CZ2009686A3 - Process for preparing (1S)-6,7-dimethoxy-1-[2-(4-trifluoromethylphenyl)ethyl]-1,2,3,4-tetrahydroisoquinoline - Google Patents

Abstract

The invention relates to (1S) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline of formula I, containing the desired S-enantiomer in an enantiomeric excess of greater than or equal to 98.0%. The invention further relates to a process for the preparation of a subject compound of formula I which is synthesized by reduction of 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline of formula II (free base or hydrochloride) using ( R, R) -N- (p-toluenesulfonyl) -1,2-diphenylethandiamine (chloro) (p-cymene) ruthenium (II) as a catalyst or using a catalyst generated in situ from a ruthenium complex and a chiral ligand using a catalyst in an amount of less than or equal to 2 mole%, based on the reduced compound of formula II.

Description

Technical field

The present invention relates to (15) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) of high enantiomeric purity and a process for its preparation by asymmetric transfer hydrogenation hydrogen.

(AND)

The compound of formula (I) is a key intermediate for the synthesis of almorexant, which is being developed by Actelion Pharmaceuticals as a medicament for the treatment of primary insomnia.

BACKGROUND OF THE INVENTION

In the basic patent W02004 / 085403 is described the preparation of (15) -6,7-dimethoxy-l- [2- (4-trifluoromethylphenyl) ethyl] -l, 2, ₃ 3,4'tetrahydroisochinolinu (I). The preparation consists in reducing 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) under conditions of asymmetric hydrogen transfer hydrogenation. The catalyst used was prepared in situ from N - ((1 R, 2 R) -2-amino-1,2-diphenylethyl) -2,4,6-triphenylmethylbenzene sulfonamide and dichloro (p-cymene) ruthenium (II) dimer. The same procedure has been described in WO2005 / 118548A1.

(II)

SUMMARY OF THE INVENTION

The present invention provides (15) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) of high enantiomeric purity and a process for its preparation.

Product (I) can be prepared by reducing 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline of the free base or hydrochloride using a suitable catalyst under asymmetric hydrogen transfer hydrogenation conditions with high enantioselectivity. For the reduction, a commercially available catalyst can be used, or prepared in situ from commercially available and cost-effective components, as opposed to the previously published process.

The catalyst used in WO2004 / 085403 is not commercially available and its preparation described therein requires purification by preparative HPLC chromatography. This method of preparation is very expensive and unsuitable for industrial use. The enantiosclectivity of the reduction is not mentioned in the original procedure and the reproduction of this procedure repeatedly achieved much worse enantioselectivity and purity than according to our proposed procedure.

DETAILED DESCRIPTION OF THE INVENTION

In the development of the synthesis of almorexant (α, ΙΛ) - α-phenyl-3,4-dihydro-6,7-dimethoxy-N -methyl-1- [2- [4- (trifluoromethyl) phenyl] ethyl] -2- It has been necessary to develop an industrially applicable method for preparing the key intermediate (15) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I). The only procedure published so far was based on 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II), which was reduced under conditions of asymmetric hydrogenation with hydrogen transfer in dichloromethane. The catalyst for this reaction was prepared in situ from N - ((1 R, 2 R) -2-atino-1,2-diphenylethyl) -2,4,6-trimethylbenzene sulfonamide (LI) and dichloro (p-cymene) ruthenium (II). dimer (K1).

OF

One of the problems of this process lies in the difficult preparation of M ((1A, 2A) -2-amino-1,2-diphenylethyl) -2,4,6-trimethylbenzene sulfonamide (LI). This was prepared by reacting 2,4,6-mesitylenesulfonyl chloride with 17 R, 2 R -1,2-diphenylethane-1,2-diamine, and the product thus prepared had to be purified by preparative HPLC. Another problem of reduction is the lack of enantioselectivity of the reaction. In the case described in the literature, 1 mol% of the catalyst dichloro (p-cymene) ruthenium (II) dimer (K1) and 2 mol% of the ligand 7V - ((1R, 2A) -2-amino-1,2-diphenylethyl) -2, 4,6-trimethylbenzene sulfonamide (LI) in dichloromethane (DCM). Upon reproduction of the procedure, the enantiomeric excess (ee) of the S-isomer was at most 60%. A better enantiomeric excess (ee) of 80% was achieved only by using at least 5 mol% catalyst and 10 mol% ligand. In this embodiment, however, the cost of producing the substance would reach enormous values and the synthesis would be very difficult to use. When using such high amounts of catalyst, there is a great risk that the product will be very difficult to get rid of ruthenium residues and therefore this product could not be used for the manufacture of pharmaceutical substances. In addition, the use of chlorinated solvents in production is not appropriate. Isolation of the optically pure product from a mixture of enantiomers that is poorly enriched, for example, when the enantiomeric excess (ee) is less than 80% is very difficult and results in considerable losses of the desired substance, rendering the process uneconomical.

Our method of preparation is based on the use of commercially available catalysts in small amounts and in suitable solvents. The use of commercially available ruthenium catalysts has proven suitable, of which particularly preferred was the use of (R, R) -N- (ptoluenesulfonyl) -1,2-diphenylethanediamine (chloro) (p-cymene) ruthemum (II) (K2). The catalyst was used in an amount of less than 1 mol%. Under appropriate conditions, the catalyst was used in an amount of less than 0.5 mol% (Tabulkal). The obtained reaction mixture contains the desired enantiomer in sufficient purity (ee greater than 0.8) to allow easy isolation of the optically pure product. The reaction was suitably carried out at a temperature of 15 to 80 ° C, particularly preferred at a temperature of 15 to 35 ° C. Suitable solvents for the reaction are ethers, for example diethyl ether, methyl t-butyl ether, tetrahydrofuran, or dioxane, chlorinated solvents, for example dichloromethane, chloroform, or carbon tetrachloride, aromatic hydrocarbons, for example benzene, toluene, or xylene, apolar aprotic solvents, for example acetonitrile , dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide, hydrocarbons such as heptane, cyclohexane, methylcyclohexane or alcohols such as methanol, ethanol 2-propanol, 1 propanol, 1-butanol,

2-butanol both in anhydrous solvents or mixtures thereof and in solvents or their 4

mixtures with added water. It was particularly advantageous to carry out the reaction in polar aprotic solvents, in particular dimethylformamide or to use ethers, in particular tetrahydrofuran. The hydrogen source in the reaction may be formic acid salts such as ammonium formate, isopropyl alcohol, or mixtures of formic acid with amines such as triethylamine in a molar ratio of 1: 10 to 10: 1, with a 4: 3 ratio being particularly preferred.

Another highly preferred embodiment consists in preparing the catalyst in situ from a suitable ruthenium complex and a commercially available chiral ligand. Suitable ruthenium complexes were those containing ruthenium in the oxidation stage (II), further comprising a neutral aromatic group and a halogen. The dihalogen (pcymen) ruthenium (II) dimers were best suited, particularly good results were obtained using dichloro (pcymen) ruthenium (II) dimer (K1) and diiodo (p-cymene) ruthenium (II) dimer (K3). Suitable chiral ligands for a given reaction are (1R, 4R, 3R-N-benzenesulfonyl) -1H-diphenylethanediamine (L4), (UR, 27R) - N -methanesulfonyl-1,2-diphenylethanediamine (L5), (17R, 2R). - (-) - Np-tosyl-1,2-cyclohexadiamine (L2), and particularly preferred was the use of (1 R, 2 R) - N - (p-toluenesulfonyl) -1,2-diphenylethanediamine (L 3). of a ruthenium complex with a chiral ligand in a molar ratio of 1: 1 to 1: 3, a ratio of 1: 2, with the addition of an amine, preferably triethylamine in an amount of 1 to 30 mol% (based on the reduced substance). , for example diethyl ether, methyl t-butyl ether, tetrahydrofuran, or dioxane, chlorinated solvents such as dichloromethane, chloroform, or carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, or xylene, apolar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, V- methylpyrroli donors or dimethylsulfoxide, hydrocarbons such as heptane, cyclohexane, methylcyclohexane or alcohols such as methanol, ethanol 2-propanol, 1 propanol, 1-butanol, 2-butanol or mixtures thereof. Acetonitrile was a particularly good solvent for preparing the catalyst solution. The temperature at which the catalysts were prepared was 15 ° C to the boiling point of the solvent used. The catalyst solution thus prepared was used to reduce 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] 3,4-dihydroisoquinoline (II) free base or hydrochloride in an amount of catalyst less than 1 mol%. Under appropriate conditions, the catalyst was used in an amount of less than 0.5 mol% (Table 1). The resulting reaction mixture contains the desired enantiomer in sufficient purity (ee greater than 80%) to allow easy isolation of the optically pure product. The reaction was suitably carried out at a temperature of 15 to 80 ° C, particularly preferred at a temperature of 15 to 35 ° C. Suitable solvents for the reaction are ethers, for example diethyl ether, methyl-4-butyl ether, tetrahydrofuran, or dioxane, chlorinated solvents, for example dichloromethane, chloroform, or carbon tetrachloride, aromatic hydrocarbons, for example benzene, toluene, or xylene, apolar aprotic solvents, for example acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide, hydrocarbons such as heptane, cyclohexane, methylcyclohexane or alcohols such as methanol, ethanol 2-propanol, 1-propanol, 1-butanol, 2-butanol both in anhydrous solvents or mixtures thereof and solvents or mixtures thereof with added water. It was particularly advantageous to carry out the reaction in polar aprotic solvents, in particular dimethylformamide or to use ethers, in particular tetrahydrofuran. The hydrogen source in the reaction may be formic acid salts such as ammonium formate, isopropyl alcohol, or mixtures of formic acid with amines such as triethylamine in a molar ratio of 1: 10 to 10: 1, with a 4: 3 ratio being particularly preferred. .

The (15) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) thus obtained is preferably purified as a suitable salt. Salts with carboxylic acids such as formic acid, acetic acid, propionic acid, fumaric acid, oxalic acid, benzoic acid, tartaric acid, mandelic acid and others have proven suitable, with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. . Other suitable salts were salts with inorganic acids such as sulfuric acid, phosphoric acid, hydrobromic acid, and conversion to the hydrochloric acid salt and isolation of (15) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] were particularly preferred. 1 -1,3,3,4-tetrahydroisoquinoline (I) in the form of the hydrochloride. Conversion to salts and subsequent crystallization was carried out in suitable solvents such as alcohols such as methanol, ethanol, 2-propanol, 1-propanol, 1-butanol, 2-butanol, both in anhydrous solvents or mixtures thereof and in solvents or mixtures thereof with water, particularly preferred was the use of a mixture of methanol and 2-propanol, as well as in dipolar solvents such as acetone, 2-butanone, methylisopropyl ketone, ethyl acetate both in anhydrous solvents or mixtures thereof and in solvents or mixtures thereof with water or for example, diethyl ether, methyl t-butyl ether, tetrahydrofuran, or dioxane. Thus, it was possible to obtain salts with both chemical purity and ee (enantiomeric excess) greater than 98% and, if appropriate, salts with chemical purity and ee greater than 99%.

Table 1 summarizes the results of each experiment.

Table 1.

··

Enantioselective reduction of compound II to form compound I

Catalyst (mol%) Ligand Solvent Conversion% (4h) ee (%) K1 (2) IF DCM 90 59 K2 (l) - DCM > 99 85 K2 (0,5) - DCM > 99 82 K2 (0,2,5) - DCM > 99 80 K1 (2) L2 DMF > 99 81 K1 (1) L2 DMF > 99 80 K1 (2) L3 DMF > 99 93 K1 (1) L3 DMF > 99 94 K1 (0,5) L3 DMF > 99 93 K1 (0.25) L3 DMF > 99 92 K3 (1) L3 THF > 99 84 K3 (0.5) L3 THF > 99 84 K1 (1) L4 DCM > 99 85 K1 (1) L5 DCM > 99 88

DCM - dichloromethane DMF - dimethylfumarate THF - tetrahydrofuran

Analytical procedure

Dilute samples of the reaction mixture to 1 mg / ml with methanol R in a graduated flask and mix in an ultrasonic bath. The sample is analyzed immediately after preparation.

Chemical purity

Test solution: solution in methanol R at a concentration of 1 mg / ml

Column:

- dimensions · 1 = 0.10 m, 0 = 2.1 mm / 6 '• ··

- stationary phase: Cl 8, particle size 2,7 μτη

- temperature: 40 ° C.

Mobile phase:

A: phosphate buffer (0.02 M potassium hydrogen phosphate, pH adjusted to 7.5 ± 0.05 with 1 M potassium hydroxide); 8: acetonitrile R;

gradient elution:

Time (min) Flow rate (ml / min) % A % B 0 0.5 70 30 1 0.5 70 30 6 0.5 20 May 80 7 0.5 70 30 9 0.5 70 30

Detection: spectrophotometer 220 nm

Optical purity

Test solution: 1 mg / ml solution of methanol R

Column:

dimensions: stationary phase: temperature: 1 - 0.15 m, 0 = 4.6 mm Cellucoat, particle size 3.0 µm Deň: 22 ° C Mobile phase: hexane / ethanol 90/10 v / v Eluce: isocratic Flow: 1.0 ml / min Detection: 220 nm spectrophotometer Injection: 10 μΐ

The invention is illustrated by the following examples. These examples, which illustrate the improvement of the process according to the invention, are purely illustrative and do not limit the scope of the invention in any way.

·· · ·

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (16 ') - 6,7-Dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I)

To a solution of 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) (2.7 g, 7.5 mmol) in 30 mL of DCM was added a mixture of formic acid: triethylamine (3.7 g, molar ratio 4: 3) and (R, R) - (p-toluenesulfonyl) -1,2-diphenylethandiamine (chloro) (p-cymene) ruthenaium (II) (25 mg, 37.5 μιηοΐ) ). Stir under N 2 for 6 hours at reflux. The reaction mixture was diluted with 30 mL of DCM, washed with saturated NaHCO 3 solution, water and brine. After drying over MgSO ₄ , the solvent was evaporated in a vacuum evaporator. The residue was dissolved in i-PrOH and ethanolic HCl solution (5 M, 3 mL) was added dropwise with vigorous stirring. The solvent was evaporated in a vacuum evaporator and the solid residue was crystallized from CPrOH / McOH (45 mL). After aspiration and drying, 1.84 g (68%) of white crystals of the product (ee 99.2%) were obtained as the hydrochloride.

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

To a solution of 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) (2.7 g, 7.5 mmol) in 30 mL of DMF was added a mixture of formic acid and triethylamine (3.7 g, 4: 3 molar ratio) and (R, R) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine (chloro) (p-cymene) ruthenium (II) (25 mg, 37 , 5 pmol). Stir under N 2 for 3 hours at 30 ° C. The reaction mixture was evaporated and the residue was dissolved in 30 mL of DCM, washed with saturated NaHCO 3 solution, water and brine. After drying over MgSO 4, the solvent was evaporated in a vacuum evaporator. The residue was dissolved in? -PrOH and ethanolic HCl solution (5 M, 3 mL) was added dropwise with vigorous stirring. The solvent was evaporated in a vacuum evaporator and the solid residue was crystallized from z-PrOH / MeOH (45 mL). After aspiration and drying, 2.25 g (83%) of white crystals of the product (ee 99.6%) were obtained as the hydrochloride.

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

X

Dichloro (p-cymene) ruthenium (II) dimer (11.5 mg, 18.8 pmol) was added to a solution of (1R, 2R) -N (p-toluenesulfonyl) -1,2-diphenylethanediamine (13.7 mg, 37, μπιοί) and triethylamine (150 mg,

1.5 mmol) in acetonitrile (1.2 mL). The solution was stirred for 1 h at 80 ° C and then added to a solution of 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) (2.7 g, 7 , 5 mmol) in 30 mL of DCM. After addition of a mixture of formic acid and triethylamine (3.7 g, in a molar ratio of 4: 3), everything was stirred under N 2 for 6 hours at reflux. The reaction mixture was diluted with 30 mL of DCM, washed with saturated NaHCO 3, water and brine. After drying over MgSO ₄ , the solvent was evaporated in a vacuum evaporator. The residue was dissolved in z-PrOH and ethanolic HCl solution (5 M, 3 mL) was added dropwise with vigorous stirring. The solvent was evaporated in a vacuum evaporator and the solid residue was crystallized from z-PrOH / MeOH (45 mL). After aspiration and drying, 2.05 g (75%) of white crystals of the product (ee 99.1%) were obtained as the hydrochloride.

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

Dichloro (p-cymene) ruthenium (II) dimer (263 mg, 0.43 mmol) was added to a solution of (1R, 2R) -7 N (p-toluenesulfonyl) -1,2-diphenylethanediamine (315 mg, 0.86 mmol) ) and triethylamine (1.74 g, 21.4 mmol) in acetonitrile (25 mL). The solution was stirred for 1 h at 80 ° C and then added to a solution of 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) (39 g, 107 mmol) in 250 ml DMF. After addition of a mixture of formic acid and triethylamine (61 g, in a molar ratio of 4: 3), everything was stirred under N 2 for 3 hours at 35 ° C. The reaction mixture was evaporated and the residue was dissolved in 250 mL of ethyl acetate, washed with saturated NaHCO 3, water and brine. After drying over MgSO ₄ , the solvent was evaporated in a vacuum evaporator. The residue was dissolved in z-PrOH and ethanolic HCl solution (5 M, 40 mL) was added dropwise with vigorous stirring. The solvent was evaporated in a vacuum evaporator and the solid residue was crystallized from z-PrOH / MeOH (150 mL). After aspiration and drying, 38 g (88%) of white crystals of the product (ee 99.8%) were obtained as the hydrochloride.

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

Dichloro (p-cymene) ruthenium (II) dimer (11.5 mg, 18.8 pmol) was added to a solution of (1R, 2R) -ptosyl-1,2-cyclohexadiamine (10.0 mg, 37.5 μπιοί) and triethylamine (75 mg, 0.75 mmol) in acetonitrile (1 mL). The solution was stirred for 1 h at 80 ° C and then added to the solution 6.7X

4ο dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) (1.3 g, 3.8 mmol) in 30 mL of DCM. After addition of a mixture of formic acid and triethylamine (1.9 g, in a molar ratio of 4: 3), everything was stirred under N 2 for 6 hours at reflux. The reaction mixture was diluted with 30 mL of DCM, washed with saturated NaHCO 3, water and brine. After drying over MgSO 4, the solvent was evaporated in a vacuum evaporator. The residue was dissolved in z-PrOH and ethanolic HCl solution (5 M, 1.5 mL) was added dropwise with vigorous stirring. The solvent was evaporated in a vacuum evaporator and the solid residue was crystallized from t-PrOH / MeOH (20 mL). After aspiration and drying, 0.72 g (55%) of white crystals of the product (ee 99.0%) were obtained as the 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 pmol) was added to a solution of (1R, 2R) -7 N (p-toluenesulfonyl) -1,2-diphenylethanediamine (13.7 mg, 37.5 pmol) and triethylamine (75 mg, 0.75 mmol) in acetonitrile (1 mL). The solution was stirred for 1 h at 80 ° C and then added to a solution of 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) (1.3 g, 3 , 8 mmol) in 30 mL THF. After addition of a mixture of formic acid and triethylamine (1.9 g, in a molar ratio of 4: 3), everything was stirred under N 2 for 6 hours at 40 ° C. The reaction mixture was evaporated and the residue was dissolved in 30 mL of DCM, washed with saturated NaHCO 3 solution, water and brine. After drying over MgSO 2, the solvent was evaporated in a vacuum evaporator. The residue was dissolved in i-PrOH and ethanolic HCl solution (5 M, 1.5 mL) was added dropwise with vigorous stirring. The solvent was evaporated in a vacuum evaporator and the solid residue was crystallized from z-PrOH / MeOH (20 mL). After aspiration and drying, 1.07 g (82%) of white crystals of the product (ee 99.4%) were obtained as the hydrochloride.

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

Dichloro (p-cymene) ruthenium (II) dimer (11.5 mg, 18.8 pmol) was added to a solution of (1R, 2R) - N (benzenesulfonyl) -1,2-diphenylethanediamine (13.0 mg, 37 , 5 pmol) and triethylamine (75 mg, 0.75 mmol) in acetonitrile (1 mL). The solution was stirred for 1 h at 80 ° C and then added to a solution of 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) (1.3 g, 3 (8 mmol) in 30 mL of DCM. After addition of a mixture of formic acid and triethylamine (1.9 g, in a molar ratio of 4: 3), everything was stirred under N 2 for 8 hours at reflux.

The reaction mixture was diluted with 30 mL of DCM, washed with saturated NaClCCE solution, water and brine. After drying over MgSO 4, the solvent was evaporated in a vacuum evaporator. The residue was dissolved in t -PrOH and ethanolic HCl solution (5 M, 1.5 mL) was added dropwise with vigorous stirring. The solvent was evaporated in a vacuum evaporator and the solid residue was crystallized from t-PrOH / MeOH (20 mL). After aspiration and drying, 0.85 g (65%) of white crystals of the product (ee 99.0%) were obtained as the hydrochloride.

Example 8 (1 < 6 &gt;) 6,7-Dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) (11.5 mg, 18.8 μηιοί) was added to a solution of (1R, 2R) - N -methanesulfonyl-1,2-diphenylethanediamine (11.0 mg, 37.5 μιηοΐ) and triethylamine (75 mg, 0.75 mmol) in acetonitrile (1 mL). The solution was stirred for 1 h at 80 ° C and then added to a solution of 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) (1.3 g, 3). (8 mmol) in 30 mL of DCM. After addition of a mixture of formic acid and triethylamine (1.9 g, in a molar ratio of 4: 3), everything was stirred under N ₂ for 12 hours at reflux. The reaction mixture was diluted with 30 mL of DCM, washed with saturated NaHCO 3 solution, water and brine. After drying over MgSO 4, the solvent was evaporated in a vacuum evaporator. The residue was dissolved in z-PrOH and ethanolic HCl solution (5 M, 1.5 mL) was added dropwise with vigorous stirring. The solvent was evaporated in a vacuum evaporator and the solid residue was crystallized from z-PrOH / MeOH (20 mL). After aspiration and drying, 0.68 g (52%) of white crystals of the product (ee 99.0%) were obtained as the hydrochloride.

Example 9 (1S) -6,7-Dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I)

Dichloro (p-cymene) ruthenium (II) dimer (69 mg, 0.11 mmol) was added to a solution of (1R, 2R) -7 N (p-toluenesulfonyl) -1,2-diphenylethanediamine (82 mg, 0.22 mmol) ) and triethylamine (0.76 g,

7.5 mmol) in acetonitrile (6 mL). The solution was stirred for 1 h at 80 ° C and then added to a solution of 6,7-dimethoxy-1- [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 DMF. After addition of a mixture of formic acid and triethylamine (20.4 g, in a molar ratio of 4: 3), everything was stirred under N ₂ for 3 hours at 35 ° C. The reaction mixture was poured into 400 mL of water and extracted with 3 x 50 mL of ethyl acetate. The combined extracts were washed with 3 x 50 mL brine. After drying over MgSO 4, a solution of HCl (g) in EtOH (5M, 8.5 g) was added dropwise. After stirring for 30 minutes, the solid was filtered off with suction, washed with 50 ml of ethyl acetate and dried in a vacuum oven. Recrystallization from i-PrOH / MeOH (150 mL) gave 13 g (86%) of white crystals of the product (ee 100%) as the hydrochloride.

Example 10 (Reproduction of the procedure described in the literature - WO2004 / 085403) (15 ') - 6,7-Dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) Dichloro (p-cymene) ruthenium (II) dimer (120 mg, 0.2 mmol) was added to a solution of (1R, 2R) - N (2,4,6-trimethylbenzenesulfonyl) -1,2-diphenylethanediamine (150 mg, 0.4 mmol) and triethylamine (80 mg, 0.8 mmol) in acetonitrile (3 mL). The solution was stirred for 1 h at 80 ° C and then added to a solution of 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) (10.2 g, 28 mmol) in 30 mL DCM. After addition of a mixture of formic acid and triethylamine (5: 2, 14 ml), the mixture was stirred for 16 hours. The reaction mixture was washed with saturated NaHCO 3 solution, water and brine. After drying over MgSO 4, the solvent was evaporated in a vacuum evaporator. The residue was dissolved in i-PrOH and a solution of HCl (g) in i-PrOH (5 M, 10 mL) was added dropwise with vigorous stirring. After aspiration, 9.6 g (85%) of pale yellow crystals of the product (ee 59%) were obtained as the hydrochloride.

Claims (35)

PATENT CLAIMS (15) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) containing the desired S-enantiomer in an enantiomeric excess greater than or equal to 98.0% . (1S) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) according to claim 1, containing the desired S enantiomer in an enantiomeric excess of greater or equal to 99.0%. (1S) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) according to claim 1, containing the desired S enantiomer in an enantiomeric excess of greater or equal to 99.5%. (1S) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) according to claim 1, containing the desired S enantiomer in an enantiomeric excess of greater or equal to 99.9%. A process for the preparation of (1S) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) according to claim 1 (i), characterized in that the substance is: (I) synthesized by reduction of 6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline (II) free base or hydrochloride (II) using (R, R) -N- (p- toluenesulfonyl) -1,2-diphenylethanediamine (chloro) (pymene) ruthenium (II) as a catalyst or using a catalyst generated in situ from a ruthenium complex and a chiral ligand using a catalyst in an amount of less than or equal to 2 mol% based on the reduced compound (II). A process according to claim 5, characterized in that the catalyst is used in an amount of less than or equal to 1 mol%, based on the reduced substance (II). A process according to claims 5 to 6, characterized in that the reduction is carried out under conditions of asymmetric hydrogen transfer hydrogenation. Process according to Claims 5 to 7, characterized in that a ruthenium complex containing ruthenium in the oxidation stage (II) and / or a neutral aromatic group and / or halogen is used to prepare the catalyst generated in situ. Method according to claims 5 to 8, characterized in that the source of ruthenium is dimer dihalogen (p-cymene) ruthenium (II), The process according to claim 9, wherein the ruthenium source is a dimer of dichloro (p-cymene) ruthenium (II). The process according to claim 9, characterized in that the diiodo (p-cymene) ruthenium (II) dimer is used as the source of ruthenium. A process according to claims 5 to 11, wherein the chiral ligand is a ligand selected from the series; (1R, 2R) -N- (benzenesulfonyl) -1,2-diphenylethanediamine, (1R, 2R) -N-methanesulfonyl-1,2-diphenylethanediamine, (1R, 2R) - (-) - Np-tosyl-1 , 2cyclohexadiamine, or particularly preferably (1R, 2R) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine. 13. A process according to claim 12, wherein (1R, 2R) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine is used as the chiral ligand. Process according to claims 5 to 13, characterized in that the catalyst is prepared in situ by mixing the ruthenium complex with the chiral ligand in a molar ratio of 1: 1 to 1: 3. 15. A process according to claim 14 wherein the catalyst is prepared in situ by mixing the ruthenium complex with the chiral ligand in a molar ratio of 1: 2. 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 the addition of an amine. A 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 the addition of triethyl amine. 18. The process of claim 17 wherein the catalyst is prepared in situ by mixing the ruthenium complex with a chiral ligand with triethylamine in an amount of 1 to 30 mol% based on the reduced material. 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 of from 15 ° C to the boiling point of the solvent used. Process according to one of Claims 5 to 19, characterized in that the catalyst is prepared in situ in acetonitrile. Method according to one of Claims 5 to 20, characterized in that the reduction of the substance (I) is carried out in a solvent selected from the series: ethers: diethyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane chlorinated solvents: dichloromethane, chloroform, carbon tetrachloride aromatic hydrocarbons: benzene, toluene, xylene polar aprotic solvents: acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulphoxide hydrocarbons: heptane, cyclohexane, methylcyclohexane alcohols: methanol, ethanol 2-propanol, 1 propanol, 1-butanol, 2-butanol both in anhydrous solvents or their mixtures and in solvents or their mixtures with the addition of water . The method of claim 21, wherein the reduction is carried out in a polar aprotic solvent. A process according to claim 22, wherein the reduction is carried out in dimethylformamide. 24. The method of claim 21 wherein the reduction is carried out in a solvent selected from ethers. 25. The method of claim 24, wherein the reduction is carried out in tetrahydrofuran. A method according to claims 5 to 25, characterized in that the reduction is carried out at a temperature of 15 to 80 ° C. A method according to any one of claims 5 to 26, characterized in that the reduction is carried out at a temperature of 15 to 35 ° C. Method according to one of Claims 5 to 27, characterized in that salts of formic acid, preferably ammonium formate, or mixtures of formic acid with amines are used as the hydrogen source. A process according to any one of claims 5 to 28, wherein the enantiomeric excess of the desired enantiomer is (1S) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3, The 4-tetrahydroisoquinoline in the reaction mixture after the reaction is greater than 80%. The method of claim 29, wherein (1S) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I), obtained from of the reaction mixture 4 »44 •« 4 » 4 * · · 4 * φ · Containing substance (I) in an enantiomeric excess ee of greater than 80%, converted to a salt, which is then crystallized from a suitable solvent, A process according to claim 30, characterized in that substance (I) is converted to the hydrochloride. Process according to claims 30 to 31, characterized in that a branched or unbranched C 1 -C 5 aliphatic alcohol or mixtures thereof with a water content of 0 to 10% by weight is used as the solvent for crystallization. Process according to claims 30 to 32, characterized in that a mixture of methanol and isopropanol is used as the solvent for crystallization. A process for the production of (1S) -6,7-dimethoxy-1- [2- (4-trifluoromethylphenyl) ethyl] -1,2,3,4-tetrahydroisoquinoline (I) according to claims 5 to 33, characterized in that the product is obtained in an enantiomeric excess of ee greater than 99%. 35. The process according to claims 5 to 33, wherein the product is obtained in an enantiomeric excess ee of greater than 99.5%.