Optimization For The Synthesis Of An Ezetimibe Based On Asymmetric Hydrogenation Reduction

[research objective]: cardiovascular and cerebrovascular disease has become one of the high incidence of urban and rural people in china With the gradual improvement of people's living standards. Dyslipidemia has become an important risk factor for the health of people in China, High blood lipids can lead to atherosclerosis, coronary heart disease and so on, increase the incidence of cardiovascular and cerebrovascular disease and mortality. In the clinical treatment of dyslipidemia, there are 6 major categories: 1) statins; 2) fibrates; 3) Niconitoc acid; 4)Resines; 5) cholesterol absorption inhibitor; 6) others. The new cholesterol absorption inhibitor, its good lipid-lowering effect and less side effect, representative drug is ezetimibe. In the present report, its synthesis process is mostly complex, so its synthesis process optimization is a hot spot in the field of pharmaceutical research.[research method]: After researched into the reported references carefully, we designed a new synthetic route. Compared with the reported routes, some synthetic steps were optimized. This new synthetic route could be summed up as follows: With p-hydroxybenzaldehyde as the starting material, 3-(4-(benzyloxy)phenyl)- 3-Oxopropionic acid ethyl ester(intermediate C) was synthesized by two steps. Subsequently, the chiral side chain was introduced into the intermediate C with(S)-1-(1-(benzyloxy)-3-iodopropyl)-4-fluorobenzene(intermediate S9). And then, the product was reacted with 4-Fluoroaniline to obtain an enamine. Using asymmetric silicon hydrogen reduction, this enamine was turned into the related amine, which had the desired configuration. After four membered lactam ring was prepared, the protective group of Ezetimibe was removed.[Research results]: This topic is designed to optimize the route one, when the intermediate D(containing the amine structure) is reduced to intermediate e, this route is characterized by the application of asymmetric silicon hydrogen reduction, this enamine was turned into the related amine, which had the desired configuration. The advantages of this method are: the catalyst dosage is low, the reaction conditions are mild, high yield and high ee value.Will optimize the design of the route one to improve, get the optimization design of the route two. When the intermediate E was reduced to intermediate F by asymmetric reduction of silicon, the reaction was found to be two product points, which were confirmed by mass spectrometry and 1H-NMR, and the two product points were intermediate F. However, the distinction of the specific configurations of these two products is also needed.[conclusion]: The appearance of cholesterol absorption inhibitors in order to further reduce the hope of LDL-C, its unique mechanism of action determines that he has a good safety and tolerance. It can be used alone, combined with statins can be a synergistic effect. Ezetimibe drug market has a broad prospect, but its industrial production methods are limited, the summary of the research group reported synthetic route, the optimization design of the two routes, of which there are advantages and disadvantages, for the future study on the process of providing some experience. I believe that with the deepening of the research, the synthesis process of Ezetimibe will be updated and higher level.