HK1081531B - Process for the enantioselective hydrogenation of amino alcohols - Google Patents

Description

Process for the enantioselective hydrogenation of amino alcohols

The invention relates to a method for the enantioselective preparation of amino alcohols of the formula I,

wherein

R¹Represents unsubstituted or substituted by R³And/or R⁴Mono-or polysubstituted saturated, unsaturated or aromatic carbocyclic or heterocyclic radicals,

R²represents an alkyl group having 1 to 20C atoms or H,

R³、R⁴each independently of the other represents H, an alkyl or alkoxy group having 1 to 20C atoms, an aryl group, an aryloxy group or COOR²、F、Cl、Br、OH、CN、NO₂、N(R²)₂Or NHCOR₂，

And

n represents 0, 1, 2 or 3,

the process is prepared by enantioselective hydrogenation of aminoketones of the formula II in the presence of a non-racemic catalyst,

wherein

R¹、R²And n has the meanings given aboveCharacterized in that the catalyst is a transition metal complex in which a transition metal is complexed with a chiral diphosphine ligand A

Wherein

R⁵、R⁶、R⁷And R⁸Each independently of the other represents H, alkyl or alkoxy having 1 to 20C atoms, aryl, aryloxy or F, Cl, Br, N (R)²)₂Or NHCOR₂，

R⁹And R¹⁰Each independently represent

Or a cyclohexyl group,

R¹¹represents H, alkyl or alkoxy having 1 to 20C atoms, aryl, aryloxy or SO₃Na、COOR¹²、F、Cl、N(R¹²)₂Or NHCOR¹²，

R¹²Represents an alkyl group having 1 to 20C atoms or H,

and

m represents 0, 1, 2 or 3,

wherein R is⁵And R⁶、R⁶And R⁷And R⁷And R⁸May also represent- (CH) together₂)₄-、-CH＝CH-CH＝CH-、

Or

Or with B

Wherein

Y represents OH, P (cyclohexyl)₂P (3, 5-dimethylphenyl)₂Or P (C (CH)₃)₃)₂，

Z represents H or P (phenyl)₂，

Q represents PPh₂P (cyclohexyl)₂P3, 5-bis (trifluoromethyl) phenyl]₂P (4-methoxy-3, 5-xylyl)₂Or P (C (CH)₃)₃)₂，

And

ph represents a phenyl group, an o-, m-or p-methylphenyl group or a dimethylphenyl group.

In the compound of formula A, R⁹And R¹⁰Preferred expression(s)

Or a cyclohexyl group.

Particularly preferred are compounds of formula Al

Wherein Ph has the meaning given above, X tableH, alkyl, O (alkyl), Cl, or F, R' represents alkyl O (alkyl) or F. Particularly preferred are compounds of formula A3 wherein Ph represents phenyl, X represents H, and R' represents OCH₃。

Preferred compounds of formula a are symmetrical.

The compounds of the formula II are preferably used in the form of acid addition salts, in particular of strong acids, such as, for example, hydrohalic acids, methyl, p-toluene or benzenesulfonic acid, perchloric acid, sulfuric acid or phosphoric acid, and in addition acetic acid, formic acid or propionic acid are also suitable. Particularly preferred are the acid addition salts of the compounds of formula II with sulfuric acid or hydrochloric acid. The acid addition salts of the compounds of the formula I are obtained by acid addition salts of the compounds of the formula II to which the free base can be liberated by addition of strong bases, for example alkali metal carbonates or hydroxides.

The present invention therefore relates inter alia to a process for the preparation of optically active forms, as well as salts, hydrates and solvates, e.g. alcoholates, of compounds of formula I, in particular of compounds of formula I in which n represents 1.

Preferably, the present invention facilitates the synthesis of optically active aryl-substituted 3-monoalkylaminopropanols which are suitable as intermediates in the preparation of antidepressants.

In particular, the invention makes it possible to prepare enantiomerically pure or enantiomerically enriched (S) -3-methylamino-1- (2-thienyl) -1-propanol from 3-methylamino-1- (2-thienyl) -1-propanone in a simple manner. Analogously, enantiomerically pure or enantiomerically enriched (S) -3-methylamino-1-phenyl-1-propanol can be prepared in a simple manner from 3-methylamino-1-phenyl-1-propanone.

Cleavage of the racemic alcohol allows the desired 3-methylamino-1- (2-thienyl) -1-propanol enantiomer to be obtained naturally in a maximum yield of 50% (see, for example, Chirality2000, 12, 26 or EP 650965).

Labelled Compd. radiopharm.1995, 36(3), 213 and Tetrahedron Lett.1990, 31(49), 7101 describe asymmetric synthesis methods of (S) -3-methylamino-1- (2-thienyl) -1-propanol. However, both synthetic routes require further transformations or the use of chiral reagents in stoichiometric amounts. In contrast, the process of the invention described herein allows the desired enantiomer of the final product to be obtained in high selectivity and yield, without further conversion.

Homogeneous hydrogenation of 3-aminoketones is generally considered to be problematic because in most cases elimination of the product is obtained instead of the desired alcohol (J.organomet. chem.1982, 232, C17 or Synlett, 1997, 1306). In the process of the invention, this elimination reaction proves to be minor (the proportion of elimination product is less than 2%).

Similar methods for the preparation of 3-aminoalcohols are described in Synlett 1991, 689, but similar compounds are reduced to give the corresponding alcohols with rather poor enantioselectivity. In contrast to the process of the present invention, complicated demethylation is subsequently required in order to obtain the desired (S) -3-methylamino-1- (2-thienyl) -1-propanol or (S) -3-methylamino-1-phenyl-1-propanol, although homogeneous ruthenium catalysts are used in org.Lett.2000, 2(12), 1749, which give equally good selectivity for the alcohol in the hydrogenation of 3-dimethyl-aminoketone. The formation of toxic carcinogenic methyl chloride is considered to be particularly disadvantageous here.

The object of the present invention was therefore to find a process for preparing compounds which are useful in particular as intermediates in the synthesis of pharmaceuticals, which does not have the disadvantages mentioned above.

It has been found that compounds of formula I and salts thereof, which are important intermediates in the preparation of pharmaceuticals, in particular those active, for example, in the central nervous system, can be prepared by enantioselective hydrogenation of compounds of formula II in the presence of chiral, non-racemic transition metal catalysts.

In this context, unless otherwise stated, the radical R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²Q, Y and Z and the indices m and n have the meanings indicated in the formulae I, II, A and B. If they occur more than once in the formula, the radicals have the meaning independently of one another.

In the above formulae, the alkyl group has 1 to 20C atoms, preferably 1 to 6, in particular 1, 2, 3 or 4C atoms. Alkyl preferably denotes methyl or ethyl, and also propyl, isopropyl, and also butyl, isobutyl, sec-butyl or tert-butyl.

R¹Preferably unsubstituted or substituted by R³And/or R⁴A substituted aromatic carbocyclic or heterocyclic group. The radical may be monocyclic or polycyclic, preferably monocyclic or bicyclic, particularly preferably monocyclic.

R¹Particular preference is given to unsubstituted.

If R is¹Denotes a carbocyclic group, which is preferably, for example, phenyl, o-, m-, p-tolyl, o-, m-, p-hydroxyphenyl, o-, m-, p-methoxyphenyl, o-, m-, p-fluorophenyl.

If R is¹Represents a heterocyclic group which is suitably preferably, for example, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1-, 2, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, and is also preferably 1, 2, 3-triazol-1-, -4-or-5-yl, 1, 2, 4-triazol-1-, -3-or 5-yl, 1-or 5-tetrazolyl, 1, 2, 3-oxadiazol-4-or-5-yl, 1, 2, 4-oxadiazol-3-or-5-yl, 1, 3, 4-thiadiazol-2-or-5-yl, 1, 2, 4-thiadiazol-3-or-5-yl, 1, 2, 3-thiadiazol-4-or-5-yl, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 4-or 5-isoindolyl, 1-, (meth) acrylic acid or methacrylic acid, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-,5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6-or 7-benzo-2, 1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-benzo [1, 4 ]]Oxazinyl, preferably also 1, 3-benzodioxol-5-yl, 1, 4-benzodioxan-6-yl, 2, 1, 3-benzothiadiazol-4-or-5-yl or 2, 1, 3-benzoxadiazol-5-yl.

The heterocyclic group may be partially or fully hydrogenated. The heterocyclic radicals used may also be, for example, 2, 3-dihydro-2-, -3-, -4-or-5-furyl, 2, 5-dihydro-2-, -3-, -4-or-5-furyl, tetrahydro-2-or-3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2-or-3-thienyl, 2, 3-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 2, 5-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 2, 3-dihydro-1-, -3-, -4-or-5-pyrrolyl, 1-, 2-or 3-pyrrolidinyl, tetrahydro-1-, -2-or 4-imidazolyl, 2, 3-dihydro-1-, -2-, -3-, -4-or 5-pyrazolyl, tetrahydro-1-, -3-or 4-pyrazolyl, 1, 4-dihydro-1-, -2-, -3-or 4-pyridyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-or 6-pyridyl, 1-, 2-, 3-or 4-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-, -3-or 4-pyranyl, 1, 4-dioxanyl, 1, 3-dioxan-2-, -4-or 5-yl, hexahydro-1-, -3-or 4-pyridazinyl, hexahydro-1-, -2-, -4-or 5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or 8-quinolinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-isoquinolinyl, 2-, 3-, 5-, 6-, 7-or 8-3, 4-dihydro-2H-benzo [1, 4 ]]Oxazinyl, preferably also 2, 3-methylenedioxyphenyl, 3, 4-methylenedioxyphenyl, 2, 3-ethylenedioxyphenyl, 3, 4- (difluoromethylenedioxy) phenyl, 2, 3-dihydrobenzofuran-5-or-6-yl, 2, 3- (2-oxomethylenedioxy) phenyl or 3, 4-dihydro-2H-1, 5-benzodioxodioxy-6-or-7-yl, further preferably 2, 3-dihydrobenzofuranyl or 2, 3-dihydro-2-oxo-furanyl.

Said heterocyclyl may also be substituted by R³And/or R⁴And (4) substitution.

R¹Particularly preferably represents phenyl or 2-thienyl.

R²Preferably represents methyl, ethyl, n-propyl or isopropyl, but particularly preferably methyl.

R³And R⁴Each independently represents H, methyl, in particular H.

R⁵And R⁶Preferably H, alkyl, O-alkyl, Cl or F.

Also preferred is where R⁵And R⁶Together form a ring system.

R⁷And R⁸Preferably represents H.

R¹¹Preferably H or methyl, especially methyl.

R¹²Preferably methyl or ethyl.

n is preferably 0 or 1, in particular 1.

m is preferably 1.

Aryloxy preferably denotes, for example, phenoxy, o-, m-or p-tolyloxy, o-, m-or p-hydroxyphenoxy, o-, m-or p-methoxyphenoxy, o-, m-or p-fluorophenoxy.

Aryl preferably denotes, for example, phenyl, o-, m-or p-tolyl, o-, m-or p-hydroxyphenyl, o-, m-or p-methoxyphenyl, o-, m-or p-fluorophenyl.

Preferably used are chiral ligands of formula a.

Ph represents phenyl, 2-, 3-or 4-tolyl, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-dimethylphenyl.

Ph preferably denotes phenyl, 4-tolyl or 3, 5-dimethylphenyl, with 4-tolyl being particularly preferred.

Y preferably represents P (C (CH)₃)₃)₂。

Z preferably represents H.

Q preferably represents P (phenyl)₂。

Preferred are those wherein Z is H and Y is P (C (CH)₃)₃)₂A chiral ligand of formula B. Preference is furthermore given to those in which Z is P (phenyl)₂And Y is OH.

Preference is furthermore given to ligands of the formula B in which the radicals Q and Y are in the following combination:

Q＝PPh₂(ii) a Y ═ P (cyclohexyl)₂

Q＝PPh₂(ii) a Y ═ P (tert-butyl)₂

Q ═ P (cyclohexyl)₂(ii) a Y ═ P (cyclohexyl)₂

Q＝PPh₂(ii) a Y ═ P (3, 5-dimethylphenyl)₂

Q ═ P [3, 5-bis (trifluoromethyl) phenyl]₂(ii) a Y ═ P (cyclohexyl)₂

Q ═ P (4-methoxy-3, 5-dimethylphenyl)₂(ii) a Y ═ P (3, 5-dimethylphenyl)₂

Q ═ P [3, 5-bis (trifluoromethyl) phenyl]₂(ii) a Y ═ P (3, 5-dimethylphenyl)₂

Q ═ P (cyclohexyl)₂(ii) a Y ═ P (tert-butyl)₂

Q ═ P (tert-butyl)₂(ii) a Y ═ P (3, 5-dimethylphenyl)₂

The process according to the invention is particularly suitable for the preparation of the alcohols (S) -3-methylamino-1-phenyl-1-propanol or (S) -3-methylamino-1- (2-thienyl) -1-propanol, which can further advantageously be converted into the active ingredients duloxetine, fluoxetine, tomoxetine and LY 227942.

The compounds of formula I have one or more chiral centers and may therefore exist in different stereoisomeric forms. The formula I of the present invention encompasses all of these forms.

The term "enantioselective preparation" means that a compound containing formula IA is prepared in general

And mixtures of compounds of formula IB as reaction products

Wherein R is¹、R²And n has the meaning given above, wherein the mixture is not racemic, preferably contains only traces of the undesired enantiomer, depending on the chirality and selectivity of the catalyst used. In this case, a process for the preparation of enantiomerically pure compounds of the formula IA or IB is suitably preferred in this context. Preferred are processes for the preparation of enantiomerically pure compounds of formula IA.

In particular, it has been found that compounds of formula II can be hydrogenated using enantiomerically pure rhodium-phosphine complexes containing phosphine A or B to give enantiomerically pure or enantiomerically enriched compounds of formula I.

The invention also relates to a process for the preparation of a compound of formula I, characterized in that the chiral, non-racemic catalyst is an enantiomerically-enriched transition metal complex comprising one or more metals selected from rhodium, iridium, ruthenium and palladium, or salts thereof. Particular preference is given to using transition metal complexes which contain rhodium and rhodium salts.

Particularly preferred are transition metal salts containing sulfate, chloride, methanesulfonate, toluenesulfonate, hexachloroantimonate, hexafluoroantimonate or trifluoromethanesulfonate as anion.

Preference is given to using enantiomerically pure transition metal complexes.

In this context, the term "enantiomerically pure" means an enantiomeric purity of > 90% ee, preferably > 92% ee, in particular > 99% ee.

Depending on the choice of the (R) -or (S) -enantiomer of the ligand in the catalyst, an excess of the (R) -or (S) -enantiomer can be obtained.

The following ligands are particularly preferred:

wherein Tol represents 4-methylphenyl. (S) -TolBINAP is particularly preferred.

The starting compounds for preparing the chiral complexes are preferably compounds such as [ Rh (COD) ]₂]OTf (cyclooctadieneylrhodium triflate), [ Rh (COD) Cl]₂、[Rh(COD)₂]BF₄、[Ir(COD)Cl]₂、[Ir(COD)₂]BF₄、[Rh(NBD)Cl]₂(norbornadiene rhodium hydrochloride), [ Rh (ethylene)₂Cl]₂、RhX₃·nH₂O, wherein X represents Cl, Br or I or [ Ru (COD) Cl₂]_x. Preferably [ Rh (COD) Cl]₂。

Other preferred rhodium complexes contain one of the following anions:

Cl、Br、I、PF₆、[PF₃(C₂F₅)₃]、SbF₆、BF₄、ClO₄、BPh₄tetrakis (3, 5-bis-trifluoromethylphenyl) borate, OOCCH₃、OOCCF₃、OOCH、OOCCH₂CH₃Triflate, p-toluenesulfonate, methanesulfonate

And

diethyl ether or the following unsaturated compounds:

1, 5-cyclooctadiene, cyclooctene, 2, 5-norbornadiene (norbonadine), norbornene.

In addition, the compounds of the formula II and also the starting materials for their preparation are prepared by known methods described in the literature (for example, standard works such as Houben-Weyl, Methodender organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart), the methods being carried out precisely under known conditions which are suitable for the reaction in question. Various modifications known in the art which are not mentioned here in detail may also be used.

If desired, the starting materials can also be formed in situ without isolation from the reaction mixture and converted directly further into the compounds of the formula I.

Suitable solvents are, for example, water, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers such as PEG, ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methyl ethyl ketone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; nitro compounds, such as nitromethane or nitrobenzene; esters, such as methyl acetate or ethyl acetate, if desired also mixtures of the solvents mentioned with one another or with water. Particularly preferred are mixtures of hydrocarbons with alcohols, especially methanol and toluene.

It is particularly preferred that in the process the hydrogenation is carried out in the presence of one or more alcohols, especially methanol.

The reaction time for the enantioselective hydrogenation is from a few minutes to 14 days, depending on the conditions used, and the reaction temperature is from 0 to 200 ℃ and usually from 10 to 150 ℃ and preferably from 20 to 130 ℃ and in particular from 20 to 70 ℃. The catalyst/substrate ratio is generally from 1:10,000 to 1:20, preferably from 1:5000 to 1:50, particularly preferably from 1:2000 to 1: 100. The reaction time is, for example, 0.1 to 30 hours, preferably 3 to 20 hours. The hydrogenation is preferably carried out under a hydrogen pressure of from 1 to 250 bar, preferably from 3 to 210 bar, in particular from 120 to 200 bar.

The reaction is preferably carried out under reaction conditions in the absence of oxygen.

For the purification of the compounds of the formula I, it is advantageous to carry out the crystallization after the hydrogenation. In this case, in particular in that R¹Represents 2-thiophenyl, R²In the case of methyl radicals, particularly high enantiomeric excesses (enantiomeric excesses) can be obtained without a significant reduction in the yield.

The invention furthermore relates to the use of the compounds of the formula I as intermediates for the synthesis of medicaments. Corresponding drugs are mentioned, for example, in j.labelled compound.radiopharm.1995, 36(3), 213.

The invention furthermore relates to the use of the compounds of the formula I as intermediates for the synthesis of medicaments active on the central nervous system.

In this context, all temperatures are in units of ℃ and pressures are in units of bar.

Example (b):

all reactions are carried out under inert conditions (i.e., anhydrous and oxygen-free reaction conditions).

1. Preparation of catalyst/substrate solutions

Example 1:

51.4mg of [ Rh (COD) Cl]₂Dissolved in 5ml of a mixture solvent of toluene, and a solution composed of 5ml of toluene and 1.1 equivalents of (S) - (-) -2, 2 '-bis (di-p-tolylphosphino) -1, 1' -binaphthyl was added.

2. Analysis of samples

The enantiomeric excess of the hydrogenation product was determined on a chiral HPLC phase.

Example 2:

in a steel autoclave, 5.3mg of dichlorobis (1, 5-cyclooctadienyl) dirhodium (I) and 17.2mg of (S) - (-) -2, 2 '-bis (di-p-tolylphosphino) -1, 1' -binaphthyl were added to 8.23g of 3-methylamino-1- (2-thienyl) -1-propanone, and 50ml of methanol and 50ml of toluene were added to the mixture. After the reactor was sealed, oxygen was evacuated from the reactor by sequentially charging nitrogen and hydrogen. The reactor was filled with 55 bar hydrogen and warmed to 50 ℃. The progress of the reaction was monitored by the pressure drop in the autoclave. The reaction was complete after 15 hours.

The enantiomeric excess of the desired alcohol was obtained as 92.8% ee.

Example 3:

the oily residue from example 2 was taken up in 300ml of water and extracted three times with 250ml of dichloromethane, the organic phase being discarded. Subsequently, 250ml of dichloromethane were added to the aqueous phase, the pH was adjusted to 14 using 41.0g of 32% sodium hydroxide solution, and the two phases were separated. The organic phase is freed of the solvent. The oil obtained is dissolved in 320g of an MTB ether/toluene mixture at 55 ℃ and 2.5g of activated carbon are added and filtered hot. After the essentially colorless solution was slowly cooled to room temperature, the reaction solution was seeded with a small amount of seed crystals while cooling at-15 ℃ for 16 hours. The precipitated crystals are filtered off with suction and dried in vacuo to give the desired (S) -N-methyl-3-hydroxy-3 (2-thienyl) propylamine in an ee of > 99%.

Example 4:

18.93g (92mmol) of 3-methylamino-1- (2-thienyl) -1-propanone are weighed into a steel autoclave, 90ml of methanol are added and the mixture is rendered inert by injecting 7 bar of nitrogen three times and then reducing the pressure again. 10.8mg (0.022mmol) of dichlorobis (1, 5-cyclooctadienyl) dirhodium (I) and 32.5mg (0.051mmol) of (S) -BINAP were weighed into a Schlenk tube and then dissolved in 18ml of toluene under argon protection. The solution was transferred into the autoclave using a cannula in a nitrogen stream. The autoclave was then aerated three times with 10 bar of hydrogen each time and then depressurized.

The autoclave was heated to 50 ℃ and after this temperature had been reached the internal pressure was adjusted to 120 bar of hydrogen. After 7 hours, hydrogen consumption was stopped, the reaction was terminated, and the resulting reaction solution was analyzed.

Conversion rate of the product: 98 percent; enantiomeric excess in the product: 94 percent.

Example 5:

495g (2.4mol) of 3-methylamino-1- (2-thienyl) -1-propanone are weighed into a steel autoclave, 2.31 methanol and 0.41 toluene are added, and the mixture is rendered inert by injecting 7 bar of nitrogen three times and then reducing the pressure again. 297mg (0.60mmol) of dichlorobis (1, 5-cyclooctadienyl) -dirhodium (I) and 900mg (1.325mmol) (S) -TolBINAP were weighed into a Schlenk flask and then dissolved in 80ml of toluene under argon protection. The solution was transferred into the autoclave using a cannula in a nitrogen stream. The autoclave was then aerated three times with 10 bar of hydrogen each time and then depressurized.

The autoclave was heated to 50 ℃ and after this temperature had been reached the internal pressure was adjusted to 60 bar of hydrogen. After 8 hours, hydrogen consumption was stopped, the reaction was terminated, and the resulting reaction solution was analyzed.

Conversion rate of the product: 99 percent; enantiomeric excess in the product: 92 percent.

Example 6:

16.46g (80mmol) of 3-methylamino-1- (2-thienyl) -1-propanone are weighed into a steel autoclave, 75ml of methanol are added and the mixture is rendered inert by injecting 7 bar of nitrogen three times and then reducing the pressure again. 5.2mg (0.011mmol) of dichlorobis (1, 5-cyclooctadienyl) -dirhodium (I) and 15.2mg (0.022mmol) (S) -TolBINAP were weighed into a Schlenk tube and then dissolved in 15ml of toluene under argon protection. The solution was transferred into the autoclave using a cannula in a nitrogen stream. The autoclave was then aerated three times with 10 bar of hydrogen each time and then depressurized. The autoclave was heated to 50 ℃ and after this temperature had been reached the internal pressure was adjusted to 120 bar of hydrogen. After 11 hours, hydrogen consumption was stopped, the reaction was terminated, and the resulting reaction solution was analyzed.

Conversion rate of the product: 99 percent; enantiomeric excess in the product: 92 percent.

Claims (12)

1. A process for enantioselectively preparing an amino alcohol of the formula I,

wherein

R¹Represents a phenyl group or a 2-thienyl group,

R²represents an alkyl group having 1 to 20C atoms or H,

and

n represents a number of 1 s, and n represents a number of 1 s,

the process is prepared by enantioselective hydrogenation of aminoketones of the formula II in the presence of a non-racemic catalyst,

wherein

R¹、R²And n has the meaning given above, characterized in that the catalyst is a transition metal complex in which a transition metal is complexed with a chiral diphosphine ligand A

Wherein

R⁵、R⁶、R⁷And R⁸Each independently of the other represents H, alkyl or alkoxy having 1 to 20C atoms, aryl, aryloxy or F, Cl, Br, N (R)²)₂Or NHCOR₂，

R⁹And R¹⁰Each independently represent

Or a cyclohexyl group,

R¹¹represents H, alkyl or alkoxy having 1 to 20C atoms, aryl, aryloxy or SO₃Na、COOR¹²、F、Cl、N(R¹²)₂Or NHCOR¹²，

R¹²Represents an alkyl group having 1 to 20C atoms or H,

and

m represents 0, 1, 2 or 3,

wherein R is⁵And R⁶、R⁶And R⁷And R⁷And R⁸May also represent- (CH) together₂)₄-、-CH＝CH-CH＝CH-、

Or

Or with B

Wherein

Y represents OH, P (cyclohexyl)₂P (3, 5-dimethylphenyl)₂Or P (C (CH)₃)₃)₂，

Z represents H or P (phenyl)₂，

Q represents PPh₂P (cyclohexyl)₂P3, 5-bis (trifluoromethyl) phenyl]₂P (4-methoxy-3, 5-dimethylphenyl)₂Or P (C (CH)₃)₃)₂，

And

ph represents a phenyl group, an o-, m-or p-methylphenyl group or a dimethylphenyl group.

2. The method according to claim 1, wherein R²Represents a methyl group, an ethyl group, an n-propyl group or an isopropyl group.

3. The process according to claim 1 for the preparation of (S) -3-methylamino-1-phenyl-1-propanol or (S) -3-methylamino-1- (2-thienyl) -1-propanol.

4. Process according to claim 1 for the preparation of compounds of formula I, characterized in that the chiral, non-racemic catalyst is a transition metal complex containing one or more metals selected from rhodium, iridium, ruthenium and palladium or salts thereof.

5. Process for the preparation of compounds of formula I according to claim 1, characterized in that the chiral, non-racemic catalyst is a transition metal complex containing rhodium or a salt thereof.

6. A process according to claim 1, characterized in that the chiral diphosphine ligand used is a compound of formula a1-a 5:

wherein Ph has the meaning given in claim 1, X represents H, alkyl, O-alkyl, Cl or F, R' represents alkyl O-alkyl or F.

7. Process according to claim 5 or 6, characterized in that the chiral diphosphine ligand used is (S) - (-) -2, 2 '-bis (di-p-tolylphosphino) -1, 1' -binaphthyl or (S) - (-) -2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl.

8. Process according to claim 1 for the preparation of compounds of formula I, characterized in that the reaction temperature is 0-200 ℃.

9. Process according to claim 1 for the preparation of compounds of formula I, characterized in that the catalyst/substrate ratio is from 1:5000 to 1: 50.

10. Process according to claim 1 for the preparation of compounds of formula I, characterized in that the hydrogenation is carried out under a hydrogen pressure of 1 to 200 bar.

11. Process for the preparation of the compounds of formula I according to claim 1, characterized in that the hydrogenation is carried out in the presence of an alcohol.

12. The process according to claim 1 for the preparation of compounds of formula I, characterized in that the chiral, non-racemic catalyst is a catalyst containing sulfate, chloride, bromide,Iodide ion, PF₆、BF₄A transition metal complex having methanesulfonic acid group, toluenesulfonic acid group, hexachloroantimonic acid group, hexafluoroantimonic acid group or trifluoromethylsulfonic acid group as an anion.