NO772036L - PROCEDURES FOR PREPARING A DERIVATIVE OF PHENYLACIC ACID - Google Patents

Description

The invention relates to a new method for producing a phenylacetic acid derivative. O-(2,6-dichloroanilino)-phenylacetic acid, especially in the form of its sodium salt, has gained importance as an active substance for similar medicines due to its strong antiphlogistic and antirheumatic effect. The method of their manufacture is described, for example, in the English patents no. 1 139 332 and 1 183 968 as well as the corresponding patents in other countries.

The object of the invention is now a new method

. preparation of o-(2,6-dichloroanilino).-phenylacetic acid and their salts with bases. This method is characterized by a compound with the general formula I

in which X means the 2-furyl residue, an optionally acetalised 5-formyl-2-furyl residue or the vanyl residue,

is subjected to an oxidative degradation reaction and the formed o-(2,6-dichloroanilino)-phenylacetic acid is transferred, if desired, into a salt with a base.

In starting materials with the general formula I, an acetalized 5-formyl-2-furyl residue contains, for example, a formyl group which exists as dimethyl acetal, diethyl acetal etc., or in the form of a lower alkylene acetal, such as ethylene acetal, propylene acetal, trimethylene acetal etc.

The oxidative degradation according to the invention is completed by means of an oxidizing agent such as e.g. ozone, hydrogen peroxide, air, salts of permanganic acid of chromic acid or meta-periodic acid or the like. One takes, for example, ozone, preferably during cooling, on a compound of the general formula I and, if desired, terminates the decomposition reaction by adding a further oxidizing agent, such as e.g.

a salt of permanganic acid or hydrogen peroxide.

In particular, a compound of formula I, in which X is embodied by the 2-furyl residue or any 5-formyl-2-furyl residue acetalized in the above-mentioned manner, is allowed to be dissolved in a solvent which does not delay the reaction, such as . acetone, methyl ethyl ketone, dichloroethane, toluene, pyridine or the like, ozone affects a temperature between -70°C to +50°C or if X is the 2-furyl residue up to room temperature - for 1 to 10 minutes, especially in 4- 5 minutes or for larger mixtures also for a longer time, immediately add - then an oxidizing agent such as a salt of permanganic acid, e.g. potassium permariganate or hydrogen peroxide together with water or an alkaline aqueous solution, e.g. an aqueous sodium hydroxide solution and allows the resulting mixture, preferably with stirring, to react at a temperature between

-40°C and room temperature for approx. 10 minutes to 5 hours, preferably approx. 30 minutes to 5 hours. The o-(2,6-dichloroanilino)-phenylacetic acid formed can then be separated by conventional methods and/or transferred into a salt with an inorganic or organic base, e.g. in sodium salt. Compound of the general formula I in which X is embodied by the vinyl residue, oxidizes in essentially the same way, carrying out, if necessary, the post-oxidation of the ozonation product, e.g. by means of a salt of permanganic acid such as potassium permanate, at higher than room temperature, for example at the boiling temperature of the reaction mixture, which, however, is also possible by post-oxidation of the reaction products formed from other starting materials.

The starting material with the 2-furyl residue as X,- 2,6-dichloro-2'-furfuryl-diphenylamine can in turn be prepared in certain ways by reduction of 2,6-dichloro-2'-furfuroyldiphenylamine according to the method of Wolff-Kishner, Clemmensen , Bouveault-Blanc and similar reduction procedures. If the preparation is carried out according to the method of Wolff-Kishner, preferably 1 to 10 mol, especially 3 to 5 mol of hydrazine per moles of 2,6-dichloro-2'-furfuroyldiphenylamine in the presence of ethylene glycol, diethylene glycol or triethylene glycol at. a temperature from 80 to 200°C, preferably 130 to 170°C. The previously mentioned 2,6-dichloro-2'-furfuroyldiphenylamine can be easily prepared by reacting N-(2,6-dichlorophenyl)-anthranilic acid in an ethereal solvent, especially in dioxane or the like, especially in diethyl ether or tetrahydrofuran, by a temperature between -40°C to the boiling temperature of the solvent used, preferably at 0°C to room temperature, with furyllithium.

Starting materials with an acetalized 5-formyl-2-furyl group X are obtained by reacting the Grignard compound of a corresponding acetal of a 5"halo-2-furaldehyde, e.g. an acetal or 5-bromo-or 5-iodo-2-furaldehyde and magnesium in an ethereal solvent such as tetrahydrofuran or diethyl ether with 2-(chloromethyl)-2'6'-dichloroordiphenylamine. Preferably, the reaction takes place during the heating for 1-3 hours. The acetals thus formed can. e.g. by hydrolysis at room temperature in the presence of dilute sulfuric acid, dilute hydrochloric acid or similar agents is transferred in a compound with formula I with free 5-formyl-2-furyl groups as residue X. N-(o-allylphenyl)-2,6 -dichloroaniline, the compound of formula I with the vinyl residue as X can, for example, be prepared by reacting it with a vinyl halide, e.g. vinyl bromide and magnesium in an ethereal solvent such as tetrahydrofuran or diethyl ether, prepare a Grignard compound with 2-( chloromethyl)-2', 6'-dichlorodiphenylamine at elevated t empire.

The following examples shall, for example, explain the implementation of the method according to the invention. The temperatures are indicated in degrees Celsius.

Example 1

A solution of 0.2 g of 2,6-dichloro-2'-furfuryldiphenylamine is introduced at a temperature of -50 to -40°C over the course of 4 minutes. Immediately thereafter, 0.1 ml of hydrogen peroxide, 0.4 ml of a 10% aqueous sodium hydroxide solution and 0.2 ml of water are added and the resulting mixture is stirred for 3 hours at a temperature which gradually increases. from -40°C to room temperature-r The acetone is then evaporated at reduced pressure. To the residue you have 2 ml of water, 0.5 ml of a 10% aqueous sodium hydroxide solution and 5 ml of ethyl acetate. The aqueous phase is separated and acidified with 10% hydrochloric acid and the formed crystalline precipitate is filtered off. Recrystallization of the filter material from a mixture of ether and hexane gives o-(2,6-dichloroanilino).-phenylacetic acid which melts

at 156-157°C

The starting material. produced as follows:

a) To 260 ml of a 10% solution of n-butyllithium

a solution is allowed to drip into the hexane with constant stirring

of 42.5 g of furan in 100 ml of ether and 50 ml of tetrahydrofuran. To the formed .'solution of. furyllithium is added dropwise over the course of 2 hours at room temperature with stirring to a solution of 35>2 g of N-(2,6-dichlorophenyl)-anthranilic acid in 300 ml of tetrahydrofuran.

The resulting mixture is stirred for 30 minutes at room temperature

and then mixed with 150 ml of ether and 250 ml of water. The organic layer is separated, washed with water and dried. The solvent is distilled off and the residue is recrystallized from isopropyl ether, giving 2,6-dichloro-2'-furfuroyldiphenylamine and melting point 129-130°C in the form of yellow needles.

b) A mixture of 1.0 g of 2,6-dichloro-2-furfuroyldiphenylamine, 4 ml of 100% hydrazine hydrate and 10 ml of diethylene glycol is stirred

initially for 3 hours at 120°C and then in an apparatus equipped with a water separator for a further 4 hours at 160°C. After cooling, 60 ml of water is added and the aqueous mixture is extracted with ethyl acetate. The organic layer is washed with water and dried, the solvent is distilled off. Chromatographic separation of the residue on silica gel gives 2,6-dichloro-2'-furfuryldiphenylamine as a colorless liquid. Its IR spectrum shows an absorption corresponding to the >NH group at 3320 cm ^ and NMR spectrum a methylene peak at 4.02 ppm.

Example 2

In a solution of 0.6 g of 5-(2-(2,6-dichloroanilino)-benzyl/-2-furaldehyde in 10 ml of acetone is introduced at -50 to -40°C

while stirring for 3 minutes ozone. 0.3 ml of a 30% hydrogen peroxide solution, 2 ml of a 10% aqueous sodium hydroxide solution and 2 ml of water are then added to the reaction mixture.

The resulting mixture is stirred until it has cooled

to room temperature. Acetone is then evaporated under reduced pressure and the residue is dissolved as far as possible in water and the undissolved is removed by extraction with benzene. The aqueous solution is cooled with ice and acidified with acetic acid. The formed crystalline precipitate is filtered off, dried and recrystallized from a mixture of petroleum ether and ether, obtaining 0.45 g of o-(2,6-dichloroanilino)-phenylacetic acid and melting point 156-158°C.

The starting material is produced as follows:

a) In a four-necked coupling, 5-6 drops of 5-iodo-2-furaldehyde-diethyl acetal and 2-3 drops of methyl iodide are added to 0.32 g of magnesium and 0.5 ml of anhydrous tetrahydrofuran. The mixture is allowed to stand until the reaction begins. Now it is stirred and at the same time the temperature is kept at 20-30°C. While stirring, a solution of 3.9 g of 5-iodo-2-furaldehyde-diethyl acetal in anhydrous tetrahydrofuran is added dropwise. After completion of the dripping, the resulting mixture is stirred for 1 hour at 40°C and then cooled to room temperature. A solution of 1.7 g of 2'-(chloromethyl)-2',6'-dichlorodiphenylamine in 15 ml of tetrahydrofuran is added and the resulting mixture is boiled and stirred for 1 hour under reflux. A liquid reaction mixture is then poured into a saturated aqueous ammonium chloride solution and thoroughly shaken.

The tetrahydrofuran layer is separated and the aqueous layer is extracted with diisopropyl ether. The extracts are combined with tetrahydrofuran, washed thoroughly with saturated aqueous sodium chloride solution and dried over anhydrous potassium carbonate. The solvent is evaporated under reduced pressure and the residue is mixed with 3 ml of 0.1-n sulfuric acid. Ethanol is then added while stirring until a homogeneous mixture is formed and the latter is left overnight. It is then evaporated under reduced pressure, mixed with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate solution and then dried over anhydrous potassium carbonate. The chloroform distills off and the residue is purified by column chromatography on silica gel, using a mixture of chloroform and n-hexane as solvent and eluent. The eluate is evaporated under reduced pressure and the residue is recrystallized from diisopropyl ether. 1.6 g of 5-(2,6-dichloroanilino)-benzyl7-2-furaldehyde is thus obtained as white crystals of melting point 93-94°C.

Example 3

Into a 500 ml four-necked flask equipped with a stirrer, gas introduction tube and thermometer is introduced a solution of 34.6 g of 5-(2-(2,6-dichloroanilino)-benzyl7-2-furaldehyde in 350 ml of acetone during 110 minutes' 4% ozone with a flow rate of

1 liter per minute, stirring the contents of the flask and cooling

kept at -40°C. 20 ml of a 30% hydrogen peroxide solution is then added and then 150 ml of a 10% aqueous sodium hydroxide solution is added dropwise over the course of 1 hour at -40 to -20°C. The resulting reaction mixture is allowed to stand for 3-4 hours and the acetone is then evaporated under reduced pressure. The still warm residue is stirred with 100 ml of -toluene and the resulting mixture is stirred under ice cooling for a further 2-3 hours. The precipitated substance is then filtered off, washed with 10 ml of cold water and recrystallized from water. This gives 23.2 g of the sodium salt of o-('2,6-dichloro-anilino)-phenylacetic acid as white, flocked crystals which melt during cleavage at 271-273°C (silicone bath).

The starting material. produced as follows:

In a 300 ml four-necked flask, add 3.65 g of iodine-activated magnesium, 7 ml of anhydrous tetrahydrofuran, 1.5 g of 5-bromo-2-furaldehyde-diethyl acetal and 2-3 drops of methyl iodide and let the mixture stand until the reaction has reached time. The mixture is then stirred and a solution of 35.9 g of 5-bromo-2-furaldehyde-diethyl acetal in 120 ml of tetrahydrofuran is added dropwise at 20-30°C. After completion of the dripping, the reaction mixture is stirred at room temperature until the end of the reaction, which lasts approx. 2 hours. 0.6 g of copper (I) iodide is then added and the reaction mixture is cooled to 5°C. A solution of 28.7 g of 2-(chloromethyl)-2',6'-dichlorodiphenylamine in 60 ml of tetrahydrofuran is now added without affecting the resulting heating. The reaction mixture is then heated to boiling under reflux for 30 minutes and stirred at the same time. The solvent is distilled off under reduced pressure and the residue is mixed with 550 ml of diisopropyl ether and 300 ml of saturated aqueous ammonium chloride solution. The organic layer is separated, washed with 5% aqueous sodium bicarbonate solution and dried over sodium sulfate. The solvent is distilled off under reduced pressure and the residue is mixed with 550 ml of warm n-hexane and set aside for approx. 15 hours. The upper layer is then decanted and the solvent is distilled off under reduced pressure. The residue is dissolved in 300 ml of ethanol, mixed with 35 ml of 0.1-n sulfuric acid, stirred for 40 minutes at room temperature, evaporated under reduced pressure and then extracted with 300 ml of chloroform. The extract is washed with 5% aqueous sodium bicarbonate solution and then dried. The chloroform is evaporated and the residue is purified by single column chromatography using 150 g of silica gel and a 1:2 mixture of chloroform and n-hexane as solvent and eluent. The solvents are evaporated from the eluate under reduced pressure and the residue is recrystallized from diisopropyl ether. Thereby, 27.6 g of 5-(2,6-dichloroanilino)-benzyl7-2-furaldehyde of melting point 91-93°C is obtained

Example 4

Into a solution of 2.0 g of 5_/2-(2,6-dichloroanilino)-benzyl7-2-furaldehyde in 30 ml of acetone is introduced with stirring at -40°C during 19 minutes ozone, (0.65 mmol ozone /minute). Then 1.2 ml of 30% hydrogen peroxide is added dropwise at -40 to -20°C over the course of 45 minutes and 8.7 ml of 10% sodium carbonate solution. The mixture is stirred for 2 hours at 10-20°C. Acetone is distilled off under reduced pressure, the aqueous residue is mixed with 6 ml of toluene and the mixture is stirred for 3 hours at 0-5°C. The separated crystals are filtered off and washed with a toluene-ether mixture. The crystals are recrystallized from 6 ml of water, obtaining the sodium salt of (2,6-dichloroanilino)-phenylacetic acid and melting point 273-279°C (under decomposition).

The starting material is produced as follows:

a) A mixture of 47.0 g triethyl orthoformic acid and 38.2 g 5-bromo-2-furaldehyde is mixed in 64 ml absolute ethanol

while stirring and passing nitrogen with 2.1 ml of a

absolute with hydrogen chloride saturated ethanol solution. The solution is boiled for 90 minutes under reflux and evaporated under reduced pressure to dryness. The residue is distilled off in a ball tube, obtaining 5_bromo-2-furaldehyde-diethyl acetal of boiling point 60°C70.05 torr as a colorless oil.

b) 365 mg magnesium is in the flask and is activated with iodine. Then add 0.7 ml of anhydrous tetrahydrofuran, 2 drops

methyl iodide and 0.15 g of 5-bromofuran-2-furaldehyde-diethyl acetal. After the reaction has started, a solution of 3359g of 5-bromo-2-furaldehyde-diethylacetal in 12 ml of anhydrous tetrahydrofuran is added dropwise at 25-30°C. The mixture is stirred for 1 hour at 25°C, cooled to 5°C and mixed with 60 mg of copper (I) iodide and dropwise a solution of 2.87 g of 2-(chloromethyl-2',6'-dichlorodiphenylamine in 6 ml of anhydrous tetrahydrofuran. The mixture is then heated for 30 minutes under reflux and evaporated it

under reduced pressure to dryness. The residue is mixed with 60 ml of diisopropyl ether and 30 ml of aqueous ammonium chloride solution. After thorough shaking, the organic phase is separated, washed with 5% sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue is mixed with 55 ml of boiling n-hexane.

It is allowed to stand for 15 hours, the solution is decanted from the solid residue and evaporated to dryness under 11 torr. The residue is mixed with 30 ml of ethanol and 35 ml of 0.1-n sulfuric acid. The solution is allowed to stand for 40 minutes at room temperature, it is evaporated under reduced pressure and the residue is extracted with 30 ml of chloroform. The organic phase is washed with 0.5-n sodium bicarbonate solution and with water, dried over magnesium sulfate and evaporated. The residue, a brown oil, is chromatographed on 20 g of silica gel. Fraction 2-]6, eluted with a chloroform-hexane (1:2) mixture, is evaporated and crystallized from ether. 5-(2-(2,6-dichloroanilino)-benzyl/-2-furaldehyde of melting point 90-92°C is thus obtained.

Example 5

In a solution of 0.5 g of N-(o-allylphenyl)-2,6-dichloroaniline in 10 ml of acetone, ozonized oxygen is introduced with stirring at -50 to -40°C over the course of 7 minutes. 0.5 g of potassium permanganate is then added and the resulting mixture is first allowed to react for 1 hour at room temperature and then also for 1 hour under reflux. The liquid reaction mixture is then filtered and the filter material consisting of manganese dioxide is thoroughly washed with warm water. The filtrate is evaporated and the concentrate is mixed with water and toluene. Add a few drops of 10% aqueous sodium hydroxide solution to this mixture while heating. The aqueous layer is separated and neutralized under ice-cooling with concentrated hydrochloric acid. The formed crystalline precipitate is filtered off, suspended in a small amount of water and made strongly alkaline with a 10% aqueous sodium hydroxide solution. The alkaline solution is cooled with ice and the precipitated crystals are filtered off. The sodium salt of o-(2,6-dichloroanilino)-phenylacetic acid is thus obtained as white crystals of melting point 281-284°C.

The starting material is produced as follows:

a) In a dry four-necked flask, 2.72 g of magnesium are activated by heating with a little iodine at 50°C. 5 ml of tetrahydrofuran and then 2 ml of a solution of 12 g of vinyl bromide in 54 ml of tetrahydrofuran are then added. Next, 1-2 drops of methyl iodide are added and as soon as the reaction has started the remaining part of the above-mentioned vinyl bromide solution is slowly added while stirring and maintaining a temperature of 40-45°C.

The formed reaction mixture is stirred for a further 30 minutes at 50°C. 0.3 g of copper (I) iodide is then added and then, with stirring, a solution of 16.1 g of 2-(chloro-methyl)-2',6'-dichlorodiphenylamine in 55 ml of anhydrous tetrahydrofuran is added during 30 minutes. The reaction mixture is thereby boiled under reflux for a further 30 minutes. completion and turnover. After cooling, a saturated ammonium chloride solution is added and the tetrahydrofuran layer is separated, dried and evaporated under reduced pressure.

By recrystallization of the residue from n-hexane, N-(o-allylphenyl)-2,6-dichloroaniline of melting point 62-64°C is obtained.

Example 6

In a solution of 1.0 g of 2-allyl-2',6'-dichlorodiphenylamine in .20 ml of acetone, an ozone-oxygen mixture, (0.635 mmol ozone/minute) is introduced while stirring at -40°C over the course of 11 minutes ). Now add 1.0 g of potassium permanganate at -35°C with stirring, stir the suspension for 1 hour at room temperature and a further hour at 60°C. Manganese dioxide is then filtered off and washed with a little acetone and 40 ml of warm water. The filtrate is evaporated under reduced pressure to dryness. The residue is mixed with 12 ml of water, 10 ml of toluene and 1 ml of 10% sodium hydroxide solution. The mixture is heated to 55°C and filtered through a layer of "Hyflo". The aqueous phase is separated from the filtrate and acidified at 0°C with concentrated hydrochloric acid. The separated oil is dissolved

in ether. The ether phase is dried over magnesium sulfate and evaporated to dryness below 11 torr. The residue is dissolved in 1.5 ml of 10% sodium carbonate solution and the solution is cooled, the sodium salt of o-(2,6-dichloroanilino).-phenylacetic acid crystallising out, melting point 269-274°C.

The starting material is produced as follows:

a) 1.36 g of magnesium is kept in a flask and activated with

iodine. The activated magnesium is mixed with 2.5 ml anhydrous

tetrahydrofuran and then dropwise at 35°C with approx. 1/10 of a solution of 6.0 g of vinyl bromide in 28 ml of anhydrous tetrahydrofuran. By adding 2 drops of methyl iodide, the reaction is started and the remaining vinyl bromide solution is added dropwise at 40-45°C. The mixture is stirred for 30 minutes at 50°C, mixed with 0.15 g of copper (I) iodide and at 30-40°C with a solution of 8.05 g of 2-(chloromethyl)-2',6'- dichlorodiphenylamine in 28 ml anhydrous tetrahydrofuran. The mixture is then boiled for 30 minutes under reflux and cooled and mixed with 50 ml of saturated ammonium chloride solution. One filters through a layer of "Hyflo", . separates from the filtrate the organic phase, washes it with ammonium chloride solution, dries it over magnesium sulfate, evaporates under reduced pressure to dryness. The residue, a brown oil, is crystallized from ether and the resulting by-product is filtered off. The filtrate is evaporated and the residue is crystallized from n-hexane, obtaining 2-allyl-2',6'-dichloro-diphenylamine of melting point 52-57°C.

Claims (9)

1. Process for the preparation of a phenylacetic acid derivative, characterized in that a compound with the general formula I in which X means 2-furylfestkflL an optionally acetalized 5_formyl- CHRISTMAS 2-furyl residue or vinyl residue, is subjected to an oxidative degradation reaction and the formed o-(2,6-dichloroanilino)-phenylacetic acid is transferred, if desired, into a salt with a base. 2. Method according to claim 1, characterized by. that a compound of the general formula I is used as starting material, in which X means the 2-furyl residue. 3. Process according to claim 1, characterized in that a compound of the general formula I is used as starting material, in which X means an optionally acetalized 5-formyl-2-furyl residue. 4. Process according to claims 1 and 3, characterized in that 5-(2-(2,6-dichloroanilino)-benzyl?-2-furaldehyde is used as starting material. 5. Method according to claim 1, characterized v. e d that the compound with the general formula I, in which X means the vinyl residue, is used as starting material. 6. Method according to claim 5, characterized in that ozone is used as oxidizing agent. 7. Method according to claim 1, characterized in that the oxidative decomposition is carried out, primarily allowing ozone to act on a compound of the general formula I and completing the decomposition reaction by adding a further oxidizing agent. 8. Method according to claims 1 and 7, characterized in that it is used as an additional oxidizing agent •a salt of permanganic acid. 9.' Method according to claims 1 and 7, characterized in that hydrogen peroxide is used as a further oxidizing agent.