DE2719304A1 - PROCESS FOR THE MANUFACTURING OF CARBON ACIDS OR CARBON ACIDS AND THE INTERMEDIATE PRODUCTS USED THEREOF - Google Patents

Description

Henkel, Kern, Feiler & ■ Hänzel patent attorneys

- ". , " Möhlstrasse 37

The Upoohn Company D-8000 Munich

KalamazOO, Mich., V.St.A. Tel .: 089 / 982085-87

Telex: 0529802 hnkld telegrams: ellipsoid

April 29, 1977

Process for the production of carboxylic acids or carboxylic acid esters and intermediate products used in this process

The invention relates to chemical processes for the production of 2-arylalkanecarboxylic acid compounds, in particular to an improved process for the production of 2-aryl-Cp- to -Cg-alkanecarboxylic acids. The invention preferably relates to an improved process for the production of 2-aryl-C ₂ -bis -Cg -alkanecarboxylic acids, which are suitable as anti-inflammatory or anti-inflammatory and analgesic and antipyretic drugs, e.g. for the production of the 2- (4 -Isobutylphenyl propionic acid.

A number of arylalkanecarboxylic acids are known to be effective anti-inflammatory or anti-inflammatory properties and represent analgesic, antipyretic and antithrombotic drugs. Some of the better known compounds from this range of drugs are the 2-arylpropionic acid derivatives, such as fenoprofen, i.e.

-2-

Dr.F / rm

70984Ö / 070I

2- (3-phenoxyphenyl) propionic acid and related compounds (cf. US Pat. No. 3,600,437), Ibuprofen, namely 2- (4-isobutylphenyl) propionic acid and related compounds (cf. US Pat. No. 3,385,886), and naproxen, namely 2- (6-methoxy-2-naphthy1) propionic acid and related compounds (cf. * BE-PS 747 812). In addition, a number of other 2-aryl-C ₂ - to -Cg -alkanecarboxylic acid compounds are also 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 biphenylalkanecarboxylic acids).

Thus there is a wide variety of 2-aryl-Cp- to -Cgalkanecarboxylic acids and the most diverse uses for it. No doubt there will be others too Connections and uses for this are found and described.

The patents mentioned also describe a number of process variants for the preparation of useful 2-aryl-C ₂ -bis -Cg -alkanecarboxylic acids. However, some of the known methods 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 elimination or avoidance of which require greater own costs. As a result, further chemical processes for better and more economical production of useful 2-ATyI-Cp- to -Cg-alkanecarboxylic acids, in particular 2-arylpropionic acids, are being tried out and newly developed.

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709846/070

/ ί? 271930Α

In most processes, compounds with an aromatic ring constituent are used as reactants. For example, there are processes for the production of 2- (substituted phenyl) propionic acids a) from aromatic glycidonitriles (see Argentine patents 198 097 and 198 595), b) from aromatic glycidyl esters (cf. DT-OS 2 404 159) and c) from aromatic Alkyl cyanides. A number of other process variants are also known. All such procedural variations use reactants with aromatic constituents (see, for example, US Pat. No. 3,600,437).

BE-PS 820 267 discloses a process for the production of p-isobutylhydratropic acid, also as 2- (4-isobutylphenyl) propionic acid (Ibuprofen) designated, became known, when carrying out an aliphatic compound of Formula:

CH ₃ I.

O C = O

H ₃ C. Il I

y CH-Ch ₂ -C-CH ₂ -CH ₂ -C-COOR HaC ^ I

CH-CH ₃

COOR

wherein each R represents an alkyl radical having 1 to 5 carbon atoms stands with a strong acid solution at a temperature of 200 ° to 240 ° C or in a dry state treated with a strong acid salt and an organic base for 30 minutes to 3 hours. From BE-PS 820 267 is

-A-

70984 * 70701

it is also known that the compound of the formula II described therein is not isolated prior to the acid treatment it is necessary that they are rather in crude product form by reacting the vinyl isobutyl ketone with alkyl a-acetyl-amethyl succinate or by reacting an acetoacetic acid ester with an alkyl-oc-halogenpropionate and then can be obtained with vinyl isobutyl ketone.

In BE-PS 820 267 reference is also made to known processes and earlier patents, for example GB-PS 1,265,800. The latter describes the preparation of a methyl or ethyl 2- (4-isobutyl-2-oxocyclohex-3-enyl) propionate in unspecified yield. In BE-PS 820 267 it is said that when the experiments 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 preparation of p-isobutylhydratropic acid (ibuprofen) cannot be carried out industrially. In BE-PS 820 267 it is further stated that the advantages of the process described therein for the preparation of 2- (4-isobutyl-2-oxo-3-cyclohexenyl) propionic acid intermediate are that no expensive and dangerous reagents, eg Silver nitrate or cyanide ions are required. The process known from the aforementioned Belgian patent for the production of ibuprofen from 2- (4-isobutyl-2-oxo-3-cyclohexenylpropionic acid is based on the aromatization which occurs when a dialkyl-ocacetyl-a - [(5-methyl-3- oxo) -hexyl] -A'-methylsuccinats takes place with a strong acid to temperatures of about 200 ° to 240 ⁰ C. in carrying out the known from the Belgian patent specification process temperatures are required above 200 ⁰ C.

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When carrying out the known from GB-PS 1,265,800 the process must be heated to temperatures above 200 ^0C. In addition, corrosive substances are used.

The invention was based on the object of creating a technically simple one-step process for the preparation of 2-aryl-C ₂ - to -Cg -alkanecarboxylic 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 asked Task can be solved via new butenolide intermediates.

The invention relates to a process for the preparation of 2-aryl-C ₂ - to -Cg -alkanecarboxylic acids and their esters of the formula (I) by heating a mixture with at least one compound consisting of (A) a 2- (substituted 2- 0xo-3-cyclohexenyl) -C ₂ - bis -Cg -alkanecarboxylic acid or an ester thereof of the formula (II), a succinic acid or an ester precursor thereof of the formula (III), an oc-acetyl-a- (substituted-3-oxopropyl ) -succinic acid or a Esterderivats of formula (IV) or a Butenolidverbindung of formula (V) or (VI) in the presence of a sulfonic acid or Fhosphonsäure to a temperature of about 75 ° to 130 ⁰ C until the formation of 2-aryl C ₂ - to -Cg -alkanecarboxylic acid or an ester or a mixture thereof, precautions being taken so that water can be removed from the mixture during the heating process.

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The invention also relates to new butenolide compounds of the formula V and VI per se. These compounds can be used in the process according to the invention produce in the reaction mixture.

In an advantageous embodiment of the process according to the invention, 2-aryl-Cp- to -Cg-alkanecarboxylic acids of the formula I are obtained via these butenolides by adding one of the 2- (substituted-2-oxo-3-cyclohexenyl) -C2- to -Cg -alkanecarboxylic acid of the formula II, acetic anhydride and a basic acid scavenger containing mixture prepared, the mixture is allowed to stand until the acetate intermediate of the formula XI is formed and then the reaction mixture obtained is heated to a temperature of about 75 ° to about 130 ° C. The heating should continue for so long that a mixture with at least one of the butenolide intermediates of the formulas V and VI is formed. A carboxylic acyl halide, such as acetyl chloride, and a stoichiometric amount of water are then added to form acetic acid and a mineral acid, such as hydrochloric acid, in the mixture. Finally, the reaction mixture is heated to a temperature of approximately up to approximately 130 ° C. for the 2-aryl-C ₂ - to -Cgalkanecarboxylic acid or its ester product of the formula I to be formed. On the other hand, the butenolide intermediates of the formula V and VI can be mixed with a sulfonic acid or phosphonic acid and heated in the form of the mixture with (simultaneous) removal of the water from the reaction mixture to a temperature of about 75 ° to about 130 ° C. until the desired 2 -ArVl-C ₂ - to -Cg -alkanecarboxylic acid or its ester product of the formula I forms.

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709849/0701

The invention relates in particular to a process for the preparation of compounds of the formula:

XH

where mean:

R is a hydrogen atom or an alkyl radical having 1 to A carbon atoms;

R is a hydrogen atom, an alkyl radical with 1 to 6 Carbon atoms or a mixture thereof and

Ar is an aromatic radical having 6 to 12 carbon atoms, the aryl ring portion consists of a phenyl or naphthyl ring to which the carboxyl group adjacent alkanecarboxylic acid atom is bonded to a Arylringkohlenstoffatom,

which is characterized in that one is a mixture of

(A) at least one compound of the formulas:

-8- 70984 9/0708

- -er -

in which R and R have the meaning given, Y alone is an alkyl radical having 3 to 5 carbon atoms or represents a hydrogen atom, X alone denotes a hydrogen atom and Y and X together with the "carbon atoms to which they are attached, a benzo ring with a methoxy radical attached to a benzo ring carbon atom in a ß-position is bonded to the carbon atom in the Α-position of the cyclohexenyl ring, complete, or the formula:

R OOC

(IV)

COOR

in which R, R and Y have the meaning given, or of the formula:

(V)

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709849/0708

in which R, Y, ζ and X have the meaning given, or of the formula:

(Vl)

wherein R and Y have the meaning given, and

(B) a sulfonic acid preferably having 1 to 12 carbon atoms or a phosphonic acid, preferably with 1 to 12 carbon atoms

sufficient to form a compound of formula I Time heated to a temperature of about 75 ° to about 130 ⁰ C, where provision is made for it in that the (formed) water is removed from the reaction mixture during heating.

The heating of the reaction mixture containing the reactants (A) and (B) can be carried out in undiluted form, i.e. without the addition of a liquid diluent or solvent. However, it has been shown that the reaction proceeds more effectively with a view to higher yields when the reaction mixture with a non-polar organic liquid, preferably a sol

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709049/0708

chen that in the heated reaction mixture with water forms an azeotrope, is diluted.

It has been shown that the reaction product of the formula I from the starting compound II, III or IV in its ester form when heated as described usually consists of a mixture of the 2-aryl-C ₂ - to -Cg -alkanecarboxylic acid and the corresponding ester exists, so that such mixtures are included in the definition of the radical R. However, this acid / ester mixture is then treated with a hydrolyzing base to remove the ester residues and 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 conventional manner.

In the context of the process according to the invention, all readily available sulfonic or phosphonic acids can be used. In practice, however, from an economic point of view, acids of this type having 1 to 12 carbon atoms in the organic radical of these acids are of primary interest. Sulfonic and phosphonic acids which are soluble in the non-polar, organic, liquid diluent for the reactants are preferred. Examples of acids which can be used are the C ^ to C ^ alkanesulfonic acids, C ₁ to C ₁₂ alkane phosphonic acids, Cg to C ^ aryl and Cy to 0 ^ 2- ^Α ϊ ^ & ΐγΐ3υ1 ± οη- and -phosphonic acids such as methanesulfonic acid, ethanesulfonic acid, dodecanesulfonic acid, phenylsulfonic acid or preferably p-toluenesulfonic acid, or methylphosphonic acid, ethanephosphonic acid, dodecylphosphonic acid, phenylphosphonic acid, p-tolylphosphonic acid and the like. These acids

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709849/0708

can also be used in their hydrated form. If after the method according to the invention ibuprofen to be produced in toluene is p-toluenesulfonic acid monohydrate the sulfonic acid of choice. It has been shown that phenylphosphonic acid is also very suitable is, which is why this phosphonic acid is the preferred phosphonic acid. It was with others too Acids containing sulfur and phosphorus, e.g. orthophosphoric acid and sulfuric acid, worked, but this was done not nearly as good results as with sulfonic and phosphonic acids.

In a preferred embodiment of the method according to the invention, ibuprofen is made by heating a mixture from (a) at least one compound of the formula:

CH ₃ -CH-CH ₃ (b) CH ₃ -CH-CH ₃ II

CH ₂ CH ₂

OOR

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709849/0700

- 12T -

^(c) CH ₃ -CH-CH ₃
I.

CH ₂
I.
X = 0

CH ₂ CH ₃ II CH ₂ C = O

CH

H ₃ C

(IVa)

where R in the respective batch stands for a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms or a mixture thereof, and (B) one, based on the total amount of starting materials of the formulas HA, HIA and IVA, practically equimolar amount of p-toluenesulfonic acid or its hydrate or phenylphosphonic acid to form an ibuprofen compound of the formula:

H ₃ C-CH-CH ₃
I.
CH ₂

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709849/0708

wherein R has the meaning given, for a sufficient time in a non-polar, organic, liquid solvent or diluent which forms an azeotrope with water, preferably at reflux temperature in a toluene-containing diluent (about 11O ° C), to a temperature of about 100 ° C to about 130 ^c heated.

In carrying out the preferred embodiment of the method according to the invention, after heating a water addition in one to hydrate the p-toluenesulfonic acid sufficient amount to remove the hydrated acid from the liquid phase of the mixture to separate. The reaction mixture containing the Rohibuprofen product can then with an alkali metal hydroxide, carbonate or bicarbonate, preferably in the form of a aqueous solution, treated to form the ibuprofen alkali metal salt to manufacture. Any basic alkali metal compound can be used in this stage. In practice, however, from an economic point of view, you only work with sodium, potassium or Lithium hydroxide, bicarbonate or carbonate.

In an additional embodiment of the process according to the invention, it has been shown that adding acetone or an equivalent ketone, but preferably acetone, to aqueous alkali metal ibuprofen or another 2-ATyI-C ₂ - to -Cg -alkanoate salt solution is highly effective Way lets the alkali metal ibuprofen salt precipitate from the liquid phase. This property of acetone in these mixtures offers a simple and effective way to separate the ibuprofen or another 2-aryl-C ₂ - to -Cg-

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709849/0708

alkanecarboxylic acid in salt form from the reaction mixture. The amount of acetone can consist of any amount of acetone that causes the salt to precipitate. Depending on the stirring conditions and the time available for separating the salt, the amount of acetone can be equimolar amounts, based on the salt content of the mixture, up to excess volumes of acetone, based on the aqueous phases, are sufficient.

The Rohalkalimetallibuprofen- or other 2-aryl-Cp- to -Cg-alkanoate salt can then by acidification with an _{acid sufficiently strong to convert the ibuprofen or other 2-ATyI-C 2} - to -Cg-alkanoate salt into the respective free acid form the corresponding (free) acid are transferred. It is then extracted, dried and evaporated. For example, the ibuprofen or other 2-aryl-C ₂ - to -Cg -alkanoate alkali metal salt can be acidified in an aqueous medium with an economically usable mineral acid, for example 6N sulfuric acid or hydrochloric acid, and thereby converted into the form of the free acid. The reaction mixture is then extracted one or more times with a non-polar, organic, liquid solvent, for example Skellysolve B. The combined organic phases containing the temporary acid can be separated off from the aqueous phase and dried over a chemical drying agent, for example sodium sulfate. They are then evaporated, the crystalline ibuprofen or other crystalline acid remaining as the evaporation residue. The evaporation residue can then be collected and converted into the final preparation form, for example a pharmaceutical or agricultural preparation.

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709849/0708

As indicated by the above-mentioned starting materials, is the person skilled in the invention provides a workable at low temperature and operating with high yield process for the preparation of ibuprofen and related 2-aryl-C ₂ - ^Dis -CG-alkanecarboxylic acids of a-Acetylsuccinatesterderivaten of formula IV given at hand. Such α-acetyl succinate ester derivatives which can be used as starting materials are obtained by a Michael condensation reaction analogously to the measures described in GB-PS 1,265,800. Thus, according to the invention, it is not necessary to isolate the 2- (substituted-2-0xo-3-cyclohexenyl) Cpbis -Cg -alkanecarboxylic acids or their esters of the formula II per se and to separate the process according to the invention with these isolated compounds kick off. Such compounds of the formula II are formed in situ in the context of the process according to the invention if a reaction mixture containing the cx-acetyl succinate esters of the formula IV is started.

During the heating in the process according to the invention, the formation of water, an ester hydrolysis and detect decarboxylation. The water can be removed continuously by am Reaction vessel a Dean-Staik trap or equivalent Attaches device. The reaction mixture can optionally be removed from reflux to partial distillate switched or by molecular sieves, for example 4A molecular sieves, which absorb both water and alcohol, be distilled. Because of the effective azeotrope formation from toluene / ethanol / water (about 57/37/12 Volume fractions), toluene is preferably used as a non-polar diluent in the production of ibuprofen

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709849/0709

turns. The removal of alcohol and water shifts the equilibrium of any oc-acetyl succinate derivative of the formula IV containing reaction mixtures in the direction of the formation of a 2- (substituted-2-oxo-3-cyclohexenyl) propionic acid of formula (II). On further heating (to reflux temperature) the reaction mixture under conditions in which water is separated, for example by means of an attached to the reaction vessel Dean-Stark trap, the 2- (substituted-2-oxo-3-cyclohexenyl) propionic acid goes into the butenolides of the formulas V and VI. These aromatize with different reaction rates to the 2-aryl-Cp- to -Cg-alkanecarboxylic acid or their ester product of the formula I.

It has also been shown that butenolide derivative compounds of the formulas V and VI are formed in the process of 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-C ₂ - to -Cgalkanecarboxylic acids or of their ester products of the formula I. Preferred examples of such compounds of the formulas V and VI are those in which (1) Y is an isobutyl radical and R is a methyl radical and (2) Y and X, together with the carbon atoms to which they are attached, a benzo ring with a Methoxy radical bonded to a benzo ring carbon atom in a position ß to the Y position, complete.

These preferred butenolide intermediates of the formulas V and VI are suitable as intermediates in the manufacture

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709849/0708

position of the well-known drugs ibuprofen and naproxen [2- (6-Methoxy-2-naphthyl) propionic acid] in the context of the process according to the invention.

If necessary, the process conditions can be adjusted in this way that larger amounts of .den butenolide intermediates of the formulas V and VI are obtained. For example the 2- (substituted-2-oxo-3-cyclohexenyl) alkanecarboxylic acids or their esters of the formula II containing reaction mixtures with only catalytic amounts, for example 1 to 10? £ sulfonic or phosphonic acid in a non-polar, an azeotrope-forming solvent to a mixture with primarily butenolide of the formula VI and a minor amount of butenolide of the formula V are implemented. Treatment of 2- (substituted-2-oxo-3-cyclohexenyl) alkanecarboxylic acid of formula II with acetic anhydride alone or in the presence of a basic acid scavenger that does not destroy the reactants, for example with potassium carbonate or pyridine, at room temperature during one to form the unstable intermediate the formula:

(Xl)

wherein X and Y have the meaning given, and then Heating the resulting mixture to a

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709849/0708

A temperature of 75 ° to 11O ° C provides a reaction mixture, in which the butenolide intermediates primarily consist of those of the formula V and minor amounts of such of formula VI exist.

The treatment of these butenolides with a mineral acid, e.g. sulfuric acid or hydrochloric acid, in Acetic acid, the butenolides are aromatized to give the corresponding 2-aryl-Cp- to -Cg-alkanecarboxylic acid of the formula I. In the treatment of the butenolide of the formula VI with p-toluenesulfonic acid according to the invention Process measures, this is converted into his 2-ArVl-Cpbis -Cg -alkanecarboxylic acid product of the formula I.

Although the exemplary embodiments largely describe a process for producing the preferred product ibuprofen, the process according to the invention can also be carried out for obtaining other important 2-ArVl-C ₂ - to -Cg -alkanecarboxylic acid products.

If, for example, the process according to the invention is applied to the production of naproxen, namely 2- (6-methoxy-2-naphthyl) propionic acid, of the formula Ic, you can use 6-methoxy-a-tetralone of the formula:

(IX) H ₃ Cf

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709849/0708

with a base and ethyl o-chloropropionate to a iithyl-2-propionntderivat the formula:

CH ₃ H ₃ CI

H C-COOC ₂ H ₅

(X)

realize. This intermediate can be taken in the Process according to the invention directly for the production of ilaproxen, namely 2- (6-Hethoxy ~ 2-naphthyl) propionic acid of the formula Ic.

During the heating process, the water in the reaction mixture becomes removed by conventional chemical, physical or mechanical means. To ensure full effective The sulfonic acid or phosphonic acid is preferred for implementation in an approximately equimolar amount, based on that actually or theoretically contained in the reaction mixture Starting material (A), brought to use. However, are such stoichiometric amounts of sulfonic or phosphonic acid e not required. It is so that the preferred sulfonic or phosphonic acid for reuse in the frame of the method according to the invention can be recovered substantially quantitatively, so that the economy the method according to the invention does not depend on the amount of sulfonic acid or phosphonic acid used.

In the context of the method according to the invention, all non-polar, organic, liquid Verdüruiungs-

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7O9849 / 0708

BATH ORIGINAL

agents that are stable and preferably dissolve the reactants at the temperatures used will. The organic liquids should preferably also be in the temperature range to be maintained boil and with water and any alcohols formed during heating, form an azeotrope. In the manufacture of ibuprofen toluene is the preferred solvent. However, other organic liquids, e.g. Xylene ,. Ilesitylene, heptane, octane and commercial mixtures such organic liquids with boiling points within the scope of the method according to the invention heating range to be observed, e.g. Skellysolve C and D, can be used. Mixtures can also be used organic liquids, the polar components and one or more of the mentioned, non-polar components and have boiling points within the heating range.

To remove or inactivate the in the reaction mixture contained 'v / ater during heating can be seen in the usual known chemical and / or physical Operate measures.

The best yields of 2- (aryl) -C ₂ - to -Cg -alkanecarboxylic acids or their esters of the formula I are obtained when the reaction mixture contains a liquid or a liquid mixture which forms an azeotrope with water and is in the form of water-containing azeotrope distilled off from the reaction mixture during the heating process. There are numerous chemical compounds that have binary or tertiary hydrous azeotropes

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Boiling points that distill off during heating sufficient, educate. Such chemical compounds are, for example, Cc to Cg alkanes and aromatic compounds Cg to Cg hydrocarbons, halogenated hydrocarbons, in particular those with 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, edited by N / A. Lange, 9th Edition (1956), Handbook Publishers, Inc. Sandusky, Ohio, pages 1484 through i486 and 1493 as well Chemical Rubber Co., Handbook of Chemistry and Physics, 45th Edition, pages D-1 to C-18 (1964 to 1965)). Preferably should select the liquid capable of forming a water-containing azeotrope in the reaction mixture a readily available, inexpensive, inert organic liquid that may also contain a solvent represents for the reaction mixture exist. Examples of suitable water azeotrope-producing liquids, which are heavier than water and can be used are 1,2-dichloroethane, chloroform, methylene chloride and carbon tetrachloride. Examples of suitable water azeotrope-producing liquids which Benzene, toluene, xylene, pentane, hexane, and heptane are lighter than water and can be used like that.

It has been shown that the 2- (substituted-2-oxo-3-cyclohexenyl) -C2- to -Cg -alkanecarboxylic acids of the formula II to the corresponding 2- (aryl) -C ₂ - to -Cg -alkanecarboxylic acids of Formula I can be converted by adding it to molten p-toluenesulfonic acid monohydrate or an equivalent sulfonic or phosphonic acid 5 bis

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709849/0708

Heated to a temperature of about 120 ^° C. for 20 h. However, the yield of the desired 2- (aryl) -C ₂ - to -Cg -alkanecarboxylic acid is not as high as when a solvent is used for the reaction mixture.

The following examples are intended to illustrate the invention in more detail. Unless otherwise stated, all temperature data mean ⁰ C.

Example 1 (use of toluene as solvent)

A 10 ml flask is filled with about 1.01 g (4.52 χ 10 "^ Hol) of crystalline 2- (4-isobutyl -2-oxo-3-cyclohexenyl) propionic acid, 0.8596 g of p-toluenesulfonic acid monohydrate (4 , 52 χ 10 ~ ³ Hol) and 5 ml of toluene charged.

Thereafter, the flask under a nitrogen atmosphere with a Dean-Stark trap and a condenser is provided, and the flask and its contents in an oil bath at reflux temperature: heated (boiling point of toluene 110 ⁰ C.). The water collects in the Dean-Stark trap.

After a total of about 1 hour and 20 minutes, thin-layer chromatography shows Analysis of part of the reaction mixture that almost all of the 2- (4-isobutyl-2-oxo-3-cyclohexenyl) propionic acid is used up. The reaction mixture is now refluxed for a further 4.5 hours heated to ensure complete implementation. The total reaction time is about 6 hours. In the end the reaction mixture is allowed to cool to room temperature. A thin layer chromatographic analysis of the reaction mixture shows that the reaction is complete.

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For the pure preparation of the ibuprofen product from the reaction mixture the flask and its contents are treated as follows:

About 50 µl of water is added to the flask containing the reaction mixture, the p-toluenesulfonic acid monohydrate fails. The mixture is then cooled in an ice bath and filtered. The filter cake will washed with toluene, whereupon the filtrate and the toluene wash are combined.

The ibuprofen is obtained from the toluene mixture by extracting the toluene with 0.2062 g of sodium hydroxide (1.805 g = 4.52 χ 10 "- ⁵ mol) obtained in about 20 ml of water The toluene phase is a second time with a 5 / iigen sodium bicarbonate solution. The combined aqueous basic fractions are back-extracted to remove all neutral substances (organic soluble substances) with Skellysolve B. The combined Skellysolve B and toluene fractions are combined with one another, dried over sodium sulfate and finally evaporated, with 89.3 ng (96% strength) Yield) of a gold-colored evaporation residue.

The aqueous basic fraction with the sodium ibuprofen salt is acidified with 6N sulfuric acid, then with sodium chloride added and finally extracted twice with Skellysolve B, whereby the ibuprofen acid passes into the extractant. The Skellysolve B phase will eventually dried over sodium sulfate and then evaporated to give 867.7 mg of ibuprofen in a 93.2% yield. This shows, as determined by gas / liquid chromatography, a purity of 99.9%.

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0.7895 g of the ibuprofen obtained are redissolved in 3 ml of hot Skellysolve B. When the solution cools, the ibuprofen crystallizes out. There is obtained 0.6982 g of white crystalline ibuprofen, mp. 74.5 ° to 75 ⁰ C.

Example 2 (use of melted p-toluenesulfonic acid)

0.9756 g of 2- (4-isobutyl-2-oxo-3-cyclohexenyl) propionic acid (4.265 x 10 "x ⁵ WOI) and 1.0046 g p-toluenesulfonic acid monohydrate (mp .: 104 ° to 106 ⁰ C) are Nitrogen was introduced into a 15 ml flask fitted with a condenser and a agitator stirrer, after which the flask and its contents are heated in an oil bath for a total of 14 hours continued until a total heating time of 23 h is reached.

The reaction mixture obtained is then dissolved in toluene, crystals of p-toluenesulfonic acid precipitating out. These are filtered off after adding 1 molar equivalent of water. Now the toluene phase with 5% sodium bicarbonate solution extracted, dried over sodium sulfate and finally evaporated, leaving 0.0739 g (8.2% of the theoretical Ibuprofen yield) of a brown oil is obtained.

The aqueous sodium bicarbonate phase is acidified and three times with Skellysolve B, which is dried over sodium sulfate was extracted. Evaporation gives a crude ibuprofen product in an amount of 0.7065 g (78.8% the theoretical ibuprofen yield). This yield is preserved despite overflow of the reaction mixture.

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272.3 mg of the Rohibuprofen obtained are from Skellysolve D recrystallized, giving 251.2 mg (pure) ibuprofen (92.39% yield).

Example 3 (Use of Catalytic Amounts of an Acid Catalyst)

A equipped with a Dean-Stark trap and a cooler, 15 ml single-necked flask is filled with 0.0937 g of p-toluenesulfonic acid monohydrate, 0.9935 g of crystalline 2- (4-isobutyl-2-oxo-3-cyclohexenyl) propionic acid and 4 ml of toluene are charged and the reaction mixture is heated to reflux temperature under nitrogen. After heating for 5 hours show a thin-layer chromatograph! see and gas / liquid chromatographic analysis of the reaction mixture very small amounts of ibuprofen product and 2- (4-isobutyl-2-oxo-3-cyclohexenyl) propionic acid as well as a larger amount of the two butenolide intermediates va and via of the formulas:

and

(Va) (via)

In the formulas, “ibu” means in each case an isobutyl radical.

The compounds Va and VIa can be obtained by extracting the cooled reaction mixture with 5% aqueous sodium bicarbonate solution, Washing the toluene phase with water, drying the same over sodium sulfate and evaporating the

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70984970708

Isolate toluene. The oil obtained as evaporation residue, which mainly contains a compound of the formula Via and a minor amount of the compound Va, is chromatographed over silica gel, with in
oily form pure compound of formula Va and VIa with the following physical properties are obtained:

Connection Va:

60 ITHz (CDCI ^) 0.87 sextet (6H); 1.83 doublet (5H) dissolves on addition of Eu (FOD) -, to a 2H singlet and
a 3H triplet; 5.22 singlet 1H, 5.64 ppm singlet (1H). IR spectrum (CHCl ^) 1750, 1700 cm "* ¹ .

²¹³ (7500); 278 nyi sh (ε 674)
Mass spectrum: 206 (m +), 177, 149.

Compound VIa:

601'IHz NMR (CDCl ₃ ) 0.90 (6H), 1.80 (5H), 4.96 quartet (1H), 5.45 quartet (1H)
IR spectrum: 1750, 1695 cm " ¹

220 nyi (e 5850)
Mass spectrum: 206 (m +), 177, 163, 149.

If the two intermediates of the formulas Va and VIa are exposed to the action of p-toluenesulfonic acid in toluene at reflux temperature (as before), ibuprofen is obtained.

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2 /

"jj" 271930A

Example 4 (preparation of ibuprofen from a mixture containing diethyl aacetyl-a- (5-methyl-3-oxohexyl) -ß-methylsuccinate)

A 110 ml round bottom flask equipped with a condenser and Dean-Stark trap is filled with 4.339 g of a
Mix of:

(A) Diethyl α-acetyl α- (5-methyl-3-oxo-hexyl) -β-methyl succinate (IVa), a compound of the formula:

H ₃ C-CH-CH ₃ I.

CH ₂

(IMa)

-COOC ₂ H ₅ H ₃ C XOOC ₂ H ₅

and a compound of the formula:

H ₃ C-CH-CH ₃
I.
CH ₂

H ₃ C XOOC ₂ H ₅

(Ma)

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and

(B) 2.443 g of p-toluenesulfonic acid monohydrate and 17 ml of toluene

loaded.

Under an inert atmosphere, i.e. a nitrogen atmosphere, The flask and its contents are heated to reflux temperature for 6.5 hours with the removal of water. Thereafter If the reaction mixture is charged with 115 μl of water, Immediately cooled and then refluxed for an additional 16 hours. A thin layer chromatographic Analysis shows that the reaction has ended and resulted in a mixture of ibuprofen and its ethyl ester Has.

The cooled reaction mixture is then mixed with 0.23 ml of water, p-toluenesulfonic acid monohydrate precipitating out. This is filtered off, washed with toluene and then dried.

Then the toluene filtrate under nitrogen for 22 becomes long with 4.8 ml of 33 # aqueous sodium hydroxide solution to a temperature of 60 ⁰ C warmed h. The upper organic layer is now separated from the cooled reaction mixture by decanting. The remaining aqueous basic layer is mixed with 5 ml of acetone. The suspension of the ibuprofen sodium salt formed in this way is ^{cooled to a temperature of 0 °} C. for 2 hours, then filtered off and finally washed with cold acetone.

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The ibuprofen sodium salt obtained is introduced into 5 ml of water, then _{acidified with On-H 2} SO ^ and finally extracted twice with Skellysolve B. The combined organic phases are dried over sodium sulfate and then evaporated to give 2.03 g of crystalline ibuprofen. This corresponds to a 79% yield.

Example 5 (preparation of naproxen)

A reaction vessel containing ethyl 2- (6-methoxy-1-tetralon-2-yl) propionate is filled with 1 molar equivalent of p-toluenesulfonic acid monohydrate and an amount of toluene sufficient to dissolve the mixture upon heating. Thereafter the reaction mixture is heated to a temperature of 110 ° C for about 10 hours, during which naproxen, i.e. 2- (6-methoxy-2-naphthyl) propionic acid, forms.

Example 6 (use of a phosphonic acid)

A mixture of 1.00 g (4.46 mmoles) of 2- (4-isobutyl-2-oxo-3-cyclohexenylpropionic acid and 0.70 g (4.46 mmoles) of phenylphosphonic acid in 5 ml of toluene is refluxed for about 20 hours (about 110 ^° C.) The water formed in the course of the reaction is removed by means of a suitable trap.

The phenylphosphonic acid is then filtered off from the reaction mixture. Ibuprofen [2- (4-isobutylphenyl) propionic acid] is made from the neutral by-products by extracting the filtered reaction mixture with 20 ml separated from a 10% strength aqueous sodium hydroxide solution. The dissolved sodium 2- (4-isobutylphenyl) propionate contains

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- yt -

The basic phase is then acidified again with 6N sulfuric acid. The ibuprofen it contains is made from the acidified mixture extracted with Skellysolve B. The ibuprofen crystallizes from this solution on cooling the end.

Example 7 (use of melted p-toluenesulfonic acid and acetic anhydride as water scavengers)

A melt of 1.216 g of p-toluenesulfonic acid monohydrate (6.31 mmol) acetic anhydride and 0.60 ml (6.31 mmol) is conducted at a temperature of 94 ⁰ C with 1.01 g of 2- (4-isobutyl-2-oxo- 3-cyclohexenyl) propionic acid is added, whereupon the mixture obtained is ^{heated to a temperature of 115 °} C. for 35 hours under nitrogen. Then 5 ml of heptane are introduced into the hot reaction device, whereupon it is decanted. These measures are carried out four times. The decantate is then concentrated and extracted with a 5% strength aqueous solution of sodium bicarbonate. The aqueous phase obtained is acidified to pH 2 and then extracted with Skellysolve B. Drying over sodium sulfate and evaporating the Skellysolve B phase gives 0.855 g (92.3% yield) of crystalline ibuprofen with a purity of 97.596 as determined by gas / liquid chromatography.

Example 8 (production of ibuprofen from a Michael adduct mixture)

About 400 g of a crude mixture of the compound Ha of the specified Formula in which R stands for an ethyl radical (ethyl 2- (4-isobutyl-2-oxocyclohex-3-enyl) propionate), the compound of the formula III in which R is an ethyl radical

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709849/0708

(Diethyl-a-methyl-a ^l - (4-isobutyl-2-oxocyclohex-3-enyl) succinate), and the compound of the formula IVa, in which R ^{1 is} an ethyl radical (diethyl-a-methyl-a ' Acetyla '- (5-methyl-3-oxohexyl) succinate) (which contains about 0.6 Hol starting compounds for the production of ibuprofen and 403 β (2.12 Hole) p-toluenesulfonic acid monohydrate) is under nitrogen for 2 hours at a temperature from 80 ⁰ C stirred. Thereafter, the reaction mixture is mixed with 3 parts of each 86 ml of v / ater, after which an equivalent volume of each part V / ater is distilled off at a temperature of about 120 ⁰ C before addition of the next water content. The time required for these distillations is about 4 hours. Then 695 ml of toluene are added and the mixture is distilled at reflux temperature for more than 6.5 hours. The en-one acids (Ha, IHa and IVa) aromatize with the formation of ibuprofenic acid, 2- (4-isobutylphenyl) propionic acid. At the same time, the water disappears in the form of an azeotropic mixture via a Dean-Stark trap.

The remaining solution is cooled to a temperature of 35 ° C. and p-toluenesulfonic acid monohydrate is precipitated mixed with water. The resulting slurry is cooled to a temperature of 0 ° to 5 ° C, Stirred for more than 1 hour, then filtered and washed with about 50 ml of toluene. The solid filtered off p-Toluenesulfonic acid monohydrate precipitate is suitable for reuse. About 80% (323 g) of p-toluenesulfonic acid monohydrate are obtained recovered.

Ground the toluene filtrate and toluene wash liquid with an aqueous sodium hydroxide solution (412.5 g) mixed, whereupon the organic phase with 135 ml v / ater

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is re-extracted. Then the phases separate again. The combined aqueous phases are diluted with 200 g of a 50% ^strength 14 atrium hydroxide solution and then treated with 99.75 g of solid hydroxide and 428 ml of acetone. When the aqueous mixture treated with a base is cooled to 0 ° to 5 ° C. and stirred for about 1.5 hours, sodium 2- (4-isobutylphenyl) propionate (sodium ibuprofen) crystallizes out. The crystalline precipitate formed is filtered off and washed twice with 175 ml of acetone each time at a temperature of ⁰ ° C. in order to purify the ilodium ibuprofen salt cake. The sodium ibuprofen salt cake is then added to 352 ml of water and 630 ml of Skellysolve B (hexane mixture) or hexane are added. Furthermore, 80 ml of concentrated sulfuric acid are added in order to lower the pH of the mixture to about 0.6. Then the mixture is heated to dissolve the ibuprofen acid in the Ilischung to a temperature of about 42 ⁰ C. Let 3ich the aqueous and the organic phase separate. The aqueous phase is discarded, while the organic phase is washed twice with 1200 ml of water each time. The organic phase containing the dissolved ibuprofenic acid is finally separated from the aqueous phase, ^{cooled to a temperature of 0} ° C. to 5 ^° C. and stirred for about 0.5 h until the crystallization of the ibuprofenic acid has ended. When the ibuprofen crystals are filtered off and washed with hexane, and after drying, 90 to 100 g of ibunrofenic acid are obtained.

709849/0708

Claims (1)

Henkel, Kern, Feiler Cr Hänzel patent attorneys Möhistraße 37 The Upjohn Company D-8000 Munich 80 KalamazOO, Mich., V.St.A. Tel: 089/982085 87 Telex: 0529802 hnkld telegrams: ellipsoid Claims 1. Process for the preparation of carboxylic acids and / or Carboxylic acid esters of the formula: Ar 'CH (I) where mean: R represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms; R is a hydrogen atom, an alkyl radical with 1 to 6 Carbon atoms or a mixture thereof and Ar is an aromatic radical with 6 to 12 carbon atoms, whose aryl ring part consists of a phenyl or Naphthyl ring, which is bonded to the alkanecarboxylic acid atom adjacent to the carboxyl group on an aryl ring carbon atom, -II- 709849/070 « characterized in that one is a mongrel (A) at least one compound of the formulas: or R 0OC (IN THE) COOR ^ in which R and R have the meaning given, Y alone represents an alkyl radical with 3 to 5 carbon atoms or a hydrogen atom, X alone represents a hydrogen atom and Y and X together with the carbon atoms to which they are attached represent a benzine ring with a methoxy radical which is attached to a benzo ring carbon atom is bonded in a ß-position to the carbon atom located in the 4-position of the cyclohexenyl ring, complete or of the formula ¹ ! R 0OC (IV) -III- 709849/070 » in which R, R and Y have the meaning given, or the formula: (V) in which R, Y and X have the meaning given, or of the formula: (Vl) wherein R and Y have the meaning given, and (B) a sulfonic acid having 1 to 12 carbon atoms or a phosphonic acid having 1 to 12 carbon atoms a time sufficient to form a compound of formula I to a temperature of about 75 ° to -IV- 7 0 9 8 4 9/0 7 0 β about 13O ⁰ C., whereby this provision is made that the (formed) water is removed from the reaction mixture during heating. 2. The method according to claim 1, characterized in that the mixture with a non-polar organic Liquid that forms an azeotrope with water in the heated mixture, diluted. 3. The method according to claim 1, characterized in that a compound of the formula I is prepared in which R represents an alkyl radical having 1 to 4 carbon atoms and Ar represents an alkylphenyl radical having 3 to 5 carbon atoms in the alkyl part means. 4. The method according to claim 1, characterized in that the 2-aryl-C ₂ - to -Cg-alkanecarboxylic acid and / or its ester of the formula I containing reaction mixture to form the 2-aryl-C ₂ - to -Cg -Alkanoate alkali metal salt is subjected to a treatment with an aqueous alkali metal hydroxide and acetone is added to precipitate the alkali metal salt from the liquid phase of the alkali metal-2-aryl-C ₂ - to -Cg -alkanoate salt phase. 5. The method according to claim 1, characterized in that there is a reaction mixture with a compound of Formula: -V- 709849/0708 CH ι "^ COOR (IV) where mean: Y is an alkyl radical having 3 to 5 carbon atoms; R is an alkyl radical having 1 to 4 carbon atoms and R is a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms and a sulfonic acid having 1 to 12 carbon atoms in a non-polar, organic liquid diluent that works with water in the heated reaction mixture forms an azeotrope, one to form a compound of the formula: (IA) COOR -VI- 709849/0708 -JK- 6th wherein R, R and Y have the meaning indicated, heated sufficiently long time to a temperature of about 100 ° to about 130 ⁰ C. 6. A process for the preparation of 2- (4-isobutylphenyl) propionic acid, its C ₁ - to Cg-Alkyleater or mixtures thereof, characterized in that a mixture with at least one compound of the formulas: H ₃ C-CH-CH ₃ (Ma) COOR (MIa.) ^ COOR -VII- 7098497070 R 0OC (IVa) wherein in each case R stands for a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms, and a Sulphonic acid or phosphonic acid with 1 to 12 each Carbon atoms in a non-polar, organic, liquid solvent, which is at the b.p. of the solvent forms an azeotrope in the reaction mixture with water, one to form an ibuprofen compound of the formula: (la) 7098 * 070701 -VIII- wherein R has the meaning given, a sufficiently long time at a temperature of about 100 ° to about Heated to 130 ° C. 7. The method according to claim 6, characterized in that one is additionally used for hydration after heating sufficient amount of water is added to the sulfonic acid in the reaction mixture to separate the hydrated To accomplish sulfonic acid from the liquid phase of the mixture. 8. The method according to claim 7, characterized in that the reaction mixture containing the ibuprofen product is additionally used to form ibuprofen alkali metal salts subjected to a treatment with an aqueous alkali metal hydroxide, carbonate or bicarbonate solution. 9. The method according to claim 8, characterized in that one additionally consists of an aqueous alkali metal ibuprofen salt solution existing phase one for the precipitation of the alkali metal ibuprofen salt from the liquid Phase adds sufficient amount of acetone. 10. The method according to claim 9, characterized in that additionally the respective ibuprofen alkali metal salt with a strength sufficient to convert the ibuprofen alkali metal salt to the acid ibuprofen Acidic. 11. The method according to claim 6, characterized in that the reaction mixture is used to form the ibuprofen -IX- 709849/0701 compound sufficiently long in toluene at reflux temperature heated. 12. The method according to claim 6, characterized in that the sulfonic acid used is p-toluenesulfonic acid. 13. The method according to claim 1, characterized in that a reaction mixture with a compound of the formula: (lic) where Y and X together with the carbon atoms to which they are attached form a benzo ring with a methoxy radical, which is attached to the benzo ring carbon atom in the β position that located in the 4-position of the cyclohexenyl ring Carbon atom is bonded, complete, R stands for an alkyl radical having 1 to 4 carbon atoms and R represents a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms, and a sulfon or phosphonic acid in a non-polar, organic, liquid diluent which is heated with water in the Reaction mixture forms an azeotrope, one to form an acid of the formula: -X- 709849/0708 AO COOR (lc) wherein R and R have the meaning given, heated sufficiently long time to a temperature of about 110 ° to about 13O ⁰ C. Connections of the formulas: (V) and (Vl) in which Y individually represents an alkyl radical having 3 to 5 carbon atoms or a hydrogen atom, X individually represents a hydrogen atom, Y and X together with the carbon atoms to which they are attached represent a benzo ring with a methoxy radical which is bonded to a benzo ring carbon atom in the ß-position to the carbon atom in the 4-position of the cyclohexenyl ring, complete and R represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms. -XI- 709849/0708 15. Compounds according to claim 14, characterized in that that they correspond to the formulas given in which Y is an alkyl radical having 3 to 5 carbon atoms and R represents an alkyl radical having 1 to 4 carbon atoms. 16. Compounds according to claim 15, characterized in that that they correspond to the formulas given in which Y is an isobutyl radical and R is a methyl radical. 17. The method, characterized in that one a) in the presence of a basic acid scavenger, which Reactant not destroyed, a mixture of a compound of the formula: (M) where Y alone denotes an alkyl radical having 3 to 5 carbon atoms or a hydrogen atom, X represents a hydrogen atom alone, Y and X together with the carbon atoms to which they are attached form a benzo ring with a methoxy radical attached to a benzo ring carbon atom in β-position to the -XII- 709849/070 « -JBI- in the 4-position of the cyclohexenyl ring is bonded, complete, R is a hydrogen atom or an alkyl radical with 1 to k carbon atoms and R is a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, or mixtures of such compounds and acetic anhydride are prepared, b) the mixture obtained in each case one for the formation of an acetate intermediate product of the formula: (Xl) where Ac stands for an acetyl radical and R, Y, Z and X have the meaning given are sufficient lets stand for a long time, c) the reaction mixture obtained in step b) is one for forming a mixture with at least one compound of the formulas: -XIII- 709949 / 07QS - JHHCl - and ■ R (V) (Vl) heated to a temperature of about 75 ° to about 130 ° C for a sufficiently long time, d) Acetyl chloride and about a stoichiometric equivalent of water, based on the original acetic anhydride content of the mixture, for formation of acetic acid and hydrochloric acid in a mixture is added and then e) the mixture from step d) one for the formation of a compound of the formula: (I) 0OR 709849/0701 -XIV- wherein R, R, Y, Z and X have the meaning given have heated to a temperature of about 75 ° to 130 ° C. for a sufficiently long time. 18. The method according to claim 17 »characterized in that the reaction mixture from stage c) with (ongoing) removal of the (formed) water from the reaction mixture with a sulfonic or phosphonic acid with 1 to 12 carbon atoms each to form a Compound of the formula: (I) wherein R, R, Y, Z and X are as defined in claim 17, heated sufficiently long time to a temperature of 75 ° to 13O ⁰ C. 19. The method according to claim 18, characterized in that one of a compound of the formula II in which Y is an alkyl radical having 3 to 5 carbon atoms, X represents a hydrogen atom, R represents an alkyl radical with 1 to 4 carbon atoms and R denotes a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms or mixtures thereof. 709049/0701