CH615146A5 - Process for the preparation of 5-(2,4-difluorophenyl)-salicylic acid - Google Patents

Description

The invention relates to a new process for the preparation of 5- (2,4-difluorophenyl) salicylic acid. In this process, 4- (2,4-difluorophenyl) phenol is obtained as an intermediate.

3rd

615 146

The end product of the synthesis process according to the invention is an anti-inflammatory, antipyretic and analgesic active ingredient and is described in US Pat. No. 3,714,226.

U.S. Patent No. 3,714,224 describes the preparation of phenylbenzoic acid derivatives, particularly 5- (2,4-di-fluorophenyl) salicylic acid. These compounds are obtained from a substituted aniline and nitrobenzene or anisole by a bis-aryl coupling reaction. In this patent, carboxylation using a Kolbe-Schmitt is also mentioned as the final stage.

U.S. Patent No. 3,932,499 relates to the preparation of 4-acetic acid compounds and describes a modified Gomberg reaction using 2,4-difluoro-aniline and butyl nitrite with benzene to produce 2,4-difluorobiphenyl . Then 4-acetyl-2 ', 4'-difluorobiphenyl is obtained by acylation using acetyl chloride in the presence of a Friedel-Crafts catalyst.

The compound that can be produced according to the invention has the following formula

OOH

The process according to the invention is characterized in that the following stages are carried out:

a) Oxidation of the compound of the general formula below

~ (C-i / —Alkyi)

to a compound of the general formula below

O-d-CC,, -alkyl)

b) saponification of the product from stage a) to 4- (2,4-di-fluorophenyl) phenol or its alkali salt and c) carboxylation of the product from stage b).

Another method according to the invention for producing the compound mentioned is characterized in that the following stages are carried out:

a) acylation of 2,4-difluorobiphenyl with a C2_5-alkanoic anhydride or a C2_s-alkanoic acid halide in the presence of a Friedel-Crafts catalyst to give a 4- (C2_5-alkanoyl) -2 ', 4'-difluorobiphenyl,

b) oxidation of the product from stage a) to a 4- (G2_s-alkanoyloxy) -2 ', 4'-difluorobiphenyl,

c) saponification of the C2_5 alkanoyl residue of the product from stage b), producing 4- (2,4-difluorophenyl) phenol or its alkali salt, and d) carboxylation of the product from stage c).

In a third method according to the invention, the procedure is as follows:

a) Implementation of

X® +

where Xe is the anion of a mineral acid or strong organic acid, in the presence of a finely divided solid substance and of copper powder or a copper salt for 1 to 20 hours at temperatures from 5 ° C. to the reflux temperature to form 2,4-difluorobiphenyl,

b) acylation of the product from stage a) in the presence of a Friedel-Crafts catalyst with a C2_5-alkanoic anhydride or a C2_s-alkanoic acid halide to give a 4- (C2_s-alkanoyl) -2 ', 4'-difluorobiphenyl,

c) oxidation of the C2_5-alkanoyl group of the product from step b) to form a 4- (C2_s-alkanoyloxy) -2 ', 4'-difluorobiphenyl,

d) saponification of the C ^ alkanoyl residue of the product from step c) to form 4- (2,4-difluorophenyl) phenol or an alkali metal salt of this compound and e) carboxylation of the product from step d) to 5- (2.4 -Difluorophenyl) salicylic acid.

In the above reaction scheme, X® means an anion derived from a mineral acid or strong organic acid, in particular BF4® or CCl3COO ©.

To carry out synthesis stage a) in the third process, 1 part of diazo-nium salt, 0 to 0.5 part of a strong organic acid (e.g. trichloroacetic or trifluoroacetic acid), 0.1 to 2 parts of copper powder and one are preferably used on a molar basis finely divided solid substance, such as silica gel, diatomaceous earth (Super-Cel), crushed glass, aluminum oxide, crushed molecular sieves or magnesium sulfate, combined in excess over the second aryl component (such as benzene, methyl salicylate or anisole), which also serves as a reaction solvent. The reaction is carried out at temperatures from 5 ° C to the reflux temperature for 1 to 20 hours, depending on the temperature.

The diazo-nium salt used in the aforementioned new process can be prepared in a separate synthesis stage and isolated in pure form, or it can be generated in situ during the coupling process.

The preparation and isolation of the diazonium salt is carried out, for. B. by (1) dissolving the starting aniline, such as 2,3-difluoroaniline, in tetrahydrofuran or a lower alkanol, such as ethanol, propanol or isopropanol, (2) the solution at -5 to + 10 ° C adds 1 to 3 mol / mol fluoroboric acid, (3) the solution obtained while maintaining a temperature of -5 to 15 ° C with an aqueous solution of 1 to 3 mol / mol of a C2_6-alkyl nitrite (e.g. isopropyl or Isoamyl nitrite) or an alkali nitrite (e.g. sodium nitrite) and (4) the precipitated aryldiazonium fluoroborate, e.g. B. 2,4-difluoro-benzenediazonium fluoroborate isolated. These diazonium salts are quite unstable in the presence of solvents containing hydroxyl groups, such as water and alcohols. It is therefore generally washed well with an alcohol, such as isopropanol, and then with another solvent (e.g. ether or methylene dichloride), which is used to remove the residues of the alcoholic solvent. The dry diazonium salt is stable when stored in a dry, cool and dark place.

In the case of the alternative procedure in which the diazonium salt is generated in situ, the new process can be modified by adding 1 part of aniline instead of the aforementioned diazonium salt and 1.1 to 1.5 parts of a strong organic acid (as described) and a Nitrogenation agents such as isopropyl nitrite can be used.

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615 146

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The fact that synthesis stage a) is carried out in the acidic region in the presence of a finely divided solid substance and copper or a copper salt as a catalyst favors a reaction mechanism which proceeds via carbonium or carbenium ions. In this way, yields of 80 to 95% are obtained and a product is obtained which can be isolated by simply evaporating the reaction mixture and, if appropriate, washing and / or recrystallization.

In contrast, the best known biaryl coupling reactions are the Gomberg-Bachmann-Hey reaction and minor modifications of this reaction, as the aforementioned US patent teaches. These reactions also take place via a diazonium intermediate, but in the neutral or alkaline pH range due to a predominantly or even completely radical mechanism, s they therefore lead to large amounts of dark-colored polymeric tar substances, which increase the yield of the desired product to about 50 % or less, and isolation and cleaning become very complicated. Because of the higher work, material and time involved, the synthesis becomes more expensive. There are also pollution problems.

Step b) of the last described procedure:

F

The 2,4-difluorobiphenyl obtained in step a) is according to Friedel-Crafts, preferably in the presence of z. B. aluminum chloride, boron trifluoride, iron (III) chloride or titanium tetrachloride, as a catalyst in an inert organic solvent, such as a chlorinated hydrocarbon (z. B. methylene dichloride, chloroform, 1,1,2,2-tetrachloroethane or carbon disulfide), with a C2_5 alkanoic anhydride or

- (C ^ alkyl)

-halide acylated. The reaction can be carried out for 2 to 4 hours at temperatures from about 10 ° C to the reflux temperature, preferably at 10 to 25 ° C. The product is usually isolated in the usual way by decomposing the excess Friedel-Crafts catalyst and evaporating the solvents.

Stage c) of the third inventive method described:

F- ^ \ -C- (CW4-alkyl)

P I

Y O

-C- (C1-4 alkyl)

The product of step b) is preferably treated with an excess of an oxidizing agent, such as pertrifluoroacetic acid, 45 m-chloroperbenzoic acid, perphthalic acid, permaleic acid, p-methoxycarbonylperbenzoic acid or peracetic acid, in an inert organic solvent, for example dimethylformamide, a chlorinated hydrocarbon (such as 1,2-dichloroethane , Chloroform or methylene dichloride) or a mixture of a chlorinated hydrocarbon and a lower alkanoic acid (such as acetic acid) with an alkanoic acid

Stage d) of the third method according to the invention:

partially implemented up to about 25% for 4 to 12 hours at temperatures from 50 ° C to the reflux temperature. Sometimes it is convenient to prepare the peracid in situ using a mixture of normal acid anhydride and an oxidizing agent such as hydrogen peroxide. The product is isolated from the cooled reaction mixture using conventional methods such as solvent evaporation and recrystallization.

(° 1 -4 ~ alkyl}

P

The ester obtained in step c) can be saponified in a conventional manner with the aid of acids or alkalis, in which case the reaction mixture is then preferably acidified. In both cases the product crystallizes out of the acidic aqueous solution and can be filtered off.

The alkaline saponification is expediently carried out for 2 to 4 hours at the reflux temperature using 50 percent

(Weight / volume) aqueous sodium or potassium hydroxide solution. The hot aqueous solution obtained is usually acidified and cooled.

In the case of acidic saponification, one heats e.g. B. the 65 ester conveniently in an aqueous or alkanolic 3 to 6n mineral acid, such as hydrochloric or sulfuric acid, 3 to 6 hours at temperatures from 50 ° C to the reflux temperature. The reaction mixture is then cooled.

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615 146

Stage e) of the third method according to the invention:

According to Kolbe-Schmitt, the 4- (2,4-difluorophenyl) phenol can be used for 4 to 8 hours at 200 to 260 ° C and a carbon dioxide pressure of 77.3 to 98.4 kp / cm2 in the presence of an alkali carbonate, preferably potassium carbonate, be carboxylated. The pressure vessel is expediently exposed to carbon dioxide at room temperature up to a pressure of 56.2 to 70.3 kgf / cm 2 and then heated to the reaction temperature. The cooled reaction mixture is usually dissolved in water, the solution is acidified (up to a pH of 2 or below) and the precipitated product is isolated.

According to an alternative method, the ester obtained in step c) can be saponified with alkali, the reaction mixture

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COOH

cool and filter off the alkali metal salt that crystallizes out. The dry salt is then preferably carboxylated in an autoclave at 200 to 260 ° C in a CO 2 atmosphere at a pressure of 77.3 to 98.4 kg / cm 2. One solves z. B. the cooled reaction mixture in water, acidifies the solution (up to a pH of 2 or below) and isolates the precipitated product.

The process described above has significant advantages over the conventional synthesis methods for 5- (2,4-difluorophenyl) salicylic acid, although it comprises 5 steps. The known synthesis consists of a smaller number of steps, namely:

20th

IH + P

However, as mentioned in 35, the diazo coupling reaction produces a mixture of isomers, which reduces the yield. What is even more important is that the isomers are so difficult to separate from one another that the method does not withstand a comparison with the process according to the invention in economic terms. 40

Another important advantage of the process according to the invention is that the acylation is the only substitution reaction on the biphenyl, which practically results exclusively in a p-isomer which can easily be converted into a 4-phenylphenol. 45

Further configurations according to the invention are the reaction sequences of stages b) to e), c) to e), a) to d), b) to d),

c) and d) and stage a).

The intermediates in the synthesis are 2,4-difluorobiphenyl, 2,4-difluoro-4 '- (C2_5-alkanoyl) biphenyls and 50 2,4-difluoro-4' - (C2_5-alkanoyloxy) biphenyls.

Preparation of 2,4-difluorobenzene diazonium fluoroborate 100 g (0.78 mol) of 2,4-difluoroaniline (98 percent)

1250 ml isopropanol

250 ml (1.86 mol) fluoboric acid (48 percent)

250 ml (1.86 mol) of isoamyl nitrite

500 ml of diethyl ether

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60

A solution of 100 g of 2,4-difluoroaniline in 250 ml of isopropanol is cooled to 0 ° C. and 250 ml of 48 percent fluoroboric acid are added. The temperature rises to 20 ° C due to the exothermic reaction. After cooling to -5 ° C., isoamyl nitrite (250 ml) is allowed to flow in with vigorous stirring, the temperature being set at 5 to 65

Holds 10 ° C. This creates a voluminous precipitate quickly. The mixture is diluted with 500 ml of isopropanol and the mixture is stirred for 10 minutes at -5 ° C. The precipitate is then filtered off, washed well with 500 ml of cold isopropanol and then 500 ml of ether and dried in vacuo at room temperature. 172 g (98%) of pure white, crystalline 2,4-difluorobenzoidiazonium fluoroborate of mp 147 ° to 150 ° C. (decomposition 220 ° C.) are obtained.

2,4-difluorobenzene diazonium fluoroborate

13 g (0.1 mol) of 2,4-difluoroaniline (98 percent)

190 ml isopropanol

30 ml (0.22 mol) fluoboric acid (48 percent)

9 g (0.13 mol) sodium nitrite

20 ml water

100 ml diethyl ether

A solution of 13 g of 2,4-difluoroaniline in 30 ml of isopropanol is cooled to 0 ° C. and 30 ml of 48 percent fluoroboric acid are added. After cooling to 0 ° C., a solution of 9 g of sodium nitrite in 20 ml of water is allowed to flow in in the form of a uniform stream while stirring vigorously, the temperature being kept at 5 to 10 ° C. A voluminous precipitate forms quickly. The mixture is diluted with 60 ml of isopropanol and the mixture is stirred at 0 to 5 ° C. for 10 minutes. Then the precipitate is filtered off, washed well with 100 ml of cold isopropanol and then with 100 ml of ether and dried in vacuo. 20 g (88%) of white, crystalline 2,4-difluorobenzene diazonium fluoroborate of mp 147 to 150 ° C. (decomposition 220 ° C.) are obtained.

2,4-difluorobenzene diazonium fluoroborate 13 g (0.1 mol) 2,4-difluoroaniline (98 percent)

190 ml isopropanol

30 ml (0.22 mol) fluoboric acid (48 percent)

12 g (0.16 mol) of dinitrogen trioxide

100 ml diethyl ether

615 146

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A solution of 13 g of 2,4-difluoroaniline in 100 ml of isopropanol is cooled to 0 ° C. and 30 ml of 48 percent fluoroboric acid are added. After cooling to 0 ° C., the mixture is introduced for 5 minutes (or until the KJ / starch test remains positive) at 0 to 5 ° C. nitrous oxide gas. The product separates slowly. The mixture is stirred for 30 minutes at 0 to 5 ° C., filtered and the filter cake is washed well with 100 ml of cold isopropanol and then 100 ml of ether. After vacuum drying, 20.5 g (90%) of pure white, crystalline 2,4-difhiorbenzene diazonium fluoroborate of mp 147 ° to 150 ° C. (decomposition 220 ° C.) are obtained.

Preparation of 2,4-difluorobenzene diazonium fluoroborate 129 g (1.0 mol) of 2,4-difluoroaniline

(98% purity) 400 ml isopropanol

200 ml (1.47 mol) fluoboric acid (48 percent)

180 g (2.0 mol) of isopropyl nitrite

200 ml methylene dichloride

A solution of 129 g of 2,4-difluoroaniline in 120 ml of iso-20-propanol is cooled to 0 ° C. with stirring and 200 ml of 48 percent fluoboric acid are then added dropwise. The temperature rises to 20 ° C due to the exotherm. After cooling to 10 ° C., the solution is added dropwise with stirring in a cooled (5 ° C.) solution 25 of 180 g of isopropyl nitrite in 100 ml of isopropanol, the temperature being kept at about 5 to 10 ° C. A voluminous precipitate forms quickly and a considerable heat of crystallization is released, which is removed by external cooling. The crystalline product is filtered off and washed well with about 180 ml of ice-cold isopropanol and then twice with about 100 ml of methylene dichloride. 211 g (93%) of 2,4-difhiorbenzene diazonium fluoroborate (II) of mp 145 ° to 148 ° C. (decomposition 220 ° C.) are obtained.

The new procedure is explained in more detail in the example below. However, the invention is not limited to the specific pressures, temperatures, reaction times and reagents used therein.

Example 40

Level A-l:

Preparation of 2,4-difluorobiphenyl 100 g (0.44 mol) of 2,4-difluorobenzene diazonium fluoroborate 3 liters of benzene

200 g silica gel, grain size 74 to 250 and 45

(60 to 200 mesh) 200 g copper powder

100 g of 2,4-difluorobenzene diazonium fluoroborate are slurried in 2.5 liters of benzene and 200 g of silica gel and 50 200 g of copper powder are added. The mixture is stirred vigorously at room temperature overnight, with a slow but constant evolution of nitrogen. The mixture is then filtered and the copper / SiO 2 filter cake is washed out with 500 ml of benzene. The combined filtrates are washed neutral 55, dried over sodium sulfate and evaporated to dryness. This gives 66 g (79%) 2,4-difluorobiphenyl of mp 59 b, s 61 ° C; gas-liquid chromatography gives a purity of 97%.

60

Level A-2:

Preparation of 2,4-difluorobiphenyl 100 g (0.44 mol) of 2,4-difluorobenzene diazonium fluoroborate

(Degree of purity 95%)

1.8 liters of benzene 65

100 g super cel

10g copper powder

25 g trichloroacetic acid

100 g of 2,4-difluorobenzenediazonium fluoroborate are slurried in 1.2 liters of benzene and 100 g of Super-Cel, 25 g of trichloroacetic acid and 10 g of copper powder are added. The mixture is stirred vigorously at the reflux temperature for four hours, with constant evolution of nitrogen and anhydrous fluoroboric acid (or HF / BF3). The mixture is then filtered hot and the copper / super-Cel filter cake washed three times with 200 ml of benzene each. The combined filtrates are washed neutral, dried over sodium sulfate and evaporated to dryness.

This gives 75 g (89%) of 2,4-difluorobiphenyl, mp. 58 to 61 ° C; Degree of purity 95% due to quantitative gas-liquid chromatography.

Level A-3:

Preparation of 2,4-difluorobiphenyl with in-situ generation of the diazonium salt 12.9 g (0.10 mol 2,4-difluoroaniline (98 percent)

14.0 g (0.152 mol) trichloroacetic acid

25.0 g (0.157 mol) of isopropyl nitrite

2.0 g (0.03 mol) copper powder

400 ml of benzene

40 g of anhydrous magnesium sulfate

3 g charcoal

5 g silica gel

150 ml hexane

A solution of 25 g trichloroacetic acid in 250 ml benzene is mixed with stirring with 2 g copper powder and 20 g anhydrous magnesium sulfate. The mixture is then cooled to 5 ° C., 14 g of isopropyl nitrite are added rapidly, and immediately afterwards a solution of 12.9 g of 2,4-difluoroaniline in 100 ml of benzene is added dropwise within about 20 minutes. Throughout the addition process, the temperature is maintained at 10-15 ° C and then allowed to rise gradually to 25 ° C. When the evolution of nitrogen has ceased after 1 to 1 1/2 hours, the solid portions are filtered off and the filtrate is washed neutral five times with 500 ml of water each time. The organic layer is dried over 20 g of magnesium sulfate, mixed with 3 g of charcoal and filtered. The filtrate is evaporated in vacuo to an oil, this is dissolved in 150 ml of hexane and the solution is stirred with 5 g of silica gel, as a result of which it is essentially decolorized. Then it is filtered and the light yellow filtrate is evaporated under reduced pressure. This gives 17.5 g (91%) of gray-white crystalline 2,4-difluorobiphenyl (II) with a melting point of 59.5 to 63 ° C. The quantitative gas chromatographic analysis shows a degree of purity of 95%. All physical values confirm the structure of the connection.

If one uses aniline instead of 2,4-difluoroaniline and m-difluorobenzene instead of benzene in stage A-3, a yield of 2,4-difluorobiphenyl of about 70% is achieved.

Level B

Preparation of 4- (2,4-difluorophenyl) acetophenone

3.1 liters of methylene dichloride, which are located in a 12 liter round bottom flask equipped with a stirrer, thermometer, reflux condenser, dropping funnel and nitrogen inlet tube, are mixed with 1.27 kg (9.55 mol) of anhydrous aluminum chloride. 449 ml (485 g; 4.75 mol) of acetic anhydride are introduced into the mixture obtained within 20 minutes at 15 to 20 ° C. 745 g (3.92 mol) of 2,4-difluorobiphenyl in 1.88 liters of methylene dichloride are added to the resulting solution with stirring within 45 minutes at 20 to 25 ° C. The reaction is complete after 2V2 hours at 25 ° C. The batch is then poured into 18.8 liters of ice water. After phase separation, the aqueous portion is extracted twice with 6.2 liters of methylene dichloride. The united methylene di

Chloride extracts are washed with 3.4 liters of water, 6.2 liters of 20 percent aqueous sodium carbonate solution and another 3.4 liters of water. The mixture is then dried over anhydrous magnesium sulfate, filtered and the methylene dichloride is evaporated off in vacuo. 895.5 g (98.5%) of product of mp 78 ° to 79 ° C. are obtained.

Level C

Preparation of 4- (2,4-difluorophenyl) phenylacetate A 1 liter three-necked round-bottomed flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel is charged with 50 g (0.216 mol) of 4- (2 ', 4'-difluorophenyl) -acetophenone, 92.2 g (0.94 mol) of maleic anhydride, 198 ml of methylene dichloride and 48.7 ml of glacial acetic acid and heated the mixture to reflux (52 ° C.). Thereafter, cold 50 percent aqueous hydrogen peroxide solution (22.2 g = 0.326 mol H202) is added dropwise at the reflux temperature. The batch is then boiled under reflux for a further 7 hours and then cooled to 25 ° C. 24 g (0.231 mol) of solid sodium bisulfite and then 4.5 ml of water are then added. After stirring for 15 minutes at 25 ° C., 7.5 g of anhydrous sodium sulfate are introduced. The mixture is stirred for 2 hours at 25 ° C., the solid portions are filtered off and washed four times with 35 ml of methylene dichloride each. The filtrate combined with the washing water is evaporated to dryness in vacuo. The residue is rinsed once with 75 ml of isopropanol, after which it is again evaporated to dryness in vacuo (75 g). The crude product obtained is recrystallized from 105 ml of isopropanol (80 ° C). The clear solution is cooled to 0 ° C. and left to stand at 0 ° C. for 2 hours. The product is then filtered off, washed twice with the mother liquors and then three times with 10 ml of isopropanol each at 0 ° C. and dried at 50 ° C. in vacuo. 48.7 g (91%) of mp 104 to 107 ° C. are obtained.

Level D

Production of 4- (2,4-difluorophenyl) phenol A 30 liter resin vessel equipped with a stirrer, thermometer and reflux condenser is charged with 2.62 kg 50 percent aqueous sodium hydroxide solution and 11.34 liters water.

Then 1.876 kg (7.55 mol) of 4- (2 ', 4'-difluorophenyl) phenylacetate are added and the batch is heated to the reflux temperature within 2V2 hours. After boiling under reflux for 2 hours (in solution at 75 ° C.), the mixture is cooled to 100 ° C. and carried for 30 minutes in a solution of 3.27 liters of concentrated hydrochloric acid in 9.8 in a 50 liter resin vessel Liter of water.

During the addition, the temperature of the acidic mixture rises to 40 ° C. The batch is cooled to 20 ° C., filtered on a 51 cm filter pot (paper and cloth) and washed four times with 4.06 liters of water each. Then the mass is air dried at 80 ° C. 1.512 kg (97.5%) of product of mp 152 ° to 154 ° C. are obtained; K.F. 0.12%.

615 146

Level E

Preparation of 5- (2,4-difluorophenyl) salicylic acid

7.2 kg (52 mol) of anhydrous potassium carbonate and 1.402 kg (6.8 mol) of 4- (2 ', 4'-difluorophenyl) phenol are mixed in a mill (Fitzmill) and poured into an 18.92 liter (5 gal ) autoclave, which was previously pressure-tested with nitrogen up to 133.6 kp / cm2 (1900 psi). The autoclave is pressurized with C02 up to a pressure of 62.6 kp / cm2 (890 psi) and the agitator is started. The batch is heated to 240 ° C. (heating up for 24 hours) and is held at 236 to 246 ° C. for 6 hours. The reaction mixture is then allowed to cool overnight and the autoclave is carefully vented. The solids (8.855 kg) are then removed and transferred to a 75.7 to 113.6 liter (20 to 30 gal) portable extractor. 20.8 liters (5.5 gal) of water are added, the mixture is stirred at 20 to 25 ° C. for 15 minutes and filtered on a cloth / paper /

Cloth-laid 48.26 cm filter bowl. The filter cake is sucked roughly dry and placed together with 140 liters (37 gal) of water in a 378.5 liter (100 gal) container. The batch is heated to 80 ° C with water vapor, 69.5 g of tetrasodium versenate and 116 g of activated carbon (Nuchar C-190N) are added, the mixture is further heated to 90 ° C and coated with a cloth / paper / cloth and precoated with Supercel Sparkler filter filtered. The filter is washed three times with 15.14 liters (4 gal) of water from 60 to 70 ° C. The filtrate and the wash water are again placed in a clean container. The batch is adjusted to a pH of 2 with 550 ml of concentrated sulfuric acid. The slurry is then left to stand for 10 minutes and then cooled to 25 ° C. The solid portions are then filtered on a 48.26 liter filter pot (cloth / paper / cloth), washed four times with 2 liters of water each and dried in vacuo at 70 ° C to a KF of 1.0%. 1.507 kg (88.5%) of crude product, mp 210 to 212 ° C., are obtained.

728.5 g of crude 5- (2,4-difluorophenyl) salicylic acid are placed in a 50 liter resin vessel equipped with a stirrer, thermometer and steam coil. 34 liters of toluene are added, the batch is heated to 104-108 ° C. and filtered through a 20.32 cm sparkler filter.

A second, identical batch is filtered through the Sparkler filter in the same manner, and this is washed out with 18.92 liters (5 gal) of hot toluene.

The combined filtrates are kept in the refrigerator over the weekend and then filtered on a 51 cm filter pot lined with cloth and paper. The solid substances are washed with 3.785 liters (1 gal) of cold toluene and sucked dry on the filter bowl. The cake is dried on trays in air at 75 ° C to constant weight. The drying process is then completed in a vacuum at 75 to 80 ° C. 1.352 kg (yield 93%) of mp 212 to 213 ° C. are obtained.

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Claims (8)

615 146 2. The method according to claim 1, characterized in that a) the oxidation with permaleic acid is carried out at temperatures from 50 ° C to the reflux temperature, b) the saponification is carried out at temperatures from 50 ° C to the reflux temperature with an aqueous alkali hydroxide or an aqueous or alkanolic mineral acid and c) the carboxylation of the phenol or its alkali salt at 77.34 to 98.43 kg / cm2 and 200 to 260 ° C with carbon dioxide and in the case of phenol in the presence of an alkali carbonate. 2nd PATENT CLAIMS 1. Process for the preparation of the compound of the formula COOH characterized by the following levels: a) Oxidation of the compound of the general formula below ! - (C1-4 alkyl) to a compound of the general formula below - (C ^ alkyl) COOH characterized by the following levels: a) acylation of 2,4-difluorobiphenyl with a C2_5 alkanoic anhydride or a C2_5 alkanoic acid halide in the presence of a Friedel-Crafts catalyst to give a 4- (C2_5 alkanoyl) -2 ', 4'-difluorobiphenyl, b) oxidation of the product from stage a) to a 4- (C2_s-alkanoyloxy) -2 ', 4'-difluorobiphenyl, c) saponification of the C2_s-alkanoyl residue of the product from stage b), producing 4- (2,4-difluorophenyl) phenol or its alkali salt, and d) carboxylation of the product from stage c). 3. Process for the preparation of the compound of formula 30th 35 45 50 60 65 characterized by the following stages: a) implementation 15 20 or F- / ~ V-Nf X® where Xe is the anion of a mineral acid or strong organic acid, in the presence of a finely divided solid substance and of copper powder or a copper salt for 1 to 20 hours at temperatures from 5 ° C. to the reflux temperature to form 2,4-difluorobiphenyl, b) acylation of the product from stage a) in the presence of a Friedel-Crafts catalyst with a C2_5-alkanoic anhydride or a Ç2_s-alkanoic acid halide to give a 4- (C2_5-alkanoyl) -2 ', 4'-difluorobiphenyl, c) oxidation of the C2_5-alkanoyl group of the product from step b) to form a 4- (C2_s-alkanoyloxy) -2 ', 4'-difluorobiphenyl, d) saponification of the C2_5 alkanoyl residue of the product from step c) to form 4- (2,4-difluorophenyl) phenol or an alkali metal salt of this compound and e) carboxylation of the product from step d) to 5- (2,4- Difluorophenyl) salicylic acid. 4. The method according to claim 3, characterized in that a) the Friedel-Crafts catalyst is aluminum chloride and the acylation is carried out at 10 to 25 ° C, b) oxidation with permaleic acid is carried out at temperatures from 50 ° C. to the reflux temperature, c) the saponification is carried out at temperatures from 50 ° C to the reflux temperature with an aqueous alkali metal hydroxide or an aqueous or alkanolic mineral acid and d) the carboxylation of the phenol or its alkali metal salt at 77.34 to 98.43 kg / cm2 and 200 to 260 ° C with carbon dioxide and in the case of phenol in the presence of an alkali carbonate. 5. Process for the preparation of the compound of formula 10th 25th b) saponification of the product from stage a) to 4- (2,4-di-fluorophenyl) phenol or its alkali salt and c) carboxylation of the product from stage b). 6. The method according to claim 5, characterized in that an isolated, essentially pure compound is used as the diazonium salt in stage a). 7. The method according to claim 5, characterized in that one carries out the reaction in step a) in the presence of a strong organic acid for 1-20 hours at temperatures from 5 ° C to the reflux temperature. 8. The method according to claim 5, characterized in that in step b) the Friedel-Crafts catalyst is aluminum chloride and the acylation is carried out at 10 to 25 ° C, in step c) the oxidation with permaleic acid at temperatures from 50 ° C to is carried out at the reflux temperature, in stage d) the hydrolysis is carried out at from 50 ° C. to the reflux temperature with an aqueous alkali metal hydroxide or an aqueous or alkanolic mineral acid and in stage e) the carboxylation of the phenol or its alkali metal salt at 77.34 to 98 , 43 kp / cm2 and 200 to 260 ° C with carbon dioxide and in the case of the phenol in the presence of an alkali carbonate.