Process for the preparation of optically active 2-amino-l-phenylethanols

The present invention refers to a process for the preparation of optically active 2-amino-l- phenylethanols of formula (I)

or its mirror image, wherein R ¹ is Ci_ ₆ alkyl or aryl-substituted Ci_ ₆ alkyl and R ² through R ⁶ are independently hydrogen, hydroxy or Ci_<s alkoxy, or a salt thereof, particularly of (i?)-(-)-l-(3'-hydroxyphenyl)-2-methylaminoethanol hydrochloride by asymmetrically hydrogenating corresponding aminoketones or their salts.

Compounds of the formula I belong to the group of sympathomimetic drugs. They generally act by binding to or activating α- and β-adrenergic receptors, resulting in numerous physiological effects like vascular constriction, reduced blood flow or decrease in mucus secreted into nasal passages. This broad scope of physiological effect make compounds of formula I important as drugs.

Until recently, sympathomimetic drugs were often commercialized as racemic mixtures because purification of one stereoisomer is expensive and time-consuming. During the past few years the demand on the more selective stereoisomer has increased as thus the required dosage and unwanted side-effects might be reduced. The most difficult step in synthesizing the amino alcohols of formula I is hydrogenation of the corresponding ketones in a way that the amino alcohols obtained are optically enriched or pure. In large quantities, this used to be carried out by hydrogenation with a palladium catalyst followed by fractional crystallization. More recently, it has been found out that optically pure products can easily be directly produced by transition metal-catalyzed asymmetric hydrogenation.

All compounds of formula I are characterized by an unprotected secondary amino group. During hydrogenation, this unprotected amino group is expected to lead to undesired side- reactions like self-condensation or even polymerization, especially in a large-scale process. It is known from prior art that asymmetric hydrogenation works well when a classically protected aminoacetophenone is reacted with a rhodium catalyst comprising a pyrrolidine- diphosphine ligand. For example, EP 1 147 075 discloses such an asymmetric hydrogenation of the corresponding N-benzyl protected aminoketone yielding phenylephrine on an industrial scale.

When taking the above-mentioned side-reactions into account, it is understandable that very few rhodium catalysts are reported for the asymmetric hydrogenation of an unprotected secondary aminoketone. These rhodium catalysts comprise only two ligand types, which are by name pyrrolidine diphosphines and hydroxyalkylferrocenyl phosphines. As an example, Knorr et al. produced the sympathomimetic drug etilefrine by means of rhodium catalysts with both ligand types in relatively low substrate/catalyst ratios and moderate stereoselectivity (Knorr Arzneim.-Forsch./Drug Res. 1984, 34 (II), No. 12, 1709-1713).

It is obvious that the route without protection and deprotection of the amino group in the aminoketone substrate is the favourite one, especially for industrial production. The object of the present invention is therefore to find an asymmetrical hydrogenation process using a rhodium complex catalyst which comprises a ligand type other than those mentioned above for unprotected secondary aminoketones leading to compounds of formula I.

The object described above is achieved by the process of claim 1.

Transition metal-catalyzed asymmetric hydrogenation is characterized in that the reaction is not only dependent on the substrate but also on the chiral ligand of the catalyst. Subtle changes in conformation, steric or electronic properties of the chiral ligands can often lead to dramatic variation of reactivity and enantioselectivity.

Surprisingly applicants have found that it is possible to prepare optically active 2-amino-l- phenylethanols of formula

or its mirror image, wherein R ¹ is C ₁ - _S alkyl or aryl-substituted Ci_ _ό alkyl and R ² through R ⁶ are independently hydrogen, hydroxy or Ci_ ₆ alkoxy, or salts thereof, by asymmetric hydrogenation of unprotected 2-aminoacetophenones of formula

or salts thereof, wherein R ¹ through R ⁶ are as defined above, characterized in that the asymmetric hydrogenation is carried out in the presence of a rhodium complex catalyst comprising a chiral diphosphine ligand, wherein each phosphorus atom is part of a heterocyclic ring system which contains at least one chiral carbon atom directly bound to the phosphorus atom.

The positive reactivity and enantioselectivity of this ligand type might have its reason in the heterocyclic ring system which restricts the conformational flexibility of the diphosphine.

Here and as follows, the term "C ₁ -,, alkyl" is to be understood to mean any linear or branched alkyl group containing 1 to n carbon atoms. For example, the term "Ci_ _ό alkyl" comprises groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), hexyl, isohexyl (4-methylpentyl) and the like.

Accordingly, the term "Ci→, alkoxy" means a group composed of a Ci_ _n alkyl group as defined above and an oxygen atom linked by a single covalent bond. The term "aryl-substituted Ci_ _n alkyl" is to be understood to mean a group composed of a Ci_ _M alkyl group as defined above which is substituted at any position of the linear or branched carbon chain with at least one phenyl group. The phenyl group may be optionally substituted with at least one substituent selected from the group consisting of hydroxy and d_ ₂ alkoxy.

Examples of aryl-substituted C _\ - _n alkyl groups are benzyl, l-(3-hydroxyphenyl)propane-2-yl or 1 -(3-methoxyphenyl)propane-2-yl.

In a preferred embodiment the heterocyclic ring of the chiral diphosphine ligand as described above, is a saturated ring selected from the group consisting of phosphetane, phospholane, phosphinane, phosphepan, 7-phosphabicyclo[2.2.1]heptane and C ₁ -4 alkyl-substituted 7-phos- phabicyclo[2.2.1]heptane, or an unsaturated ring selected from the group consisting of 2,5- dihydro-phosphole and 2,7-dihydro-phosphepin.

An example of such a chiral diphosphines ligand is "Me-PennPhos", wherein the heterocyclic ring is 2,5-dimethyl-7-phosphabicyclo[2.2.1]heptane and the heterocyclic rings are linked through a 1 ,2-phenylene group, i.e. l,2-phenylenebis-2,5-dimethyl-7-phosphabicyclo[2.2.1]- heptane.

Particularly preferred are chiral diphosphine ligands, wherein the heterocyclic rings are directly linked providing formula

<V P Hk ^Q P> _(III . _a) <V P Hk ^Q P> (iπ.b)

R ⁷ R ⁷ R ⁷ R ⁷ or mirror image thereof, wherein Q is an alkanediyl selected from the group consisting of methylene, ethylene, substituted ethylene, 1,3-propanediyl and 1 ,4-butanediyl, or an arenediyl selected from the group consisting of 1,2 -phenylene, 1,3-phenylene, 1 ,2-naphthylene, 1,3-naphthylene and 1,1'- binaphthylene-2,2'-diyl; and at each occurrence the phosphorus atom is chiral by bearing group R ⁷ , wherein R ⁷ at each occurrence is selected from the group consisting of hydrogen, Ci _-4 alkyl, phenyl and aryl-substituted C ₁ - ₄ alkyl.

Particularly preferred are diphosphines of formulas III-a and III-b, wherein Q is ethylene, 1 ,2- phenylene or l,l '-binaphthylene-2,2'-diyl. In an even more preferred embodiment at each occurrence R ⁷ is tert-butyl.

The term "substituted ethylene" for Q in formulas III-a and III-b is to be understood to mean an ethylene group which may be substituted on at least one position by hydroxy, Ci _-4 alkoxy, Ci _-4 alkoxy-Ci- ₄ -alkyl or benzyloxy-C _M -alkyl.

Examples of such chiral diphosphines of formulas III-a and III-b, each in both enantiomeric forms, are:

"TangPhos", wherein Q is ethylene and R ⁷ is tert-butyl, i.e. l,l '-di-tert-butyl[2,2']bi- phospholane; or

"DuanPhos", wherein Q is 1 ,2-phenylene and R ⁷ is ter/-butyl, i.e. 2,2'-di-tert-butyl-2,3,2',3'- tetrahydro-l,l '-bi-7H-isophosphindole; or "Binapine", wherein Q is 1 , l'-binaphthylene-2,2'-diyl and R ⁷ is tert-buty\, i.e. 4,4'-di-tert- butyl-4,4',5,5'-tetrahydro-3,3'-bi-iH-dinaphtho[2,l-c:l',2'- e]phosphepin.

The use of chiral compounds selected from the group consisting of TangPhos, DuanPhos and Binapine has proved to be particularly advantageous.

In another preferred embodiment the heterocyclic rings of the chiral diphosphine ligand are linked providing formula

or its mirror image, wherein Q is as defined above; Z is an alkanediyl selected from the group consisting of methylene, ethylene, substituted ethylene, 1 ,2-cyclopentanediyl and 2,5-furandion-3,4-diyl, or an arenediyl selected from the group consisting of 1 ,2-phenylene, substituted 1 ,2-phenylene and 1 ,2-naphthylene; and at each occurrence the carbon atoms of the heterocyclic ring system, which are adjacent to the phosphorus atom, are chiral by bearing group R , wherein R at each occurrence is selected from the group consisting of C _M alkyl, hydroxy, Ci _-4 hydroxyalkyl, Ci _-4 alkoxy, Ci _-4 alkoxy-C _M -alkyl, C _5-6 cycloalkyl and aryl.

Here and as follows, the term "substituted ethylene" for Z in formula IV means an ethylene group which may be substituted on at least one position by a substituent selected from the group consisting of Ci- ₄ -alkyl, hydroxy, Ci _-4 alkoxy and aryl. In addition, the term "substituted 1 ,2-phenylene" means a 1 ,2-phenylene group, optionally substituted with one through four substituents selected from the group consisting Of Ci _-4 alkyl, hydroxy or C i- ₂ alkoxy.

The term "aryl" is to be understood to mean a phenyl group or a substituted phenyl group wherein at least one substituent is selected from the group consisting Of Ci _-4 alkyl, hydroxy and Ci _-4 alkoxy.

In addition, particularly preferred are compounds of formula IV, wherein Q is ethylene and Z is ethylene or 1 ,2-phenylene. In an even more preferred embodiment at each occurrence R ⁸ is a Cj _-4 alkyl group like methyl, ethyl, isopropyl, or a phenyl group.

Examples of such chiral diphosphines of formula IV, in both enantiomeric forms, are:

'"Pr-BPE-4", wherein Q is methylene, Z is ethylene and R ⁸ is isopropyl, i.e. l,2-bis-(2,4-di- isopropylphosphetan- 1 -yl)ethane; or

"Cy-BPE-4", wherein Q is methylene, Z is ethylene and R ⁸ is cyclohexyl, i.e. l,2-bis-(2,4- dicyclohexylphosphetan- 1 -yl)ethane; or

"Ph-BPE", wherein Q is ethylene, Z is ethylene and R ⁸ is phenyl, i.e. l,2-bis-(2,5-diphenyl- phospholan-l-yl)ethane; or "Me-BPE", wherein Q is ethylene, Z is ethylene and R is methyl, i.e. l,2-bis-(2,5-dimethyl- phospholan-l-yl)ethane; or

"Et-BPE", wherein Q is ethylene, Z is ethylene and R ⁸ is ethyl, i.e. l,2-bis-(2,5-diethyl- phospholan-l-yl)ethane; or

'"Pr-BPE", wherein Q is ethylene, Z is ethylene and R ⁸ is isopropyl, i.e. l,2-bis-(2,5-di-iso- propy lphospholan- 1 -yl)ethane ; or

"Compound IV-a", wherein Q is ethylene, Z is ethylene and R is methoxymethyl; i.e. 1,2-bis- (2,5-dimethoxymethyl-phospholan-l -yl-)ethane; or

"Compound IV -b", wherein Q is ethylene, Z is ethylene and R is benzyloxymethyl; i.e. 1,2- bis-(2,5-dibenzyloxymethyl-phospholan- 1 -yl)ethane; or '"Pr-CnrPhos", wherein Q is methylene, Z is 1 ,2-phenylene and R ⁸ is isopropyl, i.e. 1,2-bis- (2,4-di-isopropylphosphetan- 1 -yl)benzene; or

"Cy-CnrPhos", wherein Q is methylene, Z is 1 ,2-phenylene and R is cyclohexyl, i.e. 1,2-bis- (2,4-dicyclohexylphosphetan- 1 -yl)benzene; or

"Me-DuPhos", wherein Q is ethylene, Z is 1 ,2-phenylene and R is methyl, i.e. l,2-bis-(2,5- dimethylphospholan-l-yl)benzene; or

"Et-DuPhos", wherein Q is ethylene, Z is 1 ,2-phenylene and R is ethyl, i.e. l,2-bis-(2,5- diethylphospholan- 1 -yl)benzene; or

'"Pr -DuPhos", wherein Q is ethylene, Z is 1 ,2-phenylene and R ⁸ is isopropy, i.e. l,2-bis-(2,5- di-isopropylphospholan- 1 -yl)benzene; or "BasPhos", wherein Q is ethylene, Z is 1 ,2-phenylene and R is hydroxymethyl, i.e. 1,2-bis- (2,5-dihydroxymethylphospholan- 1 -yl)benzene; or

"Me-BasPhos", wherein Q is ethylene, Z is 1 ,2-phenylene and R is methoxymethyl, i.e. 1,2- bis-(2,5-dimethoxymethylphospholan- 1 -yl)benzene; or

"Bn-BasPhos", wherein Q is ethylene, Z is 1 ,2-phenylene and R is benzyloxymethyl, i.e. 1,2- bis-(2,5-benzyloxymethylphospholan-l-yl)benzene; or

"MalPhos", wherein Q is ethylene, Z is 2,5-furandion-3,4-diyl and R is methyl, i.e. 2,3-bis- (2,5-dimethylphospholan-l-yl)maleic anhydride; or

"Compound IV-c", wherein Q is ethylene, Z is 1 ,2-cyclopentanediyl and R is methyl, i.e. 1,2- bis-(2,5-dimethylphospholan- 1 -yl)cyclopentane.

The use of chiral compounds selected from the group consisting of Me-BPE, Et-BPE, 'Pr-BPE, Ph-BPE, Me-DuPhos, Et-DuPhos and 'Pr-DuPhos has proved to be particularly advantageous. Most advantageous of formula IV turned out to be Me-DuPhos, Et-DuPhos and Ph-BPE.

In another preferred embodiment Q of formula IV is a moiety of formula

or its mirror image, wherein R ⁹ is hydroxy, Ci _-4 alkoxy, Ci _-4 alkoxy-Ci^-alkyl, benzyloxy or benzyloxy-C _M -alkyl; or both R ⁹ groups together form a moiety of formula

wherein R ¹⁰ and R ¹¹ are equal or each independently hydrogen, Ci _-4 alkyl or aryl.

Examples of such chiral diphosphines of formula V, in their enantiomeric forms, are:

"Compound V-a", wherein Z is ethylene, R ⁸ is methyl and R ⁹ is benzyloxy i.e. l,2-bis-(2,5- dimethyl-3,4-dibenzyloxyphospholan- 1 -yl)ethane; or "Compound V-b", wherein Z is ethylene, R ⁸ is methyl and R ⁹ is tert-butyl i.e. l,2-bis-(2,5- dimethyl-3 ,4-di-tert-butylphospholan- 1 -yl)ethane; or

"Compound V-c", wherein Z is 1 ,2-phenylene, R ⁸ is methyl and R ⁹ is hydroxy i.e. l,2-bis-(2,5- dimethyl-3,4-dihydroxyphospholan-l-yl)benzene; or

"Compound V-d", wherein Z is 1 ,2-phenylene, R ⁸ is ethyl and R ⁹ is hydroxy i.e. l,2-bis-(2,5- diethyl-3,4-dihydroxyphospholan-l-yl)benzene; or

"RoPhos", wherein Z is 1 ,2-phenylene, R ⁸ is methyl and R ⁹ is benzyloxy i.e. 1 ,2-bis-(2,5- dimethyl-3,4-dibenzyloxyphospholan- 1 -yl)benzene.

Example of chiral diphosphines of formula VI, in their enantiomeric forms, are:

""CCoommppoouunnd VI-a", wherein Z is 1 ,2-phenylene, R ⁸ is methyl and both R ¹⁰ and R ¹ ' are methyl; or

"Compound VI-b", wherein Z is 1 ,2-phenylene, R ⁸ is ethyl and both R ¹⁰ and R ¹¹ are methyl.

In a preferred embodiment R ¹ is methyl, ethyl or isopropyl and at least one of R to R is hydroxy. Corresponding products are compounds such as oxedrine, epinephrine, phenylephrine, etilefrine, orciprenaline and isoprenaline.

Most preferably R ¹ is methyl, R ³ is hydroxy and R ² , R ⁴ , R ⁵ and R ⁶ are hydrogen, i.e., the product is phenylephrine.

The catalyst can be obtained by dissolving a suitable rhodium salt, wherein suitable counterions are for example chloride, bromide, iodide, tetrafluoroborate, hexafluoroarsenate, hexafluoroantimonate, hexafluorophosphate, perchlorate or trifluoromethane sulfonate in a polar solvent with a suitable amount of the diphosphine ligand of this disclosure followed by isolation.

The rhodium salts preferably comprises at least one stabilizing ligand, such as an alkene, diealkene or arene. In a preferred embodiment the stabilizing ligand is 1,5-cyclooctadiene (cod), norbornadiene (nbd) or p-cymene. The thus stabilized rhodium salts might also comprise at least one polar solvent molecule as additionally stabilizing ligand, like acetonitrile, dimethylsulfoxide or dimethylformamide.

Alternatively, the catalyst can be prepared in situ from the diphosphine ligands and rhodium salts or preferred from the diphosphine ligands and a stabilized rhodium salts as described above.

In a particularly preferred embodiment the rhodium complex catalyst corresponds to an idealized formula selected from the group consisting Of [Rh(cod)(5-Binapine)]BF ₄ , [Rh(cod)(λ-Binapine)]BF ₄ , [Rh(nbd)(5'-Binapine)]SbF ₆ , and [Rh(cod)((S/?)-DuanPhos)]BF ₄ .

The preparation of the catalysts and catalyst solutions are disclosed for the BPE ligand in MJ. Burk et al., Organometallics 1990, 9, 2653-2655, for the DuanPhos ligand in X. Zhang et al, Eur. J. Org. Chem. 2005, 646-649, for the TangPhos ligand in X. Zhang et al., Angew. Chem. Int. Ed. 2002, 41, 1612-1614, and for the Binapine ligand in X. Zhang et al., Angew. Chem. Int. Ed, 2003, 42, 3509-3511.

The catalyst may be added to the reaction mixture as such or previously dissolved in a suitable solvent, or alternatively the catalyst may be prepared in situ.

The catalyst may also be polymer-bound by linkage of a suitable group of the diphosphine ligand to a resin. Polymer-bound catalysts of this kind are particularly advantageous for simple purification of the product.

As solvent, any liquid solvent which can dissolve the reactants and catalyst components may be used. Applicable solvents include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol and benzyl alcohol; mixtures of alcohol and water such as aqueous methanol

(methano I/water 5:1); halogenated alcohols such as trichloroethanol and trifluoroethanol; carboxylic esters such as methyl formate, ethyl acetate and isopropyl isobutyrate; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; ethers such as diethyl ether and tetrahydrofuran; organic solvents containing heteroatoms such as acetonitrile, dimethyl- formamide and dimethyl sulfoxide; aromatic hydrocarbons such as toluene and xylene; and aliphatic hydrocarbons such as pentane and hexane. More preferably, methanol and ethanol may be used. Also solvent mixtures comprising the above-mentioned solvents may be used as well as two-phase systems with water.

The amount of 2-aminoacetophenone of formula II (substrate) varies with the reactor volume and can be at a molar ratio relative to the rhodium complex catalyst (S/C) from 50:1 to 100,000:1, or more preferably from 500: 1 to 30,000:1.

The counterion of the 2-aminoacetophenone of formula II in its salt form may originate from any acid capable of forming a salt with the 2-aminoacetophenone of formula II. Preferred counterions are halogenide like chloride, bromide and iodide, sulphate, or carboxylate like acetate and propionate. Most preferred is the chloride salt of formula II.

Bases applicable in the present invention include inorganic and organic bases. The bases may be expressed by the general formula MY, wherein M is an alkali metal or one equivalent of an alkaline earth metal, and Y is a hydroxy group, alkoxy group, carboxylate, hydrogencarbonate or one equivalent of carbonate. More specifically, applicable bases include KOH, KOCH ₃ , KOCH(CH ₃ ) ₂ , KOC(CH ₃ ) ₃ , K ₂ CO ₃ , NaOH, NaOCH ₃ , NaOCH(CH ₃ ) ₂ , Na ₂ CO ₃ , NaOCOCH ₃ , Cs ₂ CO ₃ , CaCO ₃ and BaCO ₃ . Alternatively, the base may be an amine like ter/-butylamine, dimethylamine, diethylamine, trimethylamine or triethylamine. Most preferably K ₂ CO ₃ is used as base.

Surprisingly it was found that the rhodium catalysts of the diphosphine ligands work without addition of base, i.e. asymmetric hydrogenation proceeds on the substrate in its salt form, albeit less rapidly.

The hydrogenation process according to the invention may be carried out at typical pressures from 1 to 100 bar. Advantageously, 10 to 85 bar, in particular 30 to 65 bar are used.

The hydrogenation reactions may be carried out in a temperature range from 0 °C to 120 °C. Preferred is a temperature between 25 °C and 80 °C, and most preferred is a range from 50 °C to 75 °C.

The reaction time depends on different factors like the catalyst loading, the temperature and the hydrogen pressure. Therefore, the reaction might be completed in a period of time within a range from a few minutes to several hours or even days.

Examples

The following examples further illustrate this invention but are not intended to limit it in any way.

The stereochemistry of the ligands applied in the examples and their abbreviations are as follows:

SS-Ph-BPE 5-Binapine

₃ ) ₃

S.SλR-TangPhos S,S,R,R-O\mnPhos

Example 1: Synthesis of 2-bromo-3'-hydroxyacetophenone a) 1,4-Dioxane dibromide was prepared following a literature procedure (J. D. Billimoria, N. F. Maclagan, J. Chem. Soc. 1954, 3257-3262). Bromine (320 g, 2 mol) was added with vigorous stirring to 1,4-dioxane (180 g, 2 mol). The warm solution (ca. 60 °C) was poured into light petroleum (2 L, b.p. 30-60 °C). The yellow precipitate was filtered off and washed with light

petroleum as rapidly as possible. The compound (m.p. 60-61 °C) was used without further purification and could be stored at 0 °C.

b) 2-Bromo-3'-hydroxyacetophenone was synthesized following a slightly modified literature procedure (S. J. Pasaribu, L. R. Williams, Aust. J. Chem. 1973, 26, 1327-1331). 1,4-Dioxane dibromide (248 g, 1.0 mol, synthesized as described above) was dissolved in 500 mL 1,4-dioxane and 500 mL methyl tert-butyl ether (MTBE). The solution was added dropwise to a stirred solution of 3-hydroxyacetophenone (136.2 g, 1.0 mol) in 1 L of the same solvent mixture. After addition, the pale straw-coloured solution was poured into 6 L water and extracted with I L of MTBE. The organic layer was separated, washed twice with water, dried with anhydrous sodium sulfate and concentrated under vacuum to yield a pale yellow oil (249.6 g). The crude product was dissolved in 70 mL of toluene, firstly at a temperature below 40 °C. The resulting solution was then added into petroleum ether (PE) under stirring. After cooling to 0 ⁰ C, the formed precipitate was filtered off, washed with PE and finally dried under vacuum to afford 134.6 g (63%) white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ 4.44 (s, 2H), 5.83 (br s, IH), 7.10-7.13 (m, IH), 7.36 (t, J= 7.6 Hz, IH), 7.50-7.53 (m, 2H)

¹³ C NMR (100 MHz, CDCl ₃ ): 6 31.4, 115.3, 121.4, 121.8, 130.2, 135.0, 156.4, 192.3 MS: mlz 214 [M - H] ⁺

Example 2: Synthesis of l-(3'-hydroxyphenyl)-2-methylamino-ethanone hydrochloride The title compound was synthesized following a modified literature procedure (JP-A 63-192744). The whole procedure was performed under nitrogen atmosphere. A solution of methylamine (85 mL, 0.70 mol) in 250 mL tetrahydrofuran (THF) was cooled in an ice-salt bath. A solution of 2-bromo-3'-hydroxyacetophenone (42.5 g, 0.23 mol) in 750 mL of THF was added dropwise into the above solution within a period of 30 minutes. The temperature was kept below 5 °C, and after complete addition stirring was continued for 2 hours. At the beginning of addition, the solution became light yellow. The reaction was monitored by HPLC and TLC (eluent: CH ₂ Cl ₂ ZMeOH, v:v = 10:1). The mixture was then concentrated under vacuum to remove excess of methylamine and some solvent (about 800 mL). The resulting solution (ca. 200 mL) was filtered in order to remove the CH ₃ NH ₂ HBr deposit, and then 30 mL of concentrated HCl was added dropwise within 30 minutes while cooling in an ice bath. Then, the mixture was evaporated under vacuum. 30 mL Ethanol and 15 mL methanol were added to the dark brown residue and the mixture was refluxed for 30 to 60 minutes. After cooling to room temperature, the mixture was filtered. The precipitate was washed with 30 mL absolute ethanol and dried under vacuum to get 19.2 g (48%) pale yellow solid. ¹ H NMR (400 MHz, DMSO-J ₆ ): δ 2.60 (s, 3H), 4.69 (s, 2H), 7.13-7.16 (d, J= 7.6 Hz, IH), 7.32-7 '.47 (m, 2H), 9.15 (s, 2H), 10.11 (s, IH)

¹³ C NMR (100 MHz, DMSO-J ₆ ): 5 32.6, 53.6, 1 14.1, 1 18.9, 121.8, 130.1, 134.9, 158.0, 192.3; MS: ml z 166 [M+H] ⁺

Examples 3 to 13: Asymmetric hydrogenation of l-(3'-hydroxyphenyl)-2-methylamino- ethanone hydrochloride using different Rh-catalysts

General procedure

A 300 mL volume autoclave with a 20 mL glass vial was charged with the substrate l-(3'- hydroxyphenyl)-2-methylamino-ethanone hydrochloride, catalyst, base (if used) and oxygen- free solvent under nitrogen. The autoclave was purged with hydrogen at 30 bar five times, then charged with hydrogen to the desired pressure, stirred with a magnetic stirrer and heated in an oil bath. After hydrogen was released carefully, the reaction mixture was concentrated to dryness.

The catalyst of example 5 was prepared in situ by dissolving 0.005 mmol [Rh(COd)Cl] ₂ and 0.0055 mmol (5)-Binapine in 3 mL methanol. This solution was stirred for 30 minutes at room temperature before the substrate was added.

Details of the examples 3 to 13 with regard to the catalysts used, reaction conditions and their results are listed in table 1 and table 2. Conversion and enantiomeric excess were determined by HPLC (Chiralcel OJ-H, hexane/2-propanol 80:20). Before measurement, the product was acetylated through reaction with excess of acetic anhydride in the presence of triethylamine in dichloromethane. During this procedure, non-reacted substrate was also converted in its acetylated form, which is then well separated from the product enantiomers by HPLC. Thus, both conversion and enantiomeric excess could be determined with the same HPLC procedure.

Table 1: Example 3 to example 8, (Rh-catalysts with different ligands)

> 0.5 mmol substrate were charged in all examples,

> * referring to substrate,

> cod = 1,5-cyclooctadiene; nbd = norbornadiene; MeOH = methanol,

> * referring to substrate,

> cod = 1,5-cyclooctadiene; MeOH = methanol.

Table 2 shows the results of asymmetric hydrogenation by using [Rh(cod)(S-Binapine)]BF ₄ with increasing catalyst-loading in the absence of base and with increasing amounts of base. The enantiomeric product was isolated in good yield and good enantiomeric excess. Example

14 provides the product in preparative scale.

Example 14: Use of [Rh(cod)(R-Binapine)]BF ₄ as catalyst l-(3'-Hydroxyphenyl)-2-methylamino-ethanone hydrochloride (6.03 g, 30 mmol) and [Rh(cod)(/?-Binapine)]BF ₄ (60 mg, 0.065 mmol, S/C = 460:1) were placed in a 100 mL Pan- autoclave with overhead stirrer and heating jacket under nitrogen atmosphere. 40 mL Methanol were added through the injection port and the reaction was purged five times by pressurising to 30 bar hydrogen and releasing the pressure under stirring. The reaction was then pressurised to 30 bar hydrogen, stirred at around 1000 rpm and heated to 65 ⁰ C within 15 minutes. The reaction was stirred for further 18 hours while the hydrogen pressure was maintained between 29 and 33 bar. Finally, the hydrogen pressure was released and the solution was concentrated to a volume of 10 mL. At room temperature, 100 mL MTBE were then added slowly to give a suspension of a greenish solid. The product was filtered, washed with 30 mL MTBE and dried at 40 ⁰ C under vacuum yielding 5.20 g (85%) of l-(3'-hydroxyphenyl)-2-methylamino-ethanol hydrochlorid as an off-white solid. Purity: > 95% by HPLC. Enantiomeric purity: 93% ee (R) by HPLC. For HPLC-method, see above.