5%ee in the continuous reaction.After the catalysts were used 25 h,the ee value was not decreased.Employing macroporous-resin-supported CBS catalyst for the synthesis of（R）-phenylephrine is of great significance to the separation of product from catalyst,as well as（R）-phenylephrine can be efficiently prepared in a cost-effective way.Result show that,when the degree of cross-linking is 8%and the mole ratio of functional monomer is 10%,which produced（1R）-α-Bromo-1-（3-hydroxylphenyl）-ethanol with over 90%in continuous reaction. |
