Process for preparing Ezetimibe intermediate by an acid enhanced chemo- and enantioselective CBS catalyzed ketone reduction

The S alcohol in the benzylic position of compound 2, a key feature of a novel cholesterol lowering agent Ezetimibe, was introduced by the (R)-MeCBS catalyzed asymmetric carbonyl reduction of ketone 1 using borane tetrahydrofuran complex (BTHF) as the reducing agent. The chemo- and enantioselectivity was dramatically enhanced by using an acid as a scavenger of the stabilizer sodium borchydride present in the commercially supplied pure BTHF. The effect of the critical reaction parameters such as addition mode of reagent, temperature, acids as well as water content on the selectivity has been examined. This reaction has been successfully applied in the commercial process for the preparation of the key intermediate 2 for Ezetimibe. (C) 2003 Elsevier Science Ltd. All rights reserved.