Enantioselective preparation of metoprolol and its major metabolites

To obtain the standard compounds of metoprolol for a pharmacokinetic study, a convenient synthetic procedure to prepare enantiomers of metoprolol (3a) and its major metabolites, 2-4-(2-hydroxy-3-isopropylamino)propoxyphenylet hanol (3b) and 4-(2-hydroxy-3-isopropylamino) pro-poxyphenylacetic acid (4) , was developed from their respective starting materials, 4-(2-methoxyethvl )phenol (1a), 4-(2-hydroxyethyl)phenol (1b) and methyl 4-hydroxyphenylaceta te (1c). These phenolic compounds (1a, b, c) were converted in situ to thei r corresponding phenoxides with sodium hydroxide treatment followed by (R)- or (S)-epichlorohydrin treatment. The resulting epoxides 2 were transforme d to 3 through reaction with isopropylamine. Ester 3c was hydrolyzed to the metabolite 4. Measured using the HPLC method on chiral column without any derivatization, the optical purity of enantiomers of metoprolol and o-demet hylated metabolite 3b ranged between 96-99% ee and that of enantiomers of c arboxylic acid metabolite 4 ranged 91% ee.