Resolution methods for isolating desired enantiomers of tapentadol intermediates and use thereof for the preparation of tapentadol

A resolution process for the preparation of (−)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine of formula II:

• or an acid addition salt thereof, comprising:
• a) treating an enantiomeric pair (2R,3R)/(2S,3S)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine or an acid addition salt thereof with an optically active acid in a first solvent to produce a reaction mass containing the diastereomeric mixture;
• b) separating the desired diastereomeric salt from the diastereomeric mixture obtained in step-(a);
• and
• c) neutralizing the desired diastereomeric salt obtained in step-(b) with a base in a second solvent to produce enantiomerically pure (−)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine of formula II, and optionally converting the enantiomerically pure compound of formula II obtained into an acid addition salt thereof.

A process for preparing tapentadol, 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol, of formula I:

• or a pharmaceutically acceptable salt thereof, comprising
• a) reacting an enantiomeric pair (2R,3R)/(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol or an acid addition salt thereof with trifluoroacetic anhydride in a first solvent to produce a reaction mass;
• b) hydrogenating the reaction mass obtained in step-(a) in the presence of a hydrogenation catalyst to produce an enantiomeric pair (2R,3R)/(2S,3S)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine or an acid addition salt thereof;
• c) resolving the enantiomeric pair obtained in step-(b) with a suitable optically active acid to produce an enantiomerically pure (−)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine of formula II or an acid addition salt thereof, wherein the optically active acid is selected from the group consisting of optically active di-aroyl-tartaric acid, S-naproxen, malic acid, mandelic acid and its derivatives, and camphorsulphonic acid and its derivatives;
• d) demethylating the enantiomerically pure compound of formula II obtained in step-(c) using a demethylating agent in a second solvent to produce tapentadol of formula I, and optionally converting the tapentadol of formula I obtained into a pharmaceutically acceptable salt thereof;
• and
• e) optionally, purifying the tapentadol or a pharmaceutically acceptable salt thereof obtained in step-(d) using a third solvent to produce highly pure tapentadol or a pharmaceutically acceptable salt thereof.