Rac- and R-(+)-[4,4′,5,5′-²H₄]-2- (1′-[2″,6″-dichlorophenoxy]-ethyl)-Δ²- imidazoline (lofexidine)

The synthesis of the d₄-forms of rac- and R-lofexidine was accomplished. Two methods are described; one method is a two-step synthesis of rac-d₄-lofexidine from 2-chloropropionitrile, the second method is a three-step preparation of R-d₄-lofexidine in absolute enantiomeric purity from S-methyl lactate. The commercial availability of R-methyl lactate makes this latter enantioselective synthesis applicable also to the synthesis of S-d₄- lofexidine. These procedures also conserve the utilization of the relatively expensive [1,1′,2,2′-²H ₄]ethylene diamine precursor. The availability of S- and R-d ₄-lofexidines will enable pharmacokinetic studies to be carried out to determine if differential in vivo metabolism of the two enantiomers of lofexidine occurs.