“Fit-for-purpose” development of analytical and (semi)preparative enantioselective high performance liquid and supercritical fluid chromatography for the access to a novel σ1 receptor agonist

• Efficient screening for enantioselective analytical and semi-preparative HPLC and SFC results in methods “fit-for-purpose”.
• Analytical enantiomer separation of (R/S)-2-(4-phenylphenyl)-4-(1-piperidyl)butan-2-ol by HPLC or SFC.
• Successful scale-up in enantioselective HPLC and SFC resulting in sufficient amounts for determination of chirooptical properties and assignment of absolute configuration in less than two weeks.
• Selection of elution order for the enantiomers possible.

A rapid and straightforward screening protocol of chiral stationary phases (CSPs) in HPLC and SFC resulted in three different methods “fit-for-purpose”, i.e. analysis and scale-up to semi-preparative enantioselective chromatography. The efficient use of these three methods allowed expedited preparation of an important drug discovery target, (R/S)-1, a potent new sigma 1 (σ1) receptor agonist. The approach taken resulted in significant savings of both time and labor for the isolation of enantiomers compared to the development of a stereo-selective synthesis.The enantiomers of 1 have been isolated allowing studies of their chirooptical properties and an in-deep comparative examination of the pharmacological profile for the individual enantiomers.

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