Complete ¹H, ¹³C, and ¹⁵N assignments of the minor isomer of codeine N‐oxide

Abstract

Codeine N‐oxide 2 is an active metabolite of codeine obtained by oxidation and observed as a degradant in codeine drug products such as syrups. Oxidation of codeine's N‐methyl function can deliver two regio‐isomers due to chirality of the tetra‐substituted nitrogen. Hydrogen peroxide oxidation of codeine was performed and induced two different isomers in a 9:1 ratio; these isomers were isolated using preparative high performance liquid chromatography (HPLC) and fully characterized by nuclear magnetic resonance (NMR) techniques. We describe the complete assignment of the minor isomer of codeine N‐oxide 3 and attribute a (S) configuration (N‐methyl axial) of the tetra‐substituted nitrogen. The effects of N‐oxidation on the 15N chemical shifts of the codeine are presented. The 15N shifts were determined using the CIGAR‐HMBC experiment at natural abundance, and the nitrogen resonance of codeine shifted downfield from 42.8 to 118.7 ppm for both N‐oxide isomers.

Experimentally Established 15N NMR Absolute Shielding Scale for Theoretical Calculations

“…Nitrogen centers of many organic and inorganic molecules are active or potentially active for various non-covalent − and coordinative interactions. , The low natural abundance and the gyromagnetic ratio of the 15 N isotope make its detection difficult. However, this problem can be solved either by isotopic labeling , or by specially designed NMR methods. − In this work, the experimentally measured 15 N NMR chemical shift tensors (CSTs) will be compared with the calculated nitrogen absolute shielding tensors in order to identify the molecules for which these tensors are close up to a constant. This constant is σ ref ( 15 N).…”