Synthesize And Study On Ezetimibe

Cardiocerebral vascular disease is a kind of world today seriously endanger human life and health disease, high cholesterol concentration in plasma is cardiocerebral vascular disease and the leading cause of death. This lowers plasma cholesterol concentration, not only can reduce coronary heart disease mortality, and may atherosclerotic lesions dissipated.Ezetimibe inhibits the absorption of dietary or recyclized cholesterol in theintestine and can be used either alone or in combination with a statin which inhibits the synthesis of cholesterol in the liver. The discovery of ezetimibe is a break through of the study of the new drug to resist the assimilation of cholesterol which get the attention of Pharmaceutical Industry. There are three chiral centers in ezetimibe which requires high preparing technology and complicated synthetictechnics including the asymmetric synthesiswhich is more difficult. In this paper, the first four parts of this technics have been completed. The main researchwork is shown below:(1) (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone was synthesized through two reactions by fluorobenzene and glutaric anhydride as the starting materials and its structure was characterized. Furthermore, the influencing factors of each reaction was investigated deeply. So the most desired industrial conditions are selected. The experimental results laid solid theoretical foundation for larger scale reaction.(2) The carbonyl of (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone was reduced by (-)-DIP chloride and its structure was characterized. The absolute configuration and d.e. value was determined by Mosher's method and 1H NMR. The main reaction factors, such as reaction time, temperature are entirely discussed and compared. The experimental results laid solid theoretical foundation for larger scale reaction.(3) The reaction of the amide (4S)-3-[(5S)-5-(4-fluorophenyl)-5-[(tert-putyldimethylsilyl)-oxy]-1-oxopentyl]-4-phenyl-2-oxazolidinone with 4-(tert-putyldimethylsilyl)-oxyphenylmethylene-4-fluoroaniline were studied under two active conditions: TiCl4 and LDA. Because the activity of two reactant are relatively low and they were difficult to react, andin this step, we have done a lot of valuable experimental conditions, and provided many meaningful information.