Research On Synthesis Of Lipid-lowering Drug Ezetimibe

Ezetimibe is a new Lipid-lowering drug which was researched and developed by Merck and Schering-Plough Company. As Ezetimibe has completely innovative mechanism, it has become a new milestone in the development history of Lipid-lowering drugs following the advent of Statins in15years. Ezetimibe first appeared on the Germany and the United States market in Novermber2002, and was used in more than90countries and regions around the world rapidly. For it significant Lipid-lowering effect and favorable side profile, it is a “blockbuster”-type drug which can create tremendous economic benefits. The compound patent of Ezetimibe will expire in2014. At present, it is the third sorts of new chemical drug in China, so research on synthesis of Ezetimibe has an important academic and practical value.There are a lot of literatures research on Ezetimibe, which composes of β-lactam ring and S-hydroxyl side chain. According to the introduced order of two main structures, the synthesis method of Ezetimibe can be divided into two types: For the first type, β-lactam ring is synthesized firstly, then the side chain S-hydroxy is introduced; For the second type, the side chain S-hydroxy is introduced firstly, then β-lactam ring is synthesized. The first methods has many shortcomings, such as: harsh reaction conditions, complex aftertreatment, multi-step and dirty reactions, longer reaction time with lower yield, However, the second methods can overcome these disadvantages, So we focused on the synthesis of Ezetimibe with the second method, and the results was got as follows:1. Research on synthetic routes of EzetimibeAfter a number of experimental studies on synthetic routes, the valuable routes has been adopted, that is: This route started from (4S)-3-[5-(4-fluorophenyl)-1,5-dioxopenyl]-4-phenyl-2-oxazolidinone, introduced S-hydroxy side chain by asy-mmetric reduction, then Ezetimibe was obtained after a series of chemical reactions include nucleophilic addition, condensation, off the β-lactam ring by BSA, deprotection of hydroxyl by TBAF and recrystallization. There were four steps, each step was easy to control with high reaction yield. 2. Optimization of the synthesis conditions of EzetimibeReaction conditions of each step have been optimized on the basis of synthetic routes on Ezetimibe,(1) The first step: asymmetric reduction. Single-factor experimental method was operated to investigate the effect of reducing agent, solvent, reaction temperature, catalyst on the product yield. The optimum reaction conditions was obtained as follows: CH2Cl2is used as solvent, BH3S(CH3)2is utilized as chiral reducing agent, the molar ratio of BH3S(CH3)2and catalyst (R)-MeCBS is10:1, reaction temperature is-5℃, and reaction time is3h. The reaction product of this step was directly feed in the next reaction without after treatment.(2) The second step: imine formation. Through investgating several key reaction factors, the optimum reaction conditions can be got: sec-butanol is utilized as solvent, and the molar ratio of4-hydroxybenzaldehyde and4-fluoroaniline is1:1.03, reaction temperature is55℃, and reaction time is2h, and final yield is89.9%. Yield of the production can be increased by3%through the changing of solvents, material ratio and temperature.(3) The third step: addition reaction. Through screening several key reaction factors, the optimum reaction conditions can be got:TMSCl is used as protecting group for hydroxyl, and the molar ratio of Compound II: Compound III: TiCl4: DIPEA=1:2:1:5, reaction temperature is-15℃, reaction time is3h, methanol is used to recrystallize product. The final yield is69.9%, The change of recrystallization solvent make to improve the yield of19.2%.(4) The fourth step: off the β-lactam ring. The optimum reaction conditions was got by investgating several key reaction factors: Toluene is used as solvent, the molar ratio of TBAF3H2O and BSA is0.03:1, reaction temperature is45℃, reaction time is2h, the target product was gained after purification. Anti-solvent recrystallization has been employed for the purification of Ezetimibe, which differ from the reported methods. The chang of the reaction solvent can reduce the reaction process effectively by using methyl tert-butyl ether, the cost of the reaction was reduced significantly. And the resulting product purity is99.95%, which be in line with Pharmacopoeia requirements. In short, The optimized synthetic process of Ezetimibe obtained has made great improvement in reducing costs, improving yield and improving reaction conditions, shortening the preparation time, which provide a valuable foundation for the study of Ezetimibe and further large-scale production.