Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
  • C07C209/26—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with hydrogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
  • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to a process for the diastereoselective conversion of chiral imines of the formula I to amines of the formula II,
• R 1 R 2 d-Ce-alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 -alkyl kinyl, halo-C 2 -C 6 alkenyl, C 2 -C 6 -Haloalkynyl, C 1 -C 6 -alkoxycarbonyl, C 5 -C 6 -alkenyloxycarbonyl, C 5 -C 6 -alkynyloxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 3 -C 6 -alkenylaminocarbonyl, C 6 -C 6 -alkynylaminocarbonyl, C 1 -C 6 -alkylsulfonylaminocarbonyl, di (C 1 -C 6 -alkyl) aminocarbonyl, N- (C 3 -C 6 -alkenyl)
• radicals R 1 and R 2 are different from one another;
• R 3 is d-C ⁇ -alkyl
• R 4 aryl which may be partially or completely halogenated and / or one to three radicals from the group cyano, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxy , C 1 -C 6 -haloalkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylamino, di (C 1 -C 6 -alkyl) amino, aryl and aryl (C 1 -C 6 -alkyl);
• EP 443 606 describes the reaction of optically active 1-phenylethylamine with 4- (4-methoxyphenyl) -2-butanone and subsequent hydrogenation with hydrogen in the presence of palladium on carbon (Example 4). Furthermore, it is known that diastereoselective hydrogenations of imines wherein the substituent on the imino nitrogen carries the chirality can be made to corresponding amines in the presence of nickel skeletal catalysts (Raney TM type). EP 443 606 likewise describes the reaction of optically active 1-phenylethylamine with 4- (4-methoxyphenyl) -2-butanone and subsequent hydrogenation with hydrogen in the presence of Raney nickel (Example 1B).
• WO 01/09080 describes a process for the cis-selective preparation of cyclic amines of the sertraline type by reacting a cyclic ketone with an achiral amine to give the corresponding imine and then subjecting it to catalytic hydrogenation in the presence of a copper containing Kataysators, in particular copper chromite, is subjected.
• the inventive method is based on chiral imines of formula I, wherein the substituent on imino nitrogen (-C * HR 3 R 4 ) is optionally in R or S configuration.
• the reaction is usually carried out in a solvent.
• Suitable solvents are solvents which are inert under the reaction conditions, such as alcohols, for example methanol, ethanol, n-propanol, isopropanol, cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol, etc., aromatic hydrocarbons, for example benzene, toluene, ethylbenzene, xylene etc.
• chlorinated hydrocarbons for example methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloromethane, chlorobenzene etc.
• ethers for example diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, dipolar aprotic solvents, for example N-methylpyrrolidone, Dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide, etc., or mixtures thereof. set.
• the reaction is carried out in an alcohol such as methanol, ethanol, n-propanol, isopropanol, cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol, etc., preferably methanol, ethanol or isopropanol, or an aromatic hydrocarbon such as benzene, toluene, ethylbenzene, xylene, etc ., Preferably, toluene or ethylbenzene, or mixtures thereof.
• an alcohol such as methanol, ethanol, n-propanol, isopropanol, cyclopentanol, cyclohexanol, ethylene glycol, propylene glycol, etc.
• an aromatic hydrocarbon such as benzene, toluene, ethylbenzene, xylene, etc .
• toluene or ethylbenzene or mixtures thereof.
• the weight ratio of imine to solvent can be varied within wide limits. Usually, it is in the range of 0.01% to 99%, preferably 0.1% to 95%, especially 1% to 90%, more preferably 10% to 70%, most preferably 15-60%.
• the reaction at a temperature from room temperature to reflux temperature of the reaction mixture, usually from room temperature to 200 0 C, performed.
• the reaction is carried out at a pressure of normal pressure up to 200 bar, preferably from 40 to 150 bar, in particular from 50 to 100 bar. It is possible to increase the pressure gradually to the desired pressure or continuously.
• the hydrogen or the hydrogen of the hydrogen-containing gas stream can be completely or partially reacted. In the latter case, it may be advantageous from case to case to partially or completely recirculate this gas flow or to circulate it. In the event that the copper-containing Kataysator used is activated before the reaction, then this gas stream can also be used for this purpose.
• the hydrogen may also be in the form of a hydrogen-containing gas, i. as admixture of an inert gas, such as nitrogen, helium, neon, argon or carbon dioxide, preferably nitrogen or argon, are used.
• an inert gas such as nitrogen, helium, neon, argon or carbon dioxide, preferably nitrogen or argon
• the reaction according to the invention is carried out in the presence of a heterogeneous copper-containing catalyst.
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 0.1 to 95 wt.% Copper; 0.1-85 wt.% At least one metal selected from the group consisting of nickel, cobalt and
• Zinc 0-15% by weight of at least one promoter selected from the group iron,
• the heterogeneous copper-containing catalyst contains a carrier material.
• the carrier material is coal, z.
• suitable porous metal oxides are alumina, silica, aluminosilicates, titania, zirconia, magnesia or mixtures thereof, preferably alumina, titania or zirconia.
• the total weight of the above-mentioned catalytically active metals and optionally promoters of the heterogeneous copper-containing catalyst is at most 95% by weight, preferably at most 90% by weight.
• the heterogeneous copper-containing catalyst is a full contact.
• this contains heterogeneous copper-containing catalyst, based on the total weight of the catalyst
• Zinc 0-15% by weight of at least one promoter selected from the group iron,
• this heterogeneous copper-containing catalyst based on the
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 2-50 wt.% Copper;
• At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium, lithium, Sodium, potassium, cesium, magnesium, barium, phosphorus, arsenic, antimony, bismuth, selenium and tellurium.
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 5-40 wt.% Copper; 0-30% by weight of at least one metal selected from the group consisting of nickel and cobalt; 5 to 50% by weight of zinc;
• At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium, lithium, Sodium, potassium, cesium, magnesium, barium, phosphorus,
• Arsenic, antimony, bismuth, selenium and tellurium Arsenic, antimony, bismuth, selenium and tellurium.
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 10-35 wt.% Copper;
• At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium,
• This heterogeneous copper-containing catalyst particularly preferably contains from 10 to 35% by weight, based on the total weight of the catalyst, of copper; 10 to 40% by weight of zinc;
• At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium,
• this copper-containing catalyst contains, as catalytically active metals, only copper and zinc, in particular (but independently of one another) from 5 to 50% by weight, particularly preferably from 10 to 45% by weight, in particular preferably from 20 to 40% by weight, based on the total weight of the catalyst.
• the carrier material is preferably a porous metal oxide, in particular aluminum oxide, titanium dioxide or zirconium dioxide.
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 2-50 wt.% Copper; 0.1-70% by weight of nickel 0-30% by weight of at least one metal selected from the group of cobalt and zinc;
• At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium,
• this contains heterogeneous copper-containing catalyst, based on the total weight of the catalyst
• At least one promoter selected from the group consisting of iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold,
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 2-25 wt.% Copper;
• At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium, lithium, Sodium, potassium, cesium, magnesium, barium, phosphorus, arsenic, antimony, bismuth, selenium and tellurium.
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 2-25 wt.% Copper; 3 - 50% by weight nickel; 0 - 5% wt.% At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium, lithium, Sodium, potassium, cesium, magnesium, barium, phosphorus, arsenic, antimony, bismuth, selenium and tellurium, preferably molybdenum.
• this copper-containing catalyst as catalytically active metals only copper and nickel, in each case (but independently) 2 to 15 wt.%, Particularly preferably 2 to 10 wt.%, Particularly preferably 3 to 8 wt.%, Based on the total weight of the catalyst.
• a suitable carrier material is preferably a porous metal oxide, in particular aluminum oxide, titanium dioxide or zirconium dioxide.
• this copper-containing catalyst as catalytically active metals or promoters only copper, nickel and molybdenum, in particular 2 to 25 wt.% Copper, 20 to 60 wt.% Nickel, 0.01 to 5 wt.% Molybdenum, particularly preferably 5 to 20% by weight of copper, 30 to 50% by weight of nickel, 0.1 to 2% by weight of molybdenum, in particular preferably 10 to 15% by weight of copper, 35 to 45% by weight of nickel, 0.5 to 1, 5 wt.% Molybdenum based on the total weight of the catalyst.
• the carrier material is preferably a porous metal oxide, in particular aluminum oxide, titanium dioxide or zirconium dioxide.
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 2-40 wt.% Copper; 0.1-80% by weight of at least one metal selected from the group consisting of nickel and cobalt; 0-5% by weight of at least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium, lithium, Sodium, potassium, cesium, magnesium, barium, phosphorus, arsenic, antimony, bismuth, selenium and tellurium.
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 2-40 wt.% Copper; 0.1-40% by weight nickel; 0.1-40% by weight of cobalt; 0-5% by weight of at least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium, lithium, Sodium, potassium, cesium, magnesium, barium, phosphorus, arsenic, antimony, bismuth, selenium and tellurium.
• promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium, lithium, Sodium, potassium, cesium,
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst, contains 2 to 30% by weight of copper; 0.5-35% by weight nickel; 0.5-35% by weight of cobalt;
• At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium, lithium, Sodium, potassium, cesium, magnesium, barium, phosphorus,
• Arsenic, antimony, bismuth, selenium and tellurium Arsenic, antimony, bismuth, selenium and tellurium.
• This heterogeneous copper-containing catalyst particularly preferably contains from 2 to 20% by weight, based on the total weight of the catalyst, of copper;
• At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium,
• this copper-containing catalyst containing as the catalytically active metals only copper, nickel and cobalt, in particular 2 to 25 wt.% Copper and each independently 1 to 35 wt.% Of nickel or cobalt, particularly preferably 2 to 20 wt.% Copper and each independently 10 to 30 wt.% Of nickel or cobalt, in particular preferably 5 to 15 wt.% Copper and each independently 15 to 25 wt.% Of nickel or cobalt, based on the total weight of the catalyst lysators.
• the carrier material is preferably a porous metal oxide, in particular aluminum oxide, titanium dioxide or zirconium dioxide.
• this copper-containing catalyst containing as the catalytically active metals only copper, nickel and cobalt, more preferably 2 to 10 wt.% Copper and each independently 1 to 10 wt.% Of nickel or cobalt, in particular preferably 2 to 5 wt % Copper and each independently 2 to 5 wt.% Of nickel or cobalt, based on the total weight of the catalyst.
• a carrier terial is preferably a porous metal oxide, in particular alumina, titania or zirconia, into consideration.
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 2-40 wt.% Copper; 0.1-80% by weight of cobalt;
• At least one promoter selected from the group consisting of iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin,
• this heterogeneous copper-containing catalyst based on the total weight of the catalyst 2 - 20 wt.% Copper; 2 - 20% by weight of cobalt;
• At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium,
• This heterogeneous copper-containing catalyst particularly preferably contains from 2 to 15% by weight, based on the total weight of the catalyst, of copper; 2 - 15% by weight of cobalt;
• At least one promoter selected from the group iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium,
• this copper-containing catalyst as catalytically active metals only copper and cobalt, in each case (but independently) 2 to 15 wt.%, Particularly preferably 3 to 10 wt.%, Particularly preferably 3 to 8 wt.%, Based on the total weight of the catalyst.
• the carrier material is preferably a porous metal oxide, in particular aluminum oxide, titanium dioxide or zirconium dioxide.
• this contains heterogeneous copper-containing catalyst, based on the total weight of the catalyst 5 to 40% by weight of copper;
• At least one promoter selected from the group consisting of iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium,
• This heterogeneous copper-containing catalyst particularly preferably contains from 10 to 25% by weight, based on the total weight of the catalyst, of copper; 40-70% by weight of cobalt;
• At least one promoter selected from the group consisting of iron, rhodium, ruthenium, palladium, platinum, iridium, osmium, silver, gold, molybdenum, tungsten, rhenium, cadmium, lead, manganese, tin, chromium,
• this copper-containing catalyst containing as catalytically active metals or promoters only copper, cobalt, molybdenum and manganese, in particular 5 to 40 wt.% Copper, 30 to 80 wt.% Cobalt and each independently from 0.1 to 15 wt % Molybdenum, manganese and phosphorus, particularly preferably 10 to 35 wt.% Copper, 40 to 75 wt.% Cobalt and in each case independently 0.5 to 15 wt.% Molybdenum, manganese and phosphorus, in particular preferably 12 to 25 wt.
• the catalyst usually has a BET surface area (determined to DIN 66131) of 50 to 150 m 2 / g, preferably from 70 to 130 m 2 / g, in particular from 75 to 120 m 2 / g.
• the pore volume of the catalyst is 0.1 to 0.4 ml / g, preferably 0.15 to 0.35 ml / g, in particular 0.15 to 0 , 3 ml / g.
• the preparation of the catalyst can also be carried out by customary processes (A. Farkas, in Ullmann's Encyclopedia of Industrial Chemistry, Electronic Release 2000, Chapter 5.3, 5.4, 5.6 to 5.10).
• the carrier from corresponding compounds which convert to the oxide of the respective carrier during calcining.
• hydroxides, carbonates and carboxylates are suitable.
• the oxide or the corresponding precursor, which is converted into the oxide of the respective carrier during calcination can be prepared by processes known per se, for example by the sol-gel process, by precipitation, dehydration of the corresponding carboxylates, dry mixing, slurrying or spray-drying.
• the precipitation usually soluble salts of aluminum, titanium, zirconium, etc. are used, such as the corresponding halides, preferably chloride, alkoxides, nitrate, etc., preferably nitrate of aluminum, titanium, zirconium, etc.
• stabilizers in the carrier it is possible stabilizers in the carrier to be installed according to usual procedures.
• adjuvants can be incorporated into the carrier which facilitate the shaping of the carrier, such as graphite or stearic acid. Subsequently, the shaping takes place.
• strands, tablets, spheres, chippings, monoliths, etc. are prepared by the usual methods.
• the calcination is usually carried out with air or a mixture of air and nitrogen, at a temperature of 300 to 800 0 C, preferably at 500 to 600 0 C. It may be advantageous to add water vapor to the air or the air / nitrogen mixture.
• the catalytically active metals or promoters according to the invention can now be applied to the support.
• the carrier is impregnated with a solution of a corresponding metal precursor or promoter precursor or soaked in it.
• the impregnation can be carried out by the incipient-wetness method, wherein the porous volume of the carrier is filled by approximately the same volume of impregnating solution and - possibly after maturation - dries the carrier; or you work with an excess of solution, the volume of this solution is greater than the porous volume of the carrier.
• the carrier is mixed with in the impregnating solution and stirred for a sufficient time.
• the excess impregnating solution is shaken off, centrifuged off or separated by filtration.
• the addition of acids, neutral salts or bases may also facilitate impregnation / impregnation.
• Continuous impregnation of the support can be achieved on a case by case basis, e.g. the solution is heated during the impregnation / impregnation, surface-active substances are added or the support is evacuated.
• the corresponding support is treated with a solution of the corresponding metal precursor or promoter precursor, which is dimensioned so that the support receives the solution.
• Suitable metal precursors or promoter precursors are corresponding soluble metal salts, including halides, in particular chloride, nitrate, acetate, alkaline carbonates, formate, oxalate, citrate, tartrate.
• the support on which the catalytically active metal precursors according to the invention are applied is now calcined.
• the calcination is usually carried out with air or a mixture of air and nitrogen, at a temperature of 300 to 800 0 C, preferably at 400 to 600 0 C. It may be advantageous to add water vapor to the air or the air / nitrogen mixture.
• the heterogeneous copper-containing catalyst is suitably conditioned, whether it is adjusted by grinding to a certain grain size or that it is mixed after its milling with molding aids such as graphite or stearic acid, pressed by means of a tablet press to formations and tempered (heat treated).
• the tempering temperatures generally correspond to the temperatures during the calcination.
• precipitation methods can also be used for the preparation of the heterogeneous copper-containing catalysts.
• Promoter precursors are obtained from an aqueous salt solution containing these metals / promoters by means of mineral bases in the presence of a slurry of a sparingly soluble, oxygen-containing Colourprecursorver- bond or the support itself and subsequent washing, drying and calcination of the resulting precipitate.
• Oxides, oxihydrates, phosphates, borates and silicates for example oxides, oxihydrates, phosphates, borates and silicates, such as eg zirconium dioxide, zirconium oxide hydrate, zirconium phosphates, borates and silicates, silicates, can be used as sparingly soluble, oxygen-containing carrier precursor compounds or carriers themselves.
• ciumdioxid, alumina, Aluminiumoxihydrat, titanium dioxide and other, known in the art and suitable for this purpose compounds can be prepared by suspending fine-grained powder of Rauchprecursortagenen or carrier itself in water with vigorous stirring.
• the heterogeneous copper-containing catalysts according to the invention are prepared via a common precipitation (mixed precipitation) of all their components.
• an aqueous salt solution containing the catalyst components is expediently mixed with an aqueous mineral base, in particular an alkali metal base - for example sodium carbonate, sodium hydroxide, potassium carbonate or potassium hydroxide while stirring - until the precipitation is complete.
• an alkali metal base for example sodium carbonate, sodium hydroxide, potassium carbonate or potassium hydroxide
• the nature of the salts used is generally not critical - since it depends primarily on the water solubility of the salts in this approach, one criterion is their water solubility required for the preparation of these relatively highly concentrated salt solutions. It is taken for granted that when selecting the salts of the individual components, of course, only salts with such anions are chosen which do not lead to disturbances, either by causing undesired precipitation or by complicating or preventing precipitation by complex formation.
• the precipitates obtained in these precipitation reactions are generally chemically non-uniform and consist, inter alia. from mixtures of the oxides, oxide hydrates, hydroxides, carbonates and insoluble and basic salts of the metals / promoters used. It may prove beneficial for the filterability of the precipitates when they are aged, i. if left for some time after precipitation, optionally in heat or by passing air through it.
• the precipitates obtained by this precipitation process are processed as usual to the heterogeneous copper-containing catalysts according to the invention. After washing, they are generally dried at 80 to 200 0 C, preferably at 100 to 150 0 C, and then calcined.
• the calcination (heat treatment) is generally carried out at temperatures between 300 and 800 0 C, preferably at 400 to 600 0 C, particularly at 450 to 550 0 C.
• the heterogeneous copper-containing catalyst is suitably conditioned, whether it is adjusted by grinding to a certain grain size or that it is mixed after its milling with molding aids such as graphite or stearic acid, pressed by means of a tablet press to formations and tempered (heat treated).
• the tempering temperatures generally correspond to the temperatures during the calcination.
• the heterogeneous copper-containing catalysts prepared in this way comprise the catalytically active metals / promoters in the form of a mixture of their oxygen-containing compounds, ie in particular as oxides and mixed oxides.
• the heterogeneous copper-containing catalysts prepared in this way can be stored as such.
• the catalyst thus obtained can be activated before its use, in the diaselective hydrogenation of compounds of the formula I.
• it is treated with hydrogen or a mixture of hydrogen and nitrogen at temperatures of 100 to 300 0 C.
• Production The Vorre- can be carried out, up to 200 0 C over a period of 12 to 20 hours in a nitrogen / hydrogen atmosphere, and are then continued in an atmosphere of hydrogen until about 24 hours at 200 to 300 0 C initially at 150th
• the activation of the catalyst is usually carried out in the reactor in which the hydrogenation according to the invention is to take place. However, it is also possible to carry out the activation of the catalyst before installation in the corresponding reactor.
• the catalyst is used in reduced form in the hydrogenation according to the invention.
• it may be advantageous to reactivate the catalyst present in reduced form.
• it is reacted with hydrogen or a mixture of hydrogen and an inert gas, such as nitrogen, at temperatures from room temperature to 300 0 C, preferably at 150 to 300 0 C, and a hydrogen pressure of 10 to 60 bar, preferably at max. 50 bar, treated.
• an inert gas such as nitrogen
• the process according to the invention can be carried out batchwise, semicontinuously or continuously.
• reaction mixture is worked up by conventional methods, e.g. separating the catalyst, for example by filtration, settling and separating the liquid phase or by
• the hydrogenation according to the invention is carried out in the hydrogenation reactors known to the person skilled in the art. Examples include so-called slurry reactors, trickle bed reactors and bubble columns (PN Rylander, Ullmann's Encyclopedia, Electronic Relese 2007, chapter Hydrogenation and Dehydrogenation, p. 2-3).
• the hydrogenation of the imines of formula I in the liquid phase for example in a stirred autoclave, a bubble column, a circulation reactor, such as a loop reactor or a fixed bed reactor, take place.
• the fixed bed reactor can be operated in both the bottom and in the trickle mode.
• the reaction can be worked up and purified by the usual methods. For this purpose, for example, distillation, liquid extraction and / or crystallization into consideration.
• the compounds of the formula II obtained by the process according to the invention have a diastereomeric ratio of> 0.70, preferably> 0.9, in particular> 0.95, most preferably of> 0.98 (the diastereomeric ratio being the molar ratio of the desired diastereomer: is undesirable diastereomers). If it is desired to achieve an even higher diastereomeric ratio, the diastereostereomeric ratio of the compounds of formula II obtained by the process of the invention may be determined by known methods, e.g. Recrystallization, to be increased.
• the diastereomer ratio can be determined by methods customary to the person skilled in the art; this is usually determined indirectly via the rotation value or directly by gas or liquid chromatography. The determination can be made directly or via appropriate derivatives of the target compound.
• the catalyst can be used again in the process according to the invention.
• the ketone of formula III and the amine of formula IV are used in stoichiometric amounts. From case to case it may also be advantageous to use one or the other educt in excess.
• the reaction is carried out in a solvent.
• Suitable solvents are inert solvents, such as, for example, alcohols, ethers, hydrocarbons, halogenated hydrocarbons, etc., especially those which react with water to form an azeotrope, e.g. Toluene or ethylbenzene, form and so the resulting water in the reaction can be separated.
• one of the educts used forms an azeotropic mixture with water
• this educt can be used in excess and the water formed can be removed azeotropically. This can be done in the presence or absence of an additional solvent.
• catalytic amounts of acid e.g. p-toluenesulfonic acid
• the reaction can also be carried out in the presence of heterogeneous catalysts such as, for example, aluminum oxides, titanium dioxide, zirconium dioxide, silicon oxides or clay minerals such as montmorillonite.
• reaction usually takes place at a temperature from room temperature to the reflux temperature of the reaction mixture.
• the work-up of the reaction mixture is carried out by the methods known in the art.
• the compounds of the formula I can also be obtained by reacting an alkyne of the formula V with an amine of the formula IV.
• R 2 to R 4 correspond to those which are given for the compounds of the formula I.
• R 1 ' - CH 2 stands for the meanings of R 1 which are compatible with it. The same applies to R 1 ' .
• the alkyne of the formula V and the amine of the formula IV are used in the stoichiometric ratio. However, it may be advantageous to use the alkyne of the formula V in excess.
• the reaction is usually carried out in an inert solvent, such as e.g. an ether, a hydrocarbon, a halogenated hydrocarbon, etc., or mixtures thereof, at room temperature to reflux temperature of the reaction mixture. In general, the reaction is carried out at atmospheric pressure. On a case-by-case basis, it may also be advantageous to carry out the reaction at elevated pressure, preferably in the range from 10 to 200 bar. After the reaction has taken place, the reaction is carried out by the methods known to the person skilled in the art.
• radicals R 1 to R 4 have the meaning mentioned under the compounds of the formula I.
• the phosphorylide of the formula VI and the nitroso compound of the formula VII are used in the stoichiometric ratio.
• the reaction is generally carried out in an inert solvent, such as an ether, a hydrocarbon, a halogenated hydrocarbon, etc., or mixtures thereof, at room temperature to reflux temperature of the reaction mixture.
• an inert solvent such as an ether, a hydrocarbon, a halogenated hydrocarbon, etc., or mixtures thereof.
• the reaction is carried out at normal pressure. After the reaction is worked up by the methods known to those skilled in the art.
• the representation of the imines of the formula I can be carried out continuously, semi-continuously or batchwise.
• imines of the formula I are preferably used, or amines of the formula II are prepared, the radicals having the following meanings independently of one another:
• R 1 R 2 d-Ce-alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 -alkyl kinyl, halo-C 2 -C 6 alkenyl, C 2 -C 6 -Haloalkynyl or C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkyl, where the said alkyl, cycloalkyl and alkoxy radicals may be partially or completely halogenated and / or may carry one to three of the following groups: cyano, hydroxy, ci -C 4 alkyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy-Ci-C4-alkyl, -C 4 - alkoxy-Ci-C4-alkoxy-Ci-C4-alkyl, Ci-C 4 alkoxy, Ci-C4 alkylthio, amino,
• R 3 is C 1 -C 4 -alkyl, preferably methyl
• R 4 aryl which may be partially or fully halogenated and / or one to three radicals from the group cyano, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, aryl and aryl may carry (C 1 -C 6 -alkyl); preferably phenyl or 1-naphthyl;
• imines of the formula I are used in the process according to the invention, or amines of the formula II are prepared, where the radicals independently of one another have the following meanings:
• R 1 , R 2 is Ci-C ⁇ -alkyl or Cs-C ⁇ -cycloalkyl, wherein said alkyl or cycloalkyl radicals may be partially or fully halogenated and / or may carry one to three of the following groups: cyano, hydroxy, Cs C ⁇ -cycloalkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio , Amino, C 1 -C 4 -alkylamino, di (C 1 -C 4 -alkyl) amino, C 1 -C 4 -alkylcarbonyloylamino, hydroxycarbonyl, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl, C 1
• Alkylaminocarbonyl di (C 1 -C 4 -alkyl) aminocarbonyl or C 1 -C 4 -alkylcarbonyloxy; in particular C 1 -C 6 -alkyl or C 5 -C 6 -cycloalkyl, where the said alkyl or cycloalkyl radicals may be partially or completely halogenated and / or may carry one of the following groups: cyano, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl 4- alkylthio, di (C 1 -C 4 -alkyl) amino, C 1 -C 4 -alkoxycarbonyl, di (C 1 -C 4 -alkyl) aminocarbonyl or
• CrC 4 -Alkylcarbonyloxy also in particular C 1 -C 6 -alkyl or C 5 -C 6 -cycloalkyl, where the alkyl or cycloalkyl radicals mentioned may be partially or completely halogenated and / or may carry one to three of the following groups: cyano, C 1 -C 4 -alkoxycarbonyl, di (C 1 -C 4 ) C 4 alkyl) aminocarbonyl or C 1 -C 4 alkylcarbonyloxy; particularly preferably C 1 -C 6 -alkyl, where the said alkyl radical may be partially or completely halogenated and / or may carry one to three of the following groups: cyano, di (C 1 -C 4 -alkyl) amino, C 1 -C 4 - alkoxycarbonyl, di (CrC 4 - alkyl) aminocarbonyl or Ci-C4-alkylcarbonyloxy; most preferably Ci-C ⁇ -alky
• C ⁇ -alkyl in particular phenyl, phenyl-C 1 -C 4 -alkyl, phenyl-C 2 -C 4 -alkenyl, phenyl-C 1 -C 4 -haloalkyl, phenyl-C 1 -C 4 -hydroxyalkyl, phenylcarbonyl-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -alkylcarbonyl -C-C4 alkyl, Phenyloxycarbonyl Ci-C 4 alkyl, phenyloxy-Ci-C4-alkyl, phenylamino-Ci-C4-alkyl, phenylthio-Ci-C 4 - alkyl, phenylsulfonyl-Ci-C4-alkyl,
• C 1 -C 4 -alkyl where the abovementioned radicals may be partially or completely halogenated and / or one to three radicals from the group cyano, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy, C 1 -C 4 -alkyl Hydroxyalkyl, C 1 -C 6 -alkoxy, CIC 6 -
• R 3 is C 1 -C 4 -alkyl, preferably methyl
• R 4 aryl which may be partially or fully halogenated and / or one to three radicals from the group cyano, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, aryl and aryl may carry (C 1 -C 6 -alkyl); preferably phenyl or 1-naphthyl;
• R 1 , R 2 is Ci-C ⁇ -alkyl or Cs-C ⁇ -cycloalkyl, wherein said alkyl or cycloalkyl radicals may be partially or fully halogenated and / or may carry one to three of the following groups: cyano, hydroxy, Cs C ⁇ -cycloalkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, amino, Ci-C 4 -alkyl-amino, di (Ci-C 4 alkyl) amino, dd alkyl carbonylamino, hydroxycarbonyl, Ci-C 4 alkoxycarbonyl, aminocarbonyl, CrC 4 - alkylaminocarbonyl, di (Ci-C 4
• R 3 is dd-alkyl, preferably methyl
• R 4 aryl which may be partially or completely halogenated and / or one to three radicals from the group cyano, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, aryl and aryl may carry (C 1 -C 6 -alkyl); preferably phenyl or 1-naphthyl, which may be partially or completely halogenated, and / or one to three radicals from the group cyano, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -C 1-C 6 Alkoxy, Ci-C ⁇ -haloalkoxy, aryl and aryl (Ci-C6-alkyl) can carry; in particular phenyl or 1-naphthyl.
• imines of the formula I are used, or amines of the formula II are prepared, the radicals having the following meanings independently of one another:
• R 1 is Ci-C ⁇ -alkyl or Cs-C ⁇ -cycloalkyl, wherein said alkyl or cycloalkyl radicals may be partially or completely halogenated and / or may carry one to three of the following groups: cyano, hydroxy, Cs-C ⁇ -cycloalkyl , Ci-C ⁇ - alkoxy-Ci-C4-alkyl, Ci-C4-alkoxy-Ci-C4-alkoxy-Ci-C4-alkyl, Ci-C 4 alkoxy, Ci-C 4 - alkylthio, amino, C 1 -C 4 -alkylamino, di (C 1 -C 4 -alkyl) amino, C 1 -C 4 -alkylcarbamoylamino, hydroxycarbonyl, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, Di (C 1 -C 4
• Alkoxycarbonyl di (C 1 -C 4 -alkyl) aminocarbonyl or C 1 -C 4 -alkylcarbonyloxy; particularly preferably C 1 -C 6 -alkyl, where the said alkyl radical may be partially or completely halogenated and / or may carry one to three of the following groups: cyano, di (C 1 -C 4 -alkyl) amino, C 1 -C 4 - alkoxycarbonyl, di (CrC 4 - alkyl) aminocarbonyl or Ci-C4-alkylcarbonyloxy; most preferably Ci-C ⁇ -alkyl;
• R 2 is aryl, aryl-Ci-C4-alkyl, aryl-C 2 -C 4 alkenyl, aryl-C 2 -C 4 alkynyl, aryl-Ci-C 4 -halogenated alkyl, aryl-C2-C4 -haloalkenyl, aryl-C3-C4-haloalkynyl, aryl-Ci-C4 hydroxy-alkyl, arylcarbonyl-Ci-C 4 alkyl, aryl-Ci-C 4 alkyl carbonyl-Ci-C 4 alkyl, Arylcar bonyloxy-C 1 -C 4 -alkyl, aryloxycarbonyl-C 1 -C 4 -alkyl, aryloxy-C 1 -C 4 -alkyl, aryl-amino-C 1 -C 4 -alkyl, arylthio-C 1 -C 4 -al
• C 1 -C 6 -haloalkyl hydroxy, C 1 -C 6 -hydroxyalkyl, hydroxycarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, hydroxycarbonyl, Ci-C ⁇ -alkoxycarbonyl, aminocarbonyl, (d-Ce-Alky ⁇ aminocarbonyl, di (Ci-C6-alkyl) aminocarbonyl, hydroxycarbonyl-Ci-C ⁇ -alkoxy, Ci-C ⁇ -alkoxycarbonyl-Ci-C ⁇ -alkoxy, amino , Ci-C ⁇ -alkylamino, di (Ci-C6-alkyl) amino, Ci-C ⁇ -alkyl) amino, Ci-C ⁇ -alkyl
• Alkylsulfonylamino, Ci-C ⁇ -haloalkylsulfonylamino, (Ci-C6-alkyl) amino carbonylamino, di (Ci-C6-alkyl) aminocarbonylamino, aryl and aryl (Ci-C6-alkyl) can carry;
• heterocyclyl-C 1 -C 4 -alkyl heterocyclyl-C 2 -C 4 -alkenyl, heterocyclyl-C 2 -C 4 -alkynyl, heterocyclyl-C 1 -C 4 -haloalkyl, heterocyclyl-C 2 -C 4 -halo-alkenyl, heterocyclyl-C 1 -4 -haloalkynyl, Heterocyclyl-C 1 -C 4 -hydroxyalkyl, heterocyclic-carbonyl-C 1 -C 4 -alkyl, heterocyclyl-C 1 -C 4 -alkyl-carbonyl-C 1 -C 4 -alkyl, heterocycliccarbonyloxy-C 1 -C 4 -alkyl, heterocyclyloxycarbonyl-C 1 -C 4 -alkyl alkyl, heterocyclyloxy-C 1 -C 4 -alkyl, heterocyclylamin
• phenyl in particular phenyl, phenyl-C 1 -C 4 -alkyl, phenyl-C 2 -C 4 -alkenyl, phenyl-C 1 -C 4 -haloalkyl, phenyl-C 1 -C 4 -hydroxyalkyl, phenylcarbonyl-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -alkyl carbonyl-Ci-C4 alkyl, Phenyloxycarbonyl-C 1 -C 4 -alkyl, phenyloxy-C 1 -C 4 -alkyl, phenylamino-C 1 -C 4 -alkyl, phenylthio-C 1 -C 4 -alkyl, phenylsulfonyl-C 1 -C 4 -alkyl, Heterocyclyl, heterocyclyl-C 1 -C 4 -alky
• C 1 -C 4 -alkyl where the abovementioned radicals may be partially or completely halogenated and / or one to three radicals from the group cyano, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy, C 1 -C 6 -cycloalkyl Hydroxyalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, (C 1 -C 6)
• phenyl particularly preferably phenyl, phenyl-C 1 -C 4 -alkyl, phenyl-C 1 -C 4 -haloalkyl,
• Phenylcarbonyloxy-dd-alkyl phenyloxycarbonyl-C 1 -C 4 -alkyl, phenyloxy-C 1 -C 4 -alkyl,
• R 3 is C 1 -C 4 -alkyl, preferably methyl
• R 4 aryl which may be partially or completely halogenated and / or one to three
• Radicals from the group cyano, nitro, C-i-C ⁇ -alkyl, C-i-C ⁇ -haloalkyl, C-i-C ⁇ -alkoxy, C-i-C ⁇ -haloalkoxy, aryl and aryl (Ci-C6-alkyl) can carry; preferably phenyl or 1-naphthyl.
• the amines of the formula II can be hydrogenolyzed to the chiral amines of the formula VIII,
• this hydrogenolysis is carried out in an inert solvent, e.g. an alcohol such as methanol, ethanol, isopropanol or butanol, an ether such as e.g. Tetrahydrofuran, dioxane, a hydrocarbon, e.g. Benzene, toluene, ethylbenzene, or xylene, or mixtures thereof.
• the hydrogenolysis can be carried out by means of hydrogen in the presence of a catalytic amount of a platinum group metal element, preferably Pt / C, Pd / C or Pd / AbCh, more preferably Pd / C or Pd / AbCh. In this case, the hydrogen is generally used in excess.
• the reaction is usually carried out at room temperature to reflux temperature of the reaction mixture and atmospheric pressure up to a pressure of 200 bar. After completion of the reaction, the reaction mixture is worked up by methods known to those skilled in the art.
• metal hydrides e.g. Lithium aluminum hydride, sodium borohydride, Natriumcycanoborant, Diboran etc.
• the reactants are usually used in a stoichiometric ratio. It may also be advantageous on a case-by-case basis to use the metal hydride in excess.
• the reaction is usually carried out at room temperature to reflux temperature of the reaction mixture, at atmospheric pressure. After completion of the reaction, the reaction mixture is worked up by methods known to those skilled in the art.
• the hydrogenolysis of the amines of formula II can be carried out continuously, semi-continuously or discontinuously.
• radicals R 1 and R 2 of the compounds of the formula I, II, III, VI and VIII and the radical R 1 'of the compounds of the formula V can carry further chiral centers, depending on the substitution pattern. These compounds are also the subject of the present invention.
• All hydrocarbon chains can be straight-chain or branched.
• halogenated substituents preferably carry one to five identical or different halogen atoms.
• the meaning halogen in each case stands for fluorine, chlorine, bromine or iodine.
• - Aryl mono- to trinuclear aromatic carbocycle having 6 to 14 ring members, such as phenyl, naphthyl and anthracenyl, preferably phenyl, naphthyl;
• Heterocycyl monocyclic, saturated or partially unsaturated Kohlenwasserstof- Fe with three to six ring members, which in addition to carbon atoms one to four
• Nitrogen atoms or one to three nitrogen atoms and one oxygen or sulfur atom, or one to three oxygen atoms, or may contain one to three sulfur atoms, and which may be linked via a C atom or an N atom, e.g.
• 4,5-dihydropyrrol-1-yl 2,5-dihydropyrrol-1-yl, 4,5-dihydroisoxazol-2-yl, 2,3-dihydroisoxazol-1-yl, 4,5-dihydroisothiazol-1-yl, 2,3-dihydroisothiazol-1-yl, 2,3-dihydroisothiazol-1-yl, 2,3-dihydropyrazol-1-yl, 4,5-dihydropyrazol-1-yl, 3,4-dihydropyrazol-1-yl, 2,3-dihydroimidazole 1-yl, 4,5-dihydroimidazol-1-yl, 2,5-dihydroimidazol-1-yl, 2,3-dihydrooxazol-2-yl, 3,4-dihydrooxazol-2-yl, 2,3-dihydrothiazole 2-yl, 3,4-d
• 2-piperidinyl 3-piperidinyl, 4-piperidinyl, 1, 3-dioxan-2-yl, 3-dioxan-4-yl, 1, 3-dioxan-5-yl, 1, 4-dioxan-2-yl 1,1,3-Dithian-2-yl, 1,4-dithian-3-yl, 1,3-dithian-4-yl, 1,4-dithian-2-yl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4 -Tetrahydropyranyl, 2-
• Heteroaryl mono- or bicyclic aromatic heteroaryl having 5 to 10 ring members which, in addition to carbon atoms, contains 1 to 4 nitrogen atoms, or 1 to 3 nitrogen atoms and one oxygen or one sulfur atom, or an oxygen or a sulfur atom,
• Pyrrolyl eg pyrrol-2-yl, pyrrol-3-yl
• pyrazolyl eg pyrazol-3-yl, pyrazol-4-yl
• isoxazolyl eg isoxazol-3-yl, isoxazol-4-yl, isoxazole -5-yl
• isothiazolyl eg isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl
• imidazolyl eg imidazol-2-yl, imidazol-4-yl
• oxazolyl eg oxazol-2-yl, oxazol-4-yl, Oxazol-5-yl
• thiazolyl eg, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl
• oxadiazolyl eg, 1, 2,3-oxadiazol
• Bicyclic compounds such as the benzanellated derivatives of the aforementioned monocycles, e.g. Quinolinyl, isoquinolinyl, indolyl, benzthienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, benzopyrazolyl, benzothiadiazolyl, benzotriazole
• 5- or 6-membered heteroaryl having one to four nitrogen atoms, or one to three nitrogen atoms and one oxygen or sulfur atom, or with an oxygen or sulfur atom: e.g. C-atom linked aromatic 5-membered heterocycles which may contain, besides carbon atoms, one to four nitrogen atoms, or one to three nitrogen atoms and one sulfur or oxygen atom, or a sulfur or oxygen atom as ring members, e.g. 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl,
• 3-Pyrrolyl 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5- Oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1, 2,4-oxadiazol-3-yl, 1, 2,4-oxadiazol-5-yl, 1, 2, 4-thiadiazol-3-yl, 1, 2,4-thiadiazol-5-yl, 1, 2,4-triazol-3-yl, 1, 3,4-oxadiazol-2-yl, 1, 3,4- Thiadiazol-2-yl and 1, 3,4-triazol-2-yl;
• aromatic 6-membered ring heterocycles linked via a carbon atom which may contain, besides carbon atoms, one to four, preferably one to three, nitrogen atoms as ring members, e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 1, 3,5-triazin-2-yl and 1, 2,4-triazine-3-yl.
• the copper-containing catalysts used in the following examples were prepared as described in the following documents: DE 19826396, DE 4428004, EP 383132 and DE 371711 1
• the diastereomeric ratio of the compounds shown in Examples I and II below was determined as follows: derivatization with trifluoroacetic acid, gas chromatographic separation on column BGB 175.
• the diastereomer ratio of the compounds shown in Examples III and VI below was determined as follows: derivatization with trifluoroacetic acid, gas chromatographic separation on column Hydrodex beta 6-TBDM.
• the diastereomeric ratio of the compounds shown in Example VII below was determined as follows: gas chromatographic separation on column CP-SIL 19 CB.
• the diastereomer ratio of the compounds shown in Example VIII below was determined as follows: gas chromatographic separation on column OV1701.
• Example IX The diastereomeric ratio of the compounds shown in Example IX below was determined as follows: gas chromatographic separation on column RTX-5-amine.
• Phenyl-1-ethanone 315 mg of catalyst were placed in a 15 mL autoclave and made inert with nitrogen. Subsequently, the catalyst was preactivated for 2 hours at a pressure of 50 bar at the temperature indicated in Table 12 with hydrogen. It was then purged again with nitrogen, cooled to room temperature, and then under nitrogen a mixture of 3.5 ml of (R) - (1-phenylethylidene) - (1-phenyl-ethyl) amine and 3.5 ml of ethylbenzene was added. Subsequently, hydrogen was injected until a pressure of about 20 bar was reached and the reaction mixture was heated to 100 0 C. After reaching this temperature, the pressure was increased to 70 bar with hydrogen and the stirrer started at 1000 rev / min. After 3 hours under these reaction conditions, a sample was taken and analyzed by gas chromatography. The results are shown in Table 12 below.
• the imines can be prepared according to a modified protocol by Charles et al., Bull. Soc. Chim. Fr. 1970, 12, 4439-4446.
• the ketone is diluted with 1.25 eq. of your enantiomer of (i-phenyl-ethyl) -amine and 0.01 eq. P-toluenesulfonic acid in toluene presented.
• the resulting water of reaction is removed continuously by azeotropic distillation. If no further conversion is detected by GC, the solvent is removed and the product is purified by means of a fractional distillation.

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