CH636592A5 - Process for preparing 2-aryl-C(2)-C(6)-alkanoic acids - Google Patents

Abstract

2-Aryl-C2- to C6-alkanoic acids of the formula <IMAGE> in which: Y denotes alkyl having 3 to 5 C atoms or hydrogen, and R denotes hydrogen or alkyl having 1 to 4 C atoms, are prepared by a novel process. Firstly, a mixture is prepared consisting of an appropriate cycloxenone derivative of the formula <IMAGE> in which R<1> denotes hydrogen or C1-C6-alkyl, and of acetic anhydride. The reaction mixture is firstly left to stand and is then heated at 75 - 110 DEG C until corresponding butenolides are formed. These latter are treated with mineral acid and acetic acid, resulting in the formation of a compound of the formula I. The compounds which are obtained can be used in agents against inflammations, pains, fevers and thromboses.

Description

The invention relates to a process for the preparation of 2-aryl-C2-C6-alkanoic acids.

The compounds which can be prepared according to the invention have the following formula

(II)

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COOR

bliss

R1 is hydrogen or Q-Q-alkyl, and produces acetic anhydride,

(b) the reaction mixture obtained in step (a) can stand long enough for the compound of the formula

Y

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(I)

(XI)

wherein

R and Y are defined above, and Ac means acetyl,

(c) the reaction mixture obtained in step (b) is heated at a temperature of 75-110 ° C. until a mixture is formed which comprises at least one compound of the formula or

(V)

(VI)

35 where:

Y alkyl with 3 to 5 carbon atoms or hydrogen and R hydrogen or alkyl with 1 to 4 carbon atoms. Such compounds have proven to be anti-inflammatory or anti-inflammatory and analgesic and 40 antipyretic drugs, e.g. B. the 2- (4-isobutylphenyl) propionic acid commonly known as ipuprofen.

A number of arylalkanoic acids are known to be effective antiinflammatory or antiinflammatory drugs and analgesic, antipyretic and antithrombotic drugs. Some of the better known compounds from this series of drugs are the 2-arylpropionic acid derivatives such as fenoprofen, i.e. 2- (3-phenoxyphenyl) propionic acid and related compounds (see U.S. Patent 3,600,437, for example), ibuprofen, namely 2- (4-isobutylphenyl) propionic acid and related compounds (U.S. Patent 3,385,886) ), and naproxen, namely 2- (6-methoxy-2-naphthyl) propionic acid and related compounds (cf. BE-PS 747 812). In addition, a number of other 55 of their 2-aryl-C2- to C6-alkane carboxylic acid compounds are described in the medical, pharmaceutical and agricultural literature and in the patent literature (cf. for example US Pat. Nos. 3,624,142 and 3,793,457; these patents describe some fluorine-substituted biphenyl-60 alkane carboxylic acids).

There are thus a wide variety of 2-aryl-C2- to -C6-alkanoic acids and a wide variety of uses for this. There is no doubt that other such compounds and uses for them can be found 65 and described.

The cited patents also describe a number of process variants for the preparation of useful 2-aryl-C2- to -C6-alkanoic acids. Some of the well-known

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However, driving suffer from a number of disadvantages. For example, they use expensive starting materials, lead to the formation of dangerous by-products or lead to the formation of undesirable and large amounts of by-products, the destruction or removal or avoidance of which requires greater own costs. This means that further chemical processes for the better and more economical production of usable 2-aryl-C2- to -C6-alkanoic acids, in particular of 2-arylpropionic acids, are tried out and newly developed.

Most of the processes use compounds with an aromatic ring component as reactants. For example, there are processes for the preparation of 2- (substituted phenyl) propionic acids a) from aromatic glycidonitriles (see Argentine patents 198 097 and 198 595), b) from aromatic glycidyl esters (see DE-OS 2 404 159) and c ) from aromatic alkyl cyanides. A number of further process variants are also known. All such process variants use reactants with aromatic constituents (see, for example, US Pat. No. 3,600,437).

From BE-PS 820 267 a process for the production of p-isobutylhydratropic acid, also known as 2- (4-isobutylphenyl) propionic acid (ibuprofen), has become known, when it is carried out an aliphatic compound of the formula:

ch3

I.

0 c = o

HaC. II I

CH-CH2-C-CH2-CH2-C-C00R

h3c I

ch-ch3

I.

C00R

wherein each R is an alkyl group having 1 to 5 carbon atoms, is treated with a strong acid solution at a temperature of 200 to 240 ° C or in the dry state with a strong acid salt and an organic base for 30 minutes to 3 hours. From BE-PS 820 267 it is also known that the compound of the formula II described therein does not need to be isolated before the acid treatment, but rather that it is in the crude product form by reacting the vinyl isobutyl ketone with alkyl-a-acetyl-a-methylsuccinate or by Reacting an acetoacetic acid ester with an alkyl a-halogen propionate and then with the vinyl isobutyl ketone can be obtained.

In BE-PS 820 267 reference is also made to known methods and previous patents, e.g. the GB-PS 1 265 800, referenced. The production of a methyl or ethyl 2- (4-isobutyl-2-oxocyclohex-3-enyl) propionate in unspecified yield is described in the latter. In BE-PS 820 267 it is said that when the tests described in GB-PS 1 265 800 were repeated, yields of less than 5% were obtained. From this it is concluded that the process known from GB-PS 1 265 800 for the production of p-isobutyl hydratropic acid (ibuprofen) is not feasible industrially. In BE-PS 820 267 it is further stated that the advantages of the process described therein for the production of 2- (4-isobutyl-2-oxo-3-cyclo-hexenyl) propionic acid intermediate product are

that no expensive and dangerous reagents, e.g. Silver nitrate or cyanide ions are required. The process known from the aforementioned Belgian patent for the preparation of ibuprofen from 2- (4-isobutyl-2-oxo-2-cyclo-hexenyl) propionic acid is based on the aromatization which occurs when a dialkyl-a-acetyl-a- [ (5-methyl-3-oxo) hexyl] a'-methyl succinate takes place at temperatures of about 200 to 240 ° C with a strong acid. When carrying out the process known from the Belgian patent, temperatures above 200 ° C are required.

When carrying out the process known from GB-PS 1 265 800, it is also necessary to heat to temperatures above 200.degree. Corrosive substances are also used.

The invention was based on the object of creating a process-technically simple process for the preparation of 2-aryl-C2- to C6-alkanoic acids which provides the desired compounds in high yield, does not work with polymerizable intermediates and corrosive substances and which Avoid using high temperatures.

The invention is based on the knowledge that the task can be solved via new butenolide intermediate products.

The invention relates to a process for the preparation of 2-aryl-C2- to -C6-alkanoic acids of the formula I given above.

The inventive method for the preparation of the compounds of formula I and their salts is characterized in that

(a) a mixture of a compound of formula y

l

COOR

R

wherein

R1 is hydrogen or Q-CValkyl and produces acetic anhydride,

(b) the reaction mixture obtained in step (a) can stand long enough for the compound of the formula

Y

Ac where

R and Y are defined above, and Ac means acetyl,

(c) the reaction mixture obtained in step (b) is heated at a temperature of 75-110 ° C. until a mixture is formed which contains at least one compound of the formula

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Y Y

(V) (VI)

wherein

R is defined above, contains and

(d) treating these butenolides of the formulas V and VI from stage (c) with a mineral acid in acetic acid and, if appropriate, converting the compounds obtained into the corresponding salts.

Step (a) of the process according to the invention is preferably carried out in the presence of an acid trap which does not attack the reactants.

Heating the reaction mixture containing the reactants can be carried out in undiluted form, i.e. without the addition of a liquid diluent or solvent. However, it has been found that the reaction proceeds more effectively with a view to higher yields if the reaction mixture is diluted with a non-polar organic liquid, preferably one which forms an azeotrope with water in the heated reaction mixture.

It has been shown that the reaction product of the formula I from the starting compound II in its ester form, when heated as a rule, consists of a mixture of 2-aryl-C2- to -C6-alkanoic acid. However, this acid mixture can then be treated with a hydrolyzing base to form the salt form of the reaction product of the formula I. The free acid form of the reaction product of the formula I can be restored from the salt form in a known manner.

In the context of an additional embodiment of the process according to the invention, it has been shown that the addition of acetone or an equivalent ketone, but preferably acetone, to aqueous alkali metal ibuprofen or another 2-aryl-C2 to -C6-alkanoate salt solution lets the alkali metal ibuprofen salt precipitate out of the liquid phase in a highly effective manner. This property of acetone in these mixtures offers a simple and effective way of separating the ibuprofen or another 2-aryl-C2- to -C6-alkanoic acid in salt form from the reaction mixture. The amount of acetone can consist of any amount of acetone causing the salt to precipitate. Depending on the stirring conditions and the time available for separating the salt, the amount of acetone can range from equimolar amounts, based on the salt content of the mixture, to excess amounts of acetone, based on the aqueous phases.

The crude alkali metal ibuprofen or other 2-aryl-C2 to -C6 alkanoate salt can then be acidified with an acid which is sufficiently strong to convert the ibuprofen or other 2-aryl-C2 to -C6 alkanoate salt into the respective free acid form appropriate (free) acid are transferred. Then it is usually extracted, dried and evaporated. For example, the ibuprofen or other 2-aryl-Cz to -Ce alkanoate alkali metal salt can be used in an aqueous medium with an economically usable mineral acid, e.g. 6n-sulfuric acid or hydrochloric acid, acidified and thereby converted into the form of the free acid. Then the reaction mixture, for. B. one or more times with a non-polar, organic, liquid solvent, e.g. "Skellysolve B", extracted. The combined organic phases containing the respective acid can be separated from the aqueous phase and over a chemical drying agent, for. B. sodium sulfate, dry. Then they are usually evaporated, leaving behind the crystalline ibuprofen or other crystalline acid as evaporation residue. The evaporation residue can then be collected and put into the final preparation form, e.g. a pharmaceutical or agricultural preparation.

Due to the starting materials used, the process according to the invention can be carried out at relatively low temperatures, the compounds of the formula I described being obtained in high yield.

The formation of water and ester hydrolysis can be determined during the heating in the process according to the invention. The water can be removed continuously by e.g. attach a Dean-Stark trap or an equivalent device to the reaction vessel. If necessary, the reaction mixture can be switched from reflux to partial distillate removal or distilled through molecular sieves, for example 4A molecular sieves, which absorb both water and alcohol. Because of the effective azeotrope formation from toluene / ethanol / water (about 57/37/12 parts by volume), toluene is preferably used as the non-polar diluent in the production of ibuprofen. When the reaction mixture is heated (to reflux temperature) under conditions in which water is separated off, for example by means of a Dean-Stark trap attached to the reaction vessel, the 2- (substituted-2-oxo-3-cyclo-hexenyl) propionic acid goes into the J butenolides of formula V and VI. These aromatize with different reaction rates to the 2-aryl-C2- to -C6-alkanoic acid of formula I.

It has also been shown that butenolide derivative compounds of the formulas V and VI are formed in the process according to the invention. These butenolide compounds can optionally be isolated. However, they do not need to be isolated, since they have proven to be useful chemical intermediates in the process according to the invention for the preparation of the 2-aryl-C2- to C6-alkanoic acids of the formula I. Preferred examples of such compounds of the formulas V and VI are those in which (1) Y represents an isobutyl radical and R represents a methyl radical.

These preferred butenolide intermediates of the formulas V and VI can therefore be used as intermediates in the preparation of the known medicinal products ibuprofen and naproxen [2- (6-methoxy-2-naphthyl) propionic acid].

The treatment of 2- (substituted-2-oxo-3-cyclo-hexenyl) alkanecarboxylic acid of the formula II with acetic anhydride alone or in the presence of a basic acid scavenger which does not destroy the reactants, for example with potassium carbonate or pyridine, at room temperature during a period of Formation of the unstable intermediate of the formula:

4th

5

10th

IS

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Y

Ac in which Ac, R and Y have the meaning given, and then heating the mixture obtained to a temperature of 75 to 110 ° C. to provide a reaction mixture in which the butenolide intermediates consist primarily of those of the formula V and minor amounts of those of the formula VI .

When treating these butenolides with a mineral acid, e.g. Sulfuric acid or hydrochloric acid, in acetic acid there is an aromatization of the butenolides to the corresponding 2-aryl-C2- to -C6-alkanoic acid of the formula I.

Although the exemplary embodiment largely describes a process for the preparation of the preferred product ibuprofen, the process according to the invention can also be carried out for the production of other important 2-aryl-C2- to C6-alkanoic acid products.

Within the scope of the method according to the invention, all non-polar, organic, liquid diluents which are stable and preferably dissolve the reactants at the temperatures used can be used. The organic liquids should preferably also boil in the temperature range to be maintained and form an azeotrope with water and any alcohols which are formed during the heating. Toluene is the preferred solvent in the manufacture of ibuprofen. However, other organic liquids, e.g. Xylene, mesitylene, heptane, octane and commercially available mixtures of such organic liquids with boiling points within the heating range to be observed in the process according to the invention, e.g. "Skellysolve C" and "D" can be used. Mixtures of organic liquids which contain polar constituents and one or more of the non-polar constituents mentioned and which have boiling points within the heating range can also be used.

To remove or inactivate the water contained in the reaction mixture during heating, conventional chemical and / or physical measures can be used.

The best yields of 2- (aryl) -C2- to -C6-alkanoic acids of the formula I are obtained if the reaction mixture contains a liquid or a liquid mixture which forms an azeotrope with water and in the form of the water-containing azeotrope distilled from the reaction mixture during the heating process. There are numerous chemical compounds that form binary or tertiary water-containing azeotropes with boiling points sufficient to be distilled off during heating. Such chemical compounds are, for example, C5 to C8 alkanes and aromatic C6 to C8 hydrocarbons, halogenated hydrocarbons, in particular those having 1 to 6 carbon atoms and 1 to 4 chlorine or bromine atoms, ethers, esters, organic acids, ketones, Aldehydes and the like (see, for example, Handbook of Chemistry

636 592

by NA Lange, 9th edition [1956], Verlag Handbook Pub-lishers, Inc. Sandusky, Ohio, pages 1484 to 1486 and 1493 and Chemical Rubber Co., Handbook of Chemistry and Physics, 45th edition, pages Dl to C- 18 [1964 to 1965]). The liquid capable of forming a water-containing azeotrope in the reaction mixture should preferably consist of an easily available, inexpensive, inert organic liquid, which may also be a solvent for the reaction mixture. Examples of suitable liquids providing water azeotrope which are heavier than water and can be used are 1,2-dichloroethane, chloroform, methylene chloride and carbon tetrachloride. Examples of suitable liquids providing water azeotrope which are lighter than water and can be used are benzene, toluene, xylene, pentane, hexane, heptane and the like.

The following example is intended to illustrate the invention in more detail. Unless otherwise stated, all temperature data mean ° C.

example

1 g of 2- (4-isobutyl-2-oxo-3-cyclohexenyl) propionic acid (-en-one acid) and 100 mg of anhydrous potassium carbonate (1.5 milliequivalents) were slurried in 10 ml of acetic anhydride and kept at room temperature for 13 hours touched. The reaction mixture was then heated at 100 ° C. for a further 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. The 2- (4-isobutyl-2-acetoxy-3-cyclo-hexenyl) propionyl lactone of the formula XI was obtained.

The reaction mixture of the lactone of formula XI contained about 9 ml of unreacted acetic anhydride, so that an equivalent amount of water, namely 1.5 ml, was additionally added at room temperature. After about half an hour, a portion of 0.05 ml of concentrated hydrochloric acid was added. After further addition of 0.05 ml of hydrochloric acid, the reaction mixture was homogeneous after about an hour.

Then an additional 0.1 ml of concentrated hydrochloric acid was added dropwise and the mixture was heated to a temperature of 75 ° C. After about an hour, another 0.05 ml of hydrochloric acid solution was added. An additional 0.1 ml of hydrochloric acid solution was added after 3 and 5 hours of stirring. The reaction mixture was then heated at a temperature of 75 ° C. overnight and it could be determined by thin layer chromatography (TLC) on a sample of the reaction mixture that the reaction had ended. An additional 0.2 ml of concentrated hydrochloric acid (a total of 0.65 ml) was added and the brownish color of the reaction mixture changed to orange at the constant temperature of 70 ° C. TLC analysis of a sample of the reaction mixture showed

that the reaction was complete. The reaction mixture was then added to 100 ml of water and the mixture obtained was extracted twice with “Skellysolve B” (mixture of hexanes) and once with ethyl acetate. TLC analysis showed that the entire 2- (4-isobutylphenyl) propionic acid (ibuprofen) was in the "Skellylsolve-B" extract. The “Skellylsolve B” extracts were combined, washed once with water to neutrality and extracted twice with an aqueous sodium bicarbonate solution and then again with water. The majority of the desired product went into the aqueous sodium carbonate phase. The layer of sodium bicarbonate solution was separated off, acidified with 6n and 2n hydrochloric acid, extracted twice with “Skellylsolve B”, the “Skellylsolve B” extracts were combined and it

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was washed with water until the extracts were almost neutral. The "Skellylsolve-B" layer was dried and evaporated to dryness, using ibuprofen as a colorless oil that crystallized into white crystals

(775 mg), obtained (yield 84.3%). TLC showed that the product obtained is ibuprofen, which has a small amount of the enon acid used as the starting product.

s

Claims (2)

636 592 2nd PATENT CLAIMS 1. Process for the preparation of 2-aryl-C2- to C6-al-kanoic acids of the formula (I) CH / \ R COOH in which mean: Y alkyl with 3 to 5 carbon atoms or hydrogen and R hydrogen or alkyl with 1 to 4 carbon atoms, and their salts, characterized in that (a) a mixture of a compound of the formula wonn R is defined above and contains (d) the butenolides of the formulas V and VI from step (c) treated with a mineral acid in acetic acid and any compounds obtained are converted into the corresponding salts. 2. The method according to claim 1, characterized in that step (a) is carried out in the presence of an acid scavenger which does not attack the reactants.