Process for preparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol

Abstract

A process for preparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol, or an acid addition salt thereof, comprising the step of (a) react a compound of general formula (I), **(See formula)** where R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -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) transfer the compound of general formula (II) thus obtained, **(See formula)** where R has the meaning defined above, to a compound of general formula (III), **(See formula)** where R has the meaning defined above, v optionally in the form of an acid addition salt, (c) deprotecting the compound thus obtained of general formula (III) to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol of formula (IV), **(See formula)** (d) optionally converting the (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol thus obtained into an acid addition salt.

Description

Preparation process of (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) -phenol The present invention relates to a process for the preparation of (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol. One class of active ingredients with excellent analgesic effectiveness and very good tolerability are substituted dimethyl-(3-aryl-butyl)-amine compounds, which are known from among others from e P 0693 475. In particular, (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol has shown to be a very promising candidate for the development of an analgesic in clinical trials. An objective of the present invention was, therefore, to provide a process that allows the preparation of (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol by 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 by substrate control with the almost exclusive formation of a single diastereomer, thus eliminating elaborate purification steps for separating stereoisomers and costly reagents, catalysts, or chiral ligands. Since no unwanted byproducts are formed in the process of the present invention, each batch can operate at its optimal capacity. The objective of the present invention is achieved by providing a process for preparing (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol, or an acid addition salt thereof, comprising the step of (a) reacting a compound of general formula (I), where R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C (=O) -CH3.- C (=O) -C2Hs, -C (=O) -CH (CHs) 2 or -C (=O) -C (CH3) 3, with ethyl magnesium halide in an inert reaction medium under Grignard conditions, (b) transfer the compound of general formula (II) thus obtained, where R has the meaning defined above, to a compound of general formula (III), where R has the meaning defined above, optionally in the form of an acid addition salt, (c) deprotecting the compound thus obtained of general formula (111) to obtain (1R, 2R) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) -phenol of formula (IV) , (d) optionally converting the (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol thus obtained into an acid addition salt. Particularly preferably, R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH3 in compounds of general formula (I). More particularly preferably, R represents methyl, benzyl or tetrahydropyranyl in compounds of general formula (I). Even more preferably, R in the general formula (I) represents methyl. Therefore, (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one is very preferably reacted with ethyl magnesium halide in an inert reaction medium under Grignard conditions. 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-butyl methyl ether, or any mixture thereof. The reaction is particularly preferably carried out in tetrahydrofuran with magnesium ethyl chloride at a concentration of 0.5 M to 2 M. Particularly preferably, the reaction is carried out at a concentration of 1 M or 2 M of magnesium ethyl chloride. Particularly preferably, R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH3 in the compounds of general formulas (I), (II) and (III). More particularly preferably, R represents methyl, benzyl or tetrahydropyranyl in the compounds of general formulas (I), (II) and (III). Even more particularly preferably, R represents methyl in the general formulas (I), (II) and (III). Therefore, (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (Ia) is transformed into (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol by the following sequence of steps (scheme 1). Scheme 1 In the case where R represents methyl in the general formula (111), the compound (Illa) is preferably reacted with hydrobromic acid or methanesulfonic acid and methionine or diisobutylaluminum hydride in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether and mixtures thereof to produce (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol of formula (IV). In the case where R represents C1-6-alkyl except methyl in the general formula (III), the respective compound of general formula (III) is preferably reacted with hydrobromic acid or diisobutylaluminum hydride in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether and mixtures thereof to produce (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol of formula (IV). In the event that R represents tetrahydropyranyl 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, optionally in the presence of at least one salt, preferably at least one salt selected from the group consisting of ammonium chloride and potassium hydrogen sulfate, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether, water and mixtures thereof to produce (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol of formula (IV). In the case where R represents -C- 3-8-alkyl except methyl in the general formula (III), the respective compound of general formula (III) is preferably reacted with hydrobromic acid or diisobutylaluminum hydride in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether and mixtures thereof to produce (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol of formula (IV). In the case where R represents -C1-3-alkylene-phenyl or -C1-3-alkylene-naphthyl, a compound of general formula (III) is reacted with hydrobromic acid or diisobutylaluminum hydride in a reaction medium, preferably in a reaction medium. selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether and mixtures thereof or in the presence of hydrogen and at least one catalyst, preferably in the presence of at least one palladium or platinum-based catalyst, more preferably in the presence of palladium on carbon, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether and mixtures thereof to produce (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol of formula (IV). In the case where R represents -C(=O)-Ci-6-alkyl in the general formula (111), 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 diethyl ether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether, water and mixtures thereof to produce (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) -phenol of formula (IV) . In another embodiment of the present invention, the deprotection agents according to step c) of the process of the invention are selected from the group consisting of iodotrimethylsilane, sodium ethyl sulfide, lithium iodide and hydrobromic acid, preferably hydrobromic acid. The compound (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol may be present in the form of an acid addition salt, so 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 to a corresponding addition salt, for example, through reaction with a suitable acid, can be carried out in a manner well known to those skilled in the art. Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, and / or aspartic acid. In a preferred embodiment of the invention, the acid addition salt is the hydrochloride salt. The salt formation can preferably be carried out in a suitable solvent, including diethyl ether, diisopropyl ether, alkyl acetates, acetone, 2-butanone, or any mixture thereof. Alternatively, the reaction with trimethylchlorosilane in a suitable solvent can be used for the preparation of the hydrochloride addition salt. Preferably, a compound of general formula (I) can be obtained by (a') reacting a compound of general formula (V), where R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-CH(CH3)2 or -C(=O)-C(CH3)3, with dimethylamine hydrochloride and paraformaldehyde in an inert reaction medium under Mannich and (a") subsequent resolution of the compound thus obtained of general formula (VI) , (VI) , where R has the meaning defined above. Particularly preferably, R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl, or -C(=O)-CH3 in the compounds of general formulas (V) or (VI). More particularly preferably, R represents methyl, benzyl, or tetrahydropyranyl in the compounds of general formulas (V) or (VI). Even more particularly preferably, R represents methyl in general formulas (V) and (VI). Therefore, 1-(3-methoxyphenyl)propan-1-one is converted to 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (Via) with dimethylamine hydrochloride and paraformaldehyde in an inert reaction medium under Mannich conditions. Preferably, the resolution in step (a") is carried out 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 H2O and D-(-)-tartaric acid, the subsequent separation of the salt thus obtained and the release of the corresponding compound of general formula (I) in the form of the free base. It is preferred that the resolution be carried out in an alcoholic reaction medium selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol and any mixture thereof or in a mixture of an alcoholic reaction medium selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol and acetone. Preferably, the transfer according to step (b) is carried out by (b') subjecting the compound of general formula (II) to dehydration and (b") hydrogenation of the compound of general formula (VII) thus obtained, where R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C (=O) -CH3.- C (=O) -C2H5.- C (=O) -CH (CH3) 2 or -C (=O) -C (CH3) 3 , using a suitable catalyst in an inert reaction medium in the presence of hydrogen. Particularly preferably, R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH3 in compounds of general formula (II). More particularly preferably, R represents methyl, benzyl or tetrahydropyranyl in compounds of general formula (II). Even more particularly preferably, R represents methyl in the compound of general formula (II). Therefore, (2S, 3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol is transferred to (2R, 3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine by dehydration (step (b')) and subsequent hydrogenation (step (b")). Preferably, the hydrogenation in step (b") is carried out by homogeneous catalysis in the presence of hydrogen after the dehydration step (b'). The hydrogen is preferably in gaseous form, although it is also possible that at least some of it may be dissolved in a liquid phase. Preferably, the homogeneous catalyst used for hydrogenation in step (b") according to the present invention is a rhodium, iridium or ruthenium transition metal complex, particularly preferably a rhodium or iridium transition metal complex, more particularly a rhodium transition metal complex with diphosphine ligands. The diphosphine ligands that can be used preferentially are, for example, known from the following bibliographic references: a) H. Brunner, W. Zettlmeier, Handbook of Enantioselective Catalysis. VCH Weinheim, 1993, vol. 2; b) R. Noyori et al. in Catalytic Asymmetric Synthesis Second Edition (I. Ojima, Ed.) , Wiley-VCH, Weinheim, 2000; c) EN Jacobsen, A. Pfaltz, H. Yamamoto (Eds.) , Comprehensive Asymmetric Catalysis Vol I-III, Springer Berlin, 1999, and the references cited therein. Particularly preferably, the catalyst is chosen from the group consisting of rhodium (-)-DIPAMP [ (R, R) - (-) -1, 2-Bis[ (2-methoxyphenyl) (phenyl) phosphino]ethane], rhodium (+) -DIPAMP [ (S, S) - (+) -1, 2-Bis[ (2-methoxyphenyl) (phenyl) phosphino]ethane], rhodium R-Solphos [R-(+)-N,N'-Dimethyl-7,7'-bis(diphenylphosphine)-3,3',4,4'-tetrahydro-8,8'-bi-2H-1,4-benzoxazine] and rhodium S-Solphos [S-(-)-N,N'-Dimethyl-7,7'-bis(diphenylphosphine)-3, 3', 4, 4'-tetrahydro-8, 8'-bi-2H-1, 4-benzoxazine]. The reaction parameters for homogeneous hydrogenation in step (b"), such as, for example, pressure, temperature, or reaction time, can vary over a wide range. Preferably, the temperature during homogeneous hydrogenation in step (b") can in each case be from 0 to 250 °C, particularly preferably from 10 to 40 °C and very particularly preferably from 15 to 25 °C. The homogeneous hydrogenation in step (b") can preferably be carried out at reduced, normal, or high pressure, preferably in the range of 0.01 to 300 bar. It is especially preferred to carry out the reactions under pressure in the range of 3 to 20 bar, particularly from 8 to 12 bar. The reaction time can vary depending on several parameters, such as, for example, temperature, pressure, the nature of the compound to be reacted or the properties of the catalyst, and can be determined for the procedure in question by the expert in the field using preliminary tests. The dehydration step (b') is preferably acid-catalyzed. Preferably, the acid is selected from the group consisting of formic acid, hydrochloric acid, acetic acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, or any mixture thereof. It is preferable that the acid be used at a high concentration. Particularly preferably, the concentration of hydrochloric acid is > 20%, preferably > 30%, and particularly preferably > 35% by weight. Alternatively, the acid may also be used in gaseous form. The compounds of general formula II and VII used in step (b') according to the present invention are preferably in liquid phase and for that purpose are preferably mixed or dissolved in a reaction medium that is liquid under the particular reaction conditions. Examples of suitable reaction media include water, acetic acid, formic acid, toluene, hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, or any mixture thereof. Of course, it is also possible to use mixtures or multiphase systems comprising two or more of the aforementioned liquids in the processes according to the present invention. A reaction in supercritical CO2 as a solvent is also possible. The reaction parameters for homogeneous hydrogenation in step (b'), such as, for example, pressure, temperature, or reaction time, can vary over a wide range. It is preferable that the reaction temperature in step (b') be between 35 and 100 °C, particularly preferably between 45 and 80 °C, more particularly preferably between 50 and 60 °C. The dehydration step (b') can preferably be carried out at reduced pressure, normal pressure, or high pressure, preferably in the range of 0.01 to 300 bar. It is particularly preferred to carry out the reactions under pressure in the range of 0.5 to 5 bar, in particular from 0.5 to 1.5 bar. The reaction time can vary depending on several parameters, such as temperature, pressure, the nature of the reacting compound, or the properties of the catalyst, and can be determined for the procedure in question by someone skilled in the art using preliminary tests. It is preferable that the reaction time for step (b') be between 2 and 10 h, particularly between 3 and 8 h, and more particularly between 4 and 6 h. Continuous extraction of samples to monitor the reaction is also possible, for example by gas chromatography procedures, optionally in combination with the regulation of the corresponding procedure parameters. The concentration of the acid in the reaction medium is preferably 20 to 26 M in the case of formic acid, 5 to 18 M in the case of acetic acid, 8 to 14 M in the case of hydrochloric acid, and 4 to 36 M, more preferably 4 to 18 M, in the case of sulfuric acid. The particular compound of general formula (VII) obtained can be isolated and / or purified by conventional procedures known to the expert in the field. Alternatively, the dehydration step (b') can also be carried out in the presence of at least one acid catalyst, which can preferably be selected from the group consisting of ion exchange resins, zeolites, heteropolyacids, phosphates, sulfates and optionally mixed metal oxides. The term "catalyst" within the context of the present invention includes both the catalytically active materials themselves and inert materials containing a catalytically active material. Accordingly, the catalytically active material may, for example, be applied to an inert carrier or may be present in a mixture with an inert material. Examples of inert carriers or inert materials include carbon and other materials known to the skilled trade. Suitable catalysts and their preparation are known per se to the expert in the field, for example de Venuto, PB, Microporous Mater., 1994, 2, 297; Holderich, WF, van Bekkum, H., Stud. Surf. Sci. Catal., 1991, 58, 631, Holderich, WF, Proceedings of the 10th International Congress on Catalysis, 1992, Budapest, Guczi, L. et al. (editors), "New Frontiers in Catalysis", 1993, Elsevier Science Publishers, Kozhenikov, IV, Catal. Rev. Sci. Eng., 1995, 37, 311, Song, X., Sayari, A., Catal. Rev. Sci. Eng., 1996, 38, 329. The descriptions from the relevant literature are incorporated into this invention by reference and form part of the disclosure. They are suitable for dehydration, in particular ion exchange resins carrying sulfonic acid groups are used. Preference is given to ion exchange resins based on tetrafluoroethylene / perfluorovinyl ether copolymers, optionally in the form of their silica nanocomposites, as described, for example, in the publications of Olah et al., Synthesis, 1996, 513-531 and Harmer et al., Green Chemistry, 2000, 7-14, the corresponding descriptions of which are incorporated herein by reference and form part of the disclosure. The corresponding products are commercially available, for example, under the name Nafion®, and may also be used in that form in the processes according to the present invention. In addition, preference is given to ion exchange resins based on styrene / divinylbenzene copolymers, which can be prepared by conventional procedures known to the expert in the field. For dehydration, ion exchange resins bearing sulfonic acid groups based on styrene / divinylbenzene copolymers, such as those marketed, for example, under the name Amberlyst® by Rohm & Haas, are particularly preferred and can also be used as such in the processes according to the present invention. These ion exchange resins are distinguished in particular by their stability in the presence of water and alcohols, even at elevated temperatures, for example, from 130 to 160 °C. The degree of crosslinking and the structure of these ion exchange resins can vary. For example, there are macroporous ion exchange resins, which have a heterogeneous pore diameter distribution; isoporous ion exchange resins, which have a virtually uniform pore diameter distribution; and gel-like ion exchange resins, which have no or virtually no pores. Macroporous resins, in particular, can be used to great advantage for heterogeneous catalysis in the liquid phase. Particularly suitable macroporous resins having an average pore diameter of 20 to 30 nm and a minimum concentration of active groups from 4.70 to 5.45 equivalents per kg of resin are commercially available under the names Amberlyst® 15, Amberlyst® 35 and Amberlyst® 36 and can therefore also be used in processes according to the present invention. It is also preferable to carry out dehydration in the presence of an acid catalyst based on metal oxides such as, for example, SiO2, AbO3, TiO2, Nb2O5, B2O3 or based on mixtures of metal oxides such as, for example, AbO3 / SiO2 or AbO3 / B2O3. Preferably, the dehydration temperature (b') when using an acid catalyst as described above is in each case from 20 to 250 °C, particularly preferably from 50 to 180 °C and most particularly preferably from 100 to 160 °C. The ratio of acid catalyst to compound of general formula (II) is preferably in the range of 1:200 to 1:1, in particular 1:4 to 1:2. After dehydration, the catalyst can be easily separated from the reaction mixture, preferably by filtration. The resulting compound of general formula (VII) can then be isolated and / or purified by conventional procedures known to those skilled in the art. Alternatively, the dehydration step (b') can also be carried out by subjecting a compound of general formula (II) to an excess of thionyl chloride, optionally in a reaction medium, preferably a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether and mixtures thereof, and subsequent heating of the reaction mixture thus obtained from 40°C to 120°C, preferably from 80°C to 120°C. The hydrogenation of step (b") can also be carried out by heterogeneous catalysis with hydrogen. The hydrogen is preferably in gaseous form, although it is also possible for at least some of it to dissolve in a liquid phase. Heterogeneous catalysis in the context of the present invention means that the catalysts used in step (b") are present in each case in the solid state of aggregation. Preferably, the heterogeneous catalyst used for hydrogenation in step (b") according to the present invention contains one or more transition metals, these metals may preferably be selected from the group consisting of Cu, Ag, Au, Zn, Cd, Hg, V, Nb, Ta, Cr, Mo, W, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, especially preferably from the group consisting of Ru, Rh, Pd, Pt and Ni. The corresponding catalysts may preferably contain one or more of the aforementioned transition metals in the same or different oxidation states. It may also be preferable for the corresponding catalysts to contain one or more of the aforementioned transition metals in two or more different oxidation states. The preparation of transition metal doped catalysts can be carried out using conventional procedures known to the expert in the field. Preferably, the catalyst used for hydrogenation in step (b") is selected from the group consisting of Raney nickel, palladium, palladium on carbon (1-10 wt.%, preferably 5 wt.%), platinum, platinum on carbon (1-10 wt.%, preferably 5 wt.%), ruthenium on carbon (1-10 wt.%, preferably 5 wt.), and rhodium on carbon (1-10 wt.%, preferably 5 wt.), more preferably palladium on carbon (1-10 wt.%, preferably 5 wt.) is used as a catalyst for hydrogenation in step (b"). The compounds of general formula VII and III used in step (b") according to the present invention are preferably in liquid phase and for that purpose are preferably mixed or dissolved in a reaction medium that is liquid under the particular reaction conditions. Examples of suitable reaction media include methanol, ethanol, isopropanol, n-butanol, n-propanol, toluene, heptane, hexane, pentane, acetic acid, ethyl acetate, formic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and mixtures thereof. More preferably, ethanol is used as the reaction medium in step (b). Of course, it is also possible to use mixtures or multiphase systems comprising two or more of the aforementioned liquids in the processes according to the present invention. A reaction in supercritical CO2 as a solvent is also possible. The reaction parameters for heterogeneous hydrogenation in step (b"), such as, for example, pressure, temperature, or reaction time, can both vary within a wide range. Preferably, the temperature during heterogeneous hydrogenation in step (b") can in each case be from 0 to 250 °C, particularly preferably from 15 to 180 °C and very particularly preferably from 15 to 30 °C. The heterogeneous hydrogenation in step (b") can preferably be carried out at reduced, normal, or elevated pressure, preferably in the range of 1 to 300 bar. It is particularly preferred to carry out the reactions under pressure in the range of 2 to 10 bar, especially from 4 to 10 bar. The reaction time can vary depending on several parameters, such as, for example, temperature, pressure, the nature of the compound to be reacted or the properties of the catalyst, and can be determined for the procedure in question by the expert in the field using preliminary tests. Continuous extraction of samples to monitor the reaction is also possible, for example by gas chromatography procedures, optionally in combination with the regulation of the corresponding procedural parameters. The total amount of catalyst or catalysts used depends on several factors, such as the ratio of the catalytically active component to any inert material present, or the nature of the catalyst surface. The optimum amount of catalyst or catalysts for a particular reaction can be determined by a person skilled in the art using preliminary tests. The particular compound of general formula (III) obtained can be isolated and / or purified by conventional procedures known to the expert in the field. In another embodiment of the invention, step b) (scheme 1) is a direct substitution reaction of the OH group by H, preferably carried out in a single-pot reaction. More preferably, an OH' is replaced by H-. The steps according to the present invention can each be carried out in a discontinuous manner (in batches) or in a continuous manner, giving preference to the discontinuous procedure. They are considered as reactors for the batch process, for example, a suspension reactor, and for the continuous process, a fixed bed reactor or loop reactor. The following describes a procedure for the preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride. Example Preparation of (1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride Step (a'): Preparation of 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (Via) 1-(3-Methoxyphenyl)propan-1-one (16.42 kg, 100 mol), dimethylamine hydrochloride (8.97 kg, 110 mol), paraformaldehyde (3.30 kg, 110 mol), and aqueous hydrochloric acid (32 wt%, 1.14 kg) were dissolved in ethanol under a nitrogen atmosphere in a 100 L (L = liter) double-jacketed vessel equipped with an electric impeller stirrer, a gas transition line, Pt100 temperature measuring equipment, and a heating / cooling system. The reaction mixture was heated under reflux for 16 hours, cooled to 25 °C in 3.5 hours, and stirred for 1 hour at that temperature. The suspension was separated by centrifugation and washed three times with 7 L of acetone each time. 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one hydrochloride was dissolved in water (12.5 L) and tert-butyl methyl ether (8.5 L) and stirred at room temperature. Aqueous sodium hydroxide solution (32 wt%) was added until a pH value between 10.0 and 10.5 was reached, and the phases were allowed to separate. The organic phase was removed by distillation under reduced pressure until a pressure of 5 mbar was reached at 40 °C. 3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one was obtained as a pale yellow oil (20.75 kg, 94%) which was used in the next step without further purification. Step (a"): Preparation of (S) -3- (dimethylamino) -1- (3-methoxyphenyl) -2-methylpropan-1-one (Ia) 1. a. Preparation of (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)-O,O'-dibenzoyltartrate in acetone (2R,3R)-O,O-dibenzoyl tartaric acid monohydrate (189.1 g, 0.5 mol) was dissolved in acetone (550 mL) in a 2 L reaction plant equipped with a mechanical stirrer, temperature measuring equipment, and an oil bath, and 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (110.6 g, 0.5 mol) was added. The reaction mixture was heated from 35 °C to 40 °C for 27 hours and allowed to cool to 25 °C. The suspension was siphoned out and (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)-O,O'-dibenzoyltartrate was obtained as a colorless solid (233.2 g, 80.5% ee 96.9% ee = enantiomeric excess). 1. b. Preparation of (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)-O,O'-dibenzoyl tartrate in acetone / methanol (2R,3R)-O,O'-dibenzoyl tartaric acid monohydrate (2.1 kg, 5.5 mol) was dissolved in a mixture of methanol (555 mL) and acetone (3340 mL) in a 10 L double-jacketed vessel equipped with an electric impeller stirrer, a gas transition line, Pt100 temperature measuring equipment, and an oil-based cooling / heating system, and 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (1.23 kg, 5.56 mol) was added. The reaction mixture was heated from 35 °C to 40 °C for 24 hours and allowed to cool to 25 °C. The suspension was siphoned out and (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)-O,O'-dibenzoyl tartrate was obtained as a colorless solid (2.38 kg, 74%, ee 98.4%). 2. Preparation of (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (la) (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)-O,O'-dibenzoyl tartrate (968 g, 1.67 mmol, ee 98%) was suspended in tert-butyl methyl ether (6 L) in a 10 L double-jacketed vessel equipped with an electric impeller stirrer, a gas transition line, Pt100 temperature measuring equipment, and an oil-based cooling / heating system, and diethylamine (384 g, 5.25 mol) was added. The reaction mixture was stirred from 20 °C to 25 °C for 90 minutes, and a solid was siphoned off. The filtrate was concentrated at 40 °C under vacuum until a pressure of 4 mbar was reached. (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one was obtained as a colorless oil (356.7 g, 96.5% ee 98%). Step (a): Preparation of (2S, 3R)-1-(dimeylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (Ila) 1. Magnesium flakes (93.57 g, 3.85 mol) were suspended in dry ethyl ether (2 L) in a 10 L double-jacketed vessel equipped with an electric impeller stirrer, a gas transition line, Pt100 temperature measuring equipment, and an oil-based cooling / heating system. Ethyl bromide (25 g, 0.23 mol) was added. Once the reaction was initiated, more ethyl bromide (438.6 g, 4.02 mol) was added within 90 minutes at a temperature below 35 °C, and the reaction mixture was stirred for another hour. The reaction mixture was cooled from 10 °C to 15 °C, (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (774.6 g, 3.5 mol, ee 98%) was dissolved in diethyl ether (0.8 L) and the reaction mixture was stirred for another two hours. The reaction mixture was cooled to 5 °C and an aqueous solution of ammonium hydrogen sulfate (10 wt%, 2 L) was added.The phases were separated and the organic phase was concentrated under vacuum at 40 °C until a pressure of 5 mbar was reached. (2S, 3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (862.3 g, 98%) was obtained as a colorless oil (ee 98%). 2. (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (774.6 g, 3.5 mol, ee 95%) was dissolved in dry tetrahydrofuran (800 mL) in a 10 L double-jacketed vessel equipped with an electric impeller stirrer, a gas transition line, Pt100 temperature measuring equipment, and an oil-based heating / cooling system. Ethyl magnesium bromide (2 L, 2 M in THF) was added at 15 °C over 2 hours. The reaction mixture was stirred for two hours at this temperature, cooled to 5 °C, and an aqueous solution of ammonium hydrogen sulfate (10 wt%, 2 L) was added. The phases were separated, and the organic phase was concentrated under vacuum at 40 °C until a pressure of 5 mbar was reached. (2S, 3R) -1- (dimethylamino) -3- (3-methoxyphenyl) -2-methylpentan-3-ol (871, 1 g, 99%) was obtained as a colorless oil (ee 95%). Step (b'): Preparation of (R) -3- (3-methoxyphenyl) -N,N,2-trimethylpent-3-en-1-amine (Vila) 1. (2S, 3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol (754.1 g, 3 mol, ee 95%) was dissolved in acetone (5 L) in a 10 L double-jacketed vessel equipped with an electric impeller stirrer, a gas transition line, Pt100 temperature measuring equipment, and an oil-based cooling / heating system. Hydrogen chloride (110 g, 3.0 mol) was transferred through the reaction mixture over 15 minutes at 15 °C. The reaction mixture was cooled from 0 °C to 5 °C and, after 24 hours at that temperature, siphoned out. The product was stored at 40 °C and 10 mbar for 14 hours in a drying oven. (2S, 3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride was obtained as a colorless solid (722.3 g, 83.7% ee 100%). 2. The (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride obtained as described above was placed in a 250 mL three-necked flask equipped with a thermometer, a compressed air mechanical stirrer, a reflux condenser, and an oil bath containing aqueous hydrogen chloride solution (150 mL, 36 wt%). The reaction mixture was heated to 55 °C for 5 minutes and then cooled to 20 °C. Aqueous sodium hydroxide solution (33 wt) was added while cooling until a pH of 11 was reached. Ethyl acetate (150 mL) was added, the reaction mixture was stirred for 10 minutes, the phases separated, and the ethyl acetate was removed under vacuum at 60 °C until a pressure of 10 mbar was reached. (R) -3- (3-methoxyphenyl) -N, N, 2-trimethylpent-3-en-1-amine (21 g, 90%) was obtained as an oily residue (Z / E ratio 4.5:1). Step (b") : Preparation of (2R, 3R) -3- (3-methoxyphenyl) -N,N,2-trimethylpentan-1-amine hydrochloride (Mia) 1. (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (5 kg, 21.43 mmol) was dissolved in dry ethanol (13 L) at a temperature of 25 °C and a rotational stirring frequency of 850 ± 150 per minute in a double-jacketed hydrogenation apparatus equipped with a stationary mounted lid having a hydrogen and nitrogen supply, an electric gasification stirrer, Pt100 temperature measuring equipment, an inspection glass, and a "Büchi bpc" gas controller. The hydrogenation apparatus was filled with nitrogen. Palladium was suspended on charcoal (375 g, 5 wt.) in aqueous hydrogen chloride (675 g, 32 wt.) and added to the reaction mixture. The hydrogenation apparatus was refilled with nitrogen and the reaction was carried out at a primary hydrogen pressure of 5 bar and an internal hydrogen pressure of 1 bar until the reaction was complete.The hydrogenation apparatus was filled with nitrogen, and the catalyst was filtered through a single-layer filter with filter earth. The filtrate was concentrated under vacuum. The residue was collected in ethyl acetate, and aqueous sodium hydroxide (10 wt%, 3.7 L) was added at 20 °C until a pH of 10–12 was reached. The organic phase was concentrated under vacuum at 45–50 °C until a pressure of 5 mbar was reached. The oily residue was a mixture of (2R, 3R) -3- (3-methoxyphenyl) -N,N, 2-trimethylpentan-1-amine and (2R, 3S) -3- (3-methoxyphenyl) -N,N, 2-trimethylpentan-1-amine (4.5 kg, 95%, ratio 5.5 (R, R) :1 (R, S) ). 2. A mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine (10 kg, 42.56 mol, ratio 5.5:1) was dissolved in acetone (50 L) in a 100 L double-jacketed vessel equipped with an electric impeller stirrer, a gas transition line, Pt100 temperature measuring equipment, and an oil-based cooling / heating system. Hydrogen chloride (1.55 kg, 42.51 mol) was transferred through the reaction mixture over 15 minutes at temperatures ranging from 5 °C to 25 °C. The reaction mixture was cooled from 0 °C to 5 °C and centrifuged after 2 hours of stirring. The wet solid was placed in a stirring vessel, acetone (30 L) was added, and the reaction mixture was heated under reflux for 15 minutes. After cooling to 15 °C to 20 °C, the product was centrifuged and stored at 40 °C to 50 °C and 150 mbar for 14 hours in a drying oven.(2R, 3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine hydrochloride (7, 17 kg, 63%) was obtained as a colorless solid with a diastereomeric excess of 100%. Step (c): Preparation of (1R, 2R)-3-(3-Dimethylamino-1-ethyl-2-methylpropyl)-phenol (IV) hydrochloride 1. (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine hydrochloride (5 kg, 18.4 mol) was dissolved in methanesulfonic acid (19.5 L) in a 100 L double-jacketed vessel equipped with an electric impeller stirrer, a gas transition line, Pt100 temperature measuring equipment, and an oil-based cooling / heating system, and methionine (3.35 kg, 22.5 mol) was added. The reaction mixture was stirred at a temperature of 75 °C to 80 °C for 16 hours, cooled from 15 °C to 25 °C, and water (12.5 L) at that temperature was slowly added. Aqueous sodium hydroxide solution (approximately 28 L, 32 wt%) was added until a pH of 10–12 was reached while the temperature was maintained below 50 °C. Ethyl acetate (15 L) was added, and the reaction mixture was stirred for 15 minutes at a rotational stirring frequency of 150 revolutions per minute. The phases were separated, and the organic phase was washed with water (15 L).Activated carbon (0.05 kg) was added to the organic phase and filtered after 30 minutes of stirring. The solvent was removed under vacuum at a temperature of 40–50 °C until a pressure of 50 mbar was reached. The residue was used in the next stage without further purification. 2. The residue obtained as described above was dissolved in acetone (25 L) while stirring, and hydrogen chloride (0.78 kg, 21.4 mol) was transferred through the reaction mixture at a temperature of 20–25 °C. The suspension was stirred for 3 hours at a temperature of 0–5 °C and then centrifuged. Isopropanol (35 L) was added to the wet solid in a reaction vessel, and the reaction mixture was heated under reflux for 15 minutes. The reaction mixture was cooled from 0–5 °C and stirred for 3 hours at that temperature. After centrifugation, the product was stored at 30–40 °C and 150 mbar for 16 hours in a drying oven. (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride (4, 18 kg, 88%) was obtained as a colorless solid with a purity of 100%.

Claims

1. A process for preparing (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol, or an acid addition salt thereof, comprising the step of (a) reacting a compound of general formula (I) , where R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C (=O) -CH3.(a) -C(=O)-C2Hs, (b) -C(=O)-CH(CHs)2 or (c) -C(=O)-C(CH3)3, with ethyl magnesium halide in an inert reaction medium under Grignard conditions, (c) transferring the compound of general formula (II) thus obtained, where R has the meaning defined above, to a compound of general formula (III), where R has the meaning defined above, optionally in the form of an acid addition salt, (d) deprotecting the compound thus obtained of general formula (III) to obtain (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol of formula (IV), (e) optionally converting the (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol thus obtained into an acid addition salt.

2. A process according to claim 1, characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH3. 3.A process according to any one of claim 1 or 2, characterized in that R represents methyl, benzyl, or tetrahydropyranyl.

4. A process according to any one of claim 1 to 3, characterized in that the ethyl magnesium halide used in step (a) is the chloride or bromide.

5. A process according to any one of claim 1 to 4, characterized in that the inert reaction medium is selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, or any mixture thereof. 6.A process according to any one of claims 1 to 5, characterized in that a compound of general formula (I) was obtained by (a') reacting a compound of general formula (V), wherein R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-CH(CH3)2, or -C(=O)-C(CH3)3, with dimethylamine hydrochloride and paraformaldehyde in an inert reaction medium under Mannich conditions, and (a") further resolving the compound thus obtained of general formula (VI), wherein R has the meaning defined above.

7. A process according to claim 6, characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH3. 8.A process according to any one of claims 6 or 7, characterized in that R represents methyl, benzyl, or tetrahydropyranyl.

9. A process according to any one of claims 6 to 8, characterized in that the resolution in step (a") is carried out 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 H2O, and D-(-)-tartaric acid, the subsequent separation of the salt obtained in this manner, and the release of the corresponding compound of general formula (I) in the form of the free base.

10. A process according to claim 9, characterized in that the resolution is carried out in an alcoholic reaction medium selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, and any mixture thereof. 11.A process according to any one of claims 1 to 10, characterized in that the transfer according to step (b) is carried out by (b') subjecting the compound of general formula (II) to dehydration and (b") hydrogenation of the compound thus obtained of general formula (VII), wherein R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-CH(CH3)2, or -C(=O)-C(CH3)3, using a suitable catalyst in an inert reaction medium in the presence of hydrogen.

12. A process according to claim 11, characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH3.

13. A process according to any one of claim 11 or 12, characterized in that R represents methyl, benzyl or tetrahydropyranyl. 14.A process according to any one of claims 11 to 13, characterized in that after the dehydration step (b'), hydrogenation is carried out in step (b") by homogeneous catalysis.

15. A process according to any one of claims 11 to 13, characterized in that the dehydration step (b') is acid-catalyzed.

16. A process according to claim 15, 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.

17. A process according to any one of claims 11 to 13, characterized in that the hydrogenation of step (b") is carried out by heterogeneous catalysis. 18.A process according to claim 17, 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.

19. A process according to any one of claims 11 to 18, characterized in that the reaction medium is selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, or any mixture thereof.