NO764290L - - Google Patents

Description

=, The present invention relates to a new method for the production of indane derivatives with the general formula:

where R 1 is a hydrogen atom or an arylcarbonyl group which may be substituted; R 2 is a hydrogen atom or a cycloalkyl group and is a hydrogen atom or a halogen atom.

The indane derivatives of formula I have very good analgesic, anti-inflammatory and antipyretic properties and are important as e.g. analgesic, anti-inflammatory and antipyretic agents for humans and animals. Methods for producing these compounds are described, e.g. in US Patent No. 3,923. 866 and 3,953,500. However, these known processes are not satisfactory in terms of process steps, yield, purification, etc.

The main purpose of the present invention is to provide a new method for producing the indane derivatives of formula I, which method has advantages from an industrial point of view.

Another object of the invention is to provide a new compound which is used as an intermediate for the production of a 1-indancarboxylic acid compound (I).

According to the present invention, indane derivatives of formula I are thus prepared by (1) a compound of the formula:

where R^, R2 and R^ have the meaning given above, is reacted with a sulfonylmethylisonitrile compound of the formula: where R^ is an aryl group which may be substituted, an aralkyl group which may be substituted or an alkyl group with 1-4 carbon atoms, in presence of a base to form a methylidene indane compound of the formula:

where R 1 , R 2 , R 3 and R 1 have the above meaning, and (2) the recovered methylidene indane compound is then hydrolysed.

In the general formulas given above, the aryl part can

in the arylcarbonyl group R^ e.g. be phenyl or naphthyl. This aryl group per se can also be substituted, the substituents comprising straight or branched lower alkyl groups with 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, etc. .), lower alkoxy groups with 1-4 carbon atoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec.-butoxy, etc.), hydroxyl, halogen (e.g. fluorine, chlorine, bromine, etc.), amino, mono- or di-lower alkylamino groups whose alkyl parts are alkyl groups with 1-3 carbon atoms (e.g. N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino , methylamino, ethylamino, popylamino, etc.), and acylamino groups whose acyl moieties have 2-3 carbon atoms (eg, acetylamino, propionylamino, etc.). One or more of these substituents, which may be the same or different, may occur in optional positions in the aryl group.

In the general formulas, the cycloalkyl group R25-7 contains carbon atoms (eg cyclopentyl, cyclohexyl, cycloheptyl, etc.). The halogen atom, represented by R^, can be chlorine, bromine, fluorine and iodine. Examples of the aryl group, represented by R^ are phenyl and naphthyl. The aralkyl group, represented by R^, can e.g. be benzyl, phenethyl, etc. The aryl and aralkyl groups can have substituents in optional positions on the respective aromatic rings, as these substituents can be alkyl groups with 1-4 carbon atoms (e.g. methyl, ethyl, propyl, butyl, etc.), halogens (chlorine, bromine, fluorine and iodine) and alkoxy groups with 1-4 carbon atoms (e.g. methoxy, ethoxy, propoxy, butoxy, etc.). The alkyl group, also alternatively denoted R^, is preferably an alkyl group with 1-4 carbon atoms, such as methyl, ethylpropyl, isopropyl, butyl, iso-butyl, sec.-butyl, t-butyl, etc.

In the present method, a compound of the general formula II is first reacted with a sulfonylmethylisonitrile compound (III) in the presence of a base. As a base, e.g. a metal alkoxide is used (e.g. alkali metal alkoxide prepared from lower alcohols such as methanol, ethanol, t-butanol etc., and alkali metals such as sodium, potassium etc.), alkali metal hydride (e.g. sodium hydride and lithium hydride). When a metal alkoxide is used, it is usually most convenient to use it as a solution in the corresponding alcohol.

The reaction is preferably carried out in a solvent, such as e.g. can be an ether (such as dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like), nitrile (e.g. acetonitrile and propionitrile), alkyl halide (e.g. methylene chloride, ethylene chloride and methylene bromide) and the like.

This reaction is usually carried out at a temperature varying from -70 to 10°C, preferably at a temperature below 0°C, but higher than -50°C, and preferably at a temperature in the range of -20 to 0°C, although the most preferred temperature varies with the type of solvent and base used and other conditions. Said base is preferably used in an amount of 1-1.5 mol/mol compound II, while said sulfonylmethylisonitrile compound (III) is preferably used in an equimolar amount in relation to the base. The resulting compound (IV) can be easily separated and purified

by conventional techniques, such as extraction, recrystallization, etc.

While compound IV is normally obtained as a mixture of

two stereoisomers, it is generally suitable for crystallisation and, as such a mixture, can be easily purified. However, to obtain a compound of formula I, it is not necessary for the compound of formula IV to be purified, but the crude product can, after recovery, be directly further processed in the next reaction.

The compound of formula IV is then hydrolysed. The catalyst for use during the hydrolysis can be any acid catalyst and base catalyst. Examples of acidic catalysts include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., while the basic catalyst can for example be selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc. While water alone can be a useful solvent, the reaction time is significantly reduced by simultaneous use of one of the following substances: water-miscible ethers,

(e.g. dioxane, tetrahydrofuran, dimethoxyethane and diethoxyethane)

water-miscible alcohols (e.g. methanol, ethanol, t-butanol, etc.)

and water-miscible organic acids (eg, acetic acid and propionic acid). For commercial purposes, it is particularly advantageous to use dioxane when the catalyst is a mineral acid, or ethanol when an alkali metal hydroxide is used as catalyst. While the reaction temperature varies with different catalysts, the reaction is usually carried out at a temperature varying from 0°C to the boiling point of the solvent used. In commercial operation, it is particularly advantageous to carry out the reaction under reflux of the solvent used.

The compound (I) thus obtained can be easily separated and purified by conventional methods, such as extraction and recrystallization.

As a commercial process, the present method has a number of advantages such as a reduced number of necessary production steps, improved product yields and significantly simplified reaction procedures.

In particular, the isolation and purification of the intermediate product

IV and of the final product I significantly simplified and easily. The

is e.g. no need to use column chromatography and other complicated methods.

The following examples illustrate the invention.

Example 1

To 300 ml of dimethoxyethane was added 23.6 g of 4-benzoyl-1-indanone together with 22.0 g of tosylmethylisonitrile.

The mixture was cooled to -10°C and stirred. A solution of 22 g of 28% sodium methoxide in methanol diluted with 100 ml of dimethoxyethane was added dropwise to this solution over the course of 1 hour. • After the dropwise addition, the mixture was stirred at -10°C for 1 hour and then a solution of 7 g of acetic acid in 50 ml of dimethoxyethane was added dropwise. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with chloroform. The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. To the residue was added 350 ml of benzene and after incubation the mixture was allowed to cool. The resulting crystals were collected by filtration to give 33.4 g (77.5%) of 4-benzoyl-1-[(N-formyl-amino)tosylmethylidene]indane. Recrystallization from ethanol gave crystals melting at 230-232°C.

Elemental analysis for C2^H2^<0>^<N>S

Calcd: C, 69.58; H, 4.91; N, 3.25;

Found: C, 69.42; H, 4.92; N, 3.24.

Example 2

To 300 ml of dimethoxyethane was added 25.5 g of 4-(4-methylbenzoyl)-1-indanone together with 22.4 g of tosylmethylisonitrile. The mixture was cooled to -10°C and stirred. A solution of 22.4 g of 28% sodium methoxide in methanol diluted with 100 ml of dimethoxyethane was added dropwise to this solution over the course of 1 hour. After this addition, the mixture was stirred at -10°C for 30 min. and then a solution of 7.2 g of acetic acid in 10 ml of dimethoxyethane was added dropwise. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with chloroform and the extract washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and to the residue thus obtained was added 500 ml of benzene and, after incubation, the mixture was allowed to cool. The resulting crystals were then collected by filtration. This gave 33.8 g (74.4%) of 1-[(N-formylamino)-tosylmethylidene]-4-(4-methylbebzoyl)indane. recrystallization from ethanol gave crystals melting at 200-204°C.

Elemental analysis for C„,H„-.O.NS

26 23 4

Calculated: C, 70.10; H, 5.20; N, 3.14

Found: C, 70.15; H, 5.09; N, 3.14.

Example 3

To 30 ml of dimethoxyethane were added 2.5 g of 4-(4-methylbenzoyl)-1-indanone together with 2.2 g of tosylmethylisonitrile. The mixture was cooled to -10°C and stirred. To this solution was added dropwise a solution of sodium ethoxide (form-■V .

prepared from 250 g of sodium metal, and -3 ml of dry ethanol) diluted with 10 ml of dimethoxyethane, during 30 min.. After this addition, the mixture was stirred at -15°C for 1 hour and then a solution of 0, 7 g of acetic acid in 5 ml of dimethoxyethane added dropwise. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with chloroform. The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and to the residue was added 50 ml of benzene and after incubation the mixture was allowed to cool. The resulting crystals were collected by filtration to give 3.37 g (75.7%) of 1-[(N -formylamino)tosylmethylidene]-4-(4-methylbenzoyl)indane With regard to spectral data, this product was found to be identical to the crystals obtained in Ex. 2.

Example 4

To 15 ml of dry tetrahydrofuran was added 1.25 g of 4-(4-methylbenzoyl)-1-indanone together with 1.1 g of tosylmethylisonitrile. The mixture was cooled to -10°C and stirred. A solution of 1.1 g of 28% sodium methoxide in methanol diluted with 5 ml of dry tetrahydrofuran was added dropwise to this solution over the course of 20 minutes. After this addition, the mixture was stirred at -10°C for 1 hour and then a solution of 0.35 g of acetic acid in 5 ml of tetrahydrofuran was added dropwise. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with chloroform and the extract washed with water and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and 25 ml of benzene was added to the residue and, after incubation, the mixture was allowed to cool. The resulting crystals were collected by filtration to give 1.4 g (64%) of 1-[(N-formylamino)tosylmethylidene]-4-(4-methylbenzoyl)indane. From spectral data it was found that this product was identical to the crystals obtained in ex. 2.

Example 5

To 20 ml of dimethoxyethane was added 1.8 g of 4-(4-chlorobenzoyl)-1-indanone together with 1.5 g of tosylmethylisonitrile. The mixture was cooled to -10°C and stirred. To this solution, a solution of 1.5 g of 28% sodium methoxide in methanol diluted with 5 ml of dimethoxyethane was added dropwise over the course of 15 minutes. After this addition, the mixture was stirred at -10°C for 1 hour and then a solution of 0.5 g of acetic acid in 5 ml of dimethoxyethane was added dropwise. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with chloroform and the extract washed with water and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and 20 ml of benzene was added to the residue, and after incubation the mixture was allowed to cool. The resulting crystals were collected by filtration to give 2.45 g (79.0%) of 4-(4-chlorobenzoyl)-1-[(N-formylamino)tosylmethylid-ene]-indane. Recrystallization from ethanol gave crystals melting at 185-188°C.

Elemental analysis for C25H2Q04NSC1

Calculated:. C, 64 , 44; H, 4.33; N, 3.01; Cl, 7.61

Found: C, 64.58; H, 4.39; N, 2.99; Cl, 7.55.

Example 6

To 15 ml of dimethoxyethane was added 1.25 g of 6-chloro-5-cyclohexyl-1-indanone together with 1.1 g of tosylmethylisonitrile. The mixture was cooled to -10°C and stirred. A solution of 1.1 g of 28% sodium methoxide in methanol diluted with 5 ml of dimethoxyethane was added dropwise to this solution over the course of 15 minutes. After this addition was complete, the mixture was stirred at -10°C for 1 hour and then a solution of 0.35 g of acetic acid in 5 ml of dimethoxyethane was added dropwise. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with chloroform and the extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue was dissolved in 100 ml of ether under stirring and filtered. The filtrate was allowed to cool and the resulting crystals were collected by filtration to give 1.3 g (71%)

6-chloro-5-cyclohexyl-1-[(N-formylamino)tosylmethylidene]indane,

m.p. 195-199°C.

Elemental analysis for C„ .H_ ,0-.NSCl

24 26 j

Calcd: C, 64.92; H, 5.90; N, 3.16

Found: C, 64.94; N, 6.07; N, 3.15.

In a similar manner, 5-cyclohexyl-1-[(N-formylamino)-tosylmethylidene]indane was synthesized, m.p. 135-138°C.

Elemental analysis for C^f^yO^NS

Calculated: C, 70.38; H, 6.65; N, 3.42

Found: C, 70.05; H, 6.9.4; N, 3.39.

Example 7

To 40 ml of acetonitrile were added 2.36 g of 4-benzoyl-1-indanone together with 2.3 g of tosylmethylisonitrile. The mixture was cooled to -15°C and stirred. A solution of 2.2 g of 28% sodium methoxide in methanol was added dropwise to this solution over the course of 8 minutes. After this addition, the mixture was stirred at a temperature of -12 to -10°C for 2 hours. After 0.7 g of acetic acid had been added to the mixture, the solvent was distilled off under reduced pressure. To the residue was added water and the mixture was extracted with chloroform. The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure, and to the residue 15 ml of benzene was added and after incubation the mixture was allowed to cool. The resulting crystals were then collected by filtration.

2.4 g (56%) of 4-benzoyl-1-[(N-formylamino)tosylmethylidene]indane were thus obtained. It was found by spectral analysis that this product was identical to the crystals obtained in ex. 1.

Example 8

To 32.4 g of 1•<-[ (N-formylamino) tosylidene]-4-(4-methyl-benzoyl) indane was added 350 ml of dioxane together with 350 ml of concentrated hydrochloric acid and the mixture was refluxed in an oil bath at 110 °C for 4 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ether and the extract washed with water and extracted twice with 200 ml portions of a 5%

aqueous solution of potassium carbonate. The extracts were combined and washed with ether. The extract was then acidified with hydrochloric acid and the precipitate obtained was extracted with benzene. Benzene-

the layer was washed with water and aqueous sodium chloride, dried over anhydrous sodium sulfate and, after addition of activated carbon, was filtered. The filtrate was concentrated under reduced pressure and the residue recrystallized from a mixture of 50 ml of benzene and 150 ml of cyclohexane.

This gave 15.6 g (76.5%) of 4-(4-methylbenzoyl)-1-indan-carboxylic acid. Recrystallization from 40? aqueous ethanol gave crystals melting at 133-135°C.

Elemental analysis for cj_8H]_g°3

Calculated: C, 77.12; H, 5.75

Found: C, 77.18; H, 5.41.

In the same way, the following compounds were synthesized: 4-benzoyl-1-indanecarboxylic acid, m.p. 101.5-103°C, yield 75%

4-(4-Chlorobenzoyl)-1-indanecarboxylic acid, m.p. 137.5-139.5°C, yield 78%

6-Chloro-5-cyclohexyl-1-indanecarboxylic acid, m.p. 151-152°C, yield 76%.

Example 9

To 2.4 g of 4-benzoyl-1-[(N-formylamino)tosylmethylidene]-indane was added 15 ml of acetic acid together with 15 ml of concentrated hydrochloric acid and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure and water was added to the residue. The mixture was extracted with benzene and the extract washed with water and then extracted 3 times with 15 ml portions of a 5% aqueous solution of potassium carbonate. The extract was combined and decolorized with activated carbon. The extract was acidified with hydrochloric acid and extracted 3 times with benzene. The benzene layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue recrystallized from a mixture of 2.5 ml of benzene and 7.5 ml of cyclohexane. This gave 1.1 g (74%) of 4-benzoyl-1-indanecarboxylic acid as crystals melting at 101-103°C.

Example 10

To 60 ml of dimethoxyethane was added 5.0 g of 4-(4-methylbenzoyl)-1-indanone together with 4.4 g of tosylmethylisonitrile. The mixture was cooled to -10°C and stirred. A solution of 4.4 g of 28% sodium methoxide in methanol diluted with 20 ml of dimethoxyethane was added dropwise to this solution over the course of 30 minutes. After this addition, the mixture was stirred at -10°C for 1 hour. The solvent was distilled off under reduced pressure and 100 ml of dioxane and 100 ml of concentrated hydrochloric acid were added to the residue. The mixture was refluxed for 4 hours, and the reaction mixture concentrated under reduced pressure. To the residue was added water and the mixture was extracted with benzene. The extract was washed with water and then extracted with 5% aqueous solution of potassium carbonate. The extract was washed with benzene and acidified with hydrochloric acid and the resulting precipitate extracted with benzene. The benzene layer was washed with water and an aqueous solution of sodium chloride, dried over sodium sulfate and, after addition of activated carbon, filtered. The filtrate was concentrated and the residue recrystallized from 40% aqueous ethanol. This gave 2.82 g (50%) of 4-(4-methylbenzoyl)-1-indanecarboxylic acid. Spectral analysis showed that this product was identical to the crystals obtained in ex. 8.

In a similar manner, 1.2 g (50%) of 5-cyclohexyl-1-indancarboxylic acid was obtained from 2.1 g of 5-cyclohexyl-1-indanone and 2.2 g of tosylmethylisonitrile, m.p. 140-144°C.

Claims (7)

1. Process for the preparation of an indane derivative with the general formula: where is a hydrogen atom or an arylcarbonyl group which may be substituted; R 2 is a hydrogen atom or a cycloalkyl group with 5-7 carbon atoms; and R^ is a hydrogen or halogen atom, characterized in that (1) reacts a compound with the general formula: where R^ , R 2 and R^ have the meaning given above, with a sulfonylmethylisonitrile compound of the general formula: where R 1 is an aryl group which may be substituted, an aralkyl group which may be substituted or an alkyl group of 1-4 carbon atoms, in the presence of. a base for the formation of a methylidene indane compound with the general formula: where R^ , R2 , R^ and R^ have the meaning indicated above, and then (2) hydrolyzes the recovered methylidene indane compound. 2. Method according to claim 1, characterized in that the reaction step .(1) is carried out at a temperature varying from 10 to -70°C. 3. Method according to claim 1, characterized in that the base used in step (1) is an alkali metal alkoxide. 4. Method according to claim 1, characterized in that the reaction step (1) is carried out in the presence of an organic solvent. 5. Method according to claim 4, characterized in that an ether, nitrile or alkyl halide is used as organic solvent. 6. Method according to claim 1, characterized in that reaction step (2) is carried out in the presence of an acid or a base. 7. Method according to claim 1, characterized in that reaction step (2) is carried out at a temperature varying from 0°C to the boiling point of the solvent used.