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 hydrogen, C ₁ - _O alkyl or aryl-substituted C ₁ ^ alkyl and R ² through R ⁶ are independently hydrogen, hydroxy or C^ alkoxy, or a salt thereof, particularly of (/?)-(-)- 1 -(3 '-hydroxyphenyl)-2-methylaminoethanol hydrochloride, which can be obtained by asymmetrically hydrogenating corresponding aminoketones or its salts in the presence of a ruthenium complex catalyst comprising a chiral phosphine ligand.

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 Pd-catalyst followed by fractional crystallization. More recently, it has been found out that stereoisomers can easily be achieved by transition metal-catalyzed asymmetric hydrogenation.

All compounds of formula I are characterized by an unprotected primary or secondary amino group. During hydrogenation, these unprotected amino groups are expected to lead to undesired side-reactions like self-condensation or even polymerization, especially in a large-scale process. Noyori et al. report successful asymmetric hydrogenation by use of the [(xylbinap)RuCl ₂ (daipen)] complex but only with classically protected aminoacetophenones

like iV-acetyl-, N-benzoyl- or N-Boc-aminoacetophenone (Noyori J. Am. Chem. Soc. 2000, 122, 6510-6511). Another example is EP 1 254 885 which also discloses such protected compounds. Thus, from prior art only rhodium catalysts are described to be effective for the unprotected substrates of formula I. However, these asymmetric hydrogenations are characterized by relatively low catalyst activities and moderate stereoselectivity. As an example, Knorr et al. produced the sympathomimetic drug etilefrine by means of Rh-catalysts having a substrate to catalyst (S/C) ratio of 100:1 or 200:1 respectively (Knorr Arzneim.-Forsch./Drug Res. 1984, 34 (II), No. 12, 1709-1713). In contrast, when applying a Rh-catalyst in the industrially applicable asymmetric hydrogenation of phenylephrine, the N-benzyl protected aminoketone is used as substrate as disclosed in EP 1 147 075.

Protection and deprotection of the amine in the aminoketone substrate result in prolonged synthetic routes and much lower overall yields. These aspects are major drawbacks for industrial applicability. Consequently, there is a high need for a catalyst which can be used to asymmetrically hydrogenate aminoketone compounds without prior protection of the amino group. An object of the present invention is to provide such an economical asymmetrical hydrogenation process.

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

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 hydrogen, Ci- _δ alkyl or aryl-substituted Ci-^ alkyl and R ² through R ⁶ are independently hydrogen, hydroxy or C _1- ^ 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, in the presence of a ruthenium complex catalyst comprising a chiral phosphine ligand.

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_ ₆ alkyl" comprises groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ter/-butyl, pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), hexyl, isohexyl (4-methylpentyl) and the like.

Accordingly, the term "Ci_ _n alkoxy" means a group composed of a C ₁ -,, alkyl group as defined above and an oxygen atom linked by a single covalent bond.

In a preferred embodiment the chiral phosphine ligand is a diphosphine of formula

or its mirror image, wherein Q is nitrogen, =CH- or =CX- wherein X is halogen; R ⁷ at each occurrence is selected from the group consisting of phenyl, 4-methylphenyl and 3,5-dimethylphenyl; R at each occurrence is alkoxy, or both R ⁸ groups together form a moiety of formula

-O-(CH ₂ ) _n -O-, wherein n is an integer from 1 to 6; and R ⁹ is hydrogen, Ci_ ₄ alkyl or alkoxy.

As halogen, fluorine, chlorine, bromine and iodine can be used, most preferably chlorine.

Examples of such chiral diphosphines of formula (III), in (R) or (S) configuration, are:

"P-Phos", wherein Q is nitrogen, R ⁷ is phenyl and R ⁸ and R ⁹ are methoxy, i.e. 2,2',6,6'- tetramethyoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine, or

"Xyl-P-Phos"; wherein Q is nitrogen, R is 3,5-dimethylphenyl and R and R are methoxy, i.e. 2,2',6,6'-tetramethoxy-4,4'-bis[di(3,5-dimethylphenyl)phosph ino]-3,3'-bipyridine, or "ToI-P -Phos", wherein Q is nitrogen, R ⁷ is 4-methylphenyl and R ⁸ and R ⁹ are methoxy, i.e. 2,2',6,6'-tetramethoxy-4,4'-bis[di(4-methylphenyl)phosphino] -3,3'-bipyridine, or "MeO-Biphep", wherein Q is =CH-, R ⁷ is phenyl, R ⁸ is methoxy and R ⁹ is hydrogen, i.e. 6,6'-dimethoxy-2,2'-bis(diphenylphosphino)-l,l'-biphenyl, or

"3',5'-Me2-MeO-Biphep", wherein Q is =CH-, R ⁷ is 3,5-dimethylphenyl, R ⁸ is methoxy and R ⁹ is hydrogen, i.e. 6,6'-dimethoxy-2,2'-bis[di(3,5-dimethylphenyl)phosphino]-l,l '-biphenyl, or

"Cl-MeO-Biphep", wherein Q is =CC1-, R is phenyl, R is methoxy and R is hydrogen, i.e. 6,6'-dimethoxy-5,5'-dichloro-2,2'-bis(diphenylphosphino)-l,l '-biphenyl, or

"Bichep", wherein Q is =CH-, R is cyclohexyl, R is methyl and R is hydrogen, i.e. 6,6'-di- methyl-2,2'-bis(dicyclohexylphosphino)- 1 , 1 '-biphenyl, or "Biphemp", wherein Q is =CH-, R ⁷ is phenyl, R ⁸ is methyl and R ⁹ is hydrogen, i.e. 6,6'-di- methyl-2,2'-bis(diphenylphosphino)- 1 , 1 '-biphenyl, or

"Cl-TunePhos", wherein Q is =CH-, R ⁷ is phenyl, both R ⁸ together are -0-CH ₂ -O- and R ⁹ is hydrogen, i.e. 6,6'-bis(diphenylphosphino)-2,2'-methylenedioxybiphenyl, or "C2-TunePhos", wherein Q is =CH-, R ⁷ is phenyl, both R ⁸ together are -O-(CH ₂ ) ₂ -O- and R ⁹ is hydrogen, i.e. l,12-bis(diphenylphosphino)-6,7-dihydro-dibenzo[e,g][l,4]dio xocine, or

"C3-TunePhos", wherein Q is =CH- R ⁷ is phenyl, both R ⁸ together are -O-(CH ₂ ) ₃ -O- and R ⁹ is hydrogen, i.e. l,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[/λ][l,5] dioxonine, or "C4-TunePhos", wherein Q is =Cη- R ⁷ is phenyl, both R ⁸ together are -O-(CH ₂ ) ₄ -O-, and R ⁹ is hydrogen, i.e. l,14-bis(diphenylphosphino)-6,7,8,9-tetrahydrodibenzo[g,z][l ,6]dioxecine, or "C5-TunePhos", wherein Q is =CH- R ⁷ is phenyl, both R ⁸ together are -O-(CH ₂ ) ₅ -O-, and R ⁹ is hydrogen, i.e., l,15-bis(diphenylphosphino)-8,14-dioxa-tricyclo[13.4.0.0 ² ' ⁷ ]nonadeca- l(15),2(7),3,5,16,18-hexaene, or

"C6-TunePhos", wherein Q is =CH-, R ⁷ is phenyl, both R ⁸ together are -O-(CH ₂ ) ₆ -O-, and R ⁹ is hydrogen, i.e. l,16-bis(diphenylphosphino)-6,7,8,9,10,l l-hexahydro-5,12-dioxa- dibenzo[α,c]cyclododecene.

Particularly preferred are diphosphines of formula III wherein Q is nitrogen and R and R at each occurrence are methoxy groups. The use of chiral compounds selected from the group consisting of P-Phos and Xyl-P-Phos has proved particularly advantageous.

Furthermore, particularly preferred are diphosphines of formula III wherein Q is =CH- or

=CC1-, R is phenyl and R is a methoxy group like MeO-Biphep and Cl-MeO-Biphep.

Also particularly preferred are diphosphines of formula III wherein Q is =CH-, R ⁷ is phenyl, R ⁹ is hydrogen and both R ⁸ groups together are -O-(CH ₂ ) _n -O- wherein n is an integer from 1 to 6 like Cl-TunePhos, C2-TunePhos, C3-TunePhos, C4-TunePhos, C5-TunePhos and C6-TunePhos. Most preferably is n 3, i.e. C3-TunePhos.

In another preferred embodiment the ruthenium complex catalyst further comprises a chiral diamine ligand of formula

or its mirror image, wherein R ¹⁰ is phenyl, optionally substituted with one or more C ₁ - ₄ alkyl or Ci_ ₄ alkoxy groups, and R ¹¹ is cycloalkyl or branched C ₃ _ ₆ alkyl.

The term "cycloalkyl" is to be understood to mean mono- or bicyclic saturated groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, norcaryl, norpinanyl, and related groups, such as the above-mentioned groups being further substituted with lower alkyl substituents.

In a still more preferred embodiment R ¹⁰ is 4-methoxyphenyl and R ¹¹ is isopropyl ("DAIPEN").

In another preferred embodiment the chiral phosphine ligand is a phosphine-oxazoline of formula

or its mirror image, wherein R ¹² is Ci_ ₈ alkyl, C _7- .^ aralkyl, phenyl or substituted phenyl, R ¹³ is phenyl, substituted phenyl, naphthyl or C ₁ - ₄ alkyl and R ¹⁵ and R ¹⁶ together with the adjacent carbon atoms form a 6 π- or 10 π-electron aromatic or heteroaromatic system, optionally substituted by linear or branched C _1-8 alkyl or C _1-8 alkoxy, and possible heteroatoms are S, N or O.

Examples of such chiral phosphine-oxazolines of formula V wherein R ¹⁵ and R ¹⁶ form a sulfur- aromatic system are:

B

In another preferred embodiment in the compound of formula V R ¹⁵ and R ¹⁶ together with the adjacent carbon atoms form a benzene ring, optionally substituted by linear or branched C _1-8 alkyl or Ci _-8 alkoxy, thus forming a compound of formula

or its mirror image, wherein R ¹² and R ¹³ are defined as in formula V and R ¹⁴ is Ci_ ₈ alkyl or Ci_ ₈ alkoxy. Examples of such chiral phosphine-oxazolines of formula VI, in (R) or (S) configuration, are: "i-Pr-Phox", wherein R ¹² is isopropyl, R ¹³ is phenyl and R ¹⁴ is hydrogen, or

"Ph-Phox", wherein R , 12 is phenyl, R 13 is phenyl and R , 14 is hydrogen.

Particularly preferred are chiral phosphine-oxazolines of formula VI wherein R ¹² is isopropyl,

R ¹³ is phenyl and R ¹⁴ is hydrogen like i-Pr-Phox.

In another preferred embodiment in the compound of formula V R ¹⁵ and R ¹⁶ together with the adjacent carbon atoms form a cyclopentadienyl ring of a ferrocene system, thus forming a compound of formula

or its mirror image, wherein R ¹² and R ¹³ are defined as in formula V.

Examples of such chiral phosphine-oxazolines of formula VII, in (R) or (S) configuration, are: VII-a, wherein R ¹² is isopropyl and R ¹³ is phenyl, or

VII-b, wherein R ¹² is tert-butyl and R ¹³ is phenyl, or

VII-c, wherein R ¹² and R ¹³ are phenyl, or

VII-d, wherein R ¹² is isopropyl and R ¹³ is 3,5-dimethylphenyl, or

VII-e, wherein R ¹² is isopropyl and R ¹³ is 4-trifluoromethylphenyl, or VII-f, wherein R ¹² is isopropyl and R ¹³ is 3,5-trifluoromethylphenyl, or

VII-g, wherein R ¹² is isopropyl and R ¹³ is naphthyl.

In a preferred embodiment R ¹ is methyl, ethyl or isopropyl and at least one of R ² 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.

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 an alkaline earth metal, and Y is a hydroxy group, alkoxy group or naphthyl group. More specifically, applicable bases include KOH, KOCH ₃ , KOCH(CH ₃ ) ₂ , KOC(CH ₃ ) ₃ , NaOH, NaOCH ₃ , NaOCH(CH ₃ ) ₂ as well as quaternary ammonium salts. Most preferably KOH is used as base.

Surprisingly it was found that the Ru-catalysts of some phosphine ligands work without addition of base, i.e. asymmetric hydrogenation proceeds on the substrate in its salt form. When using a base, the thus obtained free aminoketone might undergo competing side-reactions especially when hydrogenation is slow. Without use of a base the yield and purity of the asymmetric hydrogenation is therefore expected to be higher. This is a great advantage, especially for industrial production.

The catalyst may be added as such to the reaction mixture or alternatively the catalyst may be prepared in situ from chiral ligands and suitable precursor complexes like (PPh ₃ ) ₃ RuCl ₂ .

As solvent, any liquid solvent which can dissolve the reactants and catalyst components may be used. Two-phase systems with water may also be used. Applicable solvents include aromatic hydrocarbons such as toluene and xylene, aliphatic hydrocarbons such as pentane and hexane, halogenated hydrocarbons such as methylene chloride, ethers such as diethyl ether and tetrahydrofuran, alcohols such as methanol, ethanol, 2-propanol, butanol and benzyl alcohol, and organic solvents containing heteroatoms such as acetonitrile, dimethylformamide and dimethyl sulfoxide. More preferably, 2-propanol and methanol may be used. Also solvent mixtures comprising the above-mentioned solvents may be used.

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

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 20 to 40 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 40 ⁰ C and 90 °C, and most preferred is a range from 65 °C to 85 °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.

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 1 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 °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 (IOO MHZ, CDCl ₃ ): 5 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 /Me0H, 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-^ ₆ ): 5 32.6, 53.6, 114.1, 118.9, 121.8, 130.1, 134.9, 158.0, 192.3; MS: m/z 166 [M+H] ⁺

Examples 3 to 11: Asymmetric hydrogenation of l-(3'-hydroxyphenyl)-2-methylamino- ethanone hydrochloride using different Ru-catalysts (with base and without base)

General procedure

All reactions were run in an Endeavour™ reactor (Argonaut Technologies, Inc.). The substrate l-(3'-hydroxyphenyl)-2-methylamino-ethanone hydrochloride was weighed in a glass liner and put under inert atmosphere. The catalyst was weighed with the substrate or for example 7 added as stock solution in 2-propanol. The solvent, and where applicable the base, were introduced.

The reaction were then purged with hydrogen five times, then heated to the temperature reported, pressurised to 28 bar and run for the time reported in the table. The catalyst of example 7 was introduced as 0.005 M catalyst stock solution prepared as from 0.1 mmol (5)-i-

Pr-Phox and 0.1 mmol (PPh ₃ ) ₃ RuCl ₂ in 20 mL toluene at reflux for 2 hours.

Details of the examples 3 to 12 with regard to the catalyst used, reaction conditions and the results achieved are listed in table 1 (with base) and table 2 (without base). Both conversion and enantiomeric excess were determined by HPLC. Before enantiomeric excess determination, the product was acetylated as follows. A small sample of the product was treated directly in an HPLC vial with an excess of pyridine and acetic anhydride.

Table 1: Example 3 to example 7, using base (1 mL KOH 10 M)

MeOH = methanol, acac = acetylacetonate, dmf = λVV-dimethylformamide.

Example 12: Use of [(5)-Xyl-P-Phos RuCl ₂ (S)-DAIPEN] as catalyst (with base) l-(3'-Hydroxyphenyl)-2-methylamino-ethanone hydrochloride (2.01 g, 10 mmol) and [(S)-XyI- P-Phos RuCl ₂ (S)-DAIPEN] (1.2 mg, 0.001 mmol, S/C = 10,000:1) were placed in a 50 mL Pan- autoclave with overhead stirrer and heating jacket under nitrogen atmosphere. Through the injection port 11.5 mL 2-propanol and 3.5 mL KOH (10 M) were added 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

70 °C over 15 minutes. The reaction was stirred for 2.5 hours while the hydrogen pressure was maintained between 29 and 33 bar. The hydrogen uptake took place within the first hour. The reaction was then allowed to cool to room temperature over 1 hour and the pressure released. The solution was transferred to 1 L flask and quenched by addition of 50 mL of HCl (1 M) in ethanol. The solvent was evaporated under reduced pressure, 150 mL ethanol was added and evaporated again. This procedure was repeated twice. The resulting green solid residue was suspended in 50 mL 2-propanol, refluxed for 10 minutes and filtered over a pad of celite. The white residue on the filter was washed with 50 mL 2-propanol and the combined organic solutions were evaporated under reduced pressure to give a green solid residue. The solid residue was dissolved in 3 mL methanol, then 100 mL MTBE was added to precipitate the product. The suspension was stirred at room temperature for 15 hours, then the the product was collected by filtration and dried yielding 1.60 g (80%) of l-(3'-hydroxyphenyl)-2-methylamino- ethanol hydrochloride as an off-white solid. Purity: a) 90% by HPLC (Cl 8, water/methanol 50:50 and 0.1% trifluoroacetic acid), b) > 97% by ¹ H-NMR in DMSO-J ₆ . Enantiomeric purity: 96.5 % ee (S) by HPLC on the acetylated derivative (OJ, hexane/2-propanol 80:20).

Example 13: Use of [(S)-Xyl-P-Phos RuCl (p-cymene)]Cl as catalyst (without base) l-(3'-Hydroxyphenyl)-2-methylamino-ethanone hydrochloride (2.01 g, 10 mmol) and [(S)-XyI- P-Phos RuCl (p-cymene)]Cl (10.6 mg, 0.01 mmol, S/C = 1000:1) were placed in a 25 mL Parr autoclave with overhead stirrer and heating jacket under nitrogen atmosphere. Through the injection port 10 mL MeOH was added 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 25 bar hydrogen, stirred at around 1000 rpm and heated to 80 °C over 30 minutes. The temperature was then slowly increased to 85 °C over 30 minutes and the pressure adjusted to 30 bar. The reaction was stirred for 20 hours while the hydrogen pressure was maintained between 28 bar and 31 bar. About 90% of the total hydrogen uptake took place in about 4 hours. The reaction was then allowed to cool to room temperature, the pressure released and the solvent evaporated to give a solid residue of 2.32 g (115% mass recovery). HPLC analysis indicated full conversion and ¹ H NMR analysis of the crude material indicated that the material was >95% pure. The solid residue was dissolved in 3 mL methanol. After addition of 2OmL MTBE the precipitated product was collected by filtration, washed with MTBE and dried yielding 1.75 g (87%) l-(3'-hydroxyphenyl)-2-methylamino-ethanol hydrochloride as an off-white solid. Purity: a) 96% by HPLC (Cl 8, water/methanol 50:50 and 0.1% trifluoroacetic acid), b) > 97% purity by ¹ H NMR and ¹³ C NMR in DMSO-J ₆ . Enantiomeric purity: 70 % ee (S) by HPLC on the acetylated derivative (OJ, hexane/2-propanol 80:20).