Ezetimible intermediate and synthetic method of ezetimible

Abstract

The invention provides an intermediate for synthesizing ezetimibe and a preparation process thereof, and also provides a method for synthesizing the ezetimibe by the intermediate. The synthesizing method has short route, and comprises the following concrete steps: a compound I and substituted 1, 3-propanediol react to generate a compound II; the compound II and pivalyl chloride react to generate a compound III; the compound III and a compound A react to generate a compound IV; the compound IV and a compound V react to generate a compound VI under the condition of a titanium compound catalyst; the compound VI is re-ringed to generate a compound VII with beta-lactam; the compound VII is hydrolyzed to produce a compound VIII; and the compound VII is reduced to a compound IX ezetimibe by a borane chiral reducing agent. The synthesization has short route and mild reaction condition; and the produced intermediate and final product has high yield and high purity.

Description

technical field [0001] The invention relates to the field of synthesis of ezetimibe, in particular to a method for synthesizing ezetimibe using an intermediate. Background technique [0002] Ezetimibe (Ezetimibe) was developed by Harry Davis, Margaret Van Heek and Kevin Alton at the Schering-Plough Research Center. In October 2002, Ezetimibe (Zetia) was approved by the FDA. It was first launched in Germany in November of the same year under the trade name ezetrol. Ezetimibe is the first selective cholesterol absorption inhibitor, which can interfere with the absorption of dietary cholesterol and cholesterol synthesized by the liver in the enterohepatic circulation without affecting the absorption of other nutrients. Its pharmacology only acts on the small intestine, and reduces the transport of intestinal cholesterol to the liver by inhibiting the absorption of cholesterol, reducing its storage; it can strengthen the removal of cholesterol in the blood, thereby reducing the...

AI Technical Summary

Problems solved by technology

[0009] In the route of synthesizing ezetimibe in the patent WO2007072088, the hydroxyl group on the chiral carbon of the 3-position branch is obtained by chiral reduction of the carbonyl group. Before the chiral reduction, the carbonyl group is protected by ethylene glycol for other chemical It is destroyed during the reaction, and the obtained intermediate compound IV and compound VI are relatively fine solid substances. In the process, a small part of the product will flow out with the filtrate, resulting in poor quality of the product, and it is difficult to complete the follow-up reaction, the overall yield is low, and the synthesis cost is increased.

[0010] The above-mentioned synthetic methods of ezetimibe all have the problem that the synthetic route is relatively long; or the yield and purity are low, and some synthetic routes waste more than 50% of the intermediates; or the amount of chiral reducing agent used is large , The solvent is highly toxic. In summary, the cost of the synthetic method of ezetimibe in the prior art is relatively high, which brings great inconvenience to its industrial production

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