Kinetic and mechanism study of the spontaneous, solvent- and base-catalyzed degradation of the precursor of the β-nitro alcohol metaraminol by combining HPLC/electronic circular dichroism/theoretical methods

Chiral β-nitro alcohols are key intermediates in the synthesis of a wide range of active pharmaceutical ingredients. Despite their massive use for pharmaceutical applications, in-depth kinetics studies concerning their stability during formation and transformation reactions are scarce in the literature. In this study, the (1R,2S)-1-(m-benzyloxy)-2-nitro-1-propanol) (BNA), the precursor of the metaraminol, was selected as a molecular model and the retro-Henry reaction was explored by a multidisciplinary approach involving HPLC, electronic circular dichroism and theoretical methods. The enantio-, diastereo-, and chemo-selective high-performance liquid chromatographic method for determining the purity of β-nitro alcohol during its formation and degradation is based on the use of an amylose-derived chiral stationary phase under normal-phase eluent conditions. The influence of various factors (e.g. temperature, type of reaction solvent, basic and acid catalysts) on the degradation kinetics has been investigated. The retro-Henry reaction was found to be the major degradation of BNA, under spontaneous, solvent- and base-catalyzed conditions, resulting in the formation of its precursors 3-benzyloxybenzaldehyde and nitroethane. [Display omitted] •Chiral β-nitro alcohols are key intermediates in the synthesis of many APIs.•The degradation kinetics of β-nitro alcohol metaraminol precursor are investigated.•A multidisciplinary approach involving HPLC, CD and theoretical techniques was used.•The retro-Henry reaction was found to be responsible for the degradation.•The retro-Henry reaction is faster in the protic solvents, in particular in methanol.