The condensation of 6-methoxy-1-tetralone (I) with 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (II) by means of CeCl3 and butyllithium in THF gives 1-[2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (III), which is brominated with pyridinium bromide perbromide in THF yielding the bromo derivative (IV). The condensation of (IV) with phenylboronic acid (V) by means of tetrakis(triphenylphosphonium) palladium/Na2CO3 in THF affords 1-[2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine (nafoxidene) (VI). Nadoxifene is reduced with H2 over Pd/C in ethanol/methanol giving (?-cis-1-[2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl]-pyrrolidine (VII). The demethylation of (VII) with boron tribromide in dichloromethane or 48% HBr in hot acetic acid yields (?-cis-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol (VIII), which is submitted to optical resolution by chromatography over a Chiralcell OD column in 99.95% (ethanol/heptane 5:95)/0.05% diethylamine, by crystallization with (?-(R)-1,1'- binaphthyl-2,2'-diyl hydrogenphosphate (R-binaph) or by crystallization with D-tartaric acid.
The acetylation of racemic cis-lasofoxifene (CP-319609) (I) by conventional methods gives the corresponding acetate (II), which is submitted to an enzymatic hydrolysis with cholesterol lipase (porcine pancreas) in a pH 7 phosphate buffer to yield pure lasofoxifene with an e.e. of 96% at 35% conversion. This optical purity can be improved up to 99% e.e. by crystallization in 95:5 ethanol/water.