WO1997034860A1

WO1997034860A1 - A PROCESS FOR THE PREPARATION OF α-ARYLPROPIONIC ACIDS AND THE INTERMEDIATES THEREOF

Info

Publication number: WO1997034860A1
Application number: PCT/EP1997/001258
Authority: WO
Inventors: Iacopo Degani; Stefano Dughera; Rita Fochi
Original assignee: Consiglio Nazionale Delle Ricerche
Priority date: 1996-03-15
Filing date: 1997-03-12
Publication date: 1997-09-25
Also published as: ITMI960500A0; IT1283251B1; ITMI960500A1; AU2026897A

Abstract

A process for the preparation of α-arylpropionic acids, particularly those pharmaceutically interesting, which process comprises the hydrolysis of the corresponding alkyl thiol ester. In a variation thereof, said process also allows to obtain the single enantiomers.

Description

A PROCESS FOR THE PREPARATION OF α-ARYLPROPIONIC ACIDS ANT) THE INTERMEDIATES THEREOF

The present invention relates to the preparation of pharmaceutically interesting compounds, particularly α- arylpropionic acids.

TECHNOLOGICAL BACKGROUND

The class of α-arylpropionic acids (APAs) has remarkable importance in the pharmaceutical field, in that it comprises different compounds used as effective antiinflammatory agents, belonging to the group of Non Steroidal Antiinflammatory Drugs. These acids are generally comprised in the formula

wherein *C is a chiral carbon atom and Ar is an optionally substituted aromatic residue.

Among APAs, Naproxen (Ar = 2-(6-methoxy)naphthyl), ketoprofen (Ar = 3-benzoylphenyl), and ibuprofen (Ar = 4-isobutylphenyl) can specifically be mentioned, which fill the main part of the NADS market. A great number of studies have been carried out about α-arylpropionic acids and as many researches are in progress. Among the problems to overcome, the most important relate to: i) various aspects of pharmacological nature deriving from the chirality of α-arylpropionic acids; ii) the accomplishment of novel preparation processes suitable to the preparation of both racemic and eutomeric forms. As far as i) is concerned, it should be evidenced that in the case of α-arylpropionic acids, the enantiomers (eutomers) of the S series proved to be always the active ones; the enantiomers belonging to the R series are not pgr se active; however, in some cases, depending on their structure, they have been found to be capable of converting in vivo into the active isomers, with a conversion degree which cannot be measured precisely and can vary among species and individuals belonging to the same species. Other researches are aimed at finding any interferences or adverse effects of APAs in the R form.

The finding of novel processes less expensive than those used up to now is still a real need in the chemical and pharmaceutical industries.

Considering what mentioned above in connection with uncertainties existent as to any antagonistic or even adverse side-effects of the enantiomers of the R series, the accomplishment of processes to obtain the S enantiomers free or almost free from the R enantiomers is also of interest.

The preparation of ibuprofen through hydrolysis of the corresponding methyl thiol ester (Japanese published Patent application n. 78-50137) is known. The thiol ester is obtained treating with acids 1-methylthio-1- nvethylsulfinyl-2-(4-isobutylphenyl)propene, in its turn prepared by reaction of LiCH(SCH₃) (SOCH₃) with 1- acetoxy-1-isobutylphenylethane (obtained by reduction and subsequent acetylation of 4-isobutylacetophenone) and treatment of the resulting 1-methylthio-1- methylsulfinyl-2-acetyl-2-isobutylphenylpropane with potassium tert-butylate.

Russel and Ochrymowycz (J.O.C., 35 (3), 4970, 764- 770) disclose the preparation of optionally α- substituted S-methyl phenylthioacetates by hydrolysis of ketene thioacetals.

Seebach and Burstinghaus (Synthesis, July 1975,

461-2) prepare S-methylphenylthiopropionate from acetophenone and bis(methylthio)-trimethylsilylmethyl- lithium and subsequent hydrolysis of the ketene thioacetal.

Russel and Ochrymowycz (ibid.) disclose α-keto trimethyl trithioorthoester RCOC(SCH₃)₃ as a useful intermediate for the preparation of α-keto thiol esters and α-hydroxyacid esters.

Barbero et al. (J. Chem. Soc. Perkin Trans. I,

1993, 2075-2080) illustrate the synthetic applications of tris(methylthio)methyllithium in the preparation of aliphatic methyl thiol carboxylates from the corresponding halides.

Disclosure of the invention

Now it has been found that the use of a thiol ester of the desired α-arylpropionic acid, obtained through a specific preparation process, allows to obtain the final products in very high yields.

Therefore an object of the present invention is a process for the preparation of α-arylpropionic acids of formula (I)

Ar-CH(CH₃)-COOH (I) wherein Ar is the residue of a aromatic hydrocarbon of 6 to 10 carbon atoms, optionally substituted with one or more alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, heteroaroyl groups, halogen; which process comprises the following steps:

a) reaction of an aromatic carboxylic acid derivative

Ar-CO-X reactive to acyl nucleophilic substitution; wherein X is selected from halogen, alkylthio, alkoxy, aryloxy;

with tris (alkylthio)methyllithium

(R₁S)₃C- Li⁺

wherein R₁ is the residue of a C₁-C₆ straight or branched alkyl or of an arylmethyl, to give the corresponding trithioorthoester (II)

Ar-CO-C(SR₁)₃ (II) b) isomerization of the α-keto trithioorthoester in presence of a protic or aprotic acid, in anhydrous conditions, to give the corresponding α,α- dialkylthio thiol ester (III)

Ar-C(SR₁)₂-CO-SR₁ (III) c) subsequent methyl-de-alkylthiolation to give the corresponding α-methyl-α-alkylthio thiol ester (IV)

Ar-C(CH₃)(SR₁)-CO-SR₁ (IV) wherein Ar is R₁ are as defined above;

d) subsequent proto-de-alkylthiolation to give the thiol ester (V)

Ar-CH(CH₃)-COSR₁ (V) wherein Ar and R₁ are as defined above;

e) alkali hydrolysis of the thiol ester.

It is a further object of the present invention the use of the compound of formula (III)

Ar-C(SR₁)₂-CO-SR₁ (III) as an intermediate in the process of the invention.

It is still a further object of the present invention a process for the enantiomeric resolution of the racemic α-arylpropionic acid.

The present invention allows to obtain the desired α-arylpropionic acids, particularly those for the pharmaceutical use, in high yields and using aromatic carboxylic acid esters and commercially available or easy-to-prepare reagents as the starting compounds.

These and other objects of the present invention will be described in detail hereinafter, together with some preparation examples.

Detailed disclosure of the invention

Examples of aryl group are phenyl and naphthyl, optionally substituted at the different positions with one or more substituents selected from halogen, such as fluorine, chlorine, bromine, iodine; alkyl, such as methyl, ethyl, propyl, butyl, pentyl, hexyl and related isomers; alkoxy, aryloxy, alkanoyl, aroyl, heteroaroyl.

An example of arylmethyl is benzyl.

Particularly preferred meanings for Ar are phenyl,

2-naphthyl, 4-isobutylphenyl, 4-bromophenyl, 4-chloro- phenyl, 4-methoxyphenyl, 6-methoxy-2-naphthyl, 3- benzoylphenyl.

In particular, the preparation of the thiol ester is illustrated in the following Scheme 1:

wherein X and R₁ are as defined above, R₃ is lower alkyl.

The preparation of α-keto trithioorthoesters starting from aromatic carboxylic acid esters (1^st step) is described in J. Org. Chem., 1995, 60, 6017-6024, wherein also the mechanism of the reaction between carboxylic acid esters and tris(methylthio)methyllithium is studied. In J. Chem. Soc. Perkin Trans. 1, 1993, 2075-2080 the synthetic application of tris(methylthio)- methyllithium in the preparation of aliphatic methyl thiol carboxylates from the corresponding alkyl halides is reported.

Surprisingly it has been found that the transformation of the starting aromatic carboxylic acid ester into α-keto trithioorthoester and the subsequent isomerization also take place with tris(alkylthio)- methyllithium in which the alkyl group is higher than methyl. The most favourable results are attained with the ethyl and butyl groups.

Another surprising aspect of the process described in Scheme 1 is that not only the aromatic carboxylic acid esters, but also, more generally, the derivatives most active to the acyl nucleophilic substitution among these acids, such as halides, thiol esters and anhydrides, can react with tris(alkylthio)methyllithium.

Advantageously, tris(methylthio)methyllithium is prepared starting from tris(methylthio)methane with a method described in J. Chem. Soc. cited above, which avoids the use of methyl mercaptan, which drawbacks are well known. Moreover, in step 3 the formed methyl mercaptan remains in the aqueous phase as a potassium salt and can easily by destroyed by oxidation or alternatively it can be recovered and used in step 4. In step 4, the methylthio group, which is formed as MeS⁺, reacts with MeS- to give dimethyl disulfide and therefore also in this step no methyl mercaptan is released. Tris(alkylthio)methyllithiums are prepared advantageously also starting from the corresponding tris(alkylthio)methanes with a procedure similar to that used for the preparation of tris(methylthio)- methyllithium. In particular, tris(butylthio)methyl- lithium can advantageously be prepared also from dibutyl trithiocarbonate and butyllithium. The steps 3 and 4 are carried out starting from the trialkyl trithioorthoesters with processes analogues to those used starting from the trimethyl trithioortho esters.

It has surprisingly been found that α-keto trithioorthoester (II), in the presence of a protic or aprotic acid, in anhydrous reaction conditions, isomerizes to α,α-dialkylthio thiol ester, an important intermediate which allows to obtain α-arylpropionic acids with few, convenient synthetic steps.

According to the present invention, by acid, as used in step 2, a protic or aprotic acid is meant. It is mandatory for reaction conditions to be anhydrous, since in not anhydrous conditions α-keto thiol esters form, which are useless to the purposes of the present invention.

Anhydrous reaction conditions are usually obtained by those skilled in the art, who will be able to find the most appropriate conditions and means, such as the use of anhydrous solvents, inert atmosphere and adequate means for the protection of the reaction environment.

As an example of aprotic acids, the triphenylmethyl (trityl) cation in the salt form can be cited. Examples of protic acids according to the present invention are methanesulfonic acid, p-toluenesulfonic acid, tetrafluoroboric acid-ethyl ether complex. The isomerization carried out with protic acids is preferred in that it is less expensive and it yields an isomerization product which needs no purification.

As far as step 3 of scheme 1 is concerned, the methylation is carried out according to procedures known to those skilled in the art. Potassium tert-butylate is preferred as the base. Methylation agents are, for example, dimethyl sulfate, dimethyl carbonate, methyl acetate, MeAlg.

As far as step 4 of scheme 1 is concerned, the proto-de-alkylthiolation is carried out as well according to procedures known to those skilled in the art by use of a mercaptide. Sodium mercaptide is preferred.

The alkali hydrolysis reaction is carried out with conventional procedures known to those skilled in the art. The thiol ester, optionally dissolved in a suitable solvent, for example a ketone, such as acetone, preferably a water-miscibile solvent, is treated with an aqueous alkali solution, for example 10% w/v potassium hydroxide. The reaction temperature is uncritical, even though heating from room temperature to the reflux temperature would be preferable. The reaction time can be determined depending on the reaction conditions, for example checking its progress.

The process according to the present invention yields the α-arylpropionic acid racemic mixture. Therefore, the present invention also relates to a process for the preparation of α-arylpropionic acids, which comprises the transformation of the thiol ester of formula (V)

Ar-CH(CH₃)-COSR₁ (V) wherein Ar and R₁ are as defined above, into an ester or amide of a chiral alcohol or amine, the separation of the diastereomers and the hydrolysis of the ester or amide of the desired enantiomer. The resolution of the racemic mixtures into the enantiomers via formation of diastereomers is a well known, usually employed method. In the case of α-arylpropionic acids (APAs), the corresponding thiol esters can, through said route, provide the pharmaceutically interesting (S) enantiomers as well as the not active or less active (R) enantiomers, which can be subjected to racemization and recycled .

The process according to the present invention is generally applicable, however, in case any functional groups sensitive to the reaction conditions are present, they should be suitably protected.

For example, in the case of ketoprofen, or

2-(3-benzoyl)phenylpropionic acid, the carbonyl is suitably protected during the preparation of the thiol ester.

It has been found that the protection of the carbonyl group should be suitably carried out according to the following steps:

a) transformation of the carbonyl group of the compound of formula (VI)

3-(C₆H₅-CO)C₆H₄-COOR₂ (VI) wherein R₂ is a lower alkyl group,

into the corresponding ketal;

b) subsequent preparation of the corresponding α-keto trithioorthoester;

c) restoration of the carbonyl group;

d) subsequent transformation into the corresponding thiol ester, according to what described above for the preparation of the thiol ester.

The present invention also relates to a process for the preparation of 4-isobutylbenzoic acid ester, which is a starting compound to obtain the thiol ester of formula (V) wherein Ar is 4-isobutylphenyl, and the resulting α-arylpropionic acid is 3-(4-isobutyl)- phenylpropionic acid or ibuprofen.

According to the present invention, said ester is prepared by reaction of isobutylbenzene with oxalyl dichloride and subsequent treatment with methanol, or another suitable alcohol, to give the corresponding ester. Subsequently the thiol ester is obtained as described above.

When Ar is 2-(6-methoxy)naphthyl, the process according to the invention involves 6-methoxy-2- naphthoic acid, which is not commercially available; it is therefore necessary to start from 6-methoxy-

2-naphthonitrile, which is an expensive reagent.

Now it has been found that the thiol ester of formula (V) wherein Ar is 2-(6-methoxy)naphthyl, can be prepared with a more convenient method which comprises the following steps:

a) treatment of a formic acid ester with tris(alkyl)methyllithium to give the corresponding trithioorthoester;

b) subsequent isomerization to give the corresponding α,α-dialkylthio thiol ester;

c) subsequent methylation to give the corresponding S-alkyl α,α-dialkylthiopropanthioate;

d) Friedel-Crafts reaction of 2-methoxynaphthalene with said thiol ester.

Alternatively, S-alkyl α,α-dialkylthiopropanthioate for use in the Friedel-Crafts reaction, can be obtained reacting an alkyl acetate with tris(alkylthio)- methyllithium to give the trithioorthoester, and subsequent isomerization.

Said method, in addition to give good results in the case of Naproxen, is of general applicability for the purposes of the present invention.

The following examples further illustrate the invention.

For clarity's sake, the compounds prepared in the examples are indicated as follows with respect to the general formula and Reaction Scheme 1 reported above:

Ar-CH(CH₃)-COOH

a: Ar = C₆H₅; b : Ar = 4-i-Bu-C₆H₄; c: Ar = 4-Br-C₆H₄; d: Ar = 4-Cl-C₆H₄; e : Ar = 4-MeO-C₆H₄; f : Ar =

2-naphthyl;

g: Ar = 6-MeO-2-naphthyl; h: Ar = 3-C₆H₅CO-C₆H₄.

Preparations

Methyl 4-isobutylbenzoate

First the corresponding acid chloride is prepared, following the process described in Helvetica Chimica Acta, vol. 65, Fasc. 8 (1982), Nr. 241, 2448-2449, which is then converted into the corresponding ester by reaction with methanol, in a 92% yield (kp = 80-81°C at 0.3 mm Hg). ¹H NMR: 0.88 ppm (d, J=6, 2CH₃), 1.65-2.10 (m, CH), 2.48 (d, J=7, CH₂), 3.80 (s, OCH₃), 7.05-7.80 (2d, J=8, 4H_arom)

Methyl 6-methoxy-2-naphthoate

First 6-methoxy-2-naphthonitrile (commercial product) was hydrolysed in basic medium to the corresponding carboxylic acid (96%). After that an esterification with methanol in the presence of methanesulfonic acid was carried out (90%); m.p. = 131-2°C (CHCl₃). ¹H NMR: 3.75 and 3.78 ppm (2s, 2 OCH₃), 6.82-7.10, 7.38-7.95 and 8.20-8.40 (3m, 2:3:1, 6H_arom) Example 1

Ar-CO-C(SCH₃)₃ (Ar = b, c, f, g)

Following the procedure C described in J. Org. Chem., 1995, 60, 6017-6024, page 6021, the title compounds are obtained in yields ranging from 92 to 97%: b (95%), c (92%), f (97%), g (94%).

Example 2

3-C₆H₅CO-C₆H₄-CO(SCMe)₃ (Ar = h)

1) A suspension of 3-benzoylbenzoic acid (2.26 g,

10 mmol) in methanol (10 ml) is added with methanesulfonic acid (0.19 g, 2 mmol). The mixture is heated to mild reflux under stirring for 5 hours until complete esterification, then it is cooled to room temperature, added with trimethyl orthoformate (10 ml) and stirred until methyl 3-benzoylbenzoate disappears (24 hours). The mixture is treated with aqueous sodium bicarbonate and extracted with ethyl ether (2 x 50 ml). The combined organic extracts are washed with water (2 x 100 ml), dried and the solvent is evaporated off under vacuum. Substantially pure methyl 3-(phenyl- dimethoxymethyl)benzoate is obtained in a 94% yield (2.70 g). The compound, crystallized from carbon tetrachloride-pentane, has m.p. 89-90°C. ¹H NMR: 3.02 m (s, 2 OCH₃), 3.78 (s, COOCH₃), 7.05-7.90 and 8.00-8.12 (2m, 8:1, 9_arom).

2) 2,2,2-tris(methylthio)-1-(3-phenyldimethoxymethyl)phenylethanone was prepared following the procedure C described in J. Org. Chem., 1995, 60, 6017-6024, page 6021, in a 95% yield (3.85 g). ¹H NMR: 1.98 ppm (s, C(SCH₃)₃), 3.08 (s, 2 OCH₃), 6.90-7.70 and 8.02-8.40 (2m, 7:2, 9H _arom).

3) 2,2,2-tris(methylthio)-1-(3-benzoyl)phenyl- ethanone was obtained by hydrolysis of the compound obtained in step 2) above (4.08 g, 10 mmol) with conc. HCl (2.04 g, 20 mmol) in ethyl ether (20 ml). The reaction is complete after 1 hour stirring at room temperature. The reaction mixture is diluted with ethyl ether (200 ml), neutralized with solid sodium bicarbonate, washed with water (2 x 100 ml) and dried. After evaporation of the solvent under vacuum, the substantially pure product is obtained in a 93% yield

(3.37 g).

Example 3

Ar-C(SMe)₂-COSMe (Ar = a, b, c, d, e, f, g, h)

A solution of 1,1,1-tris(methylthio)-2-phenyl- ethanone (2.58 g, 10 mmol) in dry methylene chloride (15 ml) is added in a single portion with trityl perchlorate (0.51 g, 1.5 mmol) with stirring and under a nitrogen stream. The colour of the solution immediately changes to red and tends to darken with time. After two hour stirring at room temperature, controls with TLC (SiO₂; eluent: petroleum ether/acetone, 9.5:0.5) and GC-MS evidence the disappearance of the starting compound and the presence of two products: (methylthio)tri- phenylmethane and S-methyl 2-phenylbis(methylthio)- thioacetate. The reaction mixture is poured into a 5% sodium bicarbonate aqueous solution and extracted with methylene chloride. The organic phase is washed with water and dried over sodium sulfate. The crude residue resulting from the evaporation of the solvent under vacuum is chromatographed on a silica gel column (eluent: petroleum ether/acetone, 9.5:0.5).

Three products are obtained, which are listed in the elution order:

1) (methylthio)triphenylmethane: 0.32 g (71%)

2) S-methyl 2-phenylbis(methylthio)thioacetate: 2.38 g (92%)

3) triphenylcarbinol: 0.09 g (23%).

The eluents used for the separation of the other intermediates are the following ones:

Example 4

Ar-C(SMe)₂-COSMe (Ar = a, b, c, d, e, f, g, h)

A solution of 1,1,1-tris(methylthio)-2-phenyl- ethanone (2.58 g, 10 mmol) in dry methylene chloride (25 ml) is added with methanesulfonic acid (0.5 g, 5 mmol), with stirring and under a nitrogen stream. After two hour stirring at room temperature, controls with TLC (SiO₂; eluent; petroleum ether/acetone, 9.5:0.5) and GC-MS evidence the disappearance of the starting compound and the presence of a single product. The reaction mixture is poured into a 5% sodium bicarbonate aqueous solution and extracted with methylene chloride. The combined organic extracts are washed with water and dried over sodium sulfate. The crude residue resulting from the evaporation of the solvent under vacuum is substantially pure S-methyl 2-phenylbis(methylthio )thioacetate (2.38 g, 92%).

For Ar = b, c, d, e, f, g, h, yields, in repeated tests are always higher than 92%.

Example 5

Ar-C(SMe)Me-COSMe (Ar = a, b, c, d, e, f, g, h)

A solution of potassium tert-butylate (1.35 g, 12 mmol) in dry THF (15 ml), under a nitrogen stream and with stirring is added quickly with a S-methyl 2-phenylbis(methylthio)thioacetate solution (2.58 g, 10 mmol) in dry THF (3 ml). The solution immediately changes color to golden yellow. After 10 minute stirring at room temperature, dimethyl sulfate is added quickly (1.51 g, 12 mmol) in dry THF (2 ml). After 30 minutes, controls with GC and TLC (SiO₂; eluent: petroleum ether/ethyl ether, 9.8:0.2) evidence the disappearance of the starting compound. The reaction mixture is poured into water and neutralized with concentrated hydrochloric acid, then extracted with ethyl ether. The organic phase is washed with water (100 ml) and dried over sodium sulfate. The crude residue resulting from the evaporation of the solvent under vacuum is chromatographed on a short silica gel column (eluent: petroleum ether/ethyl ether, 9.8:0.2). S-methyl 2-phenyl-2-(methylthio)thiopropionate is obtained (2.05 g, 91%).

The same solvent mixture (petroleum ether/ethyl ether, 9.8:0.2) was used for the purification of Ar = b, c, d, f. The eluent used for the purification of Ar = e, g, h is petroleum ether/ethyl ether, 4:1.

Example 6

Ar-CH(Me)-COSMe (Ar = a, b, c, d, e, f, g, h)

A suspension of sodium methanethiolate (0.84 g, 12 mmol) in dry acetonitrile (15 ml), under a nitrogen stream and with stirring, is added quickly with a solution of S-methyl 2-phenyl-2-(methylthio)thio- propionate (2.26 g, 10 mmol) in the same solvent (5 ml). The solution has a pale yellow color. After 1 hour stirring at room temperature controls with GC and TLC (SiO₂; eluent: petroleum ether/ethyl ether, 9.8:0.2) evidence the disappearance of the starting compound. The reaction mixture is then poured into water and neutralized with concentrated hydrochloric acid, then extracted with ethyl ether. The organic phase is washed with water (100) and dried over sodium sulfate. After evaporation of the solvent under vacuum, substantially pure S-methyl 2-phenylthiopropionate (1.75 g, 97%) is obtained. Said compound is used directly in the subsequent step.

The two enantiomers of the hydratropic acid thiol ester were identified by GC, using a column with a chiral stationary phase. In a test carried out on the racemic thiol ester operating with CD₃SOCD₂Na in CD₃SOCD₃, an immediate H/D exchange took place and this result is undoubtedly the proof, however indirect, of the possibility of racemization of the enantiomer R. Example 7

Ph-CH(Me)-COOH

A solution of S-methyl 2-phenylthiopropionate (1.80 g, 10 mmol) in acetone (10 ml) is added with a _10% potassium hydroxide aqueous solution (1.20 g, 20 mmol) in a single portion, under stirring. The mixture is heated to mild reflux for 2 hours, until the checking by TLC (SiO₂; eluent: petroleum ether/ethyl ether, 9.8:0.2) evidences the disappearance of the starting compound. The mixture is cooled and carefully acidified with cone, hydrochloric acid. The reaction mixture is extracted with ethyl ether and the organic phase is dried over sodium sulfate. After evaporation of the solvent under vacuum, substantially pure 2-phenylpropionic acid (hydratropic acid) is obtained (1.50 g, 100%).

The reactions carried out and the yields of the single steps are summarized in Table 1.

*J. Org. Chem., 1995, 60, 6017-6024, **Global yield of the reactions of formation of the ketal, of the α- keto trithioorthoester ketal and of the ketone.

In the following Tables 2, 3, 4, 5 and 6, the physico-chemical data of the compounds obtained in the different steps of the process according to the present invention are reported.

In the Tables, in the column Compound, the different compounds are identified depending on the Ar residue, as defined above.

Claims

1. A process for the preparation of α-arylpropionic acids of formula (I)

Ar-CH(CH₃)-COOH (I) wherein Ar is the residue of a aromatic hydrocarbon of 6 to 10 carbon atoms, optionally substituted with one or more alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, heteroaroyl groups, halogen; which comprises the following steps:

a) reaction of an aromatic carboxylic acid derivative Ar-CO-X reactive to acyl nucleophilic substitution; wherein X is selected from halogen, alkylthio, alkoxy, aryloxy;

with tris( alkylthio )methyllithium

(R₁S)₃C- Li⁺

Ar-C(CH₃)(SR₁)-CO-SR₁ (IV) wherein Ar is R₁ are as defined above;

d) subsequent proto-de-alkylthiolation to give the thiol ester (V) Ar -CH ( CH₃ ) -COSR₁ ( V ) wherein Ar and R₁ are as defined above;

e) alkali hydrolysis of the thiol ester.

2. A process according to claim 1, wherein Ar is selected from the group consisting of phenyl,

2-naphthyl, 4-isobutylphenyl, 4-bromophenyl, 4-chloro- phenyl, 4-methoxyphenyl, 6-methoxy-2-naphthyl, 3-ben- zoylphenyl.

3. The use of the compound of formula (III)

Ar-C(SR₁)₂-CO-SR₁ (III) wherein Ar is the residue of an aromatic hydrocarbon of 6 to 10 carbon atoms, optionally substituted with one or more alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl groups, halogen; and R₁ is the residue of a straight or branched alkyl of 1 to 6 carbon atoms,

as an intermediate in the process of claim 1.

4. A process for the preparation of the enantiomers of α-arylpropionic acids of formula (I)

Ar-CH(CH₃)-COOH (I) wherein Ar is the residue of an aromatic hydrocarbon of 6 to 10 carbon atoms, optionally substituted with one or more alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl groups, halogen;

which comprises the transformation of the thiol ester of formula

Ar-CH(CH₃)-COSR₁

wherein Ar is as defined above and R₁ is the residue of a straight or branched alkyl of 1 to 6 carbon atoms, into an ester or amide of a chiral alcohol or amine, the resolution of the diastereomeric mixture and the hydrolysis of the ester or amide of the desirded enantiomer.

5. A process according to claim 1, wherein Ar is 3- benzoylphenyl, in which process said thiol ester is prepared according to following steps:

a) transformation of the carbonyl group of the compound of formula (VI)

3-(C₆H₅-CO)C₆H₄-COOR₂ (VI) wherein R₂ is an alkyl group, into the corresponding ketal;

b) subsequent preparation of the corresponding trithioorthoester;

c) restoration of the carbonyl group;

d) subsequent transformation into the corresponding thiol ester according to steps c) and d) of claim 4.

6. A process according to claim 1, wherein Ar is 4- isobutylphenyl, in which process said thiol ester (V) is prepared according to the following steps:

a) reaction of isobutylbenzene with the oxalic acid dichloride and subsequent treatment with methanol to give 4-isobutylbenzoic acid methyl ester;

b) preparation of the desired compound by transformation of said ester obtained in step a) into the corresponding thiol ester according to claim 4.

7. A process for the preparation of the compound of formula (V)

Ar-CH(CH ₃)-COSR₁ (V) wherein Ar is the residue of an aromatic hydrocarbon of 6 to 10 carbon atoms, optionally substituted with one or more alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl groups, halogen; and R₁ is the residue of a straight or branched alkyl of 1 to 6 carbon atoms or of an aryl methyl,

which comprises the following steps:

a) treatment of a formic acid ester with tris(alkylthio)methyllithium to give the corresponding trithioorthoester;

b) subsequent isomerization to give the corresponding α-α-dialkylthio thiol ester;

c) subsequent methylation to give the corresponding

S-alkyl α,αdialkylthiopropanthioate;

d) Friedel-Crafts reaction of Ar-H with said thiol ester, wherein Ar is as defined above.

8. A process for the preparation of the compound of formula (V)

Ar-CH(CH₃)-COSR₁ (V) wherein Ar is the residue of an aromatic hydrocarbon of

6 to 10 carbon atoms, optionally substituted with one or more alkyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl groups, halogen; R₁ is the residue of a straight or branched alkyl of 1 to 6 carbon atoms or of an arylmethyl,

which comprises the following steps:

a) treatment of an acetic acid ester with tris(alkylthio)methyllithium to give the corresponding trithioorthoester;

c) Friedel-Crafts reaction of Ar-H with said thiol ester, wherein Ar is as defined above.