Enantioenriched chiral primary amines are a challenging family of compounds to isolate by chiral chromatography and often require derivatization to facilitate separation. Recently, it was shown that derivatization as the 4-nitrobenzyl carbamate (p-NO2-Cbz, pNZ) enabled an otherwise challenging preparative scale resolution of BRD4780, rac-3-exo-isopropylbicyclo[2.2.1]heptan-2-endo-amine, with supercritical fluid chromatography (SFC) on chiral stationary phase (CSF). In this study, we investigated whether protection with pNZ is a general method to improve separation of chiral primary amines relative to Cbz. pNZ is an achiral, UV visible protecting group that is commercially available and easily removed under mild conditions. Eleven primary amines were synthesized as the pNZ and Cbz protected compounds and profiled using SFC. Both gradient and isocratic methods were run on a suite of nine Daicel CHIRALPAK columns (IA-3 - IH-3, IJ-3) across four mobile phases: supercritical CO2 modified with MeOH, EtOH, iPrOH and MeCN. We found superior resolution was consistently achieved with pNZ for all compounds compared to Cbz. Thus, we establish derivatization of primary amines as the 4-nitrobenzyl carbamate as a valuable strategy for improving separation efficiency on CSF.

p-NO2-Cbz derivatization of primary chiral amines enables superior resolution by supercritical fluid chromatography

ACS Fall 2021

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