Study On Synthetic Process Of Ezetimibe Intermediate PFD

Ezetimibe is the first novel selective cholesterol absorption inhibitor type hypolipidemic drug jointly developed by Schering-Plough and Merck,and was first marketed in Germany in 2002.The drug compound expires in 2014 and has since become a generic drug.In various countries,the original research company must reduce the cost of production of ezetimibe and improve its international competitivenes Research must be carried out on its production process.China is a major manufacturing country of API intermediates,and it is important to better link up with original research companies.The theoretical value and practical significance.In this dissertation,L-phenylglycine was used as raw material to produce L-phenylglycine methyl ester by methyl esterification.Under the action of reducing agent,L-phenylglycine methyl ester produced L-phenyl glycine,followed by condensation with cyclic.mixture.(S)-(+)-4-Phenyl-2-oxazolidone.Using glutaric anhydride and fluorobenzene as raw materials,under the catalysis of aluminum trichloride,the fluorobenzoyl butyric acid,p-fluorobenzoyl butyric acid in the organic base triethylamine Under the action of reaction with pivaloyl chloride to form a mixed anhydride,and then reacted with(S)-(+)-4-phenyl-2-oxazolidone to produce ezetimibe intermediate under the catalytic action of 4-methylaminopyridine(4S)-3-[5-(fluorophenyl-1,5-dioxopentyl] The synthesis of chiral aryl(S)-(+)-4-phenyl-2-oxazolidinone is an important part of this dissertation.L-phenylglycine was used as the raw material and methylated,reduced and cyclized step gives(S)-(+)-4-phenyl-2-oxazolidone.The optimum process conditions are as follows: the ratio of L-phenylglycine to thionyl chloride is 1:5,the reaction temperature is 45°C～55°C,reaction time is 4～6h,and L-phenylglycine methyl ester is produced;L-phenylglycine was reduced with sodium borohydride/aluminum trichloride system to give L-phenylglycine,a material ratio of 1:2:1.5;L-phenylglycine and the cyclizing agent diethyl carbonate,under the effect of potassium carbonate,Condensation reaction occurs,the material ratio is 1:10:0.8,the reaction temperature is 110°C～115°C,(S)-(+)-4-phenyl-2-oxazolidone is produced,and the yield is 77%.The HPLC purity was96.2% and the content was 96%.The synthesis of ezetimibe intermediate uses glutaric anhydride and fluorobenzene as raw materials.Under the catalysis of aluminum trichloride,the acylation reaction proceeds at a ratio of 1:2.5:2.5 and the reaction temperature is 0°C.At 5°C,p-fluorobenzoyl butanoic acid is obtained;then,under the action of organic base triethylamine,it is reacted with pivaloyl chloride to form a mixed anhydride,which is then catalyzed by4-methylaminopyridine and(S)-(+)-4-Phenyl-2-oxazolidone,the material ratio is 1:2:0.5:1,of ezetimibe is obtained(4S)-3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4phenyl] the reaction solvent is dichloromethane,the temperature is 38°C～42°C,and the intermediate yield 74%,HPLC purity 98.8%,The content is 98%.Through a large number of experiments,the conditions for the amplification of the intermediates of ezetimibe were determined.In this project,the synthesis of ezetimibe intermediates was scaled up to a 30 L reactor to obtain ezetimibe intermediates.Purity analysis,structure analysis,and quantification were performed.The analysis confirmed that the target molecular structure was consistent with a yield of 74%.The HPLC purity was 98.8% and the content was 98%.The reaction of glutaric anhydride and fluorobenzene under the catalyzed action of aluminum trichloride,followed by Friedel-Crafts acylation to produce p-fluorobenzoyl butyric acid,using methylene chloride as the solvent,and the reaction temperature at room temperature reduced the cost of raw materials,and The reaction conditions are milder and compared to the existing literature,which is the progress of this article.