Synthesis of the Enantiomers of Reduced Haloperidol

Reduced haloperidol (RHAL) is the best known metabolite of haloperidol (HAL), having been identified in humans, rats, and guinea pigs. Since RHAL contains an asymmetric center, it can exist in two possible enantiomeric forms. However, the enantiomeric composition of the RHAL formed from HAL in vivo has never been reported. As a first step toward the enantiomeric analysis of biological samples, we have developed an efficient and stereospecific synthesis of (+)- and (–)-RHAL from readily available commercial materials. We have also identified an enantioselective chromatographic method using a chiral HPLC stationary phase which can detect as little as 1% of either enantiomer in synthetic samples of RHAL enantiomers.