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 t1/2 and clearance, and the depression of the metabolic N‐demethylation process were the only biological properties modified by the deuteration.
|Original language||English (US)|
|Number of pages||18|
|Journal||Journal of Labelled Compounds and Radiopharmaceuticals|
|State||Published - Jan 1985|
- antinociceptive activity
- isotopic effects