MXPA00008768A - Process for the cis-selective catalytic hydrogenation of cyclohexylidenamines - Google Patents

Abstract

This invention relates to a process for the cis-selective preparation of cyclic amines of the sertraline type by reductive alkylation of cyclic immines or of their precursors and for the catalytic hydrogenation in the presence of copper-containing catalysts.

Description

Process for the cis-selective catalytic hydrogenation of cyclohexylidenamines The present invention relates to a new inventive process for the cis-selective catalytic hydrogenation of cidohexylidenamines and their precursors. Cyclohexylamines can be used, inter alia, as antioxidants and as pharmaceutical active substances. An important cyclohexylamine is sertraline: Sertraline: (1S, 4S) -4- (3,4-dichlorophenyl) -1, 2,3,4-tetrahydro-N-methyl-1-naphthyl amine, see Merck Index Twelfth Edition 1996, No. 8612, is known as an antidepressant. The preparation of this compound is described in the specification of the North American patent No. 4,536,518. The hydrochloride can be obtained commercially, inter alia, under the trademarks Lustral® and Zoloft®. Cyclohexylamines of the type: (R2? H) and are in at least two isomeric forms: In another, the non-symmetric substitution in the cyclohexyl ring, the carbon atoms are chiral in positions 1 and 4. According to the nomenclature R, S, Cahn, Ingold and Prelog, sertalina has the configuration 1 S-, 4S -. Cidohexylamine is obtained, for example, by the following method: the reaction of the ketone With a primary amine, for example methylamine, it produces, with the elimination of water, a cyclohexylideneamine: , The resulting mine is then catalytically hydrogenated to the amine. These reactions proceed without stereoselectivity, or only with minimal stereoselectivity. In the case of sertraline, four enantiomers are obtained. The subject of this invention is the preparation of cyclohexylamines having a cis-isomer ratio as high as possible. To achieve this objective, the specification of the aforementioned US Patent 4,536,518 proposes to hydrogenate a mine of formula: R2 = 3,4-dicyorophenyl using palladium and carbon as substrates. This achieves 70% cis racemate and 30% trans. To further improve this production, WO 93/01161 proposes replacing palladium and carbon with Raney nickel when the mine is hydrogenated. This produces a cis / trans ratio of 8: 1. Surprisingly, it has now been discovered that a cis / trans ratio is obtained if the mine is catalytically hydrogenated in the presence of a copper. The preparation of secondary mines from intermediate ketones and intermediates by hydrogenation in the presence of copper chromite catalysts is known from R. B. Pillai J. Mol. Catalysis 84 (1993), 125-129. However, it is surprising that, starting with cyclohexylidenamines, which can only be obtained as intermediates from ketones, hydrogenation by means of a copper-containing catalyst proceeds in a diastereoselective manner and achieves a high proportion of cis isomer (> 95%). This invention relates to a process for the preparation of cis compounds of formula: wherein Ri and R2 are each independently of the other hydrocarbon radicals, and A is a substituent, and m is an integer from 0 to 4, and defines the number of substituents A, which process comprises a) hydrogenating a cyclohexylideneamine of the formula: wherein n is 0 or 1, and R1t R2, A and m have the meanings mentioned, in the presence of a copper-containing catalyst; or b) reacting a ketone of formula: wherein R2 'A and m have the meanings cited, with a compound that introduces the group R? -N? (0) n, hydrogenate the imine or nitropa (II) which is obtained as an intermediate in the presence of a catalyst containing copper, and isolate the cis (I) compound. If in a compound (I) m is 0 and the cyclohexyl ring is unsubstituted, then the two structural formulas represent identical compounds: Of the two possibilities for representing the structural formula of the cis (I) compound in the description of this invention, only the general formula is used: If in a compound (I) m is 1 to 4 (m > 0) and the cyclohexyl ring is unsymmetrically substituted, then a cis enantiomeric pair is obtained during hydrogenation, which can be separated into the optically pure antipodes by customary methods of resolution of racemates, for example, by crystallization of the mandelic acid salt by the method of WM Weich et al., in J. Med. Chem. 1984, 27, 1508-1515. The relationship between the two enantiomeric cis and trans pairs and the 4 optically pure antipodes are illustrated by the following scheme of sertraline formula: (S, R) trans (R, S) trans (RR) cis (S, S) cis In the structural formulas of the initial materials (II) and (lll), the non-cleaved binding points, to the substituent R2, mean what in the case of R2? H and of different substitution in the cyclohexyl ring, these starting materials can be used in the process in the form of racemic mixtures having identical or different proportions of antipodes, or in the form of an optically pure antipode. The process is distinguished by a high production of the desired cis compounds. In the case of the synthesis of sertraline, a ratio of the cis-to-trans enantiomeric pair that is greater than 95: 5 is obtained. In a particularly preferred embodiment of this invention, an even better ratio of more than 99: 1 is obtained. This high production of cis compound prevents cis separation from the trans enantiomeric pair, which is otherwise necessary when different substituents A (m > O) are present. The definitions and denotations used within the scope of the description of this invention preferably have the following meanings: A hydrocarbon radical R ^ or R2 is preferably selected from the group consisting of Ci-C8 alkyl, C-C12 cycloalkyl, C2 heterocycloalkyl -Cn, carbocyclic C5-C16 aryl, C2-C? Heteroaryl, carbocyclic C-C6-aralkyl and C2-C15-heteroarylalkyl, and can also be substituted with functional groups suitable, for example, with the functional groups or derivatized functional groups They consist of amino, C1-C4 dialkylamino, hydroxy, carobxy and halogen. E 'cyclohexyl ring can be substituted with 1 to 4, preferably with 2 substituents of group A containing the substituents R3, R4, F? S and Re- Suitable substituents are listed in the List of Radical Names Ñames (List of Radical Names) , valid in accordance with the IUPAC Rules, and remain unchanged under the conditions of the catalytic hydrogenation reaction. Any of the substituents can be selected. Suitable substituents A of the group R3, R4, R5 and Re are selected, for example, from the group of functional groups or derivatized functional groups consisting of amino, C1-C4 alkylamino, C1-C4 dialkylamino, hydroxy, carboxy and halogen , or are saturated or unsaturated, aliphatic, cycloaliphatic or heterocycloalphatic radicals, carbocyclic or heterocyclic aryl radicals, condensed carbocyclic, heterocyclic or carbocyclic-heterocyclic radicals, which in turn can be combined with any other of these radicals, and which can be substituted with the functional groups or derivatized functional groups mentioned. The aforementioned substituents and radicals can be interrupted with one or more of a bivalent radical from the group consisting of -O-, -C (= 0) -0-, -OC (= O) -, -C (= O) -N (C1-C4 alkyl) -) -N (C1-C alkyl) -C (= O) -l -S (= 0) 2-, -S (= 0) 2-0-, -OS (= O) 2-, -S (= O) 2-N (alkylC1-C4) -, - (alkylC? -C) NS (= O) 2-, -P (= O) -, -P (= O) -O-, -0-P (= 0) - and -0-P (= 0) -O-. In a preferred embodiment of this invention, two A substituents of the group R3, R4, R5 and R6 are bivalent groups of the type C2-C6 alkylen bridge, C4-C8 alkyldinylidene, or C4-C8 alkenyldilidene, preferably butanediylidene, more preferably 2- butenodiylidene, which is linked with the cyclohexyl ring to two adjacent carbon atoms, and which forms together with these carbon atoms a phenyl ring which can be substituted with the functional groups or substituents mentioned. Suitable substituents A of the group R3, R4I, R5 and Re are further substituents of the group of C1-C2alkyl, cycloalkylC4-Ci2, cycloalkylC7-Ci2, heterocyclicC1-Cn, carbocyclic arylC6-Ci6, heteroarylC2-C5, aralkylC- C16 carbocyclic and heteroarylalkylC2-Ci5, which can in turn be substituted with the functional groups mentioned and interrupted by divalent radicals.

AlkylCi-C? O is, for example, methyl, ethyl, n- or isopropyl, or n-, sec-, or terbutyl, and pentyl, hexyl, heptyl, octyl, isooctyl, nonyl, ter-nonyl, decyl, undecyl or straight chain or branched dodecyl. Cycloalkyl C4-C? 2 is, for example, cyclopropyl, dimethylcyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. C7-C12-cycloalkyl is, for example, bornyl or norbomyl. C2-Cn heterocycloalkyl preferably contains 4 or 5 carbon atoms and one or two heteroatoms of the group O, S and N. Examples are the substituents derived from oxirane, azirine, 1,2-oxathiolane, pyrazoline, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran or tetrahydrothiophene. C6-C16 carbocyclic aryl is, for example, mono-, bi- or tricyclic, typically phenyl, naphthyl, indenyl, azulenyl, or anthryl. HeteroarylC? -Ci5 is preferably monocyclic, or is condensed with another heterocycle or with an aryl radical, for example phenyl, and preferably contains one or two, in the case of nitrogen up to four heteroatoms of group O, S and N. Suitable substituents are derived from furan, tisphene, pyrro !, pyridine, bipyridine, picoline,? -piran,? -thiopyran, phenanthroline, pyrimidine, bipyrimidine, pyrazine, indole, coumarone, thonaphtene, carbazole, dibenzofuran, dibenzothiophene, pyrazole, imidazole, benzimidazole , oxazole, thiazole, dithiazole, isoxazole, siathiazole, quinoline, isoquinoline, acridine, chromene, phenazine, phenoxazine, phenothiazine, triazine, thiantrene, purine or tetrazole. C 1 -C carbocyclic aralkyl preferably contains 7 to 12 carbon atoms, for example, benzyl, 1- or 2-phenethyl or cinnamyl. Heteroarylalkyl C2-C? S consists of the above-mentioned heterocycles, which replace, for example, C? -C4 alkyl radicals, according to the length of the carbon chain where possible terminally, or otherwise also in position adjacent (position) or in position a (position 2).

In a preferred embodiment of this invention, a cis enantiomeric pair of the compound of the formulas is prepared: wherein Ri is C1-C4 alkyl and R2 is aryl. According to process variant a), a cyclohexylideneamine, or imine or nitrone (II), preferably the mine or nitrona of formula: wherein R.sup.1 and R.sup.2 have the meanings cited, which imine or nitrone may be in the sin- or anti-form, is hydrogenated in the presence of a copper-containing catalyst. According to process variant b), a ketone (III), preferably a ketone of formula wherein R2 has the meanings mentioned, it is reacted with a compound that introduces the group R? -N? (O) n, in particular with a primary amine, preferably methylamine or with a R-substituted hydroxylamine, preferably N- methylhydroxylamine, and the imine (II) obtained as an intermediate is hydrogenated in situ in the presence of a copper-containing catalyst. It is further possible to replace the racemic compound (II ') or (III') with an optically pure compound (II ') or (III'), and to react it with a cis (I ') compound. This invention is preferably related to a process for the preparation of the cis (! ') Compound, wherein R1 is methyl and R2 is 3,4-dichlorophenyl, which process comprises a) hydrogenating a mine or nitrona (II'), wherein R 1 is methyl and R 2 is 3,4-dichlorophenyl, in the presence of a catalyst containing copper, or b) reacting a ketone (III '), wherein R 2 is 3,4-dichlorophenyl, with methylamine or N-methylhydroxylamine , hydrogenating the mine or nitrona (II) obtained as an intermediate in the presence of a catalyst containing copper and isolating the cis (I ') compound. Suitable catalysts for the hydrogenation reaction according to variants a) and b) are copper-containing catalysts, for example copper skeleton, copper substrate, copper chromite, copper zinc oxide, copper boride or urushibara catalysts. coppermade. In a preferred embodiment of this process, other elements are present in the catalyst in addition to copper. Examples thereof are aluminum, chromium, zinc, barium, manganese, zirconium, vanadium, molybdenum, titanium, tantalum, niobium, tungsten, nickel, cobalt, bismuth, tin, antimony, hafnium, rhenium, iron, cadmium, lead or germanium. , and mixtures thereof. The amount in which the element is added can vary within wide limits, and can be from 10 ppm to 200% in relation to the amount of copper used. Particularly useful elements are aluminum, zinc, chromium, barium and manganese. The elements can be, for example, in the form of oxides or salts, such as chromates. Copper Raney is an example of a suitable copper skeleton catalyst. Examples of substrates are carbon, aluminum oxide, silicon dioxide, Cr2O3, zirconium dioxide, zinc oxide, calcium oxide, magnesium oxide, barium sulfate, calcium carbonate or aluminum phosphate. The copper may be bound on the substrate in an amount of about 1.0 - 20.0% by weight. A suitable copper chromite catalyst is represented by the empirical formula CuO »CuCr2O4. CuCr2O4 is known, see CARN 12018 -10-9, and Gmelins Handbuch der Anorganischen Chemie, 8th ed., Vol. Kupfer, part B, Delivery 3, system number 60, page 60. A common name is also copper (ll) chromate (III). The copper chromite catalysts having changing proportions of CuO and CuCr 2 O 4l the Raney copper catalysts and the copper-zinc-aluminum-oxide catalysts can be obtained commercially in pure form or in a form provided with the aforementioned elements.

In a preferred embodiment of the process, the copper-containing catalysts used are copper chromite catalysts or catalysts containing copper, zinc and aluminum in the form of oxides.

The said catalysts are present in the reaction mixture in an amount of about 0.1 to 100% by weight, preferably 1-20% by weight, based on the amount of educt used. Copper-containing catalysts can be used in different ways in the process: in the form of ready-for-use catalysts; in the form of prehydrogenated catalysts, or - in the form of catalysts prepared in situ from suitable precursors, such as oxides or copper salts, and from other compounds. For prehydrogenation it is possible to treat, for example, a suspension of the catalyst in a suitable solvent, under 5 to 150 bar of hydrogen at 80-250 ° C for half an hour to one hour at 5 hours, or the hydrogen is introduced under normal pressure up to 50 hours. bar at 100 to 500 ° C on the dry catalyst. In a preferred embodiment of the process, the catalyst used is activated by hydrogenation in the solvent that is used to hydrogenate the imine or nitrona ("prehydrogenation"). The catalysts can be removed after hydrogenation, for example, by filtration if the The process is carried out in the form of batches The mines (II) can be prepared by reacting ketones (II) with a compound that introduces the RN group, in particular with a primary amine, preferably methylamine. II) is carried out analogously to the method described in the specification of U.S. Patent No. 4,536,518.Nitrones (II) can be prepared by reacting ketones (II) with a compound that introduces group R ? N- »O, for example, Ri-substituted hydroxylamine, preferably N-methylhydroxylamine The preparation of nitrones (II) is carried out analogously to the method described in WO 98/27050.

The hydrogenation is carried out in the presence of an organic solvent. It is preferable to use non-polar or polar aprotic solvents or mixtures thereof.

Examples of suitable non-polar solvents are hydrocarbons, for example aliphatic hydrocarbons, such as hexane, heptane or petroleum ether, cycloaliphatic hydrocarbons, such as cyclohexane or methylcyclohexane, aromatic hydrocarbons, such as benzene, toluene or xylene. Examples of suitable polar aprotic solvents are ethers, such as aliphatic ethers, for example 1,2-diethoxyethane or tert-butylmethyl ether, cyclic ethers, for example tetrahydrofuran or dioxane, amides, for example dimethylformamide or N-methylpyrrolidone. The ethers are particularly suitable, especially tetrahydrofuran. According to variant b), acidic auxiliaries are added when required, for example, mono or polyvalent organic acids containing more than two carbon atoms, for example acetic acid, propionic acid or malonic acid, mineral acids such as sulfuric acid, the so-called Lewis acids, such as boron trifluoride, or the so-called solid acids, such as zeolites or Nailon® and / or dehydrating agent, such as sodium sulfate. According to variant b), an excess of up to 50 mol of the amine used is added, for example methylamine in the form of methylamine gas or as a solution, for example in ethanol. The process can be carried out in both variants, preferably in the liquid phase in batch or continuous form, preferably with a catalyst suspension as a liquid phase hydrogenation, or in a bubble column or with a catalyst formed in a bed drip The reaction can also be carried out in the gas phase with a powder catalyst in a fluidized bed, or with a catalyst formulated in a fixed bed.

The hydrogenation can be carried out over a wide range of temperatures. It has been found that temperatures in the range from 60 ° to approximately 250 ° C, preferably from 90 ° to 150 ° C, are advantageous. The hydrogen pressure may vary within a wide range during hydration, for example from 1-100, preferably from 5-50, more preferably from 10-20 bar. The decision as to which hydrogen pressure is used depends essentially on the available hydrogenation plant. At higher temperatures of about 100 ° C, the molecular hydrogen can also be replaced with a hydrogen donor, such as sodium propane.

The reaction time can vary within wide limits. It depends on the catalyst used, the hydrogen pressure, the reaction temperature and the plant used, and can be, for example, from half an hour to 24 hours. Suitable reaction times are those from about half an hour to 2 hours. The isolation of the reaction products is carried out by known methods, and is illustrated in the Examples. After separation of the catalyst and removal of the solvent, conventional separation processes can be followed, for example preparative thin layer chromatography, preparative HPLC, preparative gas chromatography, etc. The cis racemate obtained by racemic cyclohexylideneamine can be separated into the optically pure antipodes without any further purification, using known processes for separation of enantiomers, for example, by means of preparative chromatography on chiral substrates (HPLC) or by precipitation or crystallization using optically precipitating pure, for example, mandelic acid D - (-) or L - (-), or camphor sulfonic acid (+) or (-) - 10. Starting with pure enantiomeric 4-substituted cyclohexylideneamine, pure enantiomeric 4-substituted cyclohexylamine is obtained directly by the hydrogenation process of this invention.

This invention also relates to the use of copper-containing catalysts for the diastereoselective hydrogenation of cyclohexylidepamines.

In this case it is preferable to use copper chromite catalysts or CuZnAI-oxide catalysts for the diastereoselective hydrogenation of cyclohexylidenamines. The following Examples illustrate the invention: Example 1 (Hydrogenation of the imine). 0.1 g of copper chromium catalyst provided with barium (commercial product of Südchemie, Girdler G 13, comprising 29% of Cu, 26% of Cr and 13.6% of Ba) and 40 ml of THF are placed in a 100 ml autoclave (316SS stainless steel). The catalyst suspension is prehydrogenated for 1 hour at 12 bar initial pressure H at 130 ° C. The suspension is then cooled and 0.5 g of 4- (3,4-dichlorophenol) -1-methylimino-1,2,3,4-tetrahydronaphthalene is added.

Subsequently, the hydrogenation is carried out for 18 hours at 100 ° C and 12 bar initial pressure H2 (maximum pressure: 15 bar). The catalyst is removed by filtration and the product is concentrated by evaporation under vacuum and dried under high vacuum. According to the 1 H-NMR spectrum, the cis / trans ratio of the resulting 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthylamine is > 95: 5. The crude product is purified by SNAP chromatography on silica gel, to a solvent gradient of CH 2 Cl 2 to CH 2 Cl 2 / MeOH (9: 1). This provides 83% of the theoretical production of pure cis racemate.

Example 2 (Reductive Alkylation) 1.0 g of 4- (3,4-dichlorophenium) -1-oxo-1,2,3,4-tetrahydronaphthalene and 0.2 g of chromium copper catalyst provided with barium (cf. Example 1) are placed in 40 ml of THF in a 100 ml autoclave (316SS stainless steel).

Subsequently, 2.25 ml of methylamine solution in ethanol (14.2% G / v) are added by means of a syringe. Then, 120 bar of hydrogen are introduced, and the hydrogenation is carried out for 16 hours at 110 ° C and for 18 hours at 130 ° C. The catalyst is removed by filtration and the product is concentrated by evaporation under vacuum, and dried under high vacuum. According to the H-NMR spectrum, the cis / trans ratio of the resulting 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthylamine is > 9: 1. The crude product is purified by SHORT chromatography on silica gel to a solvent gradient of CH2Cl2 to CH2Cl2 / MeOH (9: 1). This provides 50% of the theoretical production of pure cis racemate.

Example 3 (Hydrogenation of the imine) 0.4 g of catalyst (commercial product of Engelhard, Cu-0890 P, comprising 35% of CuO, 42% of ZnO and 21% of AI2O3) and 80 ml of THF are placed in a 300 ml autoclave (316SS stainless steel). The catalyst suspension is prehydrogenated for 2 hours at 10 bar initial H2 pressure at 150 ° C. The suspension is then cooled and 2 g of 4- (3,4-dichlorophenyl) -1-methylimino-1,2,3,4-tetrahydronaphthalene are added. Subsequently, the hydrogenation is carried out for 30 minutes at 100 ° C and 10 bar initial pressure H2 (maximum pressure: 15 bar). The catalyst is removed by filtration (on Hyflo®) and 0.5 ml of the solution is concentrated by evaporation under vacuum. The sample is taken in isopropanol and the cis / trans ratio of the resulting 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthylamine is determined by HPLC: 97 , 3 to 2.7. Then 20 ml of a THF solution saturated with HCl, at 0 ° C, is added dropwise to the crude product solution. The corresponding crystalline hydrochloride is precipitated and collected by filtration on a glass suction filter and dried under vacuum. This provides 85% of the theoretical production of pure cis racemate. The melting point is 292-293 ° C after recrystallization from absolute methanol.

Example 4 (Hydrogenation of the mine, without prehydrogenation of the catalyst) 0.06 g of catalyst (commercial product of Engelhard, Cu-0890 P, comprising 35% of CuO, 42% of ZnO and 21% of AI2O3), ml of THF and 3 g of 4- (3,4-dichlorophenyl) -1-methyl-min-1,2,3,4-tetrahydronaphthalene are placed in a 100 ml autoclave (316SS stainless steel). The hydrogenation is then carried out for 1 Y2 hours at 150 ° C and 10 bar initial pressure H2 (maximum pressure: 15 bar). The catalyst is removed by filtration on Hyflo® and concentrated by evaporation., 1 ml of the solution by evaporation under vacuum. The sample is taken in isopropanol and the cis / trans ratio of the resulting 4- (3,4-dichlorophenol) -1, 2,3,4-tetrahydro-N-methyl-1-naphthyl amine is determined by HPLC. : 99.0: 1, 0. Subsequently, 1.5 g of D - (-) - mandelic acid is added to the crude product solution and the solvent is removed, with heating, in a rotary evaporator. After drying for 12 hours under high vacuum, 100 ml of ethanol are added and the corresponding crystalline mandelate is dissolved under reflux conditions. After heating for 20 minutes the solution is cooled and stored overnight at room temperature. The colorless crystals are filtered on a glass suction filter and the mother liquor is concentrated to half its volume, and after a brief heating, it is cooled to the second crystallization. This provides another fraction of product. The total production is 82% theory. The melting points are 191 ° C and 190 ° C for the first and second fraction, respectively.

Example 5 (Hydrogenation of nitrone, with prehydrogenation of the catalyst) 428 mg of catalyst (commercial product of Engelhard, Cu-0890 P and 35 ml of THF are placed in a 100 ml autoclave (stainless steel 316SS). It is prehydrogenated for 2 hours at 12 bar initial H2 pressure at 150 ° C. The suspension is cooled and then 3.01 g (9.4 mmol) of 4- (3,4-dichloropheni) -1-methyl are added. Oxidoimino-1, 2,3,4-tetrahydronaphthalene The hydrogenation is carried out for 90 minutes at 130 ° C and 12 bar initial pressure H. The catalyst is removed by filtration and the product is concentrated by evaporation under vacuum and dry under high vacuum The cis / trans ratio of the resulting 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-N-methyl-1-naphthyl amine according to HPLC is> 98 , 5 in favor of the cis compound.

Example 6 Analogously to Example 3, 4- (3,4-dichlorophenyl) -1-methylimino-1, 2,3,4-tetrahydronaphthalene is hydrogenated using the catalysts X 572 P (Engelhard, CuO. CaSiOxC), X 540 P (Engelhard CuO, AIOx, MnO) and Cu1890 P (Engelhard CuCrOx, 42% Cu, 31% Cr). The cis / trans ratio according to HPLC is 98.0 (X572P), 98.3 (X540P) and 99.2 (Cu 1890P) in favor of the cis compound.

Claims (7)

CLAIMS Having thus specially described and determined the nature of the present invention and the way it has to be put into practice, it is claimed to claim as property and exclusive right:

1. A process for the preparation of a compound of formula wherein Ri and R2 are each independently of the other hydrocarbon radicals, and A is a substituent, and m is an integer from 0 to 4, and defines the number of substituents A, which process comprises a) hydrogenating a cyclohexylideneamine of the formula: where n is 0 or 1, and R1, R2 | A and m have the meanings cited, in the presence of a catalyst containing copper; or b) reacting a ketone of formula: wherein R, A and m have the meanings cited, with a compound that introduces the group R? -N- »(O) n, hydrogenate the mine or nitrona (II) which is obtained as an intermediate in the presence of a catalyst containing copper, and isolate the cis (I) compound.

2. A process for the preparation of a compound of formula I, wherein the hydrocarbon radicals R1 or R2 are selected from the group consisting of C1-C20 alkyl, C4-C2 cycloalkyl, C4-C2 cycloalkenyl, and C2 heterocycloalkyl. -Cn, aryl C < carbocyclic C6-C2-C6-heteroaryl, C-C-β-carbocyclic aralkyl and C2-C6-heteroarylalkyl, and are substituted with functional groups from the group consisting of amino, alkylaminoC? -C, diacylamino C? -C4l hydroxy , carobxy and halogen, m is 2 and A is the substituent R3 and R4 which are independently of each other, or in combination, saturated aliphatic, cycloaliphatic or heterocycloaliphatic radicals, or carbocyclic, heterocyclic or carbocydic-heterocyclic radicals, which can be combined with any another of these radicals and which can be substituted with functional groups between the group consisting of amino, hydroxy, carboxy and halogen, which process comprises a) carrying out process variant a) with a corresponding substituted imine (II), in where m is 2 and R1, R2, R3 and R have the meanings cited, or b) carrying out process variant b) with a corresponding substituted ketone (II), where m is 2 and R3 and R have the meanings s cited.

3. A process according to either claim 1 or claim 2, for the preparation of the cis enantiomeric couple of the compound of formula wherein Ri is C? -C4 alkyl and R2 is aryl, which process comprises a) hydrogenating an imine or nitrone of formula wherein R1 is methyl and R2 is 3,4-diodophenyl, in the presence of a catalyst containing copper, or b) reacting a ketone of formula wherein R2 has the meanings cited, with a compound that introduces the group R? -N, hydrogenate in situ the imine or nitrone (II) which is obtained as an intermediate in the presence of a catalyst containing copper and isolate the compound (I ' ).

4. A process according to claim 3, for the preparation of the cis (I ') compound, wherein Ri is methyl and R2 is 3,4-dichlorophenyl, which comprises a) hydrogenating an imine or nitrona (IP), wherein R1 is methyl and R2 is 3,4-dichlorophenyl, in the presence of a catalyst containing copper, or b) reacting a ketone (IN '), wherein R2 is 3,4-dichlorophenyl, with methylamine or N-methylhydroxylamine, hydrogenating the imine or nitrone (II) obtained as an intermediate in the presence of a copper-containing catalyst and isolating the cis (I ') compound. A process according to any of claims 1 to 4, which comprises preparing the compound (I) by hydrogenation in the presence of a copper chromite or CuZnAI-oxide catalyst. 6. The use of a catalyst containing copper, for the cis-selective hydrogenation of cyclic mines. The use according to claim 6, of a copper chromite catalyst or CuZnAI-oxide catalyst as a catalyst for the cis-selective hydrogenation of cyclohexylidenamines.