Sulfate esters of morphine derivatives: Synthesis and characterization

Sixteen 3-O- and 6-O-sulfate esters of morphine, codeine and some of their N-methyl quaternary derivatives were synthesized by means of sulfation with pyridine–SO3 complex and sulfuric acid/N,N′-dicyclohexylcarbodiimide. Complete 1H- and 13C-NMR assignments are given for each of the synthesized compounds based on one- and two-dimensional homo- and heteronuclear measurements. Comparative analysis of chiral properties by circular dichroism and optical rotatory dispersion revealed characteristic differences in the spectra due to changes in charge, polarity and intramolecular association by strong hydrogen bonds in aqueous solution. The synthesized sulfate esters are prospective peripheral analgesics lacking central side effects and are also useful as reference substances for various analytical studies involving sulfate ester metabolites.