A kind of method of synthesizing ezetimibe

Abstract

The invention discloses a novel technical method for synthesizing ezetimibe (a compound 1), and belongs to the field of organic chemical medical synthesis. The method comprises the following steps: synthesizing a (3R, 4S)beta-lactam ring of a key intermediate (a compound 9) by taking p-anisaldehyde, 4-fluoroaniline and glutaric anhydride as main raw materials; and reducing and hydrolyzing the compound to obtain ezetimibe. The method disclosed by the invention adopts simply and easily-available materials, and is less in synthesis steps, and stable in process; a chiral four-membered ring of the key intermediate is directly constructed by virtue of one-step reaction to obtain an important intermediate (3R, 4S)-1-(4- fluorophenyl)-3-[(3S)-3-]4-fluorophenyl)-3-carbonyl propyl]-4-(4-methoxypheyl)-2-azetidinone (a compound 9); a target enantiomer proportion in the product is high, post-treatment operation is simple, and industrial large-scale production is easy to realize.

Description

technical field [0001] The invention relates to a synthesis method of ezetimibe, which belongs to the field of organic chemical medicine synthesis. Background technique [0002] Ezetimibe is a breakthrough in the research of blood lipid-lowering drugs. It was approved by the US FDA in 2002 and became the first lipid-lowering drug with a completely innovative mechanism of action since statins. The drug inhibits the absorption of cholesterol and phytosterols in food and bile at the brush border of the small intestine, reduces the transport of cholesterol from the intestine to the liver, reduces the storage of cholesterol in the liver, and increases the clearance of cholesterol in the blood, thereby reducing plasma cholesterol Level. [0003] As of 2011, ezetimibe's original single tablet and compound tablet have been approved by SFDA and launched in China. As people pay more and more attention to health, cholesterol-lowering drugs will have more and more potential for develo...

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Problems solved by technology

[0025] During the synthesis of this route, air-sensitive metal compounds Li, LDA, and TiCl were involved many times. 4 etc., and the low temperature reaction at -78°C, and the use of Pd / C under high pressure to catalyze the hydrogenation of olefinic bonds, the process is complex and the reaction conditions are harsh

[0026] Each of the existing ezetimibe synthesis routes has its own advantages and disadvantages, but it is not suitable for large-scale industrial production and the high production cost is the main problem

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