NO120372B - - Google Patents

Description

Method of preparation of therapeutic

active 5-phenyl-salicylic acid derivatives.

The present invention relates to the preparation of new substituted 5-phenyl-benzoic acids, esters, amides, anhydrides and non-toxic salts thereof. The invention thus relates to the preparation of compounds with the following general formula:

alkoxy, hydroxy-lower alkoxy, lower alkylamino, di-lower alkyl-ainino, phenyl-lower alkoxy, phenoxy, lower alkoxy-phenoxy, lower-alkanoylamlno-lower alkoxy, di-lower alkylamino-lower alkylamino, Rg is hydrogen, lower alkyl, lower alkanoyl or lower alkenyl, and R^ is hydrogen, lower alkyl or lower alkoxy,

and non-yellowing salts thereof, as well as the anhydrides of the acids qg mixed anhydrides of the acids and 2-acetoxy-benzoic acid.

In the more preferred embodiments of the invention, R 2 is hydroxy, R 2 is lower alkanoyl (especially acetyl) or hydrogen, X is chlorine or fluorine (especially fluorine), X is in the If position on the phenyl group and R 2 is hydrogen or lower alkyl in 3 -position (especially methyl).

Representative compounds produced according to the invention are as follows: 2-hydroxy-5-(^<1->fluorophenyl)-benzoic acid 2-hydroxy-5-(*+' -fluorophenyl)-benzamide

2-hydroxy-5-(^'-fluorophenyl)-3-methyl-benzoic acid 2-hydroxy-5-(^<1->fluorophenyl)-3-methyl-benzamide 2-acetoxy-5-(l^-, - fluorophenyl)-3-methyl-benzoic acid 2-acetoxy-5-C+1-fluorophenyl)-3-methyl-benzamide 2-acetoxy-5-(lf1 -fluorophenyl)-benzoic acid 2-acetoxy-5-(^'- fluorophenyl)-benzamide

aluminum-2-acetoxy-5-(V -fluorophenyl)-benzoate aluminum-2-hydroxy-5-(lf1 -fluorophenyl)-benzoate choline-2-acetoxy-5-( -fluorophenyl)-benzoate choline-2- hydroxy-5-(^'-fluorophenyl)-benzoate sodium 2-acetoxy-5-(^;,-fluorophenyl)-benzoate sodium 2-hydroxy-5-(if'-fluorophenyl)-benzoate 2-hydroxy-! ?-(pentafluorophenyl)-benzoic acid

2-acetoxy-?-(pentafluorophenyl)-benzoic acid

p-diethylaminoethyl-2-hydroxy-5-(1<-1-fluorophenyl)-benzoate

p-diethylaminoethyl-2-acetcocy-5-(<l>f<l>-fluorophenyl)-benzoate The present compound has been shown to have anti-inflammatory activity and is effective in preventing and inhibiting

edema and granuloma tissue formation. Moreover, some of them have a useful degree of antipyretic and analgesic activity. To dieijéjfortnål

they are usually administered orally in lozenges or capsules, as

the optimal dose depends on the particular compound used<p>g the type and severity of the disorder being treated. Although the optimal amounts used will depend on the compound used and the particular type of disease being treated, oral doses of the preferred compounds are in the range of 50 mg - 10 g per day useful in combating these disorders, depending on the activity of the particular compound and the patient's reaction sensitivity.

The activity of the process compounds is evident from a determination of their ability to inhibit edema caused by injection of an inflammatory (phlogistic) agent into the tissue of the foot of rats. The test compounds were administered by gastric gavage in rats in an aqueous suspension in a volume of 1 ml per 100 g body weight, immediately followed by tap water to a total amount of 3 ml per rat. Cont ro The animals only got tap water. 1 hour later, 0.1 ml of a 1% suspension of "Carrageenin" (obtained from Marine Colloids Inc.) in sterile 0.9% NaCl was injected into the plantar tissue of the right hind paw of each rat. Immediately afterwards, the volume of the injected paw was measured. Increase in paw volume was measured 3 hours later. The method for measuring the paw volume in rats was as follows: The rat's paw was immersed in mercury exactly to an ink mark on the skin over the lateral malleolus. The mercury was placed in a glass cylinder 25 mm in diameter and 60 mm deep. The mercury column was connected to a "Statham pressure transducer model P23BB" with a range of 0 - 5 cm Hg. The signal from the transducer was fed through a "Statham control unit" driven by a 12 V constant battery eliminator to a Fisher laboratory printer, The immersion of an object in the mercury causes a stroke of the pen of the printer which is calibrated, in ml volume of displaced Mercury.

All experiments were performed on adult male Sprague-Dawley rats with a body weight of 125 - 165 g.

The results of these tests for anti-inflammatory activity are indicated in the table below, the given inhibitions being the average result of 6 rats in each individual test. It is known that this test method agrees well with the anti-inflammatory activity in humans, and it is a standard test used to determine anti-inflammatory activity. This agreement has been shown by the activity of compounds known to be clinically active, such as "INDOCIN", "ASPIRIN",

"BUTAZOLIDINE", "TANDEARIL", "CORTONE", "HYDROCORTONE" and "DECADRON".

For comparison, the following four known compounds were subjected to the same test.

From these experiments it appears that the activity of the process compounds is greatly increased by the presence of a halogen group, especially the fluorine group^ on the 5-phenyl substituent, and that e.g. 2-hydroxy-5-phenylbenzoic acid when given at a dose of 90 mg/kg roughly corresponds to the effect of 2-hydroxy-5-(4'-fluorophenyl)-benzoic acid at less than 1/3 of this dose.

2-acetoxy-5-(4'-fluorophenyl)-benzoic acid was compared with three analogues and 1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl-acetic acid for its effect with respect to gastrointestinal toxicity. Examination of the gastric bleeding test showed that there was no significant difference in the effect of 2-acetoxy-5-(4'-fluorophenyl)-benzoic acid and similar compounds. As can be seen from

the table below, were high doses of the drugs '. necessary to cause gastric bleeding, and at a dose of 1024 mg/kg p.o. there was definitely little difference between the four examined compounds. In contrast, 1-p-chlorobenzoyl-2-methyl-5-methoxy-13-indolyl-acetic acid produced 100% cases of gastric bleeding at 16 mg/kg.

In the 3-day intestinal perforation test, a dose of the compounds was given to test animals that were given free access to food and water for 72 hours. At the end of this time, the animals were killed with methoxital, and the digestive tract was examined for the presence of perforations. As shown in the second table below, 2-acetoxy-5-(4'-fluorophenyl)-benzoic acid was slightly better than 5-(4'-fluorophenyl)-salicylic acid, but more toxic than 2-hydroxy-5-phenylbenzoic acid .

From these data it appears that the compounds of the salicylic acid series are similar to each other with regard to gastrointestinal toxicity." As the anti-inflammatory data show that the process compounds are more active than the previously known compounds, 2-hydroxy-5-phenylbenzoic acid, the process compounds are decidedly advantageous -like.

Tests for gastrointestinal toxicity

The above-mentioned compounds are prepared according to the invention by: (a) a phenyl-phenolate. of the formula;

where R and X are as indicated above, and A is an alkali metal, or a mixture of a compound of formula II where R and X are as indicated above, and A is hydrogen, and an alkali metacarbonate, is reacted with carbon dioxide, optionally under pressure , at elevated temperatures with subsequent acidification to form the desired 5-phenyl-salicylic acid derivative where R^ is hydroxy, and R 2 is hydrogen, and after (b) the obtained 5-phenyl-salicylic acid derivative, optionally after transfer to the corresponding acid halide, optionally reacted with an R.sup.-alcohol to form the desired 5-phenyl-salicylic acid derivative where R.sup.is different from hydroxy or an amide function and/or (c) that obtained in step (a) or (b) 5-phenyl-salicylic acid derivative, optionally after transfer to the corresponding acid halide, optionally amidated to form the desired salicylic acid derivative where R^ is different from hydroxy or a residue function, and/or (d) that in step (a), (b), or (c) obtained 5-phenyl-salicylic acid derivative optionally if is added with a lower alkanoic acid hydride in the presence of a catalyst to form the desired salicylic acid derivative where Rg is lower alkanoyl, and/or (e) the 5-phenyl-salicylic acid derivative obtained in step (a), (b) or (c) is optionally reacted with a di-(lower alkyl) sulfate or a lower alkyl tosylate in the presence of a base, and when R. in the compound of (a), (bj or (c) is hydroxy, subsequent neutralization of the reaction mixture to form the desired 5-phenyl -salicylic acid derivative where R2 is lower alkyl, and/or (f) the 5-phenyl-salicylic acid derivative obtained in step (a), (b) or (c) is optionally reacted in an inert solvent with a lower alkenyl halide in the presence of a base containing a alkali met a 11 or alkaline earth metal cation, and when R 2 of the compound of (a), (b) or (c) is hydroxy, the reaction mixture is neutralized to form the desired 5-phenyl-salicylic acid derivative where R 2 is lower alkenyl, and/ or (g) the 5-phenyl-salicylic acid derivative obtained in step (a), (d), (e) or (f) where is hydroxy, optionally neutralized to form the desired non-toxic salts of the 5-phenyl-salicylic acid derivative, and (h) the 5-phenyl-salicylic acid derivative obtained in step (a), (d), (e) or (f) optionally is transferred to the corresponding acid halide, which is then reacted with 2-acetoxy-benzoic acid or with the 5-phenyl-salicylic acid derivative from steps (a), (d), (e) or (f) to form the desired anhydride.

Some of these starting materials are prepared from the individual phenyl units of the above starting material by the well-known Gomberg reaction. Others, where the biphenyl unit is known, require appropriate reactions to obtain the functional group, if necessary, as well as the metal salts. All the compounds can, however, be obtained by first preparing an aniline compound containing X, followed by a Gomberg reaction with nitrobenzene or anisole or an R^-substituted nitrobenzene or anisole, and then reacting either the nitro group or the methoxy group (from nitrobenzene or anisole ) of the thus prepared biphenyl compound to obtain the alkali salt starting material. For example, fluoro-^-nitrobenzene can be reduced to the appropriate aniline compound required for the Gomberg reaction. The aniline compound is then reacted with nitrobenzene in the presence of isoamyl nitrite. The nitro-biphenyl compound thus obtained can easily be reduced to the amino compound and then diazotized to the corresponding hydroxy compound. Alternatively, the aniline compound can be reacted with an alkoxybenzene instead of nitrobenzene. By using this method, the alkoxy-biphenyl compound obtained by the Gomberg reaction can be transferred in one step to the corresponding hydroxy-biphenyl compound, for example by reaction with aqueous hydrogen iodide.

Although the above reaction sequence can be used when R^ is methyl, it is preferred to carry out the following reaction sequence when R^ is lower alkyl: For example, the methyl-2-hydroxy-5-(^'-fluorophenyl)-benzoate compound according to the invention is reduced to the corresponding alcohol. This alcohol compound is then acylated, after which it is then hydrogenated to the corresponding ^-(V-fluorophenyl)-2-methylphenyl-acetate. This compound is then saponified or hydrolyzed to the corresponding phenol compound, which is then carbonized to 5-(^'-fluorophenyl)-2-hydroxy-3-methylbenzoic acid.

In the above-mentioned Gomberg reaction, a mixture of isomers of the biphenyl compound is obtained, and therefore a chromatographic separation is required to obtain the desired 4-(substituted phenyl)-benzene compound in pure form.

The 4-(substituted phenyl)-phenol compounds obtained as described above can then be transferred to the corresponding alkali salt in any known manner, e.g. by reaction with a suitable alkali metal in an inert solvent.

According to the invention, the acid compounds can be prepared from the previously prepared alkali phenolate or phenolic compound. The preparation of these acid compounds is carried out using the well-known Kolbe-Schmidt carbonization method. In this carbonization step, the phenolate is reacted with carbon dioxide or the phenol is reacted with carbon dioxide in the presence of an alkali carbonate.

The procedure can be illustrated as follows:

X, R, and A are as above indicated.

Reactions and conditions

Step (1) Reaction with carbon dioxide at elevated temperatures (above 75°C, preferably above 100°C) with or without a solvent, preferably without a solvent (or if a solvent is used, any high-boiling inert can dissolve -ning agent is used) until the reaction is practically complete, and subsequent acidification of the reaction mixture.

Step f2) Reaction with carbon dioxide in the presence of an alkali carbonate, such as potassium, sodium or similar carbonate, in particular potassium carbonate, at elevated temperatures (above 75°C, preferably above 100°C)

with or without solvent, preferably without solvent (or if solvent is used, any high-boiling inert solvent) until the reaction is practically complete, with subsequent acidification of the reaction mixture.

Reaction steps (1) and (2) are the well-known Kolbe-Schmidt reaction. As the reaction conditions are not critical, the invention relates not only to the particular fremgancton method shown, but to all other variations of this carbonization step which are well known in the art.

The compounds produced according to the invention, where fL^ is such a group that the end product is an ester, (ie Rj^ is alkoxy), are prepared by any esterification method, using an esterification agent containing the appropriate R^ group. For example, the salicylic acid compound produced according to the invention can be reacted with the appropriate lower alkanol (preferably methanol) at elevated temperatures in the presence of a strong acid, such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and the like, to form the desired R1 compound.

The compounds prepared according to the invention, where R 1 is a group such that the final product is the amide (ie R 1 is amino), can be prepared by any suitable amidation reaction. For example, the salicylic acid compound (preferably the methyl or ethyl ester) can be reacted with ammonia, ammonium hydroxide or an amine compound at any suitable temperature (from room temperature to reflux). When the amino group is desired, it is preferred to carry out the reaction with ammonia, at temperatures above 100°C to form the desired amino compound. When an amide derived from an amino acid t is desired, the following reaction sequence is preferably used. The final salicylic acid compound is reacted with isobutyl chlorocarbonate while forming ay dft mixed anhydrides. This connection is traded s| down the desired amino acid ester and is then hydrolyzed to give the desired end compound, in which R2 is lower alkanoyl (cf. Vis acetyl), can be prepared by any'^.f^|r^^fft|Lka^i|^4.-ation reaction. For example, the corresponding salicylic acid, s-ester or -amide (preferably the ester), can be reacted with a lower alkanoic anhydride (preferably acetic anhydride) in the presence of a catalyst such as sulfuric acid, pyridine, p-toluenesulfonic acid and the like (preferably pyridine), at any suitable temperature (from room temperature to elevated temperatures) preferably at elevated temperatures to form the desired R 2 compound.

The final compound where R 2 is lower alkyl (preferably methyl) can be prepared by any suitable alkylation reaction. For example, the corresponding hydroxy-benzoic acid,

-ester or -amide (preferably the ester), is reacted with a di-(lower alkyl) sulfate (preferably dimethyl sulfate) in the presence of a base (such as alkali carbonate) at any suitable temperature (from room temperature to reflux, but preferably at or near reflux) with subsequent acidification of the reaction mixture, such as with hydrochloric acid, sulfuric acid and the like, to form the desired R2 compound. The final compound where R 2 is lower alkenyl (preferably allyl) can also be prepared by any suitable alkylation reaction. For example, hydroxybenzoic acid, -ester or -amide (preferably the ester), can be reacted with an alkenyl halide in the presence of a base containing an inorganic cation, sdm sodium methoxide, potassium methoxide, sodium carbonate and the like, in an inert solvent which gives at least some solution (such as dioxane, tetrafuran, lower alkanol, dimethoxyethane, acetone and the like, preferably a lower alkanol, such as methanol) at an appropriate temperature (room temperature to elevated temperatures, preferably at elevated temperatures) to form the desired R2 compound.

The salts of the final acid compounds prepared according to the invention can be prepared by any well-known substitution reaction. For example, the salicylic acid compound can be reacted with an inorganic base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, barium hydroxide and the like. The anhydrides can be prepared according to the invention by any known method.

The preparation of these compounds containing R₁ and R₂ groups other than hydrogen can be made in any order. The R 1 group can be introduced into the molecule followed by the introduction of the R 2 substituent, or by first forming the R 2 - compound followed by the introduction of the R 2 group. The order of these reactions is not critical, and they can be carried out on any

preferably the desired way.

The following examples shall be given to further illustrate the invention:

Example 1

2-hydroxy-5-(4'-fluorophenyl)-benzoic acid

A mixture of 10 g of 4-(4'-fluorophenyl)-phenol and 27.2 g of potassium carbonate is exposed to carbon dioxide at 91.4 kg/cm and 175 C. The dark mass obtained from this carbonation is then dissolved in 300 ml of water and 200 ml of methylene chloride and the two layers are separated. The aqueous layer is then extracted with 100 ml of methylene chloride and then acidified with 2.5N hydrochloric acid. This mixture is filtered and the filter cake is dried in a vacuum, whereby 5.32 g of crude product is obtained. The crude product is then recrystallized from benzene-methano1, whereby 2.7 g of material with a melting point of 200 - 204°C is obtained. A further crystallization of this semi-pure material from benzene-methanol yields analytically pure 2-hydroxy-5-(4'-fluorophenyl)-benzoic acid with melting point 199 - 203°C,

When 4-(2',4'-difluorophenyl)-phenol and 4-(3'-fluorophenyl)-phenol obtained in example 5 and 4-(2'-fluorophenyl)-phenol and 4-(penta-fluorophenyl)-phenol , obtained in example 6, is used instead of 4-(4'-fluorophenyl)-phenol in the above example, the corresponding 2-hydroxy-5-(2',4'-difluorophenyl)-benzoic acid is obtained (m.p., 210 - 211 °C), 2-hydroxy-5-(3'-fluorophenyl)-benzoic acid (m.p. 196 - 197°C), 2-hydroxy-5-(2'-fluorophenyl)-benzoic acid (m.p. 201 - 203°C) and 2-hydroxy-5-(pentafluorophenyl)-benzoic acid (m.p., 241 » 243°C).

Example 2

Sodium 2-hydroxy-5-(4'-fluorophenyl)-benzoate

A mixture of 0.1 mol of 2-hydroxy-5-(4<*->fluorophenyl)-benzoic acid and 6.1 mol of sodium hydroxide in 100 ml of water is stirred at room temperature for half an hour. The reaction mixture is concentrated in vacuo, whereby sodium 2-hydroxy-5-(4<*->fluorophenyl)-benzoate is obtained.

Example 3

Methyl 2-hydroxy-5-(4'-fluorophenyl)-benzoate

A solution of 5.0 o 2-hydroxy-5-(4,-fluorophenyl)"benzoic acid in 20 ml of methanol and 2 ml of concentrated sulfuric acid heated under reflux for five hours. The mixture is cooled and partitioned between (751150 ml) water and ethyl acetate, and the organic layer is washed with dilute sodium bicarbonate solution. The organic layer is then dried over magnesium sulfate and concentrated in vacuo, whereby 5.3 g (as an oil) of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate is obtained.

Example 4

Phenyl-2-acetoxy-5-(4'-fluorophenyl)-benzoate

A mixture of 0.1 mol of 2-acetoxy-5-(4'-fluorophenyl)-benzoic acid, 0.1 mol of phosphorus oxychloride and 0.12 mol of phenol is heated at 75°C until no more hydrogen chloride is evolved. The product, phenyl-2-acetoxy-5-(4'-fluorophenyl)-benzoate, is isolated by partitioning the reaction mixture between benzene and dilute sodium bicarbonate solution, and chromatographing the benzene solution on silica gel.

Example 5

2-hydroxy-5-(4'-fluorophenyl)-benzamide

A mixture of 5.3 g of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate and 20 ml of liquid ammonia is reacted in a bomb at 100°C for four hours. After cooling, the bomb is opened, and the ammonia is allowed to evaporate. The residue is then recrystallized from benzene, which gives 2-hydroxy-5-(4<*->fluorophenyl)-benzamide with a melting point of 206 - 207°C.

Example 6

2-acetoxy-5-(4'-fluorophenyl)-benzoic acid

A solution of 3.0 g of 2-hydroxy-5-(4'-fluorophenyl)-benzoic acid in 12 ml of pyridine and 8 ml of acetic anhydride is heated on a steam bath for 20 minutes. The mixture is then poured onto ice and the product is extracted with methylene chloride. The methylene chloride solution is dried and then evaporated. The residue is recrystallized from benzene, which gives 2-acetoxy-5-(4'-fluorophenyl)-benzoic acid with a melting point of 134 - 137°C.

Example 7

2- Allyloxy-5-(41-fluorophenyl)-benzoic acid

To a solution of 0.1 mol of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate in 400 ml of methanol is added 0.1 mol of sodium methoxide, followed by the addition of 0.1 mol of allyl chloride. This mixture is heated at 100°C for 4.5 hours. The reaction mixture is then cooled, filtered and concentrated in vacuo to an oil, filtered again and

* is distilled in vacuum, whereby methyl-2-allyloxy-5-(4'-fluorophenyl)-benzoate is obtained. This ester is then saponified by heating with ethanolic aqueous potassium hydroxide to obtain the corresponding potassium salt. This solution is then acidified with 2.5N aqueous hydrochloric acid, and the reaction mixture is concentrated in vacuo, whereby 2-allyl-

oxy-5-(4'-fluorophenyl)-benzoic acid.

Example 8

2-Methoxy-5-(4'-fluorophenyl)-benzoic acid

A solution of 0.1 mol of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate in 100 ml of acetone is treated with 20 g of potassium carbonate and 0.1 mol of dimethylsulphate. The mixture is then heated under reflux for three hours. After cooling, the solvent is removed by distillation, and the mixture is made slightly acidic with dilute aqueous hydrochloric acid. The reaction mixture is then extracted with methylene chloride and chromatographed on a silica gel column using petroleum petrol ether as eluent. The 2-methoxy-benzoate thus obtained is saponified by heating with dilute aqueous potassium hydroxide. The saponified reaction mixture is then made slightly acidic with dilute

aqueous hydrochloric acid and then concentrated in vacuo to give 2-methoxy-5-(4<*->fluorophenyl)-benzoic acid.

Example 9<!>Anhydride of ^-acetoxy^-f^ 1-fluorophenyl)-benzoic acid

A solution of 0.01 mol of 2-acetoxy-4-(4'-fluorophenyl)-benzoic acid and 0.01 mol of thionyl chloride in 30 ml of dry benzene is heated until the formation of the substituted benzoyl chloride is complete.

The resulting solution is concentrated to half the volume in vacuo and added to a solution of 0.01 mol of 2-acetoxy-4-(4'-fluorophenyl)-benzoic acid and 0.01 mol of pyridine in 30 ml of benzene. The mixture is stirred at room temperature overnight, filtered and the filtrate is washed with cold dilute sodium bicarbonate solution. After drying and upon removal of benzene, the product is recrystallized from benzene-hexane.

Alternatively, the anhydride can be prepared by reacting in 5

hours at room temperature 0.02 mol of 2-acetoxy-4-(4'-fluorophenyl)-benzoic acid and 0.01 mol of dicyclohexylcarbodiimide in 20 parts of tetrahydrofuran, followed by filtration and concentration of the filtrate to

get the anhydride. When a solution of 2-acetoxy-benzoic acid in pyridine

is used instead of 2-acetoxy-4-(4'-fluorophenyl)-benzoic acid-pyridine solution in the above example, the mixed anhydride of 2-acetoxy-4-(4'-fluorophenyl)-benzoic acid and 2-acetoxy-benzoic acid is obtained.

Example 10

5-(4-fluoropheny1)-2-hydroxy-3-methyl-benzoic acid

A. 4-(4'-fluorophenyl)-2-hydroxymethyl- phenol

A solution of 5 g of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate in 25 ml of ether is added to a stirred suspension of 1.28 g of lithium aluminum hydride in 100 ml of ether at a rate sufficient to maintain gentle reflux . Heating by

reflux temperature is continued for 0.5 hours after the addition.

Excess hydride is cleaved with ethyl acetate and sufficiently dilute hydrochloric acid is added to enable separation of the ether layer. The ether phase is washed with water, dried over magnesium sulphate and concentrated to dryness. Trituration with hexane gives 3i9394-(4<1>-fluorophenyl)-2-hydroxymethylphenol with melting point 150 - 157°C. Recrystallization from aqueous ethanol gave pure material with a melting point of 155 - 157°C

B. k - t 4'-fluorophenyl)-2-acetoxymethylphenyl-acetate

A mixture of 3.0 g of 4-(4'-fluorophenyl)-2-hydroxymethyl-phenol, 10 ml of acetic anhydride and 6 ml of pyridine is heated on a steam bath for one hour. The reaction mixture is poured into ice water, stirred for 0.5 hours, and the product is extracted into ether. After drying with magnesium sulphate and treatment with activated charcoal, 4-(4'-fluorophenyl)-2-acetoxymethylphenyl-acetate is obtained as an oil. The dividend is 3.959.

C. U - i 4'-fluorophenyl)-2-methylphenyl-acetate

A solution of 3.9 g of 4-(4'-fluorophenyl)-2-acetoxymethylphenyl acetate in 3 n»l of glacial acetic acid is hydrogenated at 2.8 kg/cm 2 and 70 oC until the uptake of hydrogen is one equivalent. Catalyst and solvent are removed, the product is taken up in ether, washed with dilute sodium bicarbonate solution, dried, and the solution is concentrated to dryness. The crude yield is 2.95 g. Chromatography of 2.6 g of the crude product on 110 g of silica gel gives 2.1 g of pure 4-(4'-fluorophenyl)-2-methylphenyl-acetate eluted with benzene, melting at 71 73°C ,

D. 4- f 4' ^- f luorf enyl) - 2 - methvl - phenol --

A mixture of 2.01 g of 4-(4*-fluorophenyl)-2-methylphenylacetate, 10 ml of ethanol and 10 ml of 1.25 N sodium hydroxide is heated under reflux for 20 minutes. The reaction mixture is concentrated to dryness in vacuo, and the residue is redissolved in water. After acidification and extraction of the product with ether, 1.6 g of 4-(4'-fluorophenyl)-2-

methylphenol with melting point 130 - 131°C.

E. 5 - ( 4'- fluorophenyl)- 2- hydroxy- 3- methyl- benzoic acid

A mixture of 1.5 g of 4-(4'-fluorophenyl)-2-methyl-phenol and 6 g of anhydrous potassium carbonate is heated in a bomb at 175°C and 59.8

kg/cm carbon dioxide pressure for 16 hours. The reaction mixture is suspended in hot water, acidified, and the cooled mixture is extracted with ethyl acetate. The ethyl acetate was extracted repeatedly with portions of 1% sodium bicarbonate solution. The combined bicarbonate extracts are acidified, and the product is extracted into ether. After treatment with magnesium sulphate and activated charcoal, the ether solution is concentrated to a small volume. Addition of hexane caused crystallization of 0.71 g of 5-(4'-fluorophenyl)-2-hydroxy-3-methyl-benzoic acid with melting point 211 - 213°C (sublimes).

Example 11

3- propyl- 5-( 4'- fluorophenyl)- 2- hydroxy- benzoic acid

A solution of 0.8 g of 3-allyl-5-(4'-fluorophenyl)-2-hydroxybenzoic acid in 25 ml of ethanol is subjected to hydrogenation at 2.8 kg/cm<o>at 25°C in the presence of 0.1 g platinum oxide. After the required amount of hydrogen has been taken up, the catalyst and the dissolution liquid are removed, and the crude product is recrystallized from benzene. The yield of 3-propyl-5-(4'-fluorophenyl)-2-hydroxy-benzoic acid is 0.72 g with a melting point of 188 - 190°C.

Some starting materials used in the present process can be prepared as follows:

A. 2'-fluoro-4-nitrobiphenyl

A mixture of 6.0 g of 2-fluoroaniline, 200 ml of nitrobenzene, and

9.0 g of isoamyl nitrite is heated on a steam bath until a vigorous reaction with evolution of gas sets in. This development is allowed to continue without heating until it has subsided, and the mixture is then heated on a steam bath for a further three hours. The excess nitrobenzene is removed in vacuo. The residue is purified from the desired isomer by elution from a silica gel column using petroleum benzine, thereby obtaining 4'-fluoro-2'-methoxy-4-triyl robifenyl.

When pentafluoroaniline is used instead of 4-fluoro-2-methoxy-aniline in the above method, 2•,3',4',5',6'-pentafluoro-4-nitrobiphenyl is obtained.

When 2-nitrotoluene, 2-ethyl-nitrobenzene, 2-methoxy-nitrobenzene, 2-ethoxy-n.it roben zen, 2-chloro -nitro-robraiz-ene, 2-bromo-nitrobenzene, 3-nitrotoluene, 3-ethyl -ni t robcm^f n, 3-Jaethoxy-nitrobenzene, 3-ethoxy-nitrobenzene, 3-chloro-nitrobenzene or 3-bromo-nitrobenzene is used instead of nitrobenzene in the above method, the corresponding 2- and 3-alkyl-, -halogen are obtained - or -Alkoxy biphenyls.

When 4-fluoroaniline and 2-methyl-nitrobenzene are used in the above method instead of 2-fluoroaniline and nitrobenzene, 4'-fluoro-3-methyl-4-nitrobiphenyl is obtained.

B. 4-(2'-fluorophenyl)-aniline

A mixture of 10 g of 2.1-fluoro-4-nitrobiphenyl in 250 ml of ethanol is reduced with hydrogen at atmospheric pressure and at room temperature using 0.5 g of 5% palladium-on-charcoal catalyst. After the required amount of hydrogen has been taken up, the mixture is filtered and the catalyst is washed with fresh ethanol. The ethanol solution is concentrated in vacuo, and the residue is crystallized from aqueous ethanol, whereby 4-(2*-fluorophenyl)-aniline is obtained.

When 21,3*,4',5',6'-pentafluoro-4-nitrobiphenyl is used instead of 2'-fluoro-4-fluorophenyl in the above method, 4-(pentafluorophenyl)-aniline is obtained.

In a similar way, when 4 1 -fluoro-3-methyl-4-nitrophenyl 1 obtained from example 2 is used instead of 2 '-fluoro-4-nitrobyl 1 in the above example, 2- methyl-4-(4'-fluorophenyl)-aniline.

C. 4-(3'-chloro-4'-fluorophenyl)-anisole

A mixture of 8.0 g of 3-chloro-4-fluorine in 1 L, 200 ml of anisole and 9.0 g of isoamyl nitrite is heated on a steam bath until a vigorous reaction with evolution of gas sets in. This development is allowed to proceed without heating until (ion gives sey, and the mixture is then heated on a steam bath for a further three hours. The excess of anisole is removed in vacuo, and the residue is chromatographed on a column of silica gel, using petroleum benzine as eluent, whereby 4-(3'-chloro-4'-fluorophenyl)-anisole is obtained.

When 2-chloro-4-fluoroaniline, 2,4-difluoroaniline and 3-fluoroaniline are used instead of 3-chloro-4-fluoroaniline in the above method, the corresponding 4-(2'-chloro-4'-fluorophenyl)-anisole is obtained , 4-(2<1>,4<*->difluoro-phenyl)-anisole and 4-(3'-fluoro-'enyl)-anisole.

P. 4-(3'-chloro-4'-fluorophenyl)-ftmol

To a solution of 2.1 g of ^-(3•-chloro-4'-fluorophenyl)-anisole in 50 ml of boiling acetic acid, 5 ml of aqueous hydrogen iodide is added, and the boiling is continued for three hours. Water is added and the reaction mixture is cooled and 4-(3'-chloro-4<»->fluorophenyl)-phenol crystallizes. Further purification is then obtained by recrystallization of the solid material from aqueous ethanol, whereby 4-(3'-chloro-4'-fluorophenyl)-phenol is obtained.

When 4-(2<->chloro-4'-fluorophenyl)-anisole, 4-(2•,4*-difluorophenyl)-anisole and 4-(3'-fluorophenyl)-anisole are used instead of 4-(3,_chloro -4'-fluorophenyl)-anisole in the above method, the corresponding 4-(2<«->chloro-4'-fluorophenyl)-phenol, 4~(2',4'-difluorophenyl)-phenol and 4-( 3'-fluorophenyl)-phenol.

E. 4-(4'-fluorophenyl)-phenol

A solution of 32.66 g of 4-(4*-fluorophenyl)-aniline in 120 ml of glacial acetic acid is cooled to 10-12°C. A solution of 12.25 g of sodium nitrite in 120 ml of water is slowly added to this solution with stirring and continued cooling. 5 minutes after this addition, the suspension of the diazonium acetate is slowly added to a boiling solution of 100 ml of concentrated sulfuric acid and 200 ml of water. After the completion of the addition of the diazonium salt, the suspension is boiled for a further 5 minutes and then allowed to cool to room temperature. The reaction mixture is then filtered off, and the cake is dried in vacuum, whereby 4-(4'-fluorophenyl)-phenol is obtained (melting point 152 -161°C, 24.07 g).

When 4-(2'-fluorophenyl)-aniline and 4-(pentafluorophenyl)-aniline are used instead of 4-(4<1->fluorophenyl)-aniline in the above method, the corresponding 4-(2'-fluorophenyl)-phenol is obtained and 4-(pentafluorophenyl)-phenol.

In a similar way, when 2-methyl-4-(4'-fluorophenyl)-aniline is used instead of 4-(4'-fluorophenyl)-aniline in the above method, 2-methyl-4-(4'-fluorophenyl)-phenol is obtained .

Claims (1)

Analogous procedure for the preparation of therapeutically active 5-phenyl-salicylic acid derivatives of the formula: where X are the same or different halogen atoms, R1 is hydroxy, amino, lower alkoxy, di-lower alkylamino-lower alkoxy, hydroxy-lower alkoxy, lower alkylamino, di-lower alkylamino., phenyl-lower alkoxy, phenoxy, lower alkoxy-phenoxy, lower-alkanoylamino-lower alkoxy, di-lower alkylamino-lower alkylamino, R2 is hydrogen, lower alkyl, lower alkanoyl or lower alkenyl, and Rg is hydrogen, lower alkyl or lower alkoxy, and non-toxic salts thereof, as well as the anhydrides of the acids and mixed anhydrides of the acids and 2-acetoxy-benzoic acid, characterized by: (a) a phenyl-phenolate of the formula: where R^ and X are as indicated above, and A is an alkali metal, or a mixture of a compound of formula 11 where R^ and X are as indicated above, and A is hydrogen, pg an alkali metal carbonate, is reacted with carbon dioxide, optionally under pressure, at elevated temperatures with subsequent acidification to form the desired 5-phenyl-salicylic acid derivative where is hydroxy, and R2 is hydrogen, and after which (b) the obtained 5-phenyl-salicylic acid derivative, optionally after transfer to the corresponding acid halide , optionally reacted with an R^-alcohol to form the desired 5-phenyl-salicylic acid derivative where R1 is different from hydroxy or an amide function, and/or (c) the 5-phenyl-salicylic acid derivative obtained in step (a) or (b) , optionally after transfer to the corresponding acid halide, optionally amidated to form the desired salicylic acid derivative where R^ is different from hydroxy or an ester function, and/or (d) that obtained in step (a), (b), or (c) 5-phenyl-salicylic acid derivative is optionally converted with a lower alkanoic acid hydride in the presence of a catalyst to form the desired salicylic acid derivative where Rg is lower alkanoyl, and/or (e) the 1 step (a), (b) or (c) obtained 5-phenyl-salicylic acid derivative is optionally reacted with a di -(lower alkyl) sulfate or a lower alkyl tosylate in the presence of a base, and when R 1 in the compound of (a), (b) or (c) is hydroxy, subsequent neutralization of the reaction mixture to form the desired 5-phenyl -salicylic acid derivative where is lower alkyl, and/or (f) the 5-phenyl-salicylic acid derivative obtained in step (a), (b) or (c) is optionally reacted in an inert solvent with a lower alkenyl halide in the presence of a base containing an alkali metal - or alkaline earth metal cation, and when R 2 of the compound of (a), (b) or (c) is hydroxy, the reaction mixture is neutralized to form the desired 5-phenyl-salicylic acid derivative wherein R 2 is lower- -alkenyl, and/or ( g) the 5-phenyl-salicylic acid derivative obtained in step (a), (d), (e) or (f) where R^ is hydroxy , optionally neutralized to form the desired non-toxic salts of the 5-phenyl-salicylic acid derivative, and/or (h) the 5-phenyl-salicylic acid derivative obtained in step (a), (d), (e) or (f) optionally is transferred to the corresponding acid halide, which is then reacted with 2-acetoxy-benzoic acid or with the 5-phenyl-salicylic acid derivative from steps (a), (d), (e) or (f) to form the desired anhydride.