WO2011082700A1

WO2011082700A1 - A method for the preparation of 6,7-dimethoxy-1-[2-(4-trifluoromethylphenyl)ethyl]-3,4- dihydroisoquinoline

Info

Publication number: WO2011082700A1
Application number: PCT/CZ2011/000001
Authority: WO
Inventors: Stanislav Radl; Josef Cerny
Original assignee: Zentiva, K.S.
Priority date: 2010-01-05
Filing date: 2011-01-05
Publication date: 2011-07-14
Also published as: CZ20106A3; CZ302637B6

Abstract

The invention relates to a method of preparing 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl) ethyl]-3,4-dihydroisoquinoline I by cyclization of substance III, wherein the R substituent is a C1-C4 alkyl group, under conditions of acidic catalysis, the acidic catalyst being a strong inorganic acid, polyphosphoric acid or phosphorus oxychloride. The compound of formula (I) represents the key intermediate of synthesis of almorexant. (Formulae (I), (III))

Description

A method for the preparation of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4- dihydroisoquinoline

Technical Field

The invention deals with a method for the preparation of 6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline I by cyclization of starting compound III under conditions of acidic catalysis.

The compound of formula I represents the key intermediate of synthesis of almorexant, which is being developed by Actelion Pharmaceuticals as a medicine for treatment of primary insomnia. Background Art

The basic patent application no. WO2004/085403 described a preparation of 6,7-dimethoxy-l - [2-(4-trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline I. The preparation method consists in closing the dihydroisoquinoline ring by means of phosphorus oxychloride under boiling conditions. The starting substance is N-[2-(3,4-dimethoxyphenyl)-ethyl]-3-(4- trifluoromethylphenyl)-propionamide (II) and the reaction was performed in acetonitrile as the solvent. The same procedure was also described in the patent application no. WO2005/1 18548A1. In the patent application no. WO2009/083899 A2 the same procedure was applied, but toluene was used as the solvent.

(II) (I)

In the course of our development of an industrial process for the synthesis of (aR,lS)-a- phenyl-3,4-dihydro-6,7-dimethoxy-N-methyl-1 2-[4-(trifluoromethyl)phenyl]ethyl]-2-(lH)- isoquinoline acetamide (almorexant), we have found desirable to develop a more

advantageous method for the preparation of the 6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline intermediate I. It was necessary to obtain this substance in the highest possible purity as it is its purity that the subsequent steps leading to production of almorexant depend on, and also in a high yield to make the process economically efficient.

Disclosure of Invention

The invention provides a new method for the preparation of 6,7-dimethoxy-l-[2-(4- trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline I. This is prepared by cyclization of the corresponding amide III under acidic catalysis in a suitable solvent. A great advantage of this way of preparation of substance I consists in nearly quantitative transformation of the amide III during the cyclization and obtaining substance I in very high purity and very good yield.

(I") (I)

Detailed Description of Invention The synthesis starts with the amide of a suitable acid IV, which reacts with 3-(4- trifluoromethylphenyl)propionyl chloride V under Friedel-Crafts acylation conditions (with aluminium chloride as a catalyst), providing the intermediate III. The reaction can be performed in solvents that are suitable for this type of reaction such as chlorinated solvents, e.g. dichloromethane, 1 ,2-dichloroethane, or in nitrated solvents such as nitromethane or nitrobenzene.

The intermediates IV that are suitable for this reaction contain as the R substituent is hydrogen, an unbranched C₁-C5 alkyl, e.g. methyl, ethyl, propyl, butyl or pentyl; a branched alkyl, e.g. isopropyl, isobutyl, tert-butyl or neopentyl; or an C₇-C8 arylalkyl, e.g. benzyl, 2- methylbenzyl, 3-methylbenzyl or 4-methylbenzyl. R in compound III has the same meaning as in compound IV. Preferably, R in compound III is a C₁ -C4 alkyl.

Cyclization of the amide III can be carried out in a suitable solvent under acidic catalysis. Suitable solvents for this reaction are ethers, e.g. diethyl ether, methyl-t-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, or dioxane; chlorinated solvents, e.g. dichloromethane, dichloroethane, chloroform or tetrachloromethane; hydrocarbons, e.g. heptane, cyclohexane or methylcyclohexane; aromatic hydrocarbons, e.g. benzene, toluene, or xylene; aliphatic ketones, e.g. acetone, 2-butanone or methyhsobutylketone. For this reaction it is suitable to use branched or unbranched Ci-C₆ alcohols, e.g. methanol, ethanol, 2-propanol, 1-propanol, 1-butanol or 2-butanol; branched or unbranched Ci-C₆ aliphatic acids, e.g. acetic or propionic acids, or esters of branched or unbranched C]-C₆ alcohols with branched or unbranched Ci-C₆ acids, such as ethyl acetate, isopropyl acetate, isobutyl acetate or butyl acetate. Also, aprotic polar solvents, e.g. acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone or dimethylsulfoxide, are suitable for the reaction. The reaction can be performed both in anhydrous solvents or their mixtures and in solvents or their mixtures with a content of water. It is convenient to use a Ci-C₆ alcohol or a Ci-C₆ aliphatic acid as the solvent. A suitable acidic reagent for the cyclization can be one of strong inorganic acids such as hydrochloric, hydrobromic, sulphuric or phosphoric acids, both concentrated and diluted. Using polyphosphoric acid or ethyl polyphosphate has also proved to be convenient. Other suitable acidic reagents are organic acids, e.g. formic, acetic or pivalic acids, and also sulfonic acids, e.g. methane sulfonic, benzene sulfonic or toluene sulfonic acids. A number of derivatives of inorganic reagents can also be used, such as phosphorus oxychloride, thionyl chloride, sulphuryl chloride, or oxalyl chloride. The cyclization is preferably performed with hydrochloric acid, sulphuric acid, phosphorus oxychloride or polyphosphoric acid.

The carrying out of the reaction consists in dissolution of the reagent HI in the corresponding solvent at a temperature from the laboratory temperature to the boiling point of the solvent. Then, the acidic reagent is added in a quantity from the catalytic quantity to 10 equivalents, preferably from 1 to 3 equivalents. The reaction itself can be carried out at temperatures from 20 °C to the boiling point of the solvent and the reaction times can vary from 2 to 24 hours depending on the conditions. After this time period, our analyses of the reaction mixture have confirmed that the reactant III had got almost quantitatively cyclized to the product I. The latter can be subsequently isolated by means of extraction from the reaction mixture and crystallization from a suitable solvent, or by evaporation of the reaction mixture and subsequent crystallization. This way, 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4- dihydroisoquinoline I can be advantageously obtained with a purity higher than 98%, usually with a purity higher than 99% and in good yields.

The invention is explained in a more detailed way in the following working examples. These examples exclusively have an illustrative character and do not limit the scope of the invention in any respect.

Workine Examples

Example 1

1 -[2-(2-Acetamidoethyl)-4,5-dimethoxyphenyl]-3-(4-trimethylphenyl)- 1 -propanone (Ilia) A solution of l-(3,4-dimethoxyphenyl)-ethyl acetamide (1 g) and 4-(trifluoromethylphenyl)- propionyl chloride (3.2 g) in nitrobenzene was cooled to 0 °C. A1C1₃ (1.2 g) was added to the solution and the reaction mixture was heated up to 35 °C. After 3 hours of stirring at 35 °C the reaction mixture was poured into a mixture of water and ice (100 g). Nitrobenzene was removed by carrier vapour distillation; the residue was cooled down and extracted with dichloromethane (2x 20 ml). The combined extracts were washed with a diluted solution of NaOH, with water and dried with MgS0₄. After evaporation of the solvent the product was crystallized from methanol. 1.05 g (55%) of a white solid substance was obtained.

Example 2

1 -[2-(2-Propionamidoethyl)-4,5-dimethoxyphenyl]-3-(4-trimethylphenyl)- 1 -propanone (Illb) A solution of l-(3,4-dimethoxyphenyl)-ethyl propionamide (1 g) and 4- (trifluoromethylphenyl)-propionyl chloride (3.2 g) in nitrobenzene was cooled to 0 °C. A1C1₃ (1.2 g) was added to the solution and the reaction mixture was heated up to 35 °C. After 4 hours of stirring at 35 °C the reaction mixture was poured into a mixture of water and ice (100 g). Nitrobenzene was removed by carrier vapour distillation; the residue was cooled down and extracted with dichloromethane (2x 20 ml). The combined extracts were washed with a diluted solution of NaOH, with water and dried with MgS0₄. After evaporation of the solvent the product was crystallized from methanol. 1.0 g (50%) of a white solid substance was obtained.

Example 3

6,7-Dimethoxy- 1 -[2-(4-trifluormethylphenyl)ethyl]-3,4-dihydroisoquinoline (I) l-[2-(2-acetamidoethyl)-4,5-dimethoxyphenyl]-3-(4-trimethylphenyl)-l-propanone (1 g) was dissolved in ethanol (40 ml) at 60 °C. After addition of hydrochloric acid (4 ml, a 15% solution) the reaction mixture was heated up to reflux. After 16 hours of refluxing the solvent was evaporated, the solid residue was crystallized from a minimum amount of dioxane. After aspiration and drying, 0.86 g (92%) of a slightly yellowish solid substance of the product in the hydrochloride form was obtained.

Example 4 6,7-Dimethoxy- 1 -[2-(4-trifluormethylphenyl)ethyl]-3,4-dihydroisoquinoline (I) l-[2-(2-propionamidoethyl)-4,5-dimethoxyphenyl]-3-(4-trimethylphenyl)-l-propanone (1 g) was dissolved in ethanol (40 ml) at 60 °C. After addition of hydrochloric acid (4 ml, a 15% solution) the reaction mixture was heated up to reflux. After 24 hours of refluxing the solvent was evaporated and the solid residue was crystallized from a minimum amount of dioxane. After aspiration and drying, 0.83 g (86%) of a slightly yellowish solid substance of the product in the hydrochloride form was obtained. Example 5

6,7-Dimethoxy- 1 -[2-(4-trifluormethylphenyl)ethyl]-3,4-dihydroisoquinoline (I) l-[2-(2-acetamidoethyl)-4,5-dimethoxyphenyl]-3-(4-trimethylphenyl)-l-propanone (1 g) was dissolved in ethanol (40 ml) at 60 °C. After addition of sulphuric acid (4 ml, a 50% solution) the reaction mixture was heated up to reflux. After 12 hours of refluxing the solvent was evaporated and the solid residue was crystallized from a minimum amount of dioxane. After aspiration and drying, 0.97 g (89%) of a slightly yellowish solid substance of the product in the hydrogensulphate form was obtained.

Example 6

6,7-Dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline (I) l-[2-(2-acetamidoethyl)-4,5-dimethoxyphenyl]-3-(4-trimethylphenyl)-l-propanone (1 g) was dissolved in 2-propanol (50 ml) at 60 °C. After addition of POCl₃ (5 ml) the reaction mixture was heated up to reflux. After 14 hours of refluxing the solvent was evaporated and the solid residue was transformed to the hydrochloride. The latter was crystallized from a minimum amount of dioxane. After aspiration and drying, 0.84 g (90%) of a slightly yellowish solid substance of the product in the hydrochloride form was obtained.

Example 7

6,7-Dimethoxy-l-[2-(4-trifluormethylphenyl)ethyl]-3,4-dihydroisoquinoline (I) To a mixture of l-[2-(2-acetamidoethyl)-4,5-dimethoxyphenyl]-3-(4-trimethylphenyl)-l- propanone (1 g) with acetic acid (10 ml), 85% polyphosphoric acid (2.5 g) was added and the mixture was refluxed for 12 h. After addition of water (25 ml) the mixture was stirred at the laboratory temperature overnight; the insoluble fraction was aspirated and the rubber-like product was then transformed to a crystalline hydrochloride in a common way, which was crystallized from a minimum amount of dioxane. After aspiration and drying, 0.83 g (86%) of a slightly yellowish solid substance of the product in the hydrochloride form was obtained.

Claims

C L A I M S

1. A method for the production of 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4- dihydroisoquinoline I

characterized in that substance of formula III

wherein R is hydrogen, a C1-C5 alkyl or C7-C8 arylalkyl group,

is cyclized under conditions of acidic catalysis.

2. The production method according to claim 1, characterized in that R is methyl.

3. The production method according to claims 1 and 2, characterized in that R is ethyl.

4. The production method according to claims 1 to 3, characterized in that the acidic catalyst is a strong inorganic acid.

5. The production method according to claims 1 to 4, characterized in that the acidic catalyst is hydrochloric acid.

6. The production method according to claim 1, characterized in that the acidic catalyst is phosphorus oxychloride.

7. The production method according to claim 1 , characterized in that the acidic catalyst is polyphosphoric acid.

8. 6,7-dimethoxy-l-[2-(4-trifluoromethylphenyl)ethyl]-3,4-dihydroisoquinoline (I), prepared by the method according to claims 1 to 7.

9. 6,7-dimethoxy-l-[2-(4-trifluormethylphenyl)ethyl]-3,4-dihydroisoquinoline (I) according to claim 8, characterized in that its purity (HPLC) is higher than 98%.

10. 6,7-dimethoxy-l-[2-(4-trifluormethylphenyl)ethyl]-3,4-dihydroisoquinoline (I) according to claim 9, characterized in that its purity (HPLC) is higher than 99%.

11. A method for the production of (aR, 1 S)-a-phenyl-3 ,4-dihydro-6,7-dimethoxy- V-methyl- 1 - [2-[4-(trifluoromethyl)phenyl]ethyl]-2-(lH)-isoquinoline acetamide (almorexant) using the compound of formula I according to claim 1 as an intermediate, characterized in that the compound of formula I is obtained by a method of any one of claims 1-7.