Synthesis Process For The Preparation Of The New Cholesterol-lowering Drugs Ezetimibe

Ezetimibe is a new selective cholesterol absorption inhibitor with unique pHarmacological effects and broad market prospect, therefore it attracted the attention of many scholars. Based on the literature, We compared the advantages and disadvantages with other different synthetic routes,such as monomethyl glutarate for intermediates 、glutaric anhydride and fluorobenzene as raw materials and so on. And then we Concluded that ezetimibe synthetic route which is accordance with glutaric anhydride and fluorobenzene as raw materials, In a sequence of Friedel-Crafts acylation、n introduction of chiral auxiliary、CBS/chiral borane reduction system、Hydroxy protection and Mannich condensation、BSA and TBAF system cyclization、Dehydroxylation protecting group, this ezetimibe synthetic route has the line is short, intermediate and easy purification, the process is simple and high yield. However, this route is in the period of patent protection for commercial production, so its industrial production will be subject to patent protection restrictions.On the basis of the route, considering the expensive reagents like CBS of CBS/chiral borane reduction reaction, high cost of production of secondary raw materials imine compound and instable protection of pHenolic hydroxyl trimethylsilyl, and low yield of chiral alcohol and imine Mannich condensation reaction,this paper design a new synthetic route which is with fluorobenzene and glutaric anhydride as raw material and through Friedel-Crafts acylation,chiral auxiliary idroxyl protection introduced, CBS/chiral borane reduction, hydroxyl protection and Mannich condensation, BSA and TBAF system cyclization and dehydroxylation protection and Pd/C hydrogenation debenzylation to obtain target product. In the route, the amount of CBS and the cost has been largely reduced after CBS/chiral borane reduction delayed. In the asymmetric Mannich condensation reaction, in order to improve the yield of the Mannich condensation reaction form 63% to 74%, the experiment used the catalyst TiCli (OiPr) 3 instead of carbon tetrachloride and lowered the reaction temperature. And the by-product 4-benzyloxy-benzaldehyde was transformed into secondary raw material by a simple process.And in the cyclization reaction, the more expensive chiral auxiliary auxiliary group (s)-phenyl oxazolidinone was recovered by recrystallization method. More importantly, the synthesis of ezetimibe contains three chiral centers precise control of the absolute configuration. But a small amount of stereoisomers of the production process is ignored by the vast majority of the literature, in this paper the type and content of the produced under different conditions stereoisomers were studied to obtain a better control of chiral synthesis conditions.In summary, this paper successfully designed an ezetimibe synthetic route which has the feature of inexpensive raw materials, intermediates and easy purification and more convenient industrial production. Compared with the original process, its simple process conditions, byproducts easily recycling and lower production costs is much more of synthetic significance.