NO145573B - INTERMEDIATE FOR USE IN THE PREPARATION OF THERAPEUTIC EFFECTIVE INDAN-1-CARBOXYLIC ACID DERIVATIVES - Google Patents

Description

The present invention relates to an intermediate for use as a starting material for the production of therapeutically effective indan-1-carboxylic acid derivatives with the general? formula:

where R"*" is a hydrogen atom, a lower-alkyl group with 1-4 carbon atoms, a lower-alkyl group with 1-4 carbon atoms, or a halogen atom, and where R is one of the groups - OE, -NH2, -NHOH or - OR<1>, where R1 is an alkyl group with 1-4 carbon atoms, or a salt thereof with a base, optionally in the form of an optical isomer. The intermediate product according to the present invention is characterized by having the general formula: where R"'" has the above meaning. The compounds according to the invention with formula I can be prepared by reacting a compound with the general formula: or a derivative derived from the compound's carboxyl function with a compound with the general formula: where R<1> has the above meaning. The derivatives of the carboxyl function of compound II can be the corresponding ester, acid amide, acid halide or salt. The esters include alkyl esters, whose alkyl moieties e.g. is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, aryl esters such as phenyl ester, aralkyl esters such as benzyl ester. The acid amides include not only those whose carboxyl parts can be represented by -CONI^f but also the hydroxamic acids represented by -CONHOH, the hydrazides represented by -CONHNH^i N-mono- or di-substituted acid amides corresponding to such organic amines as mono- or di-lower alkylamines with about 1-3 carbon atoms whose alkyl moieties may be substituted with hydroxyl (e.g. ethanolamine, diethanolamine, methylamine, ethylamine, dimethylamine, diethylamine, propylamine), arylamines (e.g. aniline, methylaniline), five- to six -linked cyclic amines containing 1-2 nitrogen atoms (e.g. morpholine, pyrrolidine, pyoeridine, piperazine, N-substituted piperazine), N-aralkyl-substituted amines (e.g. benzylamine, α-methylbenzylamine, phenethylamine), alkyl-substituted or aryl-substituted hydrazines (eg methylhydrazine, dimethylhydrazine, phenylhydrazine) and the like. As salts, mention can be made, among other things, of the salts with alkali metals (e.g. sodium, potassium), alkaline earth metals (e.g. calcium, magnesium), and metals such as aluminium, as well as ammonium salts and salts with organic amines such as organic amines exemplified as those of the residue for acid amides. When the compound II is a free carboxylic acid, it can first be converted into a reactive derivative by the carboxyl function and then the derivative can be used in the relevant reaction. When compound II is a reactive derivative, it can first be converted into the free carboxylic acid which is again used in the reaction in question. This reaction is usually and advantageously carried out in the presence of a catalyst which may be any of the agents commonly used as catalysts in Friedel-Crafts reactions; i.e. one of the so-called Friedel-Craft catalysts. Thus, mention may be made of metal halides (e.g. aluminum chloride, aluminum bromide, aluminum fluoride, iron chloride, iron bromide, antimony chloride, antimony bromide, titanium chloride, tin chloride, tin bromide, zinc chloride, zinc bromide, bismuth chloride); Lewis acids such as boron fluoride; mineral acid such as sulfuric acid, phosphoric acid, polyphosphoric acid; hydrogen fluoride. The reaction is advantageously carried out in the presence of a solvent which may be an aromatic compound of general formula III or any solvent which is inert to the reaction. Said solvents which are inert include e.g. carbon disulfide, nitrobenzene, halogenated hydrocarbons (eg methylene chloride, ethylene chloride, 1,1,2,2-tetrachloroethane). When sulfuric acid, polyphosphoric acid or hydrogen fluoride is used as a catalyst, the acid can be used in a large excess so that it simultaneously acts as a solvent. When using a Friedel-Craft catalyst, it is usually used in an amount of 1-6 mol per moles of the carboxylic acid of general formula II or a reactive derivative thereof. Although reaction conditions such as temperature and time are not particularly critical, the practically desirable reaction temperature is somewhere between -15°C and close to the boiling point of the solvent used. The temperature can be increased or decreased within this range. The reaction time is usually 1-5 hours, although it depends on the starting compounds, catalyst and solvent. The resulting compound of formula I can be separated and purified using methods known per se, such as distillation, recrystallization, column chromatography, etc. The compound according to the invention (I) is converted into the above-mentioned therapeutically active compounds by the following method: A compound of the formula I is first converted into a compound of the formula: where R"*" has the meaning given above, by reacting it with a sulfoylmethylisonitrile compound of the general formula:

where R 2 is an aryl, aralkyl or alkyl group. The aryl group can be phenyl or naphthyl whose aromatic nucleus can be substituted with alkyl groups (e.g. methyl, ethyl), halogen atoms (e.g. chlorine, bromine), alkyl groups (e.g. methoxy), in one or more desired positions. Particularly advantageous for practical purposes is phenyl, p-tolyl. The aralkyl group represented by R 2 can e.g. be benzyl or phenethyl; the alkyl group which also represents R 2 can e.g. be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The above-mentioned reaction consists in reacting 1-1.5 mol of the compound IV with each mol of the compound I in the presence of 1-3 mol per moles of compound I of a base in a solvent. Preferred solvents are mixtures of ethers such as dimethoxyethane, diethoxyethane, tetx-α-hydrofuran, with lower alcohols such as methanol, ethanol, tert.-butanol, and the mixing ratio is preferably 2-20 parts by volume of such an ether to each part of said alcohol,

and for achieving the best results the range is 5-10 parts to 1 part. The base can be exemplified by metal alcoholates obtained from lower alcohols, e.g. methanol, ethanol, t-butanol, and alkali metals e.g. sodium, potassium, etc.

In the presence of such a base, the reaction proceeds with increased yield.

The reaction temperature is chosen in the range 0-100°C in accordance with the reactivity of the starting compounds and the type of solvent, base, etc. used. A temperature in the range 10-40°C is particularly preferred. The reaction proceeds to completion within 1-6 hours.

Furthermore, the compound II-a is converted by solvolysis into the aforementioned therapeutically active compound, and otherwise in the manner described in Norwegian patent no. 14 3.57 3.

The solvolysis can generally be hydrolysis with water as solvent or alcoholysis with an alcohol as solvent. In addition, there are also cases where e.g. a phenol is used as solvent. The solvolysis is usually carried out in the presence of a catalyst, and examples of this are hydrogen halides (e.g. hydrogen chloride, hydrogen bromide, hydrogen iodide), mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, polyphosphoric acid; organic acids such as formic acetic acid, p-toluenesulfonic acid, (3-naphthalenesulfonic acid; Lewis acids (e.g. aluminum chloride, aluminum bromide, aluminum fluoride, ferric chloride, ferric bromide, antimony chloride, antimony bromide, titanium chloride, stannous chloride, stannous bromide, zinc chloride, zinc bromide, bismuth chloride, boron trifluoride, etc.); alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide, barium hydroxide; metal alcoholates prepared from lower alcohols comprising alkyl groups of 1-4 carbon atoms (e.g. methanol, ethanol, propanol, isopropanol, butanol , isobutanol, sec-butanol, tert-butanol) and alkali metals such as sodium, potassium; hydrogen peroxide, peracids such as peracetic acid, perbenzoic acid. These catalysts are sometimes used alone and other times in combination. While the reaction temperature varies with the type of catalyst used, the reaction is usually carried out under cooling, at room temperature or by heating, preferably s at 0-100°C. The reaction time is variable.

The therapeutically active end products have a prominent analgesic, antipyretic, anti-inflammatory effect as well as other effects, and show low toxicity and fewer side effects. On the basis of these properties, which are illustrated in more detail in NO ulegn.skrift 143,573, said compounds can be used with great safety as analgesic, antipyretic and anti-inflammatory agents. They can be administered either as such or in admixture with a pharmaceutically acceptable carrier, adjuvant and/or diluent, orally or parenterally in various dosage forms.

The examples below illustrate the preparation of the present intermediates.

Example 1

17.6 g of 1-oxoindan-4-carboxylic acid and 22.9 g of phosphorus pentachloride are added to 100 ml of dry benzene and, after stirring for 1.5 hours, 40 g of aluminum chloride are added. The mixture is stirred for 5 hours, after which the product is poured into dilute hydrochloric acid and extracted with ether. The organic layer is dried and distilled free of solvent under reduced pressure. The crystalline residue is recrystallized from cyclohexane. This gives 4-benzoylindan-l-one which melts at 87-89°C.

Example 2

17.6 g of 1-oxoindane-4-carboxylic acid and 22.9 g of phosphorus pentachloride are added to 100 ml of dry toluene. The mixture is stirred at room temperature for 1.5 hours, after which 40 g of aluminum chloride is added. The mixture is stirred overnight and then poured into 400 ml of 3N hydrochloric acid followed by extraction with benzene. The organic layer is washed with water, aqueous sodium hydroxide and water in the aforementioned order, and dried with anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting crystalline residue is purified by column chromatography on silica gel (200 g silica gel; elution with chloroform).

Finally, the eluate is recrystallized from acetone and this gives 4-(p-toluoyl)indan-1-one, which melts at 105-108°C.

Example 3

17.6 g of 1-oxoindane-4-carboxylic acid and 23 g of phosphorus pentachloride are added to 200 ml of chlorobenzene. The mixture is stirred at room temperature for 3 hours, after which 40 g of aluminum chloride is added. The mixture is stirred at approx. 65°C for 3 hours. After cooling, the mixture is poured into ice and hydrochloric acid, followed by extraction with chloroform. The extract is washed with water, a saturated aqueous solution of sodium bicarbonate and water in that order. After drying, the solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (200 g silica gel; elution with chloroform). Finally, recrystallization is carried out from a 20:5 mixture of benzene and hexane and this gives 4-(p-chlorobenzoyl)-indan-1-one as crystals melting at 144.5-146°C.

Examples 4 and 5

In a similar way as indicated in example 3 is produced

the following compounds:

The following examples illustrate the preparation of the therapeutically active indane carboxylic acid derivatives using the present intermediates.

Reference example 1-( 1)

Sodium ethoxide prepared from 1.1 g of sodium metal, dissolve in a mixture of 24 ml of dry ethanol and 48 ml of dry

dimethoxyethane and, while cooling with ice water and stirring, the resulting solution is added dropwise to a 120 ml dry dimethoxyethane solution, 9.5 g of 4-benzoylindan-1-one and 9.4 g of N-(p-toluenesulfonylmethyl)isonitrile being dissolved in the of a period of 20 minutes.. After the dropwise addition

is finished, the mixture is stirred further at the same temperature for 30 minutes and at room temperature for 3.5 hours. After addition of water, the reaction mixture is extracted with ether and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by column

chromatography on silica gel (1 kg silica gel, elution with benzene-ethyl acetate 50:1). This gives 4-benzoylindan-1-carbonitrile in the form of an oily product.

Infrared absorption spectrum (net)

1660 cm (carbonyl)

2230 cm"<1> (nitrile)

Nuclear magnetic resonance spectrum (CDCl^z 60 MHz)

6: 4.26 (1H, t, C-H)

Reference examples l-( 2) - l-( 6)

In a similar manner as stated in Reference Example 1-(1), the following compounds are obtained.

Reference example 2-( l)

3 g of 4-benzoylindan-1-carbonitrile is added to diluted sulfuric acid prepared from 54 ml of water and 45 ml of concentrated sulfuric acid. The mixture is refluxed in a stream of nitrogen gas for 3.5 hours. After cooling, the reaction mixture is diluted with water and extracted with ether. The ether layer is further extracted with a 5% aqueous solution of potassium carbonate and the extract is washed with ether and acidified with hydrochloric acid. The precipitate is extracted with chloroform and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and this gives 4-benzoylindan-1-carboxylic acid. Recrystallization from benzene-cyclohexane (7:20) gives crystals melting at 100-102°C.

Reference example 2-( 2)

To dilute sulfuric acid, prepared from 27 ml of water and 23 ml of concentrated sulfuric acid, 3 g of 4-(p-toluoyl)-indan-1-carbonitrile are added. The mixture is refluxed in a stream of nitrogen gas for 3.5 hours. After cooling, the reaction mixture is diluted with water and extracted with ether. The ether layer is extracted with a 5% aqueous solution of potassium carbonate and the extract is washed with water and acidified with hydrochloric acid. The precipitate is extracted with chloroform and the extract is washed with a saturated aqueous solution of sodium chloride and dried. The solvent is then distilled off under reduced pressure and the residue is crystallized from benzene-cyclohexane (7:20). This gives 4-p-toluoylindan-1-carboxylic acid as crystals melting at 128-131°C.

Reference example 2-( 3)

15 g of 4-benzoylindan-1-carbonitrile are dissolved in 500 ml of methanol, followed by the addition of 150 ml of a 5% aqueous solution of sodium hydroxide and 50 ml of a 30% aqueous solution of hydrogen peroxide.

The mixture is heated at 60°C for 2 hours and cooled. The reaction mixture is acidified by the addition of dilute hydrochloric acid and the resulting precipitate is extracted with ethyl acetate.

The extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (500 g of silica gel, elution with chloroform-acetone (7:3)). This gives 4-benzoylindan-1-carboxamide in the form of crystals which melt at 164.5-166°C.

Reference examples 2( 4) - 2-( 8)

In a similar manner to reference example 2-(i), the following compounds are prepared.

Reference example 2-( 9)

2 g of 4-(p-chloro-benzoyl)indan-1-carbonitrile are added to 100 g of polyphosphoric acid and the mixture is heated at 150-170°C for two hours.

The mixture is left at room temperature overnight and water is added, after which the whole is extracted with ethyl acetate. The extract is washed with 5% aqueous sodium bicarbonate and water in the order mentioned and then dried over sodium sulfate.

The solvent is distilled off under reduced pressure and the solid residue is recrystallized from 80 ml of benzene. This gives 4-(p-chlorobenzoyl)indan-1-carboxamide in the form of colorless crystals melting at 159-161°C. The crystals include

1/6 mole equivalent of benzene.

Reference example 2-( 10)

75 g of polyphosphoric acid is added to 2.3 g of 4-(p-toluoyl)indan-1-carbonitrile and the mixture is made homogeneous by heating in a water bath at 90°C for 30 minutes and then in an oil bath at 120-130°C for 30 minutes. After adding water to decompose the polyphosphoric acid, the reaction mixture is extracted with ethyl acetate. The extract is washed with water, 5% aqueous sodium bicarbonate and water in the order mentioned, and is then dried. The extract is then treated with activated carbon and concentrated under reduced pressure. The resulting crystalline residue is recrystallized from a mixture of ethanol and ethyl acetate. This gives 4-(p-toluoyl)indan-1-carboxamide in the form of crystals melting at 188-191°C.

Reference example 2-( 11)

150 g of polyphosphoric acid is added to 3.0 g of 4-(p-methoxybenzoyl)indan-1-carbonitrile and the mixture is homogenized by heating in an oil bath at approx. 120°C. After 40 minutes of heating, the mixture is left at room temperature overnight. The polyphosphoric acid is decomposed with 200 ml of water followed by extraction with ethyl acetate. The extract is washed with water and dried. The solvent is then distilled off under reduced pressure and the residue is recrystallized from benzene. This gives 4-(p-methoxy-benzoyl)indan-1-carboxamide in the form of crystals melting at 164-166°C.

Claims (1)

Intermediate for use in the production of therapeutically active indan-1-carboxylic acid derivatives with the general formula: where R"*" is a hydrogen atom, a lower alkyl group with 1-4 carbon atoms, a lower alkoxy group with 1-4 carbon atoms, or a halogen atom, and where R is one of the groups -OH, -NH2, -NHOH or - OR', where R<*>is an alkyl group with 1-4 carbon atoms, or a salt thereof with a base, optionally in the form of an optical isomer, characterized in that it has the general formula: where has the meaning stated above.