Methods for synthesizing enantiopure (S)-methadone, (R)-methadone, racemic (R,S)-methadone and related analogue substances

A method for preparing(S)-methadone, (R)-methadone or (R,S)-methadone from optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine, the method comprising:

• a ring opening reaction of optically pure ((S)- or (R)-) or racemic N-protected 4-methyl-cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to provide ((S)- or (R)-) or racemic N-protected-dinormethadone nitrile with retention of configuration;
• a two-step/one-pot deprotection/reductive amination of the N-protected-dinormethadone nitrile to provide (R)-, (S)-, or (R,S)-methadone nitrile;
• and
• a reaction of the (R)-, (S)-, or (R,S)-methadone nitrile with an organomagnesium halide reagent to form an ethyl-imine intermediate, followed by imine hydrolysis to provide (R)-, (S)-, or (R,S)-methadone.