Process for the preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol

Abstract

Process for the preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol.

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 that have excellent analgesic efficacy and very good tolerance are the substituted dimethyl-(3-aryl-butyl)-amine compounds, which are, among others, known 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 a analgesic in clinical trials. An object of the present invention was therefore to provide a method which opens the possibility for the preparation of (1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methyl- propyl)-phenol via a short reaction route with good overall yield under environmental acceptable conditions. In particular, in the present method all stereocenters can be established via substrate- control with almost exclusive formation of only a single diastereomer and thereby saving complicated purification steps for separating stereoisomers and expensive chiral reagents, catalysts or ligands. Since no unwanted by-products are formed in the method of the invention, each charge can operate at its optimum capacity. The object of the present invention is achieved by providing a method- method for the preparation of (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), R O (S) ON (IN), where R represents -C-alkyl, -C-cycloalkyl, -C-alkylene-phenyl, -C-alkylene- 1-6 3-8 1-3 1-3 naphthyl, tetrahydropyranyl or -C(=O)-C -alkyl, with ethylmagnesium halide in a 1-6 inert reaction medium under Grignard conditions. R preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C(=O)-CH , -C(=O)-CH , -C(=O)-CH(CH ) or -C(=O)- 3 2 5 3 2 C(CH ) in the compounds of general formula (I). Particularly preferably, R represents methyl, 3 3 ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydro- pyranyl or -C(=O)-CH in the compounds of general formula (I). More particularly 3 preferably R represents methyl, benzyl or tetrahydropyranyl in the compounds of general formula (I). Even more preferably, R in the general formula (I) represents methyl. Thus, as a highly preferred embodiment (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methyl- propan-1-one reacted with ethylmagnesium halide in an inert reaction medium under Grignard conditions. Ethyl magnesium bromide or ethyl magnesium chloride is preferably used as ethyl magnesium halide in step a). The reaction according to step (a) is preferably carried out in an inert reaction medium, preferably in an organic ether, for example selected from the group consisting of diethyl ether, tetrahydro- furan, 2-methyltetrahydrofuran, tert-butyl methyl ether or any mixture The reaction is particularly preferably carried out in tetrahydrofuran with ethylmagnesium chloride at a concentration of 0.5 M to 2 M of the ethylmagnesium chloride. In particular preferably the reaction is carried out at a concentration of 1 M or 2 M of ethylmagnesium the sium chloride. Another object of the present invention is a method for the preparation of (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), R O (S) ON (IN), where R represents -C-alkyl, -C-cycloalkyl, -C-alkylene-phenyl, -C-alkylene- 1-6 3-8 1-3 1-3 naphthyl, tetrahydropyranyl or -C(=O)-C -alkyl, with ethylmagnesium halide in a 1-6 inert reaction medium under Grignard conditions, (b) transferring the compound of general formula (II) thus obtained, O R HO (S) N (R) (II), where R has the meaning defined above, to a compound of general formula (III), O R (R) N (R) (III), where R has the meaning defined above, optionally in the form of an acid addition salt, (c) deprotecting the thus obtained compound of general formula (III) to obtaining (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (IV), OH (R) N (R) (IV), (d) optionally converting the thus obtained (1R,2R)-3-(3-dimethylamino-1-ethyl- 2-methyl-propyl)-phenol to an acid addition salt. R preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C(=O)-CH , -C(=O)-CH , -C(=O)-CH(CH ) or -C(=O)- 3 2 5 3 2 C(CH ) in the compounds of general formulas (I), (II) and (III). Particularly preferred 3 3 R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH in the compounds of general formulas (I), (II) 3 and (III). More particularly preferably R represents methyl, benzyl or tetrahydropyranyl in the compounds of general formulas (I), (II) and (III). When specifically preferred, R represents methyl in the general formulas (I), (II) and (III). Thus, (C)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (Ia) converted to (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol by the following series of steps (reaction scheme 1). Oh Oh HO ( S) (a) ( S) N ( R) ON (Him) (IIa) Oh OH (b) (c) ( R) ( R) NN ( R) ( R) (IIIa) (IV) Reaction Scheme 1 . In the case R represents methyl in the general formula (III) becomes compound (IIIa) initially converted 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-methyltetrahydro- furan, dioxane, tert-butyl methyl ether and mixtures thereof to obtain (1R,2R)-3-(3- dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (IV). In the case where R represents C-alkyl except methyl in the general formula (III) it becomes 1-6 the respective compound of general formula (III) 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-methyl- tetrahydrofuran, dioxane, tert-butyl methyl ether and mixtures thereof to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (IV). In the case where R represents tetrahydropyranyl in the general formula (III) it becomes the respective compound of general formula (III) 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 obtain (1R,2R)-3-(3- dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (IV). In the case where R represents -C- -cycloalkyl in the general formula (III) it becomes 3-8 the respective compound of general formula (III) 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-methyl- tetrahydrofuran, dioxane, tert-butyl methyl ether and mixtures thereof to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (IV). In the case where R represents -C-alkylene-phenyl or -C-alkylene-naphthyl, a 1-3 1-3 compound of general formula (III) reacted with hydrobromic acid or diisobutyl- aluminum 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 catalyst based on palladium or platinum, more preferably in the presence of palladium on charcoal, in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetra- hydrofuran, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether and mixtures from which to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol from formula (IV). In the case where R represents -C(=O)-C -alkyl in the general formula (III) it becomes 1-6 the respective compound of general formula (III) 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, tetrahydro- furan, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether, water and mixtures from which to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol from formula (IV). In another embodiment of the present invention, the deprotecting agent is selected according to step c) in the present process 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-methyl-propyl)-phenol may be present in the form of an acid addition salt, whereby any suitable acid capable of forming such an addition salt can be used. The conversion of the compound (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol to a corresponding addition salt via reaction with a suitable acid can be effected in a manner which are well known to those skilled in the art. Such acids include, but are not limited to limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid 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 hydro- the chloride salt. The salt formation can preferably be effected in a suitable solvent which includes diethyl ether, diisopropyl ether, alkyl acetates, acetone, 2-butanone or any mixture thereof. It is also preferred to use reaction with trimethylchlorosilane in a suitable solvent for preparing the hydrochloride addition salt. A compound of general formula (I) can preferably be obtained by (a') reacting a compound of general formula (V), RO O where R represents -C-alkyl, -C-cycloalkyl, -C-alkylene-phenyl, -C-alkylene- 1-6 3-8 1-3 1-3 naphthyl, tetrahydropyranyl or -C(=O)-C -alkyl, with dimethylamine hydrochloride and 1-6 paraformaldehyde in an inert reaction medium under Mannich conditions and (a'') subsequent cleavage of the thus obtained compound of general formula (WE), R O ON (WE), where R has the meaning defined above. R preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C(=O)-CH , -C(=O)-CH , -C(=O)-CH(CH ) or -C(=O)- 3 2 5 3 2 C(CH ) in the compounds of general formulae (V) or (VI). Particularly preferred 3 3 R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH in the compounds of general formulae (V) 3 or (VI). It is more particularly preferred that R represents methyl, benzyl or tetrahydropyranyl in the compounds of general formulas (V) or (VI). Even more particularly preferably, R represents methyl in the general formulas (V) and (VI). Thus 1-(3-methoxyphenyl)propan-1-one is converted to 3-(dimethylamino)-1-(3- methoxyphenyl)-2-methylpropan-1-one (VIa) with dimethylamine hydrochloride and paraform- aldehyde in an inert reaction medium under Mannich conditions. The cleavage in step (a'') is preferably carried out by reacting a compound of general formula (VI) with a chiral acid selected from the group consisting of L-(-)-dibenzoyltartaric acid, L- (-)-dibenzoyltartaric acid · HO and D-(-)-tartaric acid, subsequent separation of the thus 2 obtained the salt and liberation of the corresponding compound of general formula (I) in form of the free base. It is preferred that the cleavage is 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. The transfer according to step (b) is preferably carried out by (b') exposing the compound to general formula (II) for dehydration and (b'') hydrogenation of the thus obtained the compound of general formula (VII), R O (R) N (VII), where R represents -C-alkyl, -C-cycloalkyl, -C-alkylene-phenyl, -C-alkylene- 1-6 3-8 1-3 1-3 naphthyl, tetrahydropyranyl or -C(=O)-C -alkyl, using a suitable catalyst 1-6 in an inert reaction medium in the presence of hydrogen. R preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C(=O)-CH , -C(=O)-CH , -C(=O)-CH(CH ) or -C(=O)- 3 2 5 3 2 C(CH ) in the compound of general formula (II). Particularly preferably, R represents methyl, 3 3 ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydro- pyranyl or -C(=O)-CH in the compound of general formula (II). 3 It is more particularly preferred that R represents methyl, benzyl or tetrahydropyranyl in the compound of general formula (II). Even more particularly preferably, R represents methyl in the compound of general formula (II). Thus, (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'')). The hydrogenation in step (b'') is preferably effected via 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 part of this is dissolved in a liquid phase. The homogeneous catalyst used for hydrogenation in step (b'') according to the present invention is preferably a transition metal complex of rhodium, iridium or ruthenium, particularly preferred is a transition metal complex of rhodium or iridium, more specifically a transition metal complex of rhodium with diphosphine ligands. Diphosphine ligands which can be preferably used are known, for example, from the following literature 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 selected 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(diphenylphosphino)-3,3',4,4'-tetrahydro-8,8'-bi-2H-1,4-benzoxazine] and rhodium S-Solphos [S-(-)-N,N'-dimethyl-7,7'-bis(diphenylphosphino)-3,3',4,4'-tetrahydro- 8,8'-bi-2H-1,4-benzoxazine]. The reaction parameters for the homogeneous hydrogenation- none in step (b''), such as pressure, temperature or reaction time, can vary over a wide range. The temperature during the homogeneous hydrogenation in step (b'') may 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 pressure, at normal pressure or at elevated pressure, preferably in the range from 0.01 to 300 bar. It is particularly preferred to carry out the reactions under pressure in the range from 3 to 20 bar, especially from 8 to 12 bar. The reaction time may vary depending on various parameters, such as temperature, pressure, type of compound to be reacted or the properties of the catalyst, and can be determined for the indicated process by one skilled in the art the technique 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 preferred that the acid is used in a high concentration. Particularly preferred is the concentration of the hydrochloric acid > 20%, preferably > 30%, particularly preferably > 35% by weight. The acid may alternatively also used in gaseous form. The compounds of general formula II and VII used in step (b') according to the present invention invention is preferably in liquid phase and is for this purpose preferably mixed with or dissolved in a reaction medium that is liquid under the particular reaction conditions the conditions. Examples of suitable reaction media are water, acetic acid, formic acid, toluene, hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid or any mixture thereof. It is of course also possible to use mixtures or multiphase systems that include two or more of the above liquids in the methods of the present invention invention. A reaction in supercritical CO as solvent is also possible. 2 The reaction parameters for the dehydration in step (b'), such as, for example, pressure, temperature or reaction time, can vary over a wide range. It is preferred that the reaction temperature in step (b') is between 35 and 100°C, especially preferably 45 and 80°C, more particularly preferably between 50 and 60°C. The dehydration step (b') can preferably be carried out at reduced pressure, at normal pressure or at elevated pressure, preferably in the range from 0.01 to 300 bar. It is particularly It is preferred to carry out the reactions under pressure in the range from 0.5 to 5 bar, in particular from 0.5 to 1.5 bar. The reaction time may vary depending on various parameters, such as temperature, pressure, type of compound to be reacted or the catalyst properties, and can be determined for the particular method by a person skilled in the art in the art using preliminary tests. It is preferred that the reaction time in step (b') is between 2 and 10 hours, particularly preferably between 3 and 8 hours, more particularly preferably between 4 and 6 hours. The continuous removal of samples to monitor the reaction, for example by using gas chromatographic methods, is also possible, possibly in combination with regulation of the corresponding process 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 methods known to those skilled in the art. Alternatively, the dehydration step (b') can also be carried out in the presence of at least one acidic catalyst, which can preferably be selected from the group consisting of ion exchange resins, zeolites, heteropolyacids, phosphates, sulphates and possibly mixed metal oxides. The term catalyst in the present context includes both catalytically active materials themselves and inert materials provided with a catalytically active material. The catalytically active material can therefore, for example, be applied to a inert carrier or may be present in admixture with an inert material. As an inert carrier or inert material is, for example, carbon and other materials known to those skilled in the art in the field of technology, current. Suitable catalysts and their preparation are known per se to those skilled in the art. the technique, for example from Venuto, PB, Microporous Mater., 1994, 2, 297; Holderich, WF, van Bekkum, H., Stud. Surf. Sci. Catal., 1991, 58, 631, Hölderich, WF, “Proceedings of the 10th International Congress on Catalysis”, 1992, Budapest, Guczi, L. et al. (publishers), "New Frontiers in Catalysis", 1993, Elsevier Science Publishers, Kozhenikov, IV, Catal. Reef. Sci. Eng., 1995, 37, 311, Song, X., Sayari, A., Catal. Reef. Sci. Eng., 1996, 38, 329. The corresponding literature descriptions are included herein under reference and forms part of the description. They are suitable for dehydration and in particular the ion exchange resins used are: carries sulfonic acid groups. Ion exchange resins based on tetrafluoroethylene / perfluorovinyl ether are preferred. copolymers, optionally in the form of their silica nanocomposites, as described for example in the literature publications of Olah et al. Synthesis, 1996, 513-531 and Harmer et al. Green Chemistry, 2000, 7-14, the corresponding disclosures are incorporated herein by reference. by reference and form part of the description. Similar products are  commercially available, for example under the name Nafion, and can also used in that form in the methods of the present invention. Furthermore, ion exchange resins based on styrene / divinylbenzene are preferred. copolymers, and these can be prepared by conventional processes known to professionals in the field of technology. For the dehydration, sulfonic acid group-bearing ion exchangers are particularly preferred. resins based on styrene / divinylbenzene copolymers, which are marketed, for example  under the name Amberlyst by Rohm & Haas and which can also be used as such in the methods of the present invention. These ion exchange resins are particularly distinguished by their stability towards water and alcohols, even at elevated temperatures temperatures, for example from 130 to 160 C. The degree of crosslinking and structure of these ion exchange resins can vary. Examples include: example macroporous ion exchange resins that have heterogeneous pore diameter distribution, isoporous ion exchange resins having a practically uniform pore diameter distribution, or gel-like ion exchange resins which have no or practically no pores. The macroporous resins can be used with particular advantage for heterogeneous catalysis in the liquid phase. Particularly suitable macroporous resins having an average pore diameter of from 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 the methods according to the present invention. It is likewise preferred to carry out the dehydration in the presence of an acidic catalyst. based on metal oxides such as SiO, AlO, TiO, NbO, BO or 2 2 3 2 2 5 2 3 based on mixed metal oxides such as AlO / SiO or AlO / BO. 2 3 2 2 3 2 3 The temperature of dehydration (b') using an acidic catalyst such as described above is in each case from 20 to 250C, particularly preferably from 50 to 180C and very particularly preferably from 100 to 160 C. The ratio of acidic catalyst to compound of general formula (II) is preferably in the range from 1:200 to 1:1, especially from 1:4 to 1:2. After dehydration, the catalyst can be separated from the reaction mixture in a simple manner. manner, preferably by filtration. The obtained particular compound of general formula (VII) can be isolated and / or purified by conventional methods known to those skilled in the art within the field of technology. Alternatively, the dehydration step (b') can also be carried out by exposing a compound of general formula (II) for an excess of thionyl chloride, optionally in a reaction medium, preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydro- furan, toluene, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether and mixtures thereof, and subsequently heating the reaction mixture thus obtained to 40°C to 120°C, preferably to 80°C to 120°C. The hydrogenation in step (b'') can also be effected via heterogeneous catalysis with hydrogen. The hydrogen is preferably in gaseous form, although it is also possible that at least part of it this is dissolved in a liquid phase. Heterogeneous catalysis in the present context means that the catalysts used in step (b'') in each case is present in the solid state. The heterogeneous catalyst for hydrogenation in step (b'') according to the present invention invention preferably contains one or more transition metals, and these metals can 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, particularly preferably from the group consisting of Ru, Rh, Pd, Pt and Ni. The corresponding catalysts may preferably contain one or more of the above-mentioned the transition metals in the same or different oxidation states. It can also be preferably the corresponding catalysts contain one or more of the above-mentioned the transition metals in two or more different oxidation states. The preparation of catalysts doped with transition metals can be carried out by conventional methods known to those skilled in the art. The catalyst used for hydrogenation in step (b'') is preferably selected from the group consisting of Raney nickel, palladium, palladium on carbon (1 - 10 wt.%, preferably 5% by weight), platinum, platinum on carbon (1 – 10% by weight, preferably 5% by weight), ruthenium on carbon (1 - 10 wt%, preferably 5 wt%) and rhodium on carbon (1 - 10 % by weight, preferably 5% by weight), more preferably palladium on carbon (1 – 10% by weight) %, preferably 5 wt.-%) used as the catalyst for hydrogenation in step (b''). The compounds of general formula VII or III used in step (b'') according to The present invention is preferably in liquid phase and is for this purpose preferably mixed with or dissolved in a reaction medium which is liquid under the special reaction conditions. Examples of suitable reaction media are 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 reaction medium in step (b''). It is of course also possible to use mixtures of multiphase systems comprising two or more of the above liquids in the process the procedures of the present invention. A reaction in supercritical CO which 2 solvent is also possible. The reaction parameters for the heterogeneous hydrogenation in step (b''), such as for for example pressure, temperature or reaction time, can vary over a wide range. The temperature during the heterogeneous hydrogenation in step (b'') is in each case preferably 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 pressure, at normal pressure or at elevated pressure, preferably in the range from 1 to 300 bar. It It is particularly preferred to carry out the reactions under pressure in the range from 2 to 10 bar, especially from 4 to 10 bar. The reaction time may vary depending on various parameters, such as temperature, pressure, type of compound to be reacted or the properties of the catalyst creates, and can be determined for the relevant procedure by those skilled in the art the technique using preliminary tests. The continuous removal of samples to monitor the reaction, for example by using gas chromatography methods, is also possible, possibly in combination with regulation of the corresponding process parameters. The total amount of catalyst(s) used depends on various factors, such as, for example, the ratio of the catalytically active component to any inert material present, or the surface type of the catalyst(s). The optimal the amount of catalyst(s) for a particular reaction can be determined by those skilled in the art the technique using preliminary tests. The particular compound of general formula (III) obtained can be isolated and / or purified by conventional methods known to those skilled in the art. In another embodiment of the invention, step b) (reaction scheme 1) is a direct replacement reaction of the OH group with H, preferably carried out in a one-step reaction. - - More preferably, an OH is replaced with H. The steps of the present invention can each be carried out discontinuously (batchwise) or continuously, the discontinuous procedure being preferred. As a reactor for the discontinuous procedure, for example, a slurry reactor in question, and for the continuous procedure a fixed-bed reactor or loop reactor. The following describes a process for the preparation of (1R,2R)-3-(3- dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride. Example Preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)- phenol hydrochloride O.O. O O (a') (a'') (a) HO (S) (S)N O (R) ONON (Va) (VIa) (Ia) (IIa) O OH O (b') (b'') (c) HCl HCl ( R) ( R) (R) NN (R) (R) N (VIIa) (IIIa) (IV) Step (a'): Preparation of 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1- on (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) was dissolved in ethanol under a nitrogen atmosphere in a 100 L (L = liter) container with double jacket equipped with an electric paddle stirrer, a gas transfer line, Pt100 temperature measurement equipment and an oil-based cooling / heating system. Reaction mixture- none was refluxed for 16 hours, cooled to 25°C over 3.5 hours and stirred for 1 hour at this temperature. The suspension was separated via a centrifuge and washed three times times with 7 L of acetone each time. 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methyl- propan-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% by weight) was added until a pH value between 10.0 and 10.5 were obtained and the phases were allowed to separate. The organic The phase was distilled off under reduced pressure until a temperature of 40°C at a pressure of 5 mbar was obtained. 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'-dibenzoyl tartrate in acetone (2R,3R)-O,O'-dibenzoyltartaric acid monohydrate (189.1 g, 0.5 mol) was dissolved in acetone (550 mL) in a 2 L reaction vessel 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 to 35°C to 40°C for 27 hours and was allowed to cool to 25°C. The suspension was removed using a siphon and (S)-3-(dimethyl- amino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (2R,3R)-O,O'-dibenzoyl tartrate was obtained as a colorless solid (233.2 g, 80.5%, ee 96.9%, ee = enantiomeric surplus). 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'-dibenzoyltartaric 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 paddle stirrer, a gas transfer 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 to 35°C to 40°C for 24 hours and allowed to cool to 25°C. The suspension was removed by use of siphon 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 (Ia) (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 paddle stirrer, a gas transfer wire, 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 at 20°C until 25°C for 90 minutes and a solid was removed using a sieve. The filtrate was concentrated at a temperature of 40°C in vacuum until a pressure of 4 mbar was achieved. (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-(dimethylamino)-3-(3-methoxyphenyl)-2- methylpentan-3-ol (IIa) 1. Magnesium turnings (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 paddle stirrer, a gas transfer line, Pt100 temperature measuring equipment and an oil-based cooling / heating system and ethyl- bromide (25 g, 0.23 mol) was added. After the reaction had started, additional ethyl bromide (438.6 g, 4.02 mol) added over 90 minutes at a temperature of 35°C and The reaction mixture was stirred for an additional hour. The reaction mixture was cooled to 10°C to 15°C, (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one (774.6 g, 3.5 mol, ee 98%) dissolved in diethyl ether (0.8 L) was added and the reaction mixture was stirred for a further two hours. The reaction mixture was cooled to 5°C and aqueous ammonium hydrogen sulfate solution (10 wt%, 2 L) was added. The phases were separated and the organic phase was concentrated in vacuo at 40°C until a pressure of 5 mbar was reached obtained. (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 paddle stirrer, a gas transfer line, Pt100 temperature measuring equipment and an oil-based cooling / heating system, and ethylmagnesium bromide (2 L, 2 M in THF) was added at a temperature of 15°C over 2 hours. The reaction mixture was stirred for two hours at the said temperature, cooled to 5°C and aqueous ammonium hydrogen sulfate solution (10 wt%, 2L) was added. The phases were separated and the organic phase was concentrated in vacuo at 40°C until a pressure of 5 mbar was achieved. (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 (VIIa) 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 a electric paddle stirrer, a gas transfer line, Pt100 temperature measuring equipment and a oil-based cooling / heating system. Hydrogen chloride (110 g, 3.0 mol) was passed for 15 minutes at a temperature of 15°C through the reaction mixture. The reaction mixture none was cooled to 0°C to 5°C and after 24 hours at this temperature was removed by using a siphon. 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. (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 mechanical compressed air stirrer, reflux condenser and oil bath and aqueous hydrogen chloride solution (150 mL, 36 wt%) was added. The reaction mixture was heated to 55°C for 5 hours and allowed to cool to 20°C. Aqueous sodium hydroxide solution solution (33% by weight) was added with cooling until a pH value of 11 was achieved. Ethyl acetate (150 mL) was added, the reaction mixture was stirred for 10 minutes, the phases were separated. separated and ethyl acetate was removed in vacuo at 60°C until a pressure of 10 mbar was (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine (21 g, 90%) was obtained. 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 (IIIa) 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 using a rotary stirring frequency of 850  150 per minute in a double-jacketed hydrogenation apparatus equipped with a stationary mounted lid supplied with a hydrogen and nitrogen supply, electric gas supply agitator, Pt100 temperature measuring equipment, inspection window and gas regulator “Büchi bpc”. The hydrogenation apparatus was overfilled with nitrogen. Palladium on charcoal (375 g, 5 wt%) was suspended in aqueous hydrogen chloride (675 g, 32 wt.%) and added to the reaction mixture. The hydrogenation apparatus was overfilled again with nitrogen and the reaction was carried out at a primary hydrogen pressure of 5 bar and a internal hydrogen pressure of 1 bar until the reaction was complete. The hydrogenation apparatus was overflowed with nitrogen and the catalyst was filtered off on a single-layer filter with filter The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and aqueous Sodium hydroxide (10 wt%, 3.7 L) was added at 20°C until a pH of 10 to 12 was obtained. The organic phase was concentrated in vacuo at 45°C to 50°C until a pressure of 5 mbar was achieved. 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 a electric paddle stirrer, a gas transfer line, Pt100 temperature measuring equipment and a oil-based cooling / heating system. Hydrogen chloride (1.55 kg, 42.51 mol) was passed over a period of 15 minutes at a temperature of 5°C to 25°C through the reaction mixture. The reaction mixture was cooled to 0°C to 5°C and centrifuged after 2 hours with stirring. The moist solid was placed in a stirring vessel, acetone (30 L) was was added and the reaction mixture was heated to 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 hydro- chloride (7.17 kg, 63%) was obtained as a colorless solid with a diastereomeric profit of 100%. Step (c): Preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (IV) 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 paddle stirrer, a gas transfer 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 to 15°C to 25°C and water (12.5 L) was slowly added at this temperature. Aqueous sodium hydroxide solution (approx. 28 L, 32 wt%) was added until a pH value of 10 was reached. 12 was obtained while keeping the temperature below 50°C. Ethyl acetate (15 L) was added and The reaction mixture was stirred for 15 minutes at a rotary stirring frequency of 150 per minute. The phases were separated and the organic phase was washed with water (15 L). Activated charcoal (0.05 kg) was added to the organic phase and filtered off after 30 minutes of stirring. The solvent was removed in vacuo at a temperature of 40°C. to 50°C until a pressure of 50 mbar was achieved. The remainder was used in the next step without further purification. 2. The residue obtained as described above was dissolved in acetone (25 L) with stirring and hydrogen chloride (0.78 kg, 21.4 mol) was passed through the reaction mixture at a temperature of 20°C to 25°C. The suspension was stirred for 3 hours at a temperature of 0°C to 5°C and centrifuged. Isopropanol (35 L) was added to the moist solid in a reaction vessel and the reaction mixture was heated to reflux for 15 minutes. The reaction mixture was cooled to 0°C to 5°C and stirred for 3 hours at this temperature. temperature. After centrifugation, the product was stored at 30°C to 40°C and 150 mbar for 16 hours in a drying oven. (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol 5 hydrochloride (4.18 kg, 88%) was obtained as a colorless solid with a purity of 100%.

Claims

1. Process for the preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)- phenol, or an acid addition salt thereof, characterized by (a) reaction of a compound of general formula (I), R O (S) ON (IN), where R represents -C-alkyl, -C-cycloalkyl, -C-alkylene-phenyl, -C-alkylene- 1-6 3-8 1-3 1-3 naphthyl, tetrahydropyranyl or -C(=O)-C -alkyl, 1-6 with ethylmagnesium halide in an inert reaction medium under Grignard conditions, (b) transferring the compound of general formula (II) thus obtained, O R HO (S) N (R) (II), where R has the meaning defined above, to a compound of general formula (III), O R (R) N (R) (III), where R has the meaning defined above, optionally in the form of an acid addition salt, (c) deprotecting the thus obtained compound of general formula (III) to obtaining (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of formula (IV), OH (R) N (R) (IV), (d) optionally converting the thus obtained (1R,2R)-3-(3-dimethylamino-1-ethyl- 2-methyl-propyl)-phenol to an acid addition salt.

2. Method according to claim 1, characterized in that R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C(=O)-CH , -C(=O)-CH , -C(=O)-CH(CH ) or -C(=O)- 3 2 5 3 2 C(CH) . 3 3 3. Method according to claim 1 or 2, characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH . 3 4. A method according to any one of claims 1 to 3, characterized in that - provided that R represents methyl, benzyl or tetrahydropyranyl.

5. A method according to any one of claims 1 to 4, characterized in that provided that the ethylmagnesium halide used in step (a) is the chloride or the bromide.

6. A method according to any one of claims 1 to 5, characterized in that provided 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.

7. A method according to any one of claims 1 to 6, characterized in that provided that a compound of general formula (I) was obtained by (a') reaction of a compound of general formula (V), RO O (V), where R represents -C -alkyl, -C -cycloalkyl, -C -alkylene-phenyl, -C -alkylene- 1-6 3-8 1-3 1-3 naphthyl, tetrahydropyranyl or -C(=O)-C -alkyl, 1-6 with dimethylamine hydrochloride and paraformaldehyde in an inert reaction medium under Mannich conditions and (a'') subsequent cleavage of the thus obtained compound of general formula (WE), R O ON (WE), where R has the meaning defined above.

8. Method according to claim 7, characterized in that R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C(=O)-CH , -C(=O)-CH , -C(=O)-CH(CH ) or -C(=O)- 3 2 5 3 2 C(CH) . 3 3 9. Method according to claim 7 or 8, characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH . 3 10. A method according to any one of claims 7 to 9, characterized in that provided that R represents methyl, benzyl or tetrahydropyranyl.

11. A method according to any one of claims 7 to 10, characterized in that provided that the cleavage in step (a'') is carried out by reaction of a compound of general formula (VI) with a chiral acid selected from the group consisting of L- (-)-dibenzoyltartaric acid, L-(-)-dibenzoyltartaric acid · HO and D-(-)-tartaric acid, subsequent 2 separation of the salt thus obtained and liberation of the corresponding compound of general formula (I) in the form of the free base.

12. Method according to claim 11, characterized in that the cleavage is carried out in an alcoholic reaction medium selected from the group consisting of of methanol, ethanol, 1-propanol, 2-propanol and any mixture thereof.

13. A method according to any one of claims 1 to 12, characterized in that provided that the transfer according to step (b) is carried out by (b') postponing the compound of general formula (II) for dehydration and (b'') hydrogenation of the thus obtaining the compound of general formula (VII), R O (R) N (VII), where R represents -C-alkyl, -C-cycloalkyl, -C-alkylene-phenyl, -C-alkylene- 1-6 3-8 1-3 1-3 naphthyl, tetrahydropyranyl or -C(=O)-C -alkyl, 1-6 by using a suitable catalyst in an inert reaction medium in the presence of hydrogen.

14. Method according to claim 13, characterized in that R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, -C(=O)-CH , -C(=O)-CH , -C(=O)-CH(CH ) or -C(=O)- 3 2 5 3 2 C(CH) . 3 3 15. Method according to claim 13 or 14, characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or -C(=O)-CH . 3 16. A method according to any one of claims 13 to 15, characterized in that terized in that R represents methyl, benzyl or tetrahydropyranyl.

17. A method according to any one of claims 13 to 16, characterized in that terized by the fact that after the dehydration step (b') the hydrogenation in step (b'') via homogeneous catalysis.

18. A method according to any one of claims 13 to 17, characterized in that terized in that the dehydration step (b') is acid catalyzed.

19. Method according to claim 18, 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.

20. A method according to any one of claims 13 to 16, characterized in that terized in that the hydrogenation in step (b'') is carried out via heterogeneous catalysis.

21. Method according to claim 20, 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.

22. A method according to any one of claims 13 to 21, characterized in that 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 mixtures thereof.

23. A method according to any one of claims 1 to 12, characterized in that terized by the fact that step b) is a direct replacement reaction of OH the group with H, preferably carried out in a one-pot reaction.