Dielectrically controlled resolution (DCR) of 3-aminopiperidine via diastereomeric salt formation with N-tosyl-(S)-phenylalanine

A useful key intermediate for the dipeptidyl peptidase-4 (DPP-4) inhibitor, 3-aminopiperidine 1, was successfully resolved with an enantiomerically pure resolving agent, N-tosyl-(S)-phenylalanine 2, to give both stereoisomers (R)-1 and (S)-1 as a less-soluble diastereomeric salt with (S)-2, via a dielectrically controlled resolution (DCR) phenomenon.

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(R)-3-Ammoniopiperidium bis((S)-N-tosyl-2-amino-3-phenylpropanoate) monohydrateC37H48N4O9S2[α]D25=-4.6 (c 0.01, MeOH/H2O = 1/1)Source of chirality: resolutionAbsolute configuration: (R,S)

(S)-3-Ammoniopiperidium bis((S)-N-tosyl-2-amino-3-phenylpropanoate)C37H46N4O8S2[α]D25=-7.0 (c 0.01, MeOH/H2O = 1/1)Source of chirality: resolutionAbsolute configuration: (S,S)