Kinetic resolution of 7-chloro-4-{4-[ethyl(2-hydroxyethyl)amino]-1-methylbutylamino}quinoline (hydroxychloroquine) by an atropisomeric resolving agent

Abstract

The enantiomers of 7-chloro-4-{4-[ethyl(2-hydroxyethyl)amino]-1-methylbutylamino}quinoline (hydroxychloroquine) are not available by classical resolution methods. A procedure for the kinetic resolution of this compound is described in which the atropisomeric 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate stereoselectively transforms one enantiomer of the base into the diastereoisomeric salt, leaving the other enantiomer as the unchanged base. The products are easily separated, and both enantiomers of hydroxychloroquine are thus accessible in high optical purity. The (+)-enantiomer has been assigned the absolute S-configuration by the use of circular dichroism. The optical purity of the diastereomeric salts is obtained from their NMR spectra.