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′-2H4]ethylene diamine precursor. The availability of S- and R-d4-lofexidines will enable pharmacokinetic studies to be carried out to determine if differential in vivo metabolism of the two enantiomers of lofexidine occurs. Copyright © 2009 John Wiley & Sons, Ltd.