DE2614306A1 - METHOD FOR PRODUCING ISOBUTYLPHENYL COMPOUNDS - Google Patents

Description

26H306

Patent attorneys Dipl.-Ing. H. Wiuckmann, Dipl.-Phys. Dr. K. Fincke

Dipl.-Ing. F. AAVeιckmann, Dipl.-Chem. B. Huber

8 MUNICH 86, DEN

PO Box 860 820

MÖHLSTRASSE 22, CALL NUMBER 98 39 21/22

Case F.3342 / P .- (SPA 067) HtM / th

SPA Societa Prodotti Antibiotici, S.p.A., 8, Via Biella, 20143 Milan / Italy

Process for the preparation of isobutylphenyl compounds.

The invention relates to a process for the production of isobutylpheny compounds and in particular for the production of 2- (4-isobutylphenyl) propionic acid (ibuprofen) and its lower homologue, 2- (4-isobutylphenyl) acetic acid (Ibufenac), as well as the resulting products.

Among those because of their analgesic, anti-inflammatory and antipyretic effects therapeutically used phenylalkanecarboxylic acids 2- (4-Isobutylphenyl) propionic acid has a particular practical importance because it, as from the Literature is known, a high effect combined with a high tolerance, a property that many therapeutic

H fj 9 8 U 3 1 1 1 R 2

ORIGINAL INSPECTED

table used anti-inflammatory and anti-pyretic ones Compounds are not peculiar to, such as acetylsalicylic acid, Phenylbutazone, the derivatives of N- (2,3-XyIyI) anthranilic acid (Mefenamic acid) and indomethacin.

Various processes for the chemical preparation of these compounds are already known; nevertheless there is a need for not only improving the existing methods, but also developing new and beneficial methods.

Procedures carried out on a technical scale and customarily for the production of 2- (4-isobutylphenyl) propionic acid are used are described, for example, in GB-PS 971 700 and FR patents 1,549,758 and 1,545,270. These procedures can be represented by the following equations:

κ i! U B U Ί / 1 1 B 2

1) 1-CH ₀ -C ₁ -H ₁ . XC ₄ H ₉ -C ₆ H ₄ -CH ₂ Cl

'4 "9

ZnCl,

CT5 O CD OO

NaNH

a) XC ₄ H ₉ -C ₆ H ₄ -CH ₂ CN

₇ > X CH-, J

> XC ₄ H ₉ -C ₆ H ₄ -CH-CN i -;> XC ₄ H ₉ -C ₆ H ₄ -CH-CN

N / A

CH,

hydrolysis

XC.H _Q -C, H. -CH-COOH
yb 4,

b) iC, Hq-C ^ H ,, - CH ₀ CN ^ -C ₄ H ₉ -C ₆ H ₄ -CH ₂ -COOH XC ₄ H ₉ -CgH ₄ -CH ₂ -COOAt

₄ H ₉ -C ₆ H ₄ -CH ₂

(AtO) ₂ C0

XC ₄ H ₉ -CgH ₄ -C (COOH) ₂ <CH-,

Hydrolysis CH ₃ J

Well OAt

XC ₄ H ₉ -C ₆ H ₄ -C (COOXt) ₂ <j _{? I0} ^ XC ₄ H ₉ -C ₆ H ₄ -CH (COOÄt)

CH-,

XC ₄ H ₉ -C ₆ H ₄ -C-COOH CH "

Willgerodt-

Methylation via the

2 ) iC H-CH -C-CH reaction \ . mow malonic acid ester χ .- ^ _np """ _pnn "

Z) χ C ₄ H ₉ C ₆ H ₄ C CH _{3 + hydols} > ± C ₄ H ₉ CgH ₄ CH ₂ -COOH ₍ see before 1b) ^ xC ₄ H ₉ -CgH ₄ -CH-COOH

H-CH -C-CH ₄ H ₉ C ₆ H ₄ C CH _{3 + hydrolysis} > ± C ₄ H ₉ CgH ₄ CH ₂

_(see before 1b)

₄ H ₉ -CgH ₄

CD CO CO

Darzens-

H H

3) 1-CH ₀ -C ^ -C-CH, condensation ^ i_ _{c HC} , H ₄ -CC-COOR i ^ iL_> i- (

* 6 "4" ^ 3 RAW 0

₄ H ₉ -C ₆ H ₄ -C- ^

1-C ₄ H ₉ -C ₆ H ₄ -CH £ COOH

? ^H 3 oxidation

H H

CH.

1-C ₄ H ₉ -C ₆ H ₄ -CH
CHO

K ₃ 4) 1-C ₄ H ₉ -CgH ₄ -C-CH,

KCN

(NH ₄ )

-> i-C

CH.

/ 7 hydrolysis \ . _.

NH NH

CH-

NH,

Methylation

CH.

1-C ₄ H ₉ -C ₆ H ₄ -C-COOH 1-C ₄ H ₉ -CgH ₄ -C-COOH
H ]'

CO CD OO

The method 1 suffers from the practical disadvantage that starting materials, such as cyanides, which are not only toxic, but also so soluble and volatile that the entire process becomes dangerous and requires the use of selected qualified personnel.

Method 2 applies the Willgerodt reaction to form the corresponding phenylacetic acid. This reaction has the disadvantage that high temperatures and often high pressures and lengthy and 'complicated methods must be used to isolate the product, resulting in low yields. This fact together with the fact that the methylation via the malonic ester starting from the acid is no less than five stages are the reasons for the high production costs.

Method 3, which has advantages over the first two methods, requires special and expensive methods for the purification of the intermediate products, which are necessary for the production of a pure product.

It has now been found a new process for the preparation of 2- (5-isobutylphenyl) propionic acid, in which no dangerous Starting materials, such as cyanide, must be used, which leads to high yields and, in addition, the application comprised of process steps which can be carried out in very short periods of time.

The process is based on the action of thallium salts in oxidized form on 4-isobutylacetophenone or 4-isobutylpropiophenone, this action results in an oxidative rearrangement. The reaction mechanism is not complete clarified, but likely involves acid catalyzed enolization followed by thallium addition and the Decomposition of the unstable intermediate, with migration of the aryl group and simultaneous reduction of thallium to thallium.

B f J 9 8 4 'λ I 1 Ί 6 2

26U306

The invention therefore relates to a process for the preparation of isobutylphenyl compounds of the general formula I

H-C

CH - CH ₂ (S y CH - COOH (I)

H ₃ C ^ ^ y R

in which R is a hydrogen atom or a methyl group, that thereby is characterized in that a compound of the general formula II

CH - CH ₂ -Y) CO - R ¹ (II)

H ₃ C

in which R ^{1 represents} a methyl group or an ethyl group, is reacted with an alkanol in the presence of a salt of trivalent thallium to give an ester of the general formula III

^H 3 ^C

CH - _{CH 2} - U y - CH - COOAIk (III)

in which Alk is an alkyl group and R has the meanings given above, and this compound to the desired Hydrolyzed acid.

This process depends on the starting material used directly to 2- (4-isobutylphenyl) acetic acid or 2- (4-isobutylphenyl) propionic acid.

The result is a substantial reduction in the number of process steps compared to the conventional methods.

609843/1162

A) If you use 4-isobutyl-acetophenone as starting material, it is also possible, in a very advantageous manner, after carrying out a single stage, to use 2- (4-isobutylphenyl) acetic acid (Ibufenac), which is of pharmaceutical interest, but which are also methylated under suitable conditions can. This method has the advantage that only three stages are required, which can be reduced to only two stages if the 2- (4-isobutylphenyl) propionic acid is to be prepared, starting from the same starting material as the other syntheses, but requires a minimal number of steps to produce the same product.

The reaction can be represented by the following equation:

II III

₄₉₆₄

CH

According to the invention, 4-isobutyl acetophenone is converted into 2- (4-isobutylphenyl) methyl acetate converted by converting trivalent thallium, which is usually used in the form of nitrate, used in alkanolic solution and preferably in acidic methanolic solution. One can use a wide variety of solvents use, especially the alcohols in which the thallium (III) salt is soluble. The reaction can be through a strong mineral acid, for example perchloric acid, are catalyzed. The reaction can take place between -10 ° C and the boiling point of the solvent used vary, the optimum conditions depending on the thallium compound used and the Solvent depend. The response time changes accordingly

6 0 9843/1162

" ⁸ " 26U306

however, is only hours in all cases.

The ester thus obtained is made using any the usual hydrolysis methods in an aqueous medium, preferably in an alkaline phase or alternatively in an acidic one

ι
Medium, hydrolyzed to the corresponding acid. In both cases it is advantageous that direct hydrolysis is possible without isolating the ester.

However, it has been shown that it is also advantageous to carry out the hydrolysis in a special way after the ester has been isolated carry out by mixing in an anhydrous medium with potassium tert-butoxide in a polar or non-polar organic Solvent, for example tert-butanol, benzene or Diethyl ether, works.

The methylation in the (/ position of 2- (4-isobutylphenyl) acetic acid, which is in no way described or considered to be feasible in the above-mentioned patents, has been shown to be possible when working in anhydrous liquid ammonia, wherein one basic condensation agent, for example sodium amide or potassium amide, and a _(methylating agent such as methyl iodide, used.

When the 2- (4-isobutylphenyl) acetic acid in the above-described Has been formed by hydrolysis in an anhydrous medium using potassium tert-butoxide, the can Methylation can be carried out directly without isolating the acid.

It should be emphasized that the methylation can only be carried out using in situ metallic sodium or metallic potassium Sodium amide or potassium amide formed in liquid ammonia is possible, optionally using an organic solvent added as a diluent.

60984 3/1162

The effectiveness and novelty of this methylation process results from the following considerations: If one uses sodium amide in conventional organic solvents such as diethyl ether, benzene / toluene or xylene, no positive results are obtained; negative results are also obtained if the usual condensing agents are used, such as sodium hydride and alcoholates. In addition, it is not possible to methylate the derivatives of 2- (4-isobutylphenyl) acetic acid, for example the methyl ester of this acid, with either sodium and liquid ammonia or other conventional condensing agents, which, in contrast to the information in GB-PS 971 700 is where the possibility of methylation of the ester with sodium hydride is addressed. This reveals a further advantage of the process according to the invention, since it makes it possible to methylate 2- (4-isobutylphenyl) acetic acid directly with excellent yields, so that the desired end product is obtained.

B) If, on the other hand, you start from 4-isobutyl-propiophenone, you get directly 2- (4-isobutylphenyl) -propionic acid, whereby the benefits of this procedure are even more apparent.

This reaction can be represented by the following equation:

H ⁺ / CH ₃ OH CH ,,

> XC ₄ H _q -Cf-H ₄ -CH-COOCHo

Hydrolysis . 1-C ₄ H ₉ -CgH ₄ -CH -COOH

4-Isobutyl-propiophenone is produced by the action of thallium in an alkanol, preferably in methanol, in a similar way, as described above under A / in methyl 2- (4-isobutylphenyl) propionate converted. In this case, it is considered appropriate to keep the reaction temperature at room temperature and apply a reaction time of about 100 hours. However, it is also possible, at the boiling point of the

b U 9 8 A 3/1 1 6 2

-ίο- 26H306

turned solvent to work so that the reaction time can be reduced to a few hours, although in in this case the yield is lower. The ester obtained is hydrolyzed in an aqueous medium in the usual manner and

directly results in the desired product.

From the above, the advantage of the synthesis method according to the invention is compared to the conventional one Methods clearly visible, since, in addition to a considerable reduction in the process steps, reactions are used which carried out easily and in a simple manner and which do not require complicated procedures for the isolation and purification of the final product require and achieve high yields.

The salts of trivalent thallium are readily available and cheap, as they are by-products of industrial processes for treating pyrite and producing zinc.

Furthermore, in the method according to the invention, there is one less toxic, less soluble and less volatile substance used, so that the problems of environmental pollution and j Cleaning of industrial effluents can be made much easier.

The following examples serve to further illustrate the invention.

example 1

139 g of thallium (III) nitrate trihydrate are dissolved in 70 ml of methanol and gives 142 ml of 70% perchloric acid and 50 g of 4-isobutyl-acetophenone to. After stirring the reaction mixture for one hour in a stream of nitrogen at room temperature, the Thallium (I) nitrate formed in the course of the reaction in the form of a white crystalline solid is filtered off and the filtrate diluted with ... about 4 liters of water. The oil that separates out is with

6G9843 / 1162

26H306

a total of 2 liters of chloroform, which are divided into three portions, extracted.

The chloroform solution is washed well with water, with activated charcoal removed and dried. The solvent is distilled off under reduced pressure until an oily residue is obtained receives. This oil is distilled and gives methyl 2- (4-isobutylphenyl) acetic acid with a yield of 91% of theory. Boiling point = 82 ° C / 0.8mmHg.

Example 2

50 g of 4-isobutyl-acetophenone are added to a solution of 139 g of thallium (III) nitrate trihydrate in 142 ml of 70% perchloric acid and 710 ml of methanol. The mixture is stirred for 1 hour in a stream of nitrogen at room temperature. The thallium (I) nitrate formed is filtered off, after which the methanol is distilled off from the filtrate under reduced pressure. The residue is diluted with 1200 ml of water and boiled for 2 hours. After cooling, the organic phase is extracted with a total of 600 ml of diethyl ether, which is divided into three portions. After washing with water, decolorizing with activated charcoal and drying, the ethereal solution is ^{evaporated to dryness under reduced pressure 1} and gives 2- (4-isobutylphenyl) acetic acid with a yield of more than 80% of theory. Melting point = 83 to 85 ⁰ C.

Example 3

To a solution of 13.9 g of thallium (III) nitrate trihydrate in 14.2 ml of 70% perchloric acid and 70 ml of methanol are added to 5 g of 4-isobutyl-acetophenone. The reaction mixture is stirred in a stream of nitrogen for 1 hour at room temperature. The thallium (I) nitrate formed is filtered off and the methanol is distilled off from the filtrate under reduced pressure. After diluting the distillation residue with 50 ml Water and cooling in an ice bath, a solution of 20.4 g of sodium hydroxide in 7.0 ml of water is slowly added. You cook them

609843/1162

- 12 - 26U306

Solution for 30 minutes, cool and extract with 50 ml of diethyl ether to remove impurities or from Traces of unreacted material. By acidifying with Hydrochloric acid becomes the solid 2- (4-isobutylphenyl) acetic acid precipitated, which is filtered off, dried with a little water and in vacuo. Melting point = 83 to 85 ° C, yield = 90% of theory.

Example 4

1 g of methyl 2- (4-isobutylphenyl) -essxg acid and 25 ml of an 10% strength aqueous sodium hydroxide solution are heated to reflux for 2.5 hours. After cooling, the solution is extracted with 5 ml of diethyl ether to remove impurities and unreacted material. Acidification with hydrochloric acid results in the separation of an oil which solidifies on standing. The product is extracted with diethyl ether, whereupon the ether solution is washed with water, dried and evaporated to dryness and gives 2- (4-isobutylphenyl) acetic acid in the form of a crystalline solid with a yield of 93% of theory. The product is recrystallized from petroleum ether to yield needle-like crystals having a melting point of 83-85 ⁰ C. '

Example 5

Dissolve 5 g of 2- (4-isobutylphenyl) acetic acid in 100 ml of anhydrous, liquid ammonia. Then, carefully and in small portions, add 5 g of metallic sodium, which is too small Has cut pieces. Two hours after the addition is complete, 6 g of methyl iodide are added dropwise with vigorous stirring to. During this addition the color of the solution changes from blue to a milky white. After 4 hours a Sample of the mixture after acidification by thin-layer chromatography Examination of the ether extract to determine whether the reaction has ended (silica gel, eluent: Benzene / ethyl ether / acetic acid / methanol (120/60/18/1), developer: UV light λ = 254 πιμ or spraying with bromine

609843/1 1 62

26U306

cresol green). If necessary, the reaction mixture is further reacted with 3 g of sodium and 10 g of methyl iodide in order to remove all traces of unreacted starting material. Finally, the mixture is brought to room temperature by evaporation of the solvent and then 80 ml of diethyl ether are slowly added. The reaction mixture is treated with water, after which the aqueous phase is acidified after the organic phase has been separated off. An oil separates out which, on standing, solidifies to a white solid, 2- (4-isobutylphenyl) propionic acid, which is obtained with a yield of 92% of theory. The material is recrystallized from petroleum ether to yield colorless plates having a melting point of 74-76 ⁰ C.

Example 6

4 g of methyl 2- (4-isobutylphenyl) acetate are dissolved in 20 ml of tert-butanol. The solution obtained is slowly added under j Stir to a solution of 4.3 6 g of potassium tert-butoxide in 30 ml tert-butanol. The reaction mixture is left to stand for 2 hours at room temperature and then diluted with 500 ml of diethyl ether » The potassium salt which separates out in the form of a solid is filtered off and taken up with 100 ml of diethyl ether. Then 150 ml of anhydrous, liquid ammonia and 4 g of metallic sodium are added in portions to the obtained! Suspension. Two hours after the addition is complete, the reaction mixture is mixed dropwise with 10 g of methyl iodide. During the addition, the color of the solution changes from blue to milky white. After 4 hours a sample of the mixture is made examined to see if the reaction was complete is (see example 5). If necessary, the reaction mixture is mixed with a further 2 g of sodium and 5 g of methyl iodide converted to all traces of the unreacted starting material to eliminate.

Finally, the mixture is brought to room temperature by evaporation of the solvent and then slowly with 50 ml of diethyl

6 0 9 8 k Ά I 1 1 B 2 '

26U306

ether shifted. The reaction mixture is then treated with water, whereupon the organic phase is separated off and the aqueous phase is acidified. An oil separates out which solidifies on standing and gives 2- (4-isobutylphenyl) propionic acid in good yield. The material is recrystallized from petroleum ether to yield colorless plate ¹ having a melting point 74-76 ⁰ C.

Example 7

Dissolve 24 g of 4-isobutylpropiophenone in 350 ml with 63 ml 70% perchloric acid acidified methanol. Then 93 g of thallium (III) nitrate trihydrate are added in the course of two Portions to the solution, which are added with a time difference of 3 hours. The reaction mixture will in a stream of nitrogen at room temperature for 7 hours stirred, after which they are kept for a further 96 hours at room temperature lets stand. The thallium (I) nitrate formed is filtered off, after which the filtrate is diluted with about 2 liters of water and extracted with a total of 1 l of chloroform, which is divided into three portions. The chloroform solution will be fine with Washed water, removed with activated charcoal and dried. The solvent is distilled off under reduced pressure, ' until an oily residue remains, which can be column chromatographed using silica gel (particle size 0.044 mm to 0.210 mm (70 to 325 mesh)). The column is eluted with benzene, collecting the first 1000 ml. the Benzene solution is evaporated to dryness under reduced pressure and gives methyl 2- (4-isobutylphenyl) propionate in good yield, which boils at 71 ° C / 0.7mmHg,

Example 8

2 g of methyl 2- (4-isobutylphenyl) propionate and 40 ml of a 10% strength aqueous sodium hydroxide solution are heated 2 hours to reflux. After cooling, the solution is extracted with 10 ml of diethyl ether to remove the impurities to remove. By acidifying with hydrochloric acid

6 09843/1162

an oil is excreted, which solidifies when left standing. It is extracted with diethyl ether, after which the ether solution is washed, is decolorized with activated charcoal, dried and evaporated to dryness and the 2- (4-isobutylphenyl) propionic acid with gives a yield of 92% of theory. The product is recrystallized from petroleum ether and gives colorless crystals

a melting point of 74 to 76 ⁰ C.

The compounds obtained according to the invention can also be reacted with an amino acid of the following general formula

B - (CH ₀ ) - CH - COOH

in which B stands for a primary, secondary or tertiary amino group or a guanidino group or an amidino group and η mean an integer with a value of not more than 5, are converted into valuable salts. Examples of such Amino acids are lysine and arginine, which can be used in racemic or in optically active form. These salts are much more soluble than the acids used for their production and also work much faster and more effectively than these.

609843/1162

Claims (14)

Claims 1. Process for the preparation of isobutylphenyl compounds of general formula I ' (D in which R represents a hydrogen atom or a methyl group, characterized in that a compound of the general formula II CO - R '(II) in which R ^{1 represents} a methyl group or an ethyl group, with an alkanol in the presence of a salt of the trivalent ι thallium to an ester of the general formula III CH - CH ₉ - (Z 7 - CH - COOAIk (III) H ₃ C reacted, in which Alk is an alkyl group and R has the meanings given above, and this compound hydrolyzed to the desired acid. 609843/1162 26H306 2. Procedure according to. Claim 1, characterized in that that thallium (III) nitrate is used as the salt of trivalent thallium. 3. The method according to claim 1 or 2, characterized in that - Kennz eichnet that methanol is used as the alkanol. 4. The method according to any one of the preceding claims, characterized in that the reaction with the alkanol is carried out with the aid of a strong acid catalyzed. 5. The method according to claim 4, characterized in that that perchloric acid is used as the strong acid. 6. The method according to any one of the preceding claims, characterized in that the Hydrolysis with potassium tert-butoxide in a polar or a non-polar organic solvent. 7. The method according to claim 6, characterized in that that the solvent used is tert-butanol, benzene or diethyl ether. 8. The method according to any one of the preceding claims, characterized in that one Product of the general formula I, in which R represents a hydrogen atom, into the corresponding compound in which R means a methyl group, by converting the compound with a methylating agent in anhydrous, liquid ammonia in the presence of a basic condensing agent. 609843/1162 26H306 9. The method according to claim 8, characterized marked ennz eichnet that sodium amide or potassium amide is used as the basic condensing agent. 10. The method according to claim 9, characterized z eichnet that the sodium amide or the potassium amide in situ from liquid ammonia and metallic sodium or metallic potassium. 11. The method according to any one of claims 8 to 10, characterized gekennz eichnet that methyl iodide is used as the methylating agent. 12. The method according to any one of claims 8 to 11, characterized gekennz eichnet that the methylation in the presence of an organic solvent as a diluent performs. 13. Isobutylphenyl compounds obtainable by a process of claims 1 to 12. 14. Salts of acids of the general formula I according to claim 1 j with amino acids of the general formula B - (CH ₉ ) - CH - COOH δ η, in which B is a primary, secondary or tertiary amino group, a guanidino group or an amidino group and η is a mean an integer with a value of not more than 5. 609843/1 162