ASYMMETRIC-SYNTHESIS AND PHARMACOLOGY OF METHYLPHENIDATE AND ITS PARASUBSTITUTED DERIVATIVES

We report the first asymmetric synthesis of the individual enantiomers of methylphenidate (1). From d-pipecolic acid, the (2R,2'R) and (2S,2 'R) enantiomers of 1 were obtained in > 99% optical purity while the ( 2S,2'S) and (2R,2'S) enantiomers of 1 were derived from I-pipecolic ac id in 96% optical purity. The versatility of this methodology is demon strated with the synthesis of the (2R,2'R) and (2S,2'S) enantiomers of p-bromo and p-methoxy derivatives in similar yields and enantiomeric purities. Comparative neurochemical assessments of these synthesized e nantiomers at purported dopamine, norepinephrine, and serotonin uptake sites along with locomotor activity studies in rats are also reported .