DE1062692B - Process for the production of anti-inflammatory 4-hydroxy-isophthalic acid monoamides - Google Patents

Description

The present invention relates to the preparation of 4-hydroxy-isophthalic acid monoamides of the general formula

CR ₁

OH

in which one of the symbols R ₁ and R _{2 is} a hydroxyl group and the other is an unsubstituted amino group, and salts of these compounds.

The compounds of the formula I can be prepared by a) one of the ester groups a diester of 4-hydroxyisophthalic acid is split off by known methods and the monoester obtained reacts with ammonia in a manner known per se.

The diester can be a lower dialkyl ester, e.g. B. the dimethyl or diethyl ester, or a diaralkyl ester, z. B. use the benzyl ester, the 4-hydroxy-isophthalic acid.

One ester group can be split off from the 4-hydroxyisophthalic acid diester by saponification be made.

The saponification can be carried out by customary methods, but preferably by means of a aqueous or alcoholic alkali metal hydroxide solution or by means of PbO in the presence of water, if desired under pressure and / or at elevated temperature.

The amidation of the monoester obtained with ammonia can be carried out at atmospheric pressure and at room temperature take place. It is preferred to use a copious excess of ammonia, e.g. B. the ten to twenty times the amount of ammonia, based on the amount of the monoester. The amidation is expediently carried out in aqueous or alcoholic, preferably methyl alcoholic, solution.

The process described above is particularly suitable for the preparation of the 1-monoamide of 4-hydroxyisophthalic acid.

The 3-monoamide of 4-hydroxy-isophthalic acid can be prepared by b) in 2-hydroxybenzamide in the p-position to the hydroxyl group a carboxyl group with carbon dioxide according to known ones Introduces methods.

You can z. B. subject the 2-hydroxy-benzamide (salicylamide) to a Kolbe reaction, for example by making a mixture of solid salicylamide and solid

Method of manufacture
of anti-inflammatory agents
4-hydroxy-isophthalic acid monoamides

Applicant:
Dr. Hans Erlenmeyer, Basel (Switzerland)

Representative: Dr. W. Müller-Bore, patent attorney, Braunschweig, Am Bürgerpark 8

Claimed priority:
Switzerland from July 5, November 10 and December 16, 1955

Dr. Hans Erlenmeyer, Basel (Switzerland),
has been named as the inventor

Potassium carbonate or the potassium salt of salicylamide for several hours under pressure, e.g. B. at 20 atm, heated in a carbon dioxide atmosphere at about 200 ° C. This reaction produces 3-cyano-4-hydroxybenzoic acid, the z. B. hydrolyzed by means of concentrated sulfuric acid at low temperature to the 3-monoamide can.

The 4-hydroxy-isophthalic acid-3-monoamide can also be prepared in a single step by the Kolbe's reaction is carried out under different conditions. The salicylamide is used in an alcoholic, z. B. a methyl alcoholic solution of an amount of potassium hydroxide equivalent to the amount of salicylamide dissolved, whereupon kieselguhr and sea sand are added to the solution and the mixture is evaporated to dryness. About the dry solid mass is then at elevated temperature, e.g. B. at 200 to 210 ° C for several hours Stream of carbon dioxide passed. The reaction mass obtained can be separated off in an appropriate manner and purification, the 4-hydroxy-isophthalic acid-3-monoamide can be obtained directly.

Another process according to the invention for the preparation of the 3-monoamide of 4-hydroxy-isophthalic acid consists in that c) 4-hydroxy-isophthalic acid with a heavy metal salt, preferably a weak acid, in a ratio of 1 mol of 4-hydroxy-isophthalic acid to 1 / wMol heavy metal salt, where η denotes the valency of the metal, reacts in a manner known per se, an alkyl halo

909 580/416

Genid can act in a manner known per se and the 3-monoalkyl ester of 4-hydroxy-isophthalic acid obtained with ammonia by known methods to implement.

It is preferred to use a heavy metal salt of a weak acid in this process, e.g. B. a Silver, lead or copper salt, preferably silver acetate, to a 3-mono-heavy metal salt of 4-hydroxy-isophthalic acid to obtain. This reaction is expediently carried out in an aqueous medium at elevated temperature carried out. The mono-heavy metal salt of 4-hydroxy-isophthalic acid obtained is then treated with an alkyl halide, z. B. methyl iodide or ethyl bromide, reacted to form a 3-monoalkyl ester of 4-hydroxy-isophthalic acid, z. B. to obtain the 3-monomethyl or ethyl ester, which is then the amidation is subjected. The amidation can take place at ordinary pressure and room temperature or at elevated temperatures Temperature and / or elevated pressure can be carried out by means of ammonia. It will preferably be an abundant one Excess, e.g. B. a 20- to 50-fold excess of ammonia is used. The amidation is expedient carried out in aqueous or alcoholic solution.

The 1-monoamide of 4-hydroxyisophthalic acid can also be prepared by d) p-hydroxybenzamide in the presence of a basic alkali metal compound or an alkali metal salt of p-hydroxybenzamide reacts with carbon dioxide at elevated temperature and pressure.

The p-hydroxybenzamide required as the starting substance for carrying out this process can z. B. by reacting a p-hydroxybenzoic acid ester, preferably the methyl ester, with ammonia can be obtained.

According to one embodiment of the process, the p-hydroxybenzamide is in the presence of a basic Alkali metal compound and in the presence of an inert loosening agent under pressure, e.g. B. in one Autoclave, heated in a carbon dioxide atmosphere. The basic alkali metal compound can be, for. B. a Alkali carbonate or bicarbonate, such as sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, use.

An inert loosening agent is to be understood as a material which enlarges the surface area of the reaction mixture and thereby brings it into contact of the reaction mixture with the carbon dioxide facilitated without taking part in the reaction itself. As a loosening agent you can, for. B. Use Raschig rings, broken glass, pottery shards.

It is advisable to heat a solid mixture of p-hydroxybenzamide with potassium carbonate or sodium carbonate and Raschig rings for about 2 ^x / ₂ hours at about 190 ° C in a CO ₂ atmosphere under a pressure of about 50 atmospheres in an autoclave. The reaction product can be worked up by extracting the latter using a mixture of water and ether and acidifying the aqueous component using hydrochloric acid. A precipitate of crude 4-hydroxy-isophthalic acid-1-monoamide is then obtained which, for. B. can be recrystallized from water.

The alkali metal salts of p-hydroxybenzamide can also be reacted with CO ₂ . These alkali metal salts can e.g. B. can be obtained by p-hydroxybenzamide in an alcoholic alkali metal hydroxide solution, e.g. B. in ethanolic potassium or sodium hydroxide solution, and the resulting solution evaporated to dryness. The solid residue can then after the addition of an inert loosening agent, e.g. B. from Raschig rings, at elevated temperature and under pressure with CO ₂ to implement.

The 3-monoamide of 4-hydroxy-isophthalic acid obtained by this process can be used in a known manner in Salts, e.g. B. alkali metal salts are converted.

The alkali metal salts can e.g. B. can be obtained by adding the monoamide in aqueous alkali metal hydroxide solutions dissolves and the salts formed by evaporation of the aqueous solutions, optionally under

ίο reduced pressure, isolated. You can do the mono-amide react with alkali hydroxides even in alcoholic solution. The resulting salts fall into the in most cases from the alcoholic solution in crystalline form.

The 1-monoamide of 4-hydroxy-isophthalic acid obtainable according to the present invention is in water and sparingly soluble in common organic solvents. However, it can be converted into metal salts, especially in alkali metal salts, are brought into a water-soluble form. It can also be known in Way can be converted into alkaline earth metal and aluminum salts. The alkali metal salts can e.g. B. so be obtained by dissolving the 1-monoamide in aqueous sodium or potassium bicarbonate solution and the aqueous solution evaporated, preferably under reduced pressure.

The products obtainable according to the present invention are new compounds with interesting ones pharmacological properties. They are said to be preferably in the form of their sodium salts for therapeutic use Purposes find use and show a pronounced salicylic acid amide-like, anti-inflammatory Effect, are also well tolerated by the human organism and have an extremely low level Toxicity. They also have the advantage that they cause fewer unpleasant side effects than the usual ones Salicylic acid preparations.

The present invention will now be explained with reference to the following examples.

example 1

a) 2 parts of 4-hydroxy-isophthalic acid-dimethyl ester are refluxed for 50 hours in 22.2 parts of a 0.421 n-methyl alcoholic KOH solution with the addition of a little water. The reaction solution is evaporated in vacuo at 20 ° C to dryness, the residue taken up in 25 parts of water and acidified with 5 ° / _o Igei HCl. The precipitate obtained is filtered off and / treated with 5 ° _o NaHCO ₃ solution. It is filtered from the undissolved material and the filtrate washed with 5 ° / _o acidified hydrochloric acid solution. The precipitate is filtered off with suction, dried and taken up in hot benzene, the unreacted, insoluble 4-hydroxyisophthalic acid being removed by filtration and the filtrate being evaporated. In this way, 1 part of hydroxy-isophthalic acid-1-monomethyl ester is obtained, which has the following structural formula:

COOCH,

COOH

OH

In the purified state, this compound has a melting point of 190 to 192 ° C.

b) 2 parts of 4-hydroxyisophthalic acid dimethyl ester, Example 3

2.12 parts of PbO and 5 parts of water are in the pipe under -, _Γττο au α u

c-, ...., ..-, j _O1 , _c . j X ₁ Om- nr «r u-4-i o -cyano-4-hydroxy-denzoic acid

Debris heated to 120 to 135 C for ^{2 1} _{2 hours.}

This creates three solid layers. The two under- 10 parts by weight of salicylamide and 100 parts by weight of

Ren layers, consisting of reddish yellow Pb O and 5 potassium carbonate dried at 400 ° C, are in the

a gray hard mass, are crushed and placed in an autoclave with carbon dioxide under a pressure of

a methanol-water mixture (mixing ratio 2: 1) 20 atm. heated for 15 hours at 200 ° C,

suspended. In the suspension for ¹ Z ₂ hours. After cooling, the contents of the autoclave in 200 volumes

Introduced H ₂ S, whereupon the mixture is filtered. That share water and 50 parts by volume of ether added.

The filtrate is evaporated to dryness at 80 ° C. in vacuo ι ο the separated aqueous portion of the mixture obtained

and the residue at 5 ° / _o NaHCO ₃ solution behan- is again extracted by shaking with ether and finally

delt. Undissolved dimethyl ester (0.59 part) is filtered through animal charcoal. When acidifying the filtrate with

Filtration removed and the filtrate acidified with 2N H Cl. a mixture of conc, H Cl and water (mixing ratio

In this way, 0.5 part of 4-hydroxy-isone is obtained 1: 1) a precipitate is obtained which by dissolving

phthalic acid-1-monomethylester, which after purification at 15 in 5 ° / _o sodium bicarbonate, boiling the

189 to 190 ° C melts. Solution with animal charcoal, filtration and precipitation with one

c) 0.1 part of 4-hydroxy-isophthalic acid-l-monomethyl mixture of conc. Hydrochloric acid and water (mixed ratio ester, obtained according to example 1 a) or 1 b), can be cleaned with 6 parts 1: 1). Shaken by repeated um-Ien 25 ° / _O strength aqueous NH ₃ for 3 days. crystallize from water one obtains the at 265 to The solution is with strong HCl (1: 1) congo acid ge 20 266 ° C melting S-cyano ^ -hydroxy-benzoic acid.
represents, with a colorless, gelatinous precipitate from _TT

falls. For purification, the precipitate obtained in this way is 4-hydroxyisophthalic acid-3-monoamide
dissolved in NaHCO ₃ and reprecipitated with strong HCl. 2 parts by volume of 3-cyano-4-oxy-benzoic acid are intra-obtained in this way, the 4-hydroxy-isophthalic ^12:30 J ₂ hour with mechanical stirring and cooling acid-1-monoamide, with the by sublimation at 292-25 an ice-salt mixture in portions in 10 Vo-296 ° C melts. lumteile conc. Sulfuric acid entered. Of course, instead of the addition following in the examples, the mixture is cooled with ice for a further 2 hours 1 a) and 1 b), and then for 40 hours in the case of methyl ester any other diester left to stand at room temperature and then use 4-hydroxy-phthalic acid, pouring to the 30 ice. The resulting white precipitate is transferred to corresponding monoesters. recrystallized from a lot of water. The 4-hydroxy-

isophthalic acid-3-monoamide melts at 291 to 293 ° C.

Example 2 Example 4

4-Hydroxy-isophthalic acid 3-monomethyl ester ³⁵ 20 parts by weight of salicylamide are in a methyl

alcoholic solution of one of the amount of salicylamide

1 part by weight of 4-hydroxyisophthalic acid, 0.92 equivalent amount of potassium hydroxide dissolved. The received

parts by weight of silver acetate and 20 parts by weight of water become a solution, 20 parts by weight of kieselguhr and 20 parts by weight

the heated with stirring for 15 minutes at 90 ° C. soft sea sand was added, whereupon the mixture

The resulting precipitate is filtered off with suction and for 40 under reduced pressure on a water bath

Remove unreacted 4-oxy-isophthalic acid as dryness is evaporated. The residue is

repeatedly extracted with dioxane. completely dried in a vacuum at 200 ° C. About the received

1.2 parts by weight of the solid residue are dust-dry mass is then for 6 hours at 200 to finely powdered and with 18.2 parts by weight of methyl iodide at 210 ° C, a strong carbon dioxide gas stream is passed,
offset. The mixture is kept in a sealed bottle. After cooling, the reaction mixture is shaken for 2 hours. The reac- 120 parts by volume of water are taken up. After filtering off the mixture in 100 parts by volume of ether, filtered that of the Kieseigurs, the red-colored filtrate is concentrated with conc. formed Ag J and evaporated the ethereal filtrate acidified hydrochloric acid, whereby the deposition of a to dryness. The resulting mixture of 4-hydroxy dark colored oil is effected. This oil solidifies dimethyl isophthalate and 4-hydroxy-isophthalate after some time on standing. There are 2.4 weight acid-3-monomethylester is shaken with 100 parts of a Volum- at 260 to 271 ° C melting product give 5 ° / _o NaHCO ₃ solution, wherein the dimethyl hold.

ester (m.p. 94 to 95 ° C) remains undissolved. After this product is filtered with 100 parts by volume of sodium of the solid component, the filtrate is shaken with bicarbonate. After filtering off a little unconcentrated. HCl acidified, whereby the 4-hydroxy-isophthalic 55 dissolved material is concentrated to the filtrate. Hydrochloric acid to 3-monomethyl ester fails. Set by recrystalline. It turns out a brown solid body that underneath When the product is made from dioxane and water, needles of previous sublimation are transformed into star-shaped krivoms Mp. 258 to 260 ° C obtained. Stall groups and decomposition melts at 278 ° C.

The brown colored crude product is made by dissolving

4-Hydroxy-isophthalic acid-3-monoamide ^{6o in} sodium bicarbonate solution and precipitation with concentrated salt

acid and subsequent recrystallization from water

The 3-monomethyl ester obtained is purified with about and glacial acetic acid. The product obtained causes im

50 times 34 ° / _o aqueous ammonia for 20 STUN mixture with a sample of according to Example 2 or 3

which was left in a sealed bottle. 4-hydroxyisophthalic acid 3-monoamides were produced

the solution then evaporates to dryness in vacuo, no melting point depression.

dissolves the colorless residue in a little water, acidifies the. »

Solution with 2N HCl and the precipitated example 5 filtered

4-hydroxy-isophthalic acid-3-monoamide. After about 10 parts by weight of p-hydroxy-benzamide will crystallize from a lot of water, the product melts together with 100 parts by weight of potassium carbonate and 287 to 289 ° C. 70 about 250 parts by weight of Raschig rings during

2 ¹ Z ₂ hours at 190 ° C under a CO ₂ pressure of atmospheric in the autoclave. The reaction mixture is then cooled and extracted with 200 parts by volume of water and parts by volume of ether. The aqueous layer is separated off and filtered through animal charcoal. The filtrate is acidified with hydrochloric acid (conc. Hydrochloric acid and water in a ratio of 1: 1). The deposited precipitate is fractionally crystallized from water. Pure 4-hydroxy-isophthalic acid-1-monoamide which melts at 288 to 290 ° C. is obtained in this way.

The 4-hydroxy-isophthalic acid-1-monoamide can by Dissolve in aqueous sodium bicarbonate solution and evaporate the resulting solution under reduced pressure Pressure can be converted into the sodium salt.

Claims (11)

Patent claims: 1. Process for the preparation of anti-inflammatory 4-hydroxy-isophthalic acid monoamides the general formula IO OH in which one of the symbols R ₁ and R _{2 is} a hydroxyl group and the other is an unsubstituted amino group, and salts of these compounds, characterized in that a) one of the ester groups of a diester of 4-hydroxyisophthalic acid is split off by known methods and the resulting Monoester reacts with ammonia in a manner known per se or that b) introduces a carboxyl group with carbon dioxide in 2-hydroxybenzamide in the p-position to the hydroxyl group by known methods or that c) 4-hydroxyisophthalic acid with a heavy metal salt in the ratio from 1 mole of 4-hydroxy-isophthalic acid to 1 mole of heavy metal salt , where η denotes the valence of the metal, reacts in a manner known per se, and an alkyl halide in a manner known per se is added to the 3-mono-heavy metal salt of 4-hydroxy-isophthalic acid obtained can act and the resulting 3-monoalkyl ester of 4-hydroxy-isophthalic acid with ammonia by a known method n to react, or that d) p-hydroxybenzamide is reacted with carbon dioxide in the presence of a basic alkali metal compound or an alkali metal salt of p-hydroxy-benzamide at elevated temperature and under elevated pressure and the compounds obtained according to a) to d), if appropriate converted into their salts in a manner known per se. 2. The method according to claim 1, characterized in that the cleavage of one ester group by saponification of the diester by means of an alkali hydroxide in the presence of a lower alcohol or is carried out by means of PbO in the presence of water. 3. The method according to claim 1, characterized in that 2-hydroxy-benzamide with a Reacts the compound that releases potassium ions and carbon dioxide. 4. Process according to Claims 1 and 3, characterized in that there is 2-hydroxy-benzamide in Presence of potassium carbonate or the potassium salt of 2-hydroxy-benzamide at an elevated temperature and reacting with carbon dioxide under pressure and the nitrile group of the 3-cyano-4-hydroxybenzoic acid obtained saponified to a carboxamide group. 5. Process according to Claims 1 and 3, characterized in that the potassium salt of 2-hydroxy-benzamide is used in the presence of kieselguhr and sea sand at elevated temperature and at atmospheric Reacts pressure with carbon dioxide. Considered publications: U.S. Patent No. 2,220,638; Journal f. Prakt. Chem. (2), 44 (1891), p. 12; Beilstein, 4th edition, vol. 10, p. 503, and 1st supplementary work, vol. 10, p. 256; P. Karrer, Textbook of Organic Chemistry, 11th edition (1950), pp. 239, 253, 587 and 588. © 909 580/416 7.