Development of an Efficient and Stereoselective Manufacturing Route to Idoxifene

Abstract

A literature route to 1-(2-{4-[(E)-1-(4-iodophenyl)-2-phenyl-but-1-enyl]phenoxy}ethyl)pyrrolidine (idoxifene) has been modified to tackle various scale-up issues and provide initial supplies. A new highly efficient, robust, and stereoselective manufacturing route is described in detail. This route involves diastereoselective synthesis of tertiary alcohol (1RS,2SR)-1-(4-iodophenyl)-2-phenyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]butan-1-ol by Grignard addition to the ketone 1-(4-iodophenyl)-2-phenyl-1-butanone followed by derivatisation and stereoselective syn elimination to provide idoxifene in excellent yield and geometric purity. Evaluation of a more direct route to idoxifene using a McMurry low-valent titanium coupling reaction is also described.