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The synthesis of ezetimibe with high stereochemical purity

Krzysztof Bańkowski ,  Katarzyna Sidoryk ,  Katarzyna Filip ,  Joanna Zagrodzka 

Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland


Ezetimibe, (3R,4S)-1-(4-fluorophenyl)-3-((3S)-3-(4-fluorophenyl)- 3-hydroxypropyl)-4-(4-hydroxyphenyl)-2-azetidinone, is an anti-hyperlipidemic drug which is used to lower cholesterol level. It acts by decreasing cholesterol absorption in the intestine.

The three chiral centers in the ezetimibe molecule give rise to eight stereoisomers and the synthesis of stereochemical pure ezetimibe is a significant challenge. The synthesis of ezetymibe is described in many patents and patent applications, however the problem of stereochemical purity of the final product and its intermediates is almost completely omitted.

The synthesis of ezetimibe was realized by a procedure shown below, according to Schering Co. patents No US 6,207,822, EP 1137634:

We have investigated the sterochemical course of all steps of this process and found that for the preparation of optical pure ezetimibe the providing of pure (S,R,S,S) - EZ-6 is cru-cial. This diastereomer (product of anti-condensation of EZ-4 + EZ-5) is usually contaminated with (S,R,R,S) - EZ-6 isomer (syn-condensation), and also with (R,R,S,S) - EZ-6 isomer derived from small amount of (R,S)-alcohol EZ-4 which is usually occurring in required (S,S)-alcohol.  The presence of (R,R,S,S) – EZ-6 diastereomer leads to (R,R,S) -“iso-ezetimibe” which is very difficult to remove from ezetimibe.
The synthesis of ezetimibe was optimized, all chemical and sterochemical impurities were isolated and/or synthesized and characterized by NMR, MS and HPLC techniques. The method for the purification of desired key intermediate (S,R,S,S)-6 was elaborated. These al-lowed us to develop the large scale efficient synthesis of pharmaceutical pure Ezetimibe (HPLC > 99,5 %,  (R,R,S)-isomer < 0,1 %, single unknown  impurity < 0,1 %, total impurities <  0,6 % ).

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Presentation: Poster at VII Multidyscyplinarna Konferencja Nauki o Leku, by Katarzyna Sidoryk
See On-line Journal of VII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2010-03-16 09:09
Revised:   2010-04-05 20:24