Direct chromatographic resolution and isolation of the four stereoisomers of meta‐hydroxyphenylpropanolamine

Abstract

Methods for the direct chiral chromatographic separation of the four stereoisomers of meta-hydroxyphenylpropanolamine (MHPA) on an analytical and preparative scale are described. Separations were carried out on a Crownpak CR (+) chiral column with 113 mM aqueous perchloric acid as the mobile phase. Baseline resolution of the more retained (+)-stereoisomers (1S configuration) and partial resolution of the less retained (−)-stereoisomers (1R configuration) were obtained under these chromatographic conditions. Removal of the bulk of the (1R,2S)-stereoisomer (metaraminol) from the initial crude mixture by fractional crystallization as the (+)-bitartarate salt substantially improved the peak resolution factors (Rs) of the remaining three stereoisomers. Semipreparative chromatographic resolution of the latter isomeric mixture provided milligram quantities of each stereoisomer in >97% enantiomeric excess. Subsequent recrystallization of their bitartarate or fumarate salts gave enantiomeric purities >99%.

Stereospecific inhibition of monoamine uptake transporters by meta-hydroxyephedrine isomers

“…Briefly, a mixture containing the four stereoisomers of meta-hydroxyphenylpropanolamine (MHPA) was synthesized in 20% overall yield by a seven-step synthetic route from propiophenone. The individual MHPA stereoisomers were isolated from the mixture using semipreparative chiral high pressure liquid chromatography (HPLC) as described (Van Dort, 1999). Each stereoisomer of MHPA was converted to its respective carbamate derivative, which was then reduced to the respective HED stereoisomer with lithium aluminum hydride in refluxing tetrahydrofuran.…”