WO2011047643A1

WO2011047643A1 - Method for the preparation of (ls)-6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]- 1,2,3,4-tetrahydroisoquinoline

Info

Publication number: WO2011047643A1
Application number: PCT/CZ2010/000106
Authority: WO
Inventors: Josef Cerny; Stanislav Radl; Josef Reitmajer
Original assignee: Zentiva, K.S.
Priority date: 2009-10-19
Filing date: 2010-10-14
Publication date: 2011-04-28
Also published as: CZ2009686A3

Abstract

The solution relates to the substance (15)-6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline of formula I, containing the desired S-enantiomer in an enantiomeric excess higher than or equal to 98.0%. Another solution is a manufacturing process for the present substance of formula I, which is synthesized via reduction of 6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline of formula II free base or hydrochloride using (R,R)-N-(p-toluenesulfonyl)- 1,2-diphenylethanediamine (chloro)(p-cymene)ruthenium(π) as a catalyst or using a catalyst generated in situ out of a ruthenium complex and a chiral ligand, wherein the catalyst used is in an amount lower than or equal to 2 molar %, related to the reduced substance (II).

Description

Method for the preparation of (lS)-6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]- 1 ,2,3,4-tet rahy droisoquinoline

Technical Field

The invention relates to (15)-6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)- ethyl]-l,2,3,4-tetrahydroisoquinoline (I) of high enantiomeric purity and to a process for the preparation thereof by asymmetric hydrogenation with transfer of hydrogen.

The compound of formula (I) is the key intermediate of synthesis of almorexant which is being developed by the Acetolin Pharmaceuticals company as a drug for treating primary insomnia.

Background Art

The basic patent WO2004/085403 described preparation of (lS)-6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline (I). The preparation consists in reduction of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline (II) in the conditions of asymmetric transfer hydrogenation. The involved catalyst was prepared in situ from N-((li?,27?)-2-amino-l,2-diphenylethyl)-2,4,6-triphenylmethylbenzene sulfonamide and the dichloro(p-cymene)ruthenium(II) dimer. The same procedure was also described in patent WO2005/118548 Al .

Disclosure of Invention

The invention provides (15)-6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-l,2,3,4- tetrahydroisoquinoline (I) of high enantiomeric purity and a preparation method thereof.

The product (I) can be prepared via reduction of the 6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline free base or hydrochloride using an appropriate catalyst in the conditions of asymmetric transfer hydrogenation with high enantioselectivity. For the reduction, a commercially available catalyst can be used or the catalyst can be prepared in situ from commercially available and cost-effective components, compared to the previously published procedure.

The catalyst used in patent WO2004/085403 is not commercially available and its preparation described therein requires purification by preparative HPLC chromatography. This preparation method is very expensive and unsuitable for industrial purposes. The original procedure does not mention enantioselectivity of the reduction and reproduction of the procedure resulted repeatedly in far worse enantioselectivity and purity than in the procedure designed by us.

Detailed description of the invention

When developing the synthesis of almorexant, (ai?,15)-a-phenyl-3,4-dihydro-6,7-dimethoxy- N-methyl-l-[2-[4-(trifluoromethyl)phenyl]ethyl]-2-(lH)-isoquinolineacetamide, an industrially utilisable method of preparation of the key intermediate (15)-6,7-dimethoxy-l-[2- (4-trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline (I) had to be developed. The only so far published procedure started with 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)- ethyl]-3,4-dihydroisoquinoline (II), which was reduced in the conditions of asymmetric transfer hydrogenation in dichloromethane. The catalyst for the reaction was prepared in situ from N-((l/?,2R)-2-amino-l,2-diphenylethyl)-2,4,6-trimethylbenzene sulfonamide (LI) and the dichloro( -cymene)ruthenium(II) dimer (Kl).

One of the problems of this procedure involves difficult preparation of N-((lR,2R)-2- amino-l,2-diphenylethyl)-2,4,6-trimethylbenzene sulfonamide (LI). This was prepared by reaction of 2,4,6-mesitylene sulfonyl chloride with l/?,2/ ,2-diphenyl ethane- 1 ,2-diamine, and thus prepared product had to be purified by preparative HPLC. An insufficient enantioselectivity of the reaction is another problem of the reduction. In the case described in literature 1 mol. % of the catalyst dichloro( ?-cymene)ruthenium(II) dimer (Kl) and 2 mol. % of the ligand N-((li?,2 ?)-2-amino-l,2-diphenylethyl)-2,4,6-trimethylbenzene sulfonamide (LI) in dichloromefhane (DCM) were used. When reproducing the given procedure an enantiomeric excess (ee) of ^-isomer max. 60% was achieved. A better enantiomeric excess (ee) 80% was achieved only using at least 5 mol. % of the catalyst and 10 mol. % of the ligand. However, in such a design the costs of the substance production would reach enormous prices and the synthesis would be hardly applicable. Use of such high amounts of catalyst is risky as the product would be hardly cleansed of the ruthenium residues and could not be used for production of pharmaceutical substances. Moreover, use of chlorinated solvents in production is inappropriate. Isolating an optically pure product out of a mixture of enantiomers which is insufficiently enriched, e.g. if the enantiomeric excess (ee) is less than 80%, is very difficult and results in considerable losses of the desired substance, due to which the process is uneconomical.

The preparation method developed by us involves use of commercially available catalysts in small amounts and in suitable solvents. Use of commercially available ruthenium catalysts proved to be appropriate; in particular use of (i?,i?)-N-(p-toluenesulfonyl)-l,2- diphenylethanediamine(chloro)(p-cymene)ruthenium(II) (K2). This catalyst was used in an amount less than 1 mol. %. In suitable conditions this catalyst was used in an amount lower than 0.5 mol % (Table 1). The resulting reaction mixture contains the desired enantiomer in sufficient purity (ee greater than 0.8), which allows easy isolation of an optically pure product. It was convenient to conduct the reaction at a temperature of 15 to 80 °C; with a temperature between 15 and 35 °C being particularly advantageous. The solvents which are suitable for the reaction include ethers, e.g. diethylether, methyl-t-butylether, tetrahydrofuran, or dioxane, chlorinated solvents, e.g. dichloromethane, chloroform or tetrachloromethane, aromatic hydrocarbons, e.g. benzene, toluene or xylene, non-polar aprotic solvents, e.g. acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide, hydrocarbons like heptane, cyclohexane, methylcyclohexane, or alcohols like methanol, ethanol, 2-propanol, 1-propanol, 1 -butanol, 2-butanol, both in anhydrous solvents or their mixtures and in solvents or their mixtures with addition of water. Performing the reaction in polar aprotic solvents was particularly advantageous, especially in dimethylformamide, or using ethers, in particular tetrahydrofuran. The sources of hydrogen for the reaction include salts of formic acid like ammonium formate, isopropyl alcohol, or mixtures of formic acid with amines, e.g. triethylamine, namely in a molar ratio 1 : 10 to 10 : 1, with advantageous reaction in a ratio of 4 : 3.

Another, highly suitable concept lies in preparation of the catalyst in situ from an appropriate complex and a commercially available chiral ligand. The appropriate ruthenium complexes were those containing ruthenium in oxidation state (II), further containing a neutral aromatic group and a halogen. The most appropriate were: dihalo(p-cymene)ruthenium (II) dimers, particularly good results were achieved using dichloro( »-cymene)ruthenium(II) dimer (Kl) and diiodo(/?-cymene)ruthenium(Ii) dimer (K3). Suitable chiral ligands for the reaction are (li?,2i?)-N-(benzenesulfonyl)- l,2-diphenylethandiamine (L4), (li?,2i?)-N-methanesulfonyl- 1 ,2-diphenylethanediamine (L5), (l ,2i?)-(-)-N-p-tosyl-l ,2-cyclohexadiamine (L2) and use of (li?,2i?)-N-(p-toluenesulfonyl)-l ,2-diphenylethanediamine (L3) was particularly advantageous. The final catalyst was prepared in situ by mixing the ruthenium complex with the chiral ligand in a molar ratio 1 : 1 to 1 : 3, the ratio 1 : 2 being particularly suitable, with addition of an amine, preferably triethylamine in an amount 1 to 30 mol. % (related to the reduced substance). The solvents suitable for the preparation are ethers, e.g. diethylether, methyl-t-butylether, tetrahydrofuran or dioxane, chlorinated solvents, e.g. dichloromethane, chloroform, or tetrachloromethane, aromatic hydrocarbons, e.g. benzene, toluene or xylene, non-polar aprotic solvents, e.g. acetonitrile, dimethylformamide, dimethylacetamide, N- methylpyrrolidone or dimethylsulfoxide, hydrocarbons, e.g. heptane, cyclohexane, methylcyclohexane, or alcohols, e.g. methanol, ethanol, 2-propanol, 1-propanol, 1 -butanol, 2- butanol or mixtures of them. Acetonitrile was a particularly good solvent for preparation of the catalyst solution. The temperature at which the catalysts were prepared was ranging from 15 °C to boiling point of the particular solvent. Thus prepared catalyst solution was used for reduction of 6,7-dimethoxy-l -[2-(4-trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline (II) free base or hydrochloride in an amount of catalyst lower than 1 mol. %. If the conditions were suitable, the catalyst was used in an amount lower than 0.5% (Table 1). The resulting reaction mixture contains the desired enantiomer of sufficient purity (ee greater than 80%), which allows easy isolation of optically pure product. The reaction was conveniently performed at a temperature of 15 to 80 °C, the reaction at a temperature from 15 to 35 °C was particularly advantageous. The solvents suitable for the reaction are: ethers, e.g. diethylether, methyl-t- butylether, tetrahydrofuran, or dioxane, chlorinated solvents, e.g. dichloromethane, chloroform or tetrachloromethane, aromatic hydrocarbons, e.g. benzene, toluene or xylene, non-polar aprotic solvents, e.g. acetonitrile, dimethylformamide, dimethylacetamide, N- methylpyrrolidone or dimethylsulfoxide, hydrocarbons, e.g. heptane, cyclohexane, methylcyclohexane, or alcohols, e.g. methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2- butanol, both in anhydrous solvents or their mixtures and in solvents or mixtures with addition of water. Reaction in polar aprotic solvents is particularly advantageous, especially in dimethylformamide, or using ethers, in particular tetrahydrofuran. The sources of hydrogen for the reaction include salts of formic acid like ammonium formate, isopropyl alcohol, or mixtures of formic acid with amines, e.g. triethylamine, namely in a molar ratio 1 : 10 to 10 : 1, with advantageous reaction in a ratio of 4 : 3.

It is preferable to purify thus obtained (15)-6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-l, 2,3, 4-tetrahydroisoquino line (I) in the form of a suitable salt. The following salts proved to be suitable: salts with carboxylic acids such as formic acid, acetic acid, propionic acid, fumaric acid, oxalic acid, benzoic acid, tartaric acid, mandelic acid and other, sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid. Other appropriate salts are salts with inorganic acids such as sulfuric acid, phosphoric acid, hydrobromic acid, and conversion to a hydrochloric acid salt and isolation of (lS)-6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-l,2,3,4- tetrahydroisoquinoline (I) in the form of hydrochloride was particularly advantageous. Conversion to salts and subsequent crystallization was performed in suitable solvents such as alcohols, e.g. methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol, both in anhydrous solvents or their mixtures and in solvents or their mixtures with addition of water, use of a mixture of methanol and 2-propanol being especially advantageous; also in dipolar solvents such as acetone, 2-butanone, methyl isopropyl ketone, ethyl acetate, both in anhydrous solvents or their mixtures and in solvents or their mixtures with addition of water, or in ethers such as diethylether, methyl-t-butylether, tetrahydrofuran or dioxane. Thus it was possible to get salts of chemical purity and ee (enantiomeric excess) higher than 98%, and, if the reaction was properly run, salts of chemical purity and ee higher than 99%.

Table 1 summarises results of various experiments. Table 1

Enantioselective reduction of substance II with formation of substance I

DCM - dichloromethane

DMF - dimethylfumarate

THF - tetrahydrofuran

Analytical procedure

Samples of the reaction mixture are diluted in a volumetric flask with methanol R to the concentration 1 mg/ml and stirred in ultrasonic batch. The sample is analysed immediately after preparation. Chemical purity

Tested solution: solution in methanol R of concentration 1 mg/ml

Column:

- dimensions: 1 = 0.10 m, 0 = 2.1 mm

- stationary phase: CI 8, particle size 2.7 μπι

- temperature: 40°C.

Mobile phase:

A: phosphate buffer (0.02 M potassium hydrogenphosphate, pH adjusted to 7.5 ± 0.05 with 1M potassium hydroxide); B: acetonitrile R;

Gradient elution:

Detection: spectrophotometer 220 nm

Optical purity

Tested solution: solution in methanol R of concentration 1 mg/ml

Column: dimensions: 1 = 0.15 m, 0 = 4.6 mm

stationary phase: Cellucoat, particle size 3.0 μηι

temperature: 25 °C

Mobile phase: hexane/ethanol 90/10 V/V

Elution: isocratic

Flow-rate: 1.0 ml/min Detection: spectrophotometer 220 nm

Injection: 10 μΐ

The invention is specified in more detail in the following examples. The examples, illustrating improvement of the procedure according to the invention, have an exclusively illustrative character and do not limit the scope of the invention in any respect.

Examples

Example 1

( 1 S)-6,7-Dimethoxy- 1 -[2-(4-trifluoromethylphenyl)ethyl]-l ,2,3,4-tetrahydroisoquinoline (I) To a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline (II) (2.7 g, 7.5 mmol) in 30 ml of DCM a mixture of formic acid : triethylamine (3.7 g, in molar ratio 4 : 3) and (^, )-(p-toluenesulfonyl)-l,2-diphenylethanediamine- (chloro)(p-cymene)ruthenium (II) (25 mg, 37.5 μηιοΐ) was added. The total was stirred at reflux in N₂ atmosphere for 6 hours. The reaction mixture was diluted with 30 ml of DCM, washed with a saturated solution of NaHC0₃, water and brine. After drying with MgS0₄ the solvent was evaporated in a vacuum evaporator. The evaporation residue was dissolved in i- PrOH and an ethanolic solution of HCl (5 M, 3 ml) was added dropwise under intensive stirring. The solvent was evaporated in a vacuum evaporator and the solid evaporation residue was crystallized out of an /^'-PrOH/MeOH mixture (45 ml). After sucking off and drying, 1.84 g (68%) of white crystals of the product (ee 99.2%) was obtained in the form of hydrochloride.

Example 2

( 15)-6,7-Dimethoxy- 1 -[2-(4-trifluoromethylphenyl)ethyl]- 1 ,2,3,4-tetrahydroisoquinoline (I)

To a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline (II) (2.7 g, 7.5 mmol) in 30 ml of DMF a mixture of formic acid and triethylamine (3.7 g, in molar ratio 4 : 3) and (i?,i?)- V-(p-toluenesulfonyl)-l,2-diphenylethanediamine(chloro)(p- cymene)ruthenium(II) (25 mg, 37.5 μπιοΐ) was added. The total was stirred in N₂ atmosphere at 30 °C for 3 hours. The reaction mixture was evaporated and the evaporation residue was dissolved in 30 ml of DCM, washed with a saturated solution of NaHC0₃, water and brine. After drying with MgS0₄ the solvent was evaporated in a vacuum evaporator. The evaporation residue was dissolved in -PrOH and an ethanolic solution of HCl (5 M, 3 ml) was added dropwise under intensive stirring. The solvent was evaporated in a vacuum evaporator and the solid evaporation residue was crystallized out of an j^'-PrOH/MeOH mixture (45 ml). After sucking off and drying 2.25 g (83%) of white crystals of the product (ee 99.6%) was obtained in the form of hydrochloride. Example 3

(15)-6,7-Dimethoxy-l -[2-(4-trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline (I)

Dichloro(p-cymene)ruthenium(II) dimer (1 1.5 mg, 18.8 μηιοΐ) was added to a solution of (lR,2R)-N-(p-toluenesulfonyl)-l ,2-diphenylethanediamine (13.7 mg, 37 μπιοι) and triethylamine (150 mg, 1.5 mmol) in acetonitrile (1.2 ml). The solution was stirred at 80 °C for 1 hour and then added to a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]- 3,4-dihydroisoquinoline (II) (2.7 g, 7.5 mmol) in 30 ml of DCM. After a mixture of formic acid and triethylamine (3.7 g, in molar ratio 4 : 3) was added, the total was stirred at reflux in N₂ atmosphere for 6 hours. The reaction mixture was diluted with 30 ml of DCM, washed with a saturated solution of NaHC0₃, water and brine. After drying with MgS0₄ the solvent was evaporated in a vacuum evaporator. The evaporation residue was dissolved in z^'-PrOH and an ethanolic solution of HC1 (5 M, 3 ml) was added dropwise under intensive stirring. The solvent was evaporated in a vacuum evaporator and the solid evaporation residue was crystallized out of an j^'-PrOH/MeOH mixture (45 ml). After sucking off and drying 2.05 g (75%) of white crystals of the product (ee 99.1%) was obtained in the form of hydrochloride. Example 4

(l-S)-6,7-Dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline (I)

Dichloro(/?-cymene)ruthenium(II) dimer (263 mg, 0.43 mmol) was added to a solution of (lR,2R)-N-(p-toluenesulfonyl)-l ,2-diphenylethanediamine (315 mg, 0.86 mmol) and triethylamine (1.74 g, 21.4 mmol) in acetonitrile (25 ml). The solution was stirred at 80 °C for 1 hour and then added to a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]- 3,4-dihydroisoquinoline (II) (39 g, 107 mmol) in 250 ml of DMF. After a mixture of formic acid and triethylamine (61 g, in molar ratio 4 : 3) was added, the total was stirred at 35 °C in N₂ atmosphere for 3 hours. The reaction mixture was evaporated and the evaporation residue was dissolved in 250 ml ethylacetate, washed with a saturated solution of NaHC0₃, water and brine. After drying with MgS0₄ the solvent was evaporated in a vacuum evaporator. The evaporation residue was dissolved in z^'-PrOH and an ethanolic solution of HC1 (5 M, 40 ml) was added dropwise under intensive stirring. The solvent was evaporated in a vacuum evaporator and the solid evaporation residue was crystallized out of an z^'-PrOH/MeOH mixture ( 50 ml). After sucking off and drying, 38 g (88%) of white crystals of the product (ee 99.8%) was obtained in the form of hydrochloride.

Example 5 ( 15)-6,7-Dimethoxy- 1 -[2-(4-trifluoromethylphenyl)ethyl]- 1 ,2,3,4-tetrahydroisoquinoline (I)

Dichloro(p-cymene)ruthenium(II) dimer (1 1.5 mg, 18.8 μηιοΐ) was added to a solution of (lR,2R)-p-tosyl-l ,2-cyclohexadiamine (10.0 mg, 37.5 μπιοΐ) and triethylamine (75 mg, 0.75 mmol) in acetonitrile (1 ml). The solution was stirred at 80 °C for 1 hour and then added to a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline (II) (1.3 g, 3.8 mmol) in 30 ml of DCM. After a mixture of formic acid and triethylamine (1.9 g, in molar ratio 4 : 3) was added, the total was stirred at reflux in N₂ atmosphere for 6 hours. The reaction mixture was diluted with 30 ml of DCM, washed with a saturated solution of NaHC0₃, water and brine. After drying with MgS0₄ the solvent was evaporated in a vacuum evaporator. The evaporation residue was dissolved in z^'-PrOH and an ethanolic solution of HC1 (5 M, 1 .5 ml) was added dropwise under intensive stirring. The solvent was evaporated in a vacuum evaporator and the solid evaporation residue was crystallized out of an -PrOH/MeOH mixture (20 ml). After sucking off and drying, 0.72 g (55%) of white crystals of the product (ee 99.0%) was obtained in the form of hydrochloride.

Example 6

(15)-6,7-Dimethoxy- 1 -[2-(4-trifluoromethylphenyl)ethyl]- 1 ,2,3,4-tetrahydroisoquinoline (I)

Diiodo(p-cymene)ruthenium(II) dimer (18.4 mg, 18.8 μηιοΐ) was added to solution of (lR,2R)-N-(p-toluenesulfonyl)-l ,2-diphenylethanediamine (13.7 mg, 37.5 μηιοΓ) and triethylamine (75 mg, 0.75 mmol) in acetonitrile (1 ml). The solution was stirred at 80 °C for 1 hour and then added to a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]- 3,4-dihydroisoquinoline (II) (1.3 g, 3.8 mmol) in 30 ml of THF. After a mixture of formic acid and triethylamine (1 .9 g, in molar ratio 4 : 3) was added, the total was stirred at the temperature of 40 °C in N₂ atmosphere for 6 hours. The reaction mixture was evaporated and the evaporation residue was dissolved in 30 ml DCM, washed with a saturated solution of NaHC0₃, water and brine. After drying with MgS0₄ the solvent was evaporated in a vacuum evaporator. The evaporation residue was dissolved in z^'-PrOH and an ethanolic solution of HC1 (5 M, 1.5 ml) was added dropwise under intensive stirring. The solvent was evaporated in a vacuum evaporator and the solid evaporation residue was crystallized out of an i-PrOH/MeOH mixture (20 ml). After sucking off and drying 1.07 g (82%) of white crystals of the product (ee 99.4%) was obtained in the form of hydrochloride.

Example 7

( 1 £)-6,7-Dimethoxy- 1 -[2-(4-trifluoromethylphenyl)ethyl]- 1 ,2,3,4-tetrahydroisoquinoline (I) Dichloro(p-cymene)ruthenium(II) dimer (1 1.5 mg, 18.8 μιηοι) was added to a solution of (lR,2R)-N-(benzenesulfonyl)-l,2-diphenylethanediamine (13.0 mg, 37.5 μιτιοΐ) and triethylamine (75 mg, 0.75 mmol) in acetonitrile (1 ml). The solution was stirred at 80 °C for 1 hour and then added to a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4- dihydroisoquinoline (II) (1.3 g, 3.8 mmol) in 30 ml of DCM. After a mixture of formic acid and triethylamine (1.9 g, in molar ratio 4 : 3) was added, the total was stirred in at reflux N₂ atmosphere for 8 hours. The reaction mixture was diluted with 30 ml of DCM, washed with a saturated solution of NaHC0₃, water and brine. After drying with MgS0₄ the solvent was evaporated in a vacuum evaporator. The evaporation residue was dissolved in z^'-PrOH and an ethanolic solution of HC1 (5 M, 1.5 ml) was added dropwise under intensive stirring. The solvent was evaporated in a vacuum evaporator and the solid evaporation residue was crystallized out of an i-PrOH/MeOH mixture (20 ml). After sucking off and drying 0.85 g (65%) of white crystals of the product (ee 99.0%) was obtained in the form of hydrochloride.

Example 8

( liS)-6,7-Dimethoxy- 1 -[2-(4-trifluoromethylphenyl)ethyl]- 1 ,2,3,4-tetrahydroisoquinoline (I) Dichloro(p-cymene)ruthenium(II) dimer (1 1.5 mg, 18.8 μπιοΐ) was added to a solution of (lR,2R)-N-methanesulfonyl-l,2-diphenylethanediamine (1 1.0 mg, 37.5 μπιοΐ) and triethylamine (75 mg, 0.75 mmol) in acetonitrile (1 ml). The solution was stirred at 80 °C for 1 hour and then added to a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4- dihydroisoquinoline (II) (1.3 g, 3.8 mmol) in 30 ml of DCM. After a mixture of formic acid and triethylamine (1.9 g, in molar ratio 4 : 3) was added, the total was stirred at reflux in N₂ atmosphere for 12 hours. The reaction mixture was diluted with 30 ml of DCM, washed with a saturated solution of NaHC0₃, water and brine. After drying with MgS0₄ the solvent was evaporated in a vacuum evaporator. The evaporation residue was dissolved in z^'-PrOH and an ethanolic solution of HC1 (5 M, 1.5 ml) was added dropwise under intensive stirring. The solvent was evaporated in a vacuum evaporator and the solid evaporation residue was crystallized out of an z^'-PrOH/MeOH mixture (20 ml). After sucking off and drying 0.68 g (52%) of white crystals of the product (ee 99.0%) was obtained in the form of hydrochloride. Example 9

(15)-6,7-Dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-l ,2,3,4-tetrahydroisoquinoline (I)

Dichloro(p-cymene)ruthenium(II) dimer (69 mg, 0.1 1 mmol) was added to a solution of (lR,2R)-N-(p-toluenesulfonyl)-l,2-diphenylethanediamine (82 mg, 0.22 mmol) and triethylamine (0.76 g, 7.5 mmol) in acetonitrile (6 ml). The solution was stirred at 80 °C for 1 hour and then added to a solution of 6,7-dimethoxy-l -[2-(4-trifluoromethylphenyl)ethyl]-3,4- dihydroisoquinoline hydrochloride (II) (15 g, 37.5 mmol) and triethylamine (3.8 g, 37.5 mmol) in 80 ml of DMF. After a mixture of formic acid and triethylamine (20.4 g, in molar ratio 4 : 3) was added, the total was stirred in N₂ atmosphere at 35 °C for 3 hours. The reaction mixture was poured into 400 ml of water and extracted 3 times with 50 ml of ethyl acetate. The combined extracts were washed 3 times with 50 ml of brine. After drying with MgS0₄ a solution of HCl(g) in EtOH (5M, 8.5 g) was added dropwise. After stirring for 30 minutes the solid substance was sucked off, washed with 50 ml of ethyl acetate and dried in a vacuum drier. After re-crystallizing out of a mixture of -PrOH/MeOH (150 ml) 13 g (86%) of white crystals of the product (ee 100%) was obtained in the form of hydrochloride.

Example 10

(Reproduction of the procedure previously described in literature - WO2004/085403)

(lS)-6,7-Dimethoxy-l -[2-(4-trifluoromethylphenyl)ethyl]-l ,2,3,4-tetrahydroisoquinoline (I)

Dichloro(p-cymene)ruthenium(II) dimer (120 mg, 0.2 mmol) was added to a solution of (l R,2R)-N-(2,4,6-trimethylbenzenesulfonyl)-l ,2-diphenylethanediamine (150 mg, 0.4 mmol) and triethylamine (80 mg, 0.8 mmol) in acetonitrile (3 ml). The solution was stirred at 80 °C for 1 hour and then added to a solution of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]- 3,4-dihydroisoquinoline (II) (10.2 g, 28 mmol) in 30 ml of DCM. After a mixture of formic acid and triethylamine (5 :2, 14 ml) was added, the total was stirred for 16 hours. The reaction mixture was washed with a saturated solution of NaHC0₃, water and brine. After drying with MgS0₄ the solvent was evaporated in a vacuum evaporator. The evaporation residue was dissolved in z^'-PrOH and a solution of HCl(g) in z^'-PrOH (5 M, 10 ml) was added dropwise under intensive stirring. After sucking off, 9.6 g (85%) of yellowish crystals (ee 59%) was obtained in the form of hydrochloride.

Claims

1. (15 -6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-l,2,3,4- tetrahydroisoquinoline of formula I

containing the desired S-enantiomer in an enantiomeric excess higher than or equal to

98.0 .

2. ( 1 S)-6,7-dimethoxy- 1 -[2-(4-trifluoromethylphenyl)ethyl]- 1 ,2,3,4- tetrahydroisoquinoline according to claim 1 , containing the desired S-enantiomer in an enantiomeric excess higher than or equal to 99.0%.

3. (1 S)-6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-l ,2,3,4- tetrahydroisoquinoline according to claim 1 , containing the desired S-enantiomer in an enantiomeric excess higher than or equal to 99.5%.

4. (l S)-6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-l ,2,3,4- tetrahydroisoquinoline according to claim 1 , containing the desired S-enantiomer in an enantiomeric excess higher than or equal to 99.9%.

5. A process for the manufacture of (l S)-6,7-dimethoxy-l -[2-(4- trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline according to claim 1

characterized in that the substance (I) is synthesized via reduction of 6,7-dimethoxy-l- [2-(4-trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline (II) free base or hydrochloride

using (R,R)-N-(p-toluenesulfonyl)- 1 ,2-diphenylethanediamine(chloro)(p- cymene)ruthenium(II) as a catalyst or using a catalyst generated in situ from a ruthenium complex and a chiral ligand, wherein the catalyst in an amount lower than or equal to 2 molar % is used, related to the reduced substance (II).

6. The process according to claim 5, characterized in that the catalyst is used in an amount lower than or equal to 1 molar %, related to the reduced substance (II).

7. The process according to claims 5 to 6, characterized in that the reduction is performed under conditions of asymmetric transfer hydrogenation.

8. The process according to claims 5 to 7, characterized in that the catalyst generated in situ is prepared using a ruthenium complex containing ruthenium in the oxidation stage (II) and, optionally, a neutral aromatic group and/or a halogen.

9. The process according to claims 5 to 8, characterized in that dihalo(p- cymene)ruthenium(II) dimer is used as the source of ruthenium.

10. The process according to claim 9, characterized in that dichloro(p- cymene)ruthenium(II) dimer is used as the source of ruthenium.

11. The process according to claim 9, characterized in that diiodo(p-cymene)ruthenium(II) dimer is used as the source of ruthenium.

12. The process according to claims 5 to 11, characterized in that the chiral ligand used is selected from the group consisting of (lR,2R)-N-(benzenesulfonyl)-l,2- diphenylethanediamine, (lR,2R)-N-methanesulfonyl-l,2-diphenylethanediamine,

(lR,2R)-(-)-N-p-tosyl-l,2-cyclohexadiamine, or is, particularly preferably, (1R,2R)-N- (p-toluenesulfonyl)- 1 ,2-diphenylethanediamine.

13. The process according to claim 12, characterized in that (lR,2R)-N-(p- toluenesulfonyl)-l,2-diphenylethanediamine is used as the chiral ligand.

14. The process according to claims 5 to 13, characterized in that the catalyst is prepared in situ by mixing the ruthenium complex with a chiral ligand in a molar ratio of from 1 : 1 to 1 : 3.

15. The process according to claim 14, characterized in that the catalyst is prepared in situ by mixing the ruthenium complex with a chiral ligand in the molar ratio 1 : 2.

16. The process according to claims 5 to 15, characterized in that the catalyst is prepared in situ by mixing the ruthenium complex with a chiral ligand with addition of an amine.

17. The process according to claims 14 to 16, characterized in that the catalyst is prepared in situ by mixing the ruthenium complex with a chiral ligand with addition of triethylamine.

18. The process according to claim 17, characterized in that the catalyst is prepared in situ by mixing the ruthenium complex with a chiral ligand with addition of triethylamine in an amount 1 to 30 mol. %, related to the reduced substance.

19. The process according to claims 5 to 18, characterized in that the catalyst is prepared in situ by mixing the ruthenium complex with a chiral ligand in suitable solvents at a temperature from 15 °C to the boiling point of the used solvent.

20. The process according to claims 5 to 19, characterized in that the catalyst is prepared in situ in acetonitrile.

21. The process according to claims 5 to 20, characterized in that reduction of the substance of formula I is performed in a solvent selected from the group consisting of: Ethers: diethylether, methyl-t-butylether, tetrahydrofuran, dioxane Chlorinated solvents: dichloromethane, chloroform, tetrachloromethane

Aromatic hydrocarbons: benzene, toluene, xylene

Polar aprotic solvents: acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide

Hydrocarbons: heptane, cyclohexane, methylcyclohexane

Alcohols: methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol

both in anhydrous solvents or mixtures of them and in solvents or their mixtures with addition of water.

22. The process according to claim 21, characterized in that reduction is performed in a polar aprotic solvent.

23. The process according to claim 22, characterized in that reduction is performed in dimethylformamide.

24. The process according to claim 21, characterized in that reduction is performed in s solvent selected from ethers.

25. The process according to claim 24, characterized in that reduction is performed in tetrahydrofuran.

26. The process according to claims 5 to 25, characterized in that reduction is performed at a temperature of from 15 to 80 °C.

27. The process according to claims 5 to 26, characterized in that reduction is performed at a temperature of from 15 to 35 °C.

28. The process according to claims 5 to 27, characterized in that the source of hydrogen are formic acid salts, preferably ammonium formate, or mixtures of formic acid with amines.

29. The process according to claims 5 to 28, characterized in that the enantiomeric excess ee of the desired enantiomer, i.e., of (lS)-6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline, in the reaction mixture after completion of the reaction is higher than 80%.

30. The process according to claim 29, characterized in that (lS)-6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline (I), obtained from the reaction mixture containing the substance of formula I in an enantiomeric excess ee higher than 80%, is converted to a salt, which is then crystallized out of a suitable solvent.

31. The process according to claim 30, characterized in that the substance (I) is converted to hydrochloride.

32. The process according to claims 30 to 31, characterized in that a branched or non- branched C1-C5 aliphatic alcohol or a mixture thereof containing t 0 to 10 wt. % of water is used as the solvent.

33. The process according to claims 30 to 32, characterized in that a mixture of methanol with isopropyl alcohol is used as the crystallization solvent.

34. The process for the manufacture of (lS)-6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-l,2,3,4-tetrahydroisoquinoline (I) according to claims 5 to 33, characterized in that the product is obtained in an enantiomeric excess ee higher than 99%.

35. The process according to claims 5 to 33, characterized in that the product is obtained in an enantiomeric excess ee higher than 99.5%.