Stable Benzyl Cation is the Key Intermediate for the Chiral Inversion of Denopamine by Heat

Abstract

Denopamine (DP, R(-)-1-(p-hydroxyphenyl)-2-((3,4-dimethoxyphenethyl)amino)ethanol), which has been developed as a single enantiomer from its pharmacological aspect, is a clinically useful cardiotonic drug. From our previous photostability and chiral stability studies of DP, chiral inversion of DP was observed in aqueous solutions of DP drug substances and suspensions of DP tablets under the heat stress conditions dependent on the heating temperature and the storage period. In this paper, chiral inversion mechanism of DP was investigated employing phenylephrine hydrochloride (HCl) (R (-)-form) and ephedrine HCl (1R, 2S (-)-form) as samples for comparison. These drugs have the same phenylethylamine structure and the relationship between asymmetric C-atom and N-atom is similar. As a result, phenylephrine HCl and ephedrine HCl were found to be stable for heat stress. No chiral inversion was observed in both drugs. The difference between DP and phenylephrine HCl is the bond position of the hydroxy group in the phenyl group, and the difference between DP and ephedrine HCl is the existence of the hydroxy group in the phenyl group. From this study, an important step for the chiral inversion of DP was speculated as the formation of the stable benzyl cation in DP due to its hydroxy group at para-position of the phenyl group.