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Synthesize and Study on Ezetimibe

Author: ChaiLiFeng
Tutor: ZhangPing
School: Hebei Normal
Course: Organic Chemistry
Keywords: Cholesterol Yizetimai Asymmetric Reduction Hydroxyl protection Nucleophilic addition
CLC: TQ463.2
Type: Master's thesis
Year: 2008
Downloads: 101
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Abstract

Heart cerebrovascular disease is a disease of serious harm to human life and health in the world today , and plasma cholesterol concentration is too high cardiovascular and cerebrovascular diseases and the leading cause of death . Therefore a decrease in plasma cholesterol concentration, not only can reduce coronary heart disease mortality , and may make the regression of atherosclerotic lesions . Of Ezetimibe ( according Ze behalf wheat) is the first listed drugs inhibit cholesterol absorption in the gut , it can be used alone , can also be associated with statin use , achieved good results . According Ze behalf wheat discovery is a breakthrough in the lipid-lowering drug research , attaches great importance by the pharmaceutical industry at home and abroad . The product has three chiral centers, the preparation of high technology , the complexity of the synthesis process , which also relates to the difficulty of the larger the asymmetric synthesis . In this thesis, the first four steps of the process synthesis research , the main contents are: ( 1 ) fluorobenzene and glutaric anhydride synthesis of raw materials through a two-step reaction of (4S ) -3 - [ 5 - ( 4 - fluorine phenyl ) -1,5 - dioxo- pentyl ] -4 - phenyl-2 - oxazolidinone , determined the structure of the product , and optimization of the reaction conditions ; conducted under laboratory conditions , the stability of small test experiments laid the foundation for industrial production . (2) using a chiral reducing agent (4S) -3 - [5 - (4 - fluorophenyl ) -1,5 - dioxo- pentyl ] -4 - phenyl-2 - oxazolidinone ketocarbonyl asymmetric reduction, to give (4S) -3 - [ (5S ) -5 - ( 4 - fluorophenyl ) -5 - hydroxy-1 - oxo - pentyl ] -4 - phenyl-2 - evil oxazolidinones , to determine the structure of the product ; through Mosher s method and 1H NMR to determine the absolute configuration of the product and the de values ; simplify the purification method , worked out the optimum reaction conditions ; laboratory and expand the amount of experiments to lay a foundation for that step reaction of industrialization . ( 3 ), respectively , to the LDA and TiCl4 amide activating reagent , research amide ( 4S ) -3 - [ (5S) -5 - ( 4 - fluorophenyl ) -5 - ( tert - butyl-dimethyl- silyloxy ) -1 - oxo- pentyl] -4 - phenyl - 2 - oxazolidone and imine 4 - tert - butyl - dimethyl- silyloxy phenylmethylene -4 - fluoroaniline nucleophilic addition reaction . Α-carbon atom of the amide and imine addition , due to the relatively low activity of the two reactants difficult reaction , the paper a lot of valuable condition experiments provide valuable information to the theoretical research of such reaction .

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