Synthesis and physico‐chemical properties of (R, S)‐6‐ditrideuteriomethylamino‐4,4‐diphenylheptan‐3‐one hydrochloride (methadone‐d₆)

A reaction sequence is described to synthesize (R, S)‐6‐ditrideuteriomethylamino‐4,4‐diphenylheptan‐3‐one hydrochloride ( methadone‐d₆.HCl ) in 10.5% overall yield starting from dimethylamine‐d₆ hydrochloride. While methadone‐d₆.HCl had rather similar physicochemical properties compared to methadone.HCl in the solid phase, a divergent behaviour was observed in solution ( pKa, chromatographic and ¹³C‐NMR data ). A higher basicity along with a more important hydrophilicity were observed for the d₆‐derivative. A ¹³C‐NMR study showed significant differences in the ¹³C chemical shifts, which were attributed in part to the intrinsic nature of D itself and in part to a conformational perturbation. The longer duration of antinociceptive action, along with higher t_1/2 and clearance, and the depression of the metabolic N‐demethylation process were the only biological properties modified by the deuteration.