Synthesis, spectral characterization, and pro- and antioxidant activity of phosphorylated derivatives of <i>cis</i>-tramadol

<p></p> <p>A series of new N-phosphorylated derivatives of <i>cis</i>-tramadol were synthesized in a two-step process with good yields to evaluate the pro- and antioxidant activities (LPO, NO<sub>2</sub><sup>−</sup>, total SOD, and CAT). In the first step, <i>cis</i>-tramadol <b>(1)</b> was treated with 4-nitro/2-chlorophenyl phosphorodichloridate <b>(2/3)</b> in the presence of triethylamine (TEA) to yield the intermediates <b>(4/5)</b>. Further these were subsequently treated with various primary and secondary amines in the presence of TEA to afford (1R)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexyl substituted phosphonates/phosphoramidates <b>(6a-f/7a-f)</b>. Their structures were established by IR, NMR (<sup>1</sup>H, <sup>13</sup>C, <sup>31</sup>P), mass spectra, and C, H, N analysis. From the results it was disclosed that phosphonate derivatives <b>(6a-f)</b> exhibited more potent antioxidant activity than that of phosphoramidate derivatives <b>(7a-f)</b>. </p>