(3R,4S)-1-(4-Fluorophenyl)-3-[3(S)-3-(4-fluorophenyl)-3-hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone (Ezetimibe) represented by formula I is an useful hypocholesterolemic agent.

Ezetimibe is a lipid-lowering compound in the class of azetidinones that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. Ezetimibe is sold under the commercial name Zetia®.
U.S. Pat. No. 6,096,883 discloses generically and specifically ezetimibe and its related compounds along with their pharmaceutical compositions. The patent also describes a process for the preparation of ezetimibe
The process for the preparation of ezetimibe was disclosed in U.S. Pat. Nos. 5,631,365; 5,739,321; 5,856,473; 5,767,115 and 6,207,822. The prior art process used chiral auxiliary for the preparation of Ezetimibe. However, there are several drawbacks associated with the processes describe in the art. These drawbacks include the use of pyrophoric bases, such as n-butyl lithium and a metalamide, e.g., LDA, and low temperatures, e.g., below −50.degree. C., which lead to difficulties in preparation of ezetimibe on a commercial scale.
WO 20080151324 and US 2009/0047716 disclosed the reduction process for the preparation of ezetimibe using ketoreductase enzymes. The reduction of EZT-Ketone is done in the presence of a co-factor and buffer.
Accordingly, there remains a need for improved processes for preparing ezetimibe that eliminates and reduces the drawbacks of the prior art in a convenient and cost efficient manner on a commercial scale. The process according to the present invention relates to an enzymatic process for the preparation of the hydroxyl intermediate of ezetimibe. The enzymatic reduction process of the present invention is eco-friendly, cost effective and commercially viable. The present invention involves the recovery of chiral auxiliary which is cost effective.
USPTO Backgrounds
USPTO Backgrounds