WO2000008009A1

WO2000008009A1 - Process for the preparation of 2-(aminophenoxymethyl) chromans

Info

Publication number: WO2000008009A1
Application number: PCT/EP1999/005659
Authority: WO
Inventors: Ulrich Veith
Original assignee: Sankyo Company, Limited; Lonza Ag
Priority date: 1998-08-04
Filing date: 1999-08-03
Publication date: 2000-02-17
Also published as: AU5510399A

Abstract

2-(Aminophenoxymethyl)chromans of general formula (I) in which one of the radicals R1 to R5 is an amino group and the others are independently of one another hydrogen or C¿1-4?-alkyl, R?6¿ is hydrogen or methyl, and R?7 to R10¿ independently of one another are hydrogen, C¿1-4?-alkyl, hydroxyl, C1-4-alkoxy or C1-4-acyloxy, are prepared in one stage by catalytic hydrogenation of the corresponding 2-(nitrophenoxymethyl)chroman-4-ones above 100 °C on a platinum catalyst. The compounds which can be prepared according to the invention are intermediates in the synthesis of pharmaceutical active ingredients, in particular hypolipidemics.

Description

Process for the preparation of 2- (aminophenoxymethyl) chromans

The present invention relates to a process for the preparation of 2- (aminophenoxymethyl) chromans of the general formula

in which one of the radicals R¹ to R⁵ is an amino group and the others are independently of one another hydrogen or Cι_₄-alkyl,

R⁶ is hydrogen or methyl, and R⁷ to R¹⁰ independently of one another are hydrogen,

Ci-₄-alkyl, hydroxyl, Cι-₄-alkoxy or Cι_-acyloxy.

Ci-₄-Alkyl are here and below taken to mean all linear or branched, primary, secondary and tertiary alkyl groups having from 1 to 4 carbon atoms, i.e., in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Correspondingly, Ci-₄-alkoxy is taken to mean the groups composed of Cι-₄- alkyl and oxygen.

In particular, Cι-4-acyloxy is taken to mean formyloxy, acetoxy, propionyloxy, butyryloxy and isobutyryloxy .

The 2- (aminophenoxymethyl) chromans (I) which can be prepared according to the invention are intermediates for the preparation of pharmaceutical active ingredients, for example of hypolipidemies ( J. Med. Chem . 1989, 32, 421) .

It is known that compounds of the formula I, in particular those in which R¹, R², R⁴ and R⁵ are hydrogen, R³ is amino, R⁸ is hydroxyl, and R⁶, R⁷, R⁹ and R¹⁰ are C_ι-₄-alkyl, can be prepared by reduction of the corresponding (nitrophenoxymethyl) chroman-4-ones (EP-A- 0 556 830) . This reduction takes place in three stages, the nitro group firstly being reduced catalytically using hydrogen to give the amino group, then the resulting 2- (aminophenoxymethyl) chroman-4-one being reduced according to Meerwein-Ponndorf to give the corresponding chroman-4-ol, and, finally, the 3- chromene formed therefrom by elimination of water being hydrogenated catalytically to give the chroman. Although this process gives satisfactory yields, it is rather laborious.

The object of the present invention was therefore to provide a simplified process for the preparation of the 2- (aminophenoxymethyl) chromans of the general formula I.

According to the invention, this object is achieved by the process according to Patent Claim 1.

Surprisingly, it has been found that it is possible to prepare 2- (aminophenoxymethyl) chromans of the general formula

in which one of the radicals R¹ to R⁵ is an amino group and the others are independently of one another hydrogen or Cι--alkyl, R⁶ is hydrogen or methyl, and R⁷ to R¹⁰ independently of one another are hydrogen, Ci-₄-alkyl, hydroxyl, Cι-₄-alkoxy or Cι-₄-acyloxy, in a single stage by catalytic hydrogenation of the corresponding 2- (nitrophenoxymethyl) chroman-4-ones of the general formula

in which one of the radicals R^1' to R^5' is a nitro group and the others are independently of one another hydrogen or Cι-4-alkyl, and R⁶ to R¹⁰ are as defined above, in the presence of a platinum catalyst in an organic solvent at a temperature above 100°C.

This is all the more surprising since, at temperatures below 100°C using comparable catalysts, only the nitro group has been reduced and/or the keto group of the chroman-4-one has only been reduced to the chroman-4-ol

(EP-A-0 556 830), while the end product I could not be detected.

The 2- (nitrophenoxymethyl) chroman-4-ones of the general formula II are known compounds or can be prepared analogously to those by known methods (e.g. according to EP-A-0 139 421) from commercially available starting materials.

The platinum catalyst used is preferably a partially poisoned platinum catalyst. Particularly preferably partially poisoned platinum catalysts are supported platinum catalysts which have been treated with a sulphur compound.

Particularly suitable supports are activated carbon, graphite or aluminium oxide. Suitable sulphur compounds are organic or soluble inorganic sulphur compounds, in particular those in which the sulphur has an oxidation number of less than +6.

Particular preference is given to supported platinum catalysts containing activated carbon as support. Very particularly favourable results have been achieved using the platinum/activated carbon catalysts obtainable from Engelhard under the designation "sulphited". Organic solvents which can be used are, in particular, open-chain or cyclic ethers, such as, for example, methyl tert-butyl ether, tetrahydrofuran or dioxane, alcohols, such as, for example, methanol, ethanol or isopropanol, aromatic hydrocarbons, such as, for example, benzene or alkylbenzenes, or mixtures of said solvents. It has been found that small amounts of water, in particular the water present in the catalyst, which is usually supplied and stored in moist form, and/or the water which forms as byproduct during the hydrogenation, do not significantly impair the reaction.

Particularly preferred organic solvents are aromatic hydrocarbons and solvent mixtures which comprise aromatic hydrocarbons. Very particularly preferred organic solvents are toluene and toluenic solvent mixtures.

The process according to the invention is preferably carried out at temperatures of up to 180°C.

The hydrogen pressure is preferably from 1 to 50 bar.

The process according to the invention is preferably carried out with compounds in which R⁶ is a methyl group.

Likewise preferred is the preparation of those compounds (I) in which R⁸ is an optionally etherified or esterified hydroxyl group, i.e. hydroxyl, Cι-₄ ^_alkoxy or Cι_₄-acyloxy .

Also preferred is the preparation of those compounds in which R⁷, R⁹ and R¹⁰ are methyl groups. Preference is also given to the preparation of p-aminophenoxy compounds, i.e. those in which R³ is amino, and R¹, R², R⁴ and R⁵ are hydrogen atoms. The examples below illustrate how the process according to the invention is carried out but are not intended to impose any limitation.

Example 1

2- (4 -Aminophenoxymethyl) -2,5,7 , 8-tetramethylchroman-6- yl acetate

(I, R¹ = R² = R⁴ = R⁵ = H, R³ = NH₂, R⁶ = R⁷ = R⁹ = R¹⁰ = Me, R⁸ = AcO) 9.49 g (22.5 mmol) of 2, 5, 7, 8-tetramethyl-2- (4- nitrophenoxymethyl) -4-oxochroman-6-yl acetate and 8.44 g of platinum/activated carbon (3% Pt, "sulphited", Engelhard sample code 41342, water content 55.75%) were introduced into 40 ml of toluene. Hydrogen was then injected and the mixture was hydrogenated for 7 h at 147-150°C and 10 bar. The reaction mixture was filtered through a G4 glass suction filter at about 60°C and washed with 2 x 15 ml of dioxane. The catalyst was resuspended in 40 ml of dioxane and stirred at 80°C for 30 min. The mixture was then filtered again and the filtrates were combined. Concentration by evaporation under reduced pressure gave 8.63 g [55.7%; content (HPLC) : 53.7%] of the title compound.

^XH MR (DMSO-d⁶, 400 MHz) : δ = 1.29 (s, 3H) ; 1.83 (m,

1H) ; 1.91 (s, 3H) ; 1.94

(s, 3H) ; 1.98 ( , 1H) ;

2.00 (s, 3H) ; 2.30 (s,

3H) ; 2.61 ( , 2H) ; 3.82 (d, 1H) ; 3.86 (d, 1H) ;

4.58 (s, 2H) ; 6.49 ( ,

2H) ; 6.67 (m, 2H) .

Example 2 (not according to the invention) 4- [ (6-Acetoxy-2,5,7,8-tetramethyl-4-oxo-2- chromanyl ) methoxy] aniline and 2- ( -aminophenoxymethyl) - 2,5,7, 8-tetramethylchroman-6-yl acetate

9.35 g (22.5 mmol) of 2, 5, 7, 8-tetramethyl-2- ( 4- nitrophenoxymethyl) -4-oxochroman-6-yl acetate [content (HPLC) : 99.5%] and 4.22 g of platinum/activated carbon (see Example 1) were introduced into 40 ml of water. Hydrogen was then injected and the mixture was hydrogenated for 22 h at 100°C and 8.1-11.1 bar. After the pressure had been released, the reaction mixture was filtered while warm through a G4 suction filter. The catalyst was resuspended in 40 ml of dioxane and stirred at 80°C for 60 min. The mixture was then filtered again and the filtrates were combined. Concentration by evaporation under reduced pressure gave 7.34 g [74.5%; content (HPLC) : 83.1%] of 4-[(6- acetoxy-2, 5, 7, 8-tetramethyl-4-oxo-2-chromanyl]methoxy] - aniline as solid, which, according to HPLC analysis, still comprised 108 mg (1.4%) of 2- (4- aminophenoxymethyl) -2, 5, 7, 8-tetramethylchroman-6-yl acetate.

Spectroscopic data of 4- [ ( 6-acetoxy-2, 5, 7, 8- tetramethyl-4-oxochroman-2-yl) methoxy] aniline :

^XH NMR (DMSO-d⁶, 400 MHz): δ = 1.39 (s, 3H) ; 2.04 (s,

3H) ; 2.09 (s, 3H) ; 2.30

(s, 3H) ; 2.37 (s, 3H) ;

2.73 (d, 1H) ; 3.05 (d,

1H) ; 3.95 (d, 1H) ; 4.02 (d, 1H) ; 4.60 (s, 2H) ;

6.46 (m, 2H) ; 6.63 (m, 2H) .

Example 3 2- (4 -Aminophenoxymethyl) -2,5,7, 8-tetramethylchroman-6- yl acetate

9.49 g (22.5 mmol) of 2, 5, 7, 8-tetramethyl-2- (4- nitrophenoxymethyl) -4-oxochroman-6-yl acetate [content (HPLC) : 98.0%] and 4.53 g of platinum/activated carbon (5% Pt, "sulphited", Engelhard sample code 7056, water content 58.90%) were introduced into 40 ml of toluene. Hydrogen was then injected and the mixture was hydrogenated for 15 h at 130°C and 10 bar. After the pressure had been released, the mixture was worked up as in Example 1.

Concentration by evaporation under reduced pressure gave 8.78 g [41.4%; content (HPLC): 39.2%] of 2- (4-aminophenoxymethyl) -2, 5, 7, 8-tetramethylchroman-6- yl acetate.

Example 4

2- (4-Aminophenoxymethyl) -2,5,7, 8-tetramethylchroman-6- γl acetate

9.49 g (22.5 mmol) of 2, 5, 7, 8-tetramethyl-2- (4- nitrophenoxymethyl) -4-oxochroman-6-yl acetate [content

(HPLC): 98.0%] and 4.27 g of platinum/activated carbon (5% Pt, "sulphited", Engelhard sample code 41625; water content 56.47%) were introduced into 40 ml of toluene. Hydrogen was then injected and the mixture was hydrogenated for 16 h at 130°C and 7.6-11.5 bar. After the pressure had been released, the mixture was worked up as in Example 1. Concentration by evaporation under reduced pressure gave 9.06 g [23.8%; content (HPLC): 21.8%] of 2- (4-aminophenoxymethyl) -2, 5, 7, 8-tetramethyl- chroman-6-yl acetate. The residue consisted essentially of the intermediate 4- [ ( 6-acetoxy-2, 5, 7, 8-tetramethyl- 4-oxochroman-2-yl ) methoxy] aniline .

Example 5

2- (4-Aminophenoxymethyl) -2 ,5 ,7 , 8-tetramethylchroman-6- yl acetate

9.50 g (22.5 mmol) of 2, 5, 7, 8-tetramethyl-2- (4- nitrophenoxymethyl) -4-oxochroman-6-yl acetate [content

(HPLC): 98.0%] and 3.82 g of platinum/activated carbon (5% Pt, Johnson Matthey Batch No. 98188, water content 51.0%) were introduced into 40 ml of toluene. Hydrogen was then injected and the mixture was hydrogenated for 23 h at 130°C and 11-14 bar. After the pressure had been released, 11.9% of 2- (4-aminophenoxymethyl) - 2, 5, 7, 8-tetramethylchroman-6-yl acetate were found. Example 6

2- (4-Aminophenoxymethyl) -2,5,7, 8-tetramethγlchroman-6- yl acetate

4.22 g of platinum/activated carbon (see Example 1) were introduced into 30 ml of toluene and the water was removed azeotropically therefrom on a water separator. The mixture was then transferred to a hydrogenation autoclave, the flask was rinsed with 18 ml of toluene, and 9.30 g (22.5 mmol) of 2,5,7,8- tetramethyl-2- ( 4-nitrophenoxymethyl ) -4-oxochroman- 6-yl acetate [content (HPLC): >99.9%] were added. Hydrogen was injected and the mixture was hydrogenated for 18 h at 150°C and 7.2-9.8 bar. After the pressure had been released, the mixture was worked up as in Example 1. Concentration by evaporation under reduced pressure gave 9.14 g [38.9%; content (HPLC): 35.4%] of 2-(4- aminophenoxymethyl) -2,5,7, 8-tetramethylchroman- 6-yl acetate . 4- [ ( 6-Acetoxy-2, 5,7, 8-tetramethyl-4-oxo-2- chromanyl)methoxy] aniline, 2,5,7, 8-tetramethyl-2- (4- aminophenoxymethyl) -chroman-6-ol and 2- (4-acetylamino- phenoxymethyl) -2,5,7, 8-tetramethylchroman-6-yl acetate were also detected in the crude product.

Spectroscopic data of the other products: 2,5,7, 8-tetramethyl-2- (4-aminophenoxymethyl) chroman-6-ol :

^αH NMR (DMSO-d⁶, 400 MHz; δ = = 1.26 (s, 3H) ; 1.77 (m,

1H) ; 1.95 (m, 1H) ; 1.97

(s, 3H) ; 2.04 (s, 3H) ;

2.07 (s, 3H), 2.57 (m,

2H) ; 3.75 (d, 2H) ; 3.82

(d, 2H) ; 4.58 (s, 2H) ;

6.48 ( , 2H) ; 6.66 ( ,

2H) ; 7.38 (s, 1H) .

2- (4-Acetylaminophenoxymethyl) -2,5,7, 8-tetramethylchroman- 6-yl acetate:

^lE NMR (DMSO-d⁶, 400 MHz): δ = 1.33 (s, 3H) ; 1.84 (m,

1H) ; 1.92 (m, 6H) ; 1.99 ( s , 6H ) ; 2 . 01 (m, 1H ) ;

2 . 30 ( s , 3H) ; 2 . 63 (m,

2H ) ; 3 . 93 ( d, 1H) ; 3 . 97

( d, 2H ) ; 6 . 90 (m, 2H) ; ^" 7 . 45 (m, 2H) ; 9 . 74 ( s ,

1H ) .

Example 7

2- ( -Aminophenoxymethyl) -2,5,7, 8-tetramethylchroman-6- yl acetate

9.35 g (22.5 mmol) of 2, 5, 7, 8-tetramethyl-2- (4- nitrophenoxymethyl) -4-oxochroman-6-yl acetate [content

(HPLC): 99.5%] and 4.35 g of platinum/activated carbon

(see Example 1) were introduced into 40 ml of dioxane. Hydrogen was then injected and the mixture was hydrogenated firstly for 2.5 h at 80°C, then for 3 h at 100°C and finally for 15 h at 120°C. The hydrogen pressure was 10 bar in each case. After the pressure had been released, the reaction mixture was filtered whilst warm through a G4 suction filter and the filter cake was washed with 15 ml of dioxane. Concentration by evaporation under reduced pressure gave 7.99 g [8.7%; content (HPLC): 12.1%] of 2- (4-aminophenoxymethyl) - 2, 5, 7, 8-tetramethylchroman-6-yl acetate. The remainder of the crude product consisted essentially of the intermediate 4- [ ( 6-acetoxy-2, 5, 7, 8-tetramethyl-4-oxo-2- chromanyl ) methoxy] aniline .

Example 8 (not according to the invention) 2- (4-Aminophenoxymethyl) -2,5,7, 8-tetramethylchroman-6- yl acetate

9.42 g (22.5 mmol) of 2, 5, 7, 8-tetramethyl-2- (4- nitrophenoxymethyl) -4-oxochroman-6-yl acetate [content (HPLC): 98.7%] and 4.15 g of platinum/activated carbon (5% Pt, Johnson Matthey Type 131 paste, water content 54.60%) were introduced into 40 ml of toluene. Hydrogen was then injected and the mixture was hydrogenated firstly for 2 h at 80°C/6.7-8.9 bar, then for 16 h at 100°C/10 bar. The reaction mixture was filtered while warm through a G4 suction filter. The catalyst was resuspended in 40 ml of dioxane and stirred for 30 min at 80°C. The mixture was then filtered again and the filtrates were combined. Concentration by evaporation under reduced pressure gave 8.17 g of crude product with an HPLC content of 1.3% of 2- (4- aminophenoxymethyl) -2,5,7, 8-tetramethylchroman- 6-yl acetate and 68.4% of 4- [ ( 6-acetoxy-2, 5, 7, 8-tetramethyl- 4-oxo-2-chromanyl) ethoxy] aniline, corresponding to a yield of 2- (4-aminophenoxymethyl) -2, 5, 7, 8-tetramethyl- chroman-6-yl acetate of 106 mg (1.3%) and of 4-[(6- acetoxy-2, 5, 7, 8-tetramethyl-4-oxo-2-chromanyl) methoxy] - aniline of 5.59 g (64.8%).

The crude mixture also comprised 1.97 g (22.7%) of isomeric 4- [ ( 6-acetoxy-2, 5, 7, 8-tetramethyl-4- hydroxy-2-chromanyl) ethoxy] aminobenzenes .

Spectroscopic data of 4- [ ( 6-acetoxy-2, 5, 7, 8- tetramethyl-4-hydroxy-2-chromanyl ) ethoxy] aminobenzene (stereoisomeric mixture) :

²H NMR (DMSO-d⁶, 400 MHz): δ = 1.44 (s, 3H, both isomers) ; 1.93-2.24 (m,

12H, both isomers); 2.31

(s, 3H, one isomer) ; 2.32 (s, 3H, one isomer); 3.85

(d, 1H, one isomer); 3.89 (d, 1H, one isomer); 3.90 (d, 1H, one isomer); 4.04 (d, 1H, one isomer); 3.52 (s, 1H, one isomer); 3.77

(s, 1H, one isomer); 4.75 (m, 1H, one isomer); 5.07 (dd, 1H, 1 isomer) ; 6.43 (m, 2H, one isomer); 6.49 (m, 2H, one isomer); 6.58

(m, 2H, one isomer); 6.68 (m, 2H, one isomer) . Example 9

2,5,7 ,8-Tetramethyl-2- (4-aminophenoxymethyl) chroman-6-ol

(I, R¹ = R² = R⁴ = R⁵ = H, R³ = NH₂, R⁶ = R⁷ = R⁹ = R¹⁰ = Me, R⁸ = OH) ^■ 8.52 g (22.5 mmol) of 6-hydroxy-2, 5, 7, 8- tetramethyl-3- (4-nitrophenoxymethyl) chroman-4-one and 3.80 g of platinum/activated carbon (see Example 1) were introduced into 36 ml of toluene. Hydrogen was then injected and the mixture was hydrogenated for 22 h at 139-142°C and 10-15 bar. The reaction mixture was filtered while hot through a G4 suction filter and then washed with 30 ml of toluene. The catalyst was resuspended in a mixture of 48 ml of toluene and 11 ml of methanol and stirred for 40 min at 60°C. The mixture was then filtered again and the filtrates were combined. Concentration by evaporation under reduced pressure gave 7.27 g [74.7%; content (HPLC): 75.7%] of 2,5,7, 8-tetramethyl-2- (4-aminophenoxymethyl) chroman- 6-ol. The crude product was recrystallized from ethanol.

^αH NMR (DMSO-d⁶, 400 MHz) : δ 1.27 (s, 3H) ; 1.77 (m,

IH) ; 1.95 (m, IH) ; 1.96

(s, 3H) ; 2.03 (s, 3H) ;

2.08 (s, 3H) ; 2.53 (m,

2H) ; 3.78 (q, 2H) ; 4.58

(s, 2H) ; 6.49 (m, 2H) ;

6.66 (m, 2H) ; 7.39 (s,

IH) .

Claims

1. Process for the preparation of (aminophenoxymethyl) chromans of the general formula

in which one of the radicals R¹ to R⁵ is an amino group and the others are independently of one another hydrogen or C╬╣_-alkyl, R⁶ is hydrogen or methyl, and R⁷ to R¹⁰ independently of one another are hydrogen, C╬╣-₄-alkyl, hydroxyl, C╬╣_₄-alkoxy or C╬╣--acyloxy, characterized in that a 2- (nitrophenoxymethyl) chroman- 4-one of the general formula

in which one of the radicals R^1' to R^5' is a nitro group and the others are independently of one another hydrogen or C╬╣-₄-alkyl, and R⁶ to R¹⁰ are as defined above, is hydrogenated above 100┬░C in the presence of a platinum catalyst in an organic solvent.

2. Process according to Claim 1, characterized in that the platinum catalyst used is a partially poisoned platinum catalyst.

3. Process according to Claim 2, characterized in that the partially poisoned platinum catalyst used is a supported platinum catalyst treated with a sulphur compound .

4. Process according to Claim 3, characterized in that the supported platinum catalyst used is platinum on activated carbon.

5. Process according to one of Claims 1 to 4, characterized in that the organic solvent is an aromatic hydrocarbon or a solvent mixture comprising an aromatic hydrocarbon.

6. Process according to Claim 5, characterized in that the aromatic hydrocarbon used is toluene.

7. Process according to one of Claims 1 to 6, characterized in that the hydrogenation is carried out at a temperature of up to 180┬░C.

8. Process according to one of Claims 1 to 7, characterized in that R⁶ is methyl.

9. Process according to one of Claims 1 to 8, characterized in that R⁸ is hydroxyl, C╬╣_₄-alkoxy or C╬╣_₄- acyloxy.

10. Process according to one of Claims 1 to 9, characterized in that R⁷, R⁹ and R¹⁰ are methyl groups.

11. Process according to one of Claims 1 to 10, characterized in that R³ is an amino group, and R¹, R²,

R⁴ and R⁵ are hydrogen atoms .