Abstract
To obtain the standard compounds of metoprolol for a pharmacokinetic study, a convenient synthetic procedure to prepare enantiomers of metoprolol (3a) and its major metaboites, 2-4-(2-hydroxy-3-isopropylamino)propoxyphenylethanol (3b) and 4-(2-hydroxy-3-isopropylamino) pro-poxyphenylacetic acid (4), was developed from their respective starting materials, 4-(2-methoxyethyl)phenol (1a), 4-(2-hydroxyethyl)phenol (1b) and methyl 4-hydroxyphenylacetate (1c). These phenolic compounds (1a, b, c) were convertedin situ to their corresponding phenoxides with sodium hydroxide treatment followed by (R)- or (S)-epichlorohydrin treatment. The resulting epoxides2 were transformed to3 through reaction with isopropylamine. Ester3c was hydrolyzed to the metabolite4. Measured using the HPLC method on chiral column without any derivatization, the optical purity of enantiomers of metoprolol and o-demethylated metabolite3b ranged between 96–99% ee and that of enantiomers of carboxylic acid metabolite4 ranged 91% ee.
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Jung, SH., Pham Tuan Linh, Lim, HK. et al. Enantioselective preparation of metoprolol and its major metabolites. Arch Pharm Res 23, 226–229 (2000). https://doi.org/10.1007/BF02976449
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DOI: https://doi.org/10.1007/BF02976449