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EP-3210965-B2 - PROCESS FOR THE PREPARATION OF (1R,2R)-3-(3-DIMETHYLAMINO-1-ETHYL-2-METHYL-PROPYL)-PHENOL

EP3210965B2EP 3210965 B2EP3210965 B2EP 3210965B2EP-3210965-B2

Inventors

  • HELL, WOLFGANG
  • ZIMMER, OSWALD
  • BUSCHHMANN, Helmut Heinrich
  • Holenz, Jörg
  • GLADOW, STEFAN

Dates

Publication Date
20260513
Application Date
20070723

Claims (16)

  1. A process for preparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof, comprising the step of (a) reacting a compound of general formula (I), wherein R represents -C(=O)-CH 3 , -C(=O)-C 2 H 5 , -C(=O)-CH(CH 3 ) 2 or -C(=O)-C(CH 3 ) 3 , with ethyl magnesium halide in an inert reaction medium under Grignard conditions, (b) transferring the thus obtained compound of general formula (II), wherein R has the above defined meaning, to a compound of general formula (III), wherein R has the above defined meaning, optionally in form of an acid addition salt, (c) deprotecting the thus obtained compound of general formula (III) to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (IV), (d) optionally converting the thus obtained (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into an acid addition salt.
  2. A process according to claim 1, characterized in that R represents -C(=O)-CH 3 .
  3. A process according to any of claims 1 or 2, characterized in that the ethyl magnesium halide used in step (a) is the chloride or bromide.
  4. A process according to any one of claims 1 to 3, characterized in that the inert reaction medium is selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl-methylether, diisopropylether or any mixture thereof.
  5. A process according to any one of claims 1 to 4, characterized in that a compound of general formula (I) was obtained by (a') reacting a compound of general formula (V), (V), wherein R represents -C(=O)-CH 3 , -C(=O)-C 2 H 5 , -C(=O)-CH(CH 3 ) 2 or -C(=O)-C(CH 3 ) 3 , with dimethylamine hydrochloride and paraformaldehyde in an inert reaction medium under Mannich conditions and (a") subsequent resolution of the thus obtained compound of general formula (VI), wherein R has the above defined meaning.
  6. A process according to claim 5, characterized in that R represents -C(=O)-CH 3 .
  7. A process according to any of claims 5 or 6, characterized in that the resolution in step (a") is performed by reacting a compound of general formula (VI) with a chiral acid selected from the group consisting of L-(-)-dibenzoyl tartaric acid, L-(-)-dibenzoyl tartaric acid · H 2 O and D-(-)-tartaric acid, subsequent separation of the thus obtained salt and liberation of the corresponding compound of general formula (I) in form of the free base.
  8. A process according to claim 7, characterized in that the resolution is performed in an alcoholic reaction medium selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol and any mixture thereof.
  9. A process according to any of claims 1 to 8, characterized in that the transfer according to step (b) is performed by (b') subjecting the compound of general formula (II) to dehydration and (b") hydrogenation of the thus obtained compound of general formula (VII), wherein R represents -C(=O)-CH 3 , -C(=O)-C 2 H 5 , -C(=O)-CH(CH 3 ) 2 or -C(=O)-C(CH 3 ) 3 , using a suitable catalyst in an inert reaction medium in the presence of hydrogen.
  10. A process according to claim 9, characterized in that R represents -C(=O)-CH 3 .
  11. A process according to any of claims 9 or 10, characterized in that after the dehydration step (b') the hydrogenation in step (b") is effected via homogeneous catalysis.
  12. A process according to any of claims 9 or 10, characterized in that the dehydration step (b') is acid-catalysed.
  13. A process according to claim 12, characterized in that the acid is selected from the group consisting of formic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrobromic acid or any mixture thereof.
  14. A process according to any of claims 9 or 10, characterized in that the hydrogenation of step (b") is effected via heterogeneous catalysis.
  15. A process according to claim 14, characterized in that the catalyst used for hydrogenation is selected from the group consisting of Raney nickel, palladium, palladium on carbon, platinum, platinum on carbon, ruthenium on carbon or rhodium on carbon.
  16. A process according to any of claims 9 to 15, characterized in that the reaction medium is selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl-methylether, diisopropylether or any mixtures thereof.

Description

The present invention relates to a process for the preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol. A class of active ingredients having excellent analgesic effectiveness and very good tolerability are the substituted dimethyl-(3-aryl-butyl)-amine compounds, which are known inter alia from EP 0 693 475. In particular, (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol has proven to be a very promising candidate for the development of an analgesic in clinical trials. An object of the present invention was, therefore, to provide a process which allows for the preparation of (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol via a short route with good overall yield under environmentally acceptable conditions. In particular, in the process of the present invention all stereocenters can be established via substrate control with almost exclusive formation of only a single diastereomer thus sparing elaborate purification steps to separate stereoisomers and costly chiral reagents, catalysts or ligands. As there are not any undesired side products formed in the process of the present invention, each batch can work at its optimal capacity. The object of the present invention is met by providing a process for preparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof, comprising the step of (a) reacting a compound of general formula (I), wherein R represents-C(=O)-CH3, -C(=O)-C2H5, -C(=O)-CH(CH3)2 or -C(=O)-C(CH3)3, with ethyl magnesium halide in an inert reaction medium under Grignard conditions,(b) transferring the thus obtained compound of general formula (II), wherein R has the above defined meaning, to a compound of general formula (III), wherein R has the above defined meaning, optionally in form of an acid addition salt,(c) deprotecting the thus obtained compound of general formula (III) to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (IV), (d) optionally converting the thus obtained (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into an acid addition salt. Particularly preferably R represents -C(=O)-CH3 in the compounds of general formula (I). Preferably ethyl magnesium bromide or ethyl magnesium chloride are used as ethyl magnesium halide in step a). The reaction according to step (a) is carried out in an inert reaction medium, preferably in an organic ether, for example, selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether or any mixture thereof. The reaction is particularly preferably carried out in tetrahydrofuran with ethyl magnesium chloride at a concentration from 0.5 M to 2 M of the ethyl magnesium chloride. Particularly preferably the reaction is carried out at a concentration of 1 M or 2 M of the ethyl magnesium chloride. Particularly preferably R represents -C(=O)-CH3 in the compounds of general formulae (I), (II) and (III). As R represents a specific -C(=O)-C1-6-alkyl in the general formula (III), the respective compound of general formula (III) is preferably reacted with at least one inorganic acid, preferably with at least one inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, or with at least one inorganic base, preferably with at least one inorganic base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate in a reaction medium, preferably in a reaction medium selected from the group consisting of diethylether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl-methylether, water and mixtures thereof to yield (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (IV). In another embodiment of the present invention the agent for deprotecting according to step c) of the inventive process are selected from the group consisting of iodotrimethylsilane, sodium ethyl suphide, lithium iodide and hydrobromic acid, preferably hydrobromic acid. The compound (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol may be present in form of an acid addition salt, whereby any suitable acid capable of forming such an addition salt may be used. The conversion of the compound (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methylpropyl)-phenol into a corresponding addition salt via reaction with a suitable acid may be effected in a manner well known to those skilled in the art. Suitable acids include but are not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and aspartic acid. In a preferred embodiment the acid addition salt is the hydrochloride salt. The salt formation may preferably be effected in a suitable solvent including diethyl ether, diisopropyl ether, alkyl acetates, a