DK156898B - PROCEDURE FOR THE PREPARATION OF 2-ARYL PROPIONIC ACIDS USING DIRECT CLUTCH USING A MIXED MAGNESIUM HALOGENIDE COMPLEX - Google Patents

Description

DK 156898 B

The present invention relates to a process for the preparation of a 2-arylpropionic acid in which aryl is selected from the group consisting of 6-methoxy-2-naphthyl, 4-alkylphenyl and 4-1-fluoro-4-biphenyl. of a solution of an aryl-magnesium bromide, wherein the aryl group is as defined above, with a solution of a magnesium compound of α-bromopropionic acid in an aprotic organic solvent medium comprising an ether and acidification of the resulting product .

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One of the most frequently used synthetic methods for preparing arylalkanoic acids has been the coupling of an aryloro-organometal reagent with a halogenoalkanoic acid derivative such as a haloalkanoic acid ester. This method has been found to be of particular importance in the preparation of the valuable anti-inflammatory agent 2- (6-methoxy-2-naphthyl) propionic acid. Particularly for the preparation of this compound, couplings involving an α-halogenopropionic acid ester and 2- (6-methoxynaphthyl) copper (U.S. Patent No. 3,658,863), zinc-20 (U.S. Patent No. 3,663) have been used. 584) and cadmium (U.S. Patent No. 3,658,858 and No. 3,694,476) reagents. A disadvantage of these methods is that the organometallic reagent used for the coupling must be prepared from the corresponding Grignard reagent, so that an additional chemical reaction, an additional 25 reagents, etc. are required.

German Publication No. 2145650 describes the direct coupling of arylmagnesium halides with potassium 2-iodine propionate. More recently, U.S. Patent No. 3,959,364 (~ DK 153,138 B) has shown that an improved direct coupling could be obtained by reacting an aryl-Grignard reagent with the lithium, sodium, magnesium or calcium salts of 2-bromopropionic acid of the formula CH3CH (X) COM wherein X is bromine and M represents OLi, ONa, 0 (Mg) jg or 0 (Ca) 2 (see Table II of U.S. Patent No. 3,959,364). However, it has been found that the preparation of 2-arylpropionic acids, especially the valuable compound 2- (6-methoxy-2-naphthyl) -propionic acid, suffers from this method from a number of associated deficiencies including

DK 156898 B

2, the preparation of a halogen propionate salt in the aprotic solvent media to be used for the coupling reaction, which results in poor results when used on a large scale.

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It would therefore be of great value to have a coupling process which, by utilizing an aryl-Grignard reagent and an appropriate halogenopropionic acid derivative, provides the desired 2-arylpropionic acids readily and in reproducibly high yield and high purity, and 10 which can easily be used for large scale production.

The present invention thus relates to a particular method of preparing known valuable anti-inflammatory agents, namely 2-arylpropionic acids, such as 2- (6-methoxy-2-naphthyl) propionic acid disclosed in U.S. Patent No. 3,904 .682, and the method is peculiar to that of the distinguishing de! of claim 1.

Any reference to 2-arylpropionic acids in the specification and in the patent claims relates to the racemic form of these compounds.

Examples of the 2-aryl propionic acids whose preparation is within the scope of the present invention are those wherein the aryl portion is 6-methoxy-2-naphthyl, i.e. 2- (6-methoxy-2-naphthyl) propionic acid, 4-alkylphenyl, wherein "alkyl" represents straight and branched chain saturated hydrocarbon groups of 1-4 carbon atoms, e.g. 2- (4-methylphenyl) propionic acid, 2- (4-isopropylphenyl) propionic acid and 2- (4-isobutylphenyl) propionic acid, and 41-fluoro-4-biphenyl, i.e. 21 - (4'-Fluoro-4-biphenyl) -propionic acid.

As mentioned above, U.S. Patent No. 3,959,364 describes the preparation of arylalkanoic acids by the direct coupling of 3

DK 156898 B

an aryl-Grignard reagent with the Na, Li, Ca 2 and Mg 2 salts of α-bromopropionic acid.

It has now surprisingly been found that an improved coupling reaction is obtained if, instead of one of the aforementioned salts, a mixed magnesium halide complex of α-bromo propionic acid is used, i.e. a form of the formula CH3CH (Br) CQOMgX wherein X is chlorine or bromine. A direct correlation between the magnesium salt of α-bromopropionic acid (prepared by both methods described in U.S. Patent No. 3,959,364) and the novel complex herein disclosed shows a remarkable difference in yield of obtained salts (in one case twice the yield as in the other case) and is set out in more detail in the Examples. It is a further advantage of the present coupling process that the yields thus obtained are not affected by the manufacture. of the mixed magnesium halide complex to the extent that the yields of the coupling process according to U.S. Patent No. 3,959,364 are affected by the process for preparing the 2-20 bromopropionate salt (cf. U.S. Patent No. 3,959,364, column 3, 1i ni 10 and 11). .

The mixed magnesium halide complex of α-bromopropionic acid can be prepared by treating the free acid with a suitable 25 Grignard reagent. Although the nature of the hydrocarbon portion of 6 r in the g -nard reagent is not critical, it is preferred that the free hydrocarbon formed during the reaction of α-bromopropionic acid with the Grignard reagent does not interfere with the coupling step or preparation. For this reason, Grignard reagents derived from hydrocarbons which are gaseous or liquid at the reaction temperatures are particularly suitable, e.g. alkylmagnesium-Grignard reagents having 1-12 carbon atoms or arylmagnesium-Grignard reagents having 6-9 carbon atoms. Specific Grigard reagents that can be used for this purpose are methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, phenyl magnesium chloride and o-, m- or p-tolyl magnesium chloride and the like. Methylmagnesium chloride and methylmagnesium bromide

DK 156898 B

4 is particularly preferred, inasmuch as they are readily available, readily and lead to the formation of methane gas which escapes from the reaction mixture and does not interfere with the reaction or the work-up. Surprisingly, it has been found that the addition 5 of one of the aforementioned Grignard reagents to α-bromopropionic acid primarily results in the formation of the aforementioned complex. Addition of the Grignard reagent over the carbonyl portion of the carboxylic acid, a reaction that would normally be expected to proceed to a greater extent, is found to be minimal even when a molar excess of Grignard reagent is used.

The preparation of the mixed magnesium halide complex is usually carried out in an aprotic solvent medium comprising an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, di- (n-butyl) ether and the like. The solvent medium may comprise other aprotic solvents such as aromatic hydrocarbons, e.g. benzene or toluene. A preferred solvent for complexing is tetrahydro uranium. Although the order of addition of reagents is not very critical, it is usually preferred to add the Grignard reagent to the α-bromopropionic acid. The Grignard reagent in solution is preferably from ca. 1 to 4M, best from approx. 2 to approx. 3 M. An end-to-end complex solution for use in the direct coupling step of approx. 1 to approx. 2 M, preferably from ca. 1.0 to 1.5 M, is desirable. The temperature of the complex formation step is usually maintained between about -20 ° C and + 30 ° C, preferably between ca. -10 ° C and + 20 ° C.

The coupling reaction itself is conveniently carried out by contacting a solution of the mixed magnesium halide complex of α-bromopropionic acid with the arylmagnesium bromide in an anhydrous aprotic organic solvent medium. Suitable solvent media for the reaction include organic ethers and mixtures of organic ethers with aromatic hydrocarbons 35 mentioned above in connection with the complex formation step.

A particularly preferred solvent medium for the coupling reaction is tetrahydrofuran. It is preferred that the arylmagnesium bromide solution is between 0.5 and 2M, preferably about 0.5m.

1.0 M.

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The coupling process itself can be carried out within a temperature range of approx. 0 to approx. 100 ° C, preferably between ca. 10 ° C and 60 ° C. It is especially preferred to allow the temperature to rise gradually during the addition up to approx. 40-60 ° C and then drop 5 again to ambient temperature until the individual reaction rate has been achieved.

Although the coupling reaction can be carried out using the reagents in different proportions, it is preferred that approximately equimolar amounts of the mixed magnesium halide complex and the aryl-Grignard reagent be used. Pre-drawn conditions are from approx. 0.9: 1.1 to 1.1: 0.9 complex: Grig-nard reagent.

The reaction may conveniently be carried out by contacting the two reagents in the solvent medium in any of the methods known in the art. However, it is especially preferred to add the mixed magnesium halide complex to the Grignard reagent and keep these reagents intimately mixed until the desired reaction is complete.

The time required to carry out the desired reaction will, of course, be related to the specially selected reagents, solvents and the selected reaction temperature and will be adjusted in the usual manner by the person skilled in the reaction to achieve the optimum production of the individual. product. However, such a reaction time will, of course, be of the order of ca. 10 minutes to approx. 20 hours and is usually in the interval easily from approx. 1 to 30 approx. 5 hours.

After the coupling reaction is preceded to the individual extent, the reaction mixture containing the coupled complex aryl-CH (CH3) C00MgX is precipitated rapidly with a dilute acid, preferably a dilute aqueous mineral acid, such as hydrochloric acid or sulfuric acid. usual way for Grignard reactions. The free 2-arylpropionic acid product can then be isolated and purified from the cooled reaction mixture in the usual manner

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6 such as extraction with aqueous alkali (e.g. aqueous sodium or potassium hydroxide), separation of the aqueous alkaline phase from the organic phase and acidification of the aqueous alkaline phase to release the desired acid, which may optionally be extracted with an organic solvent or directly purified in the usual manner such as by washing and / or crystalization.

The crude reaction product, if desired, can be directly converted to a pharmaceutically acceptable derivative of the carboxylic acid such as a site, an ester or an amide thereof or cleaved into optical in the summers.

The process according to the invention is easily and conveniently carried out on a large scale and yields purified products on the order of 50-75%.

The following examples illustrate the process of the present invention.

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Preparation Method 1

Preparation of 2- (6-methoxynaphthyl) magnesium bromide 2-Bromo-6-methoxynaphthalene (23.7 g, 0.1 mol) is dissolved in toluene (30 ml) and tetrahydrofuran (40 ml) under heating. This solution is then added over 10-15 minutes to an excess of magnesium metal (3 g, 0.12 mol), toluene (15 ml) and tetrahydrofuran (15 ml) under a nitrogen atmosphere. The resulting mixture is then cooled and stirred for an additional 1 hour at 25-30 ° C. The reaction mixture is then freed of magnesium excess and transferred to a pure ter container under nitrogen and stored at 10 ° C to obtain a 1.0 M Grignard reagent.

35 Using a similar procedure, the Grignard reagent can be prepared using tetrahydrofuran as the sole solvent.

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By using a smaller amount of solvent, a more concentrated Grignard reagent, e.g. a 1.5 M reagent.

Preparation Method 2

Mixed magnesium halide complex of α-bromopropionic acid 15.3 g (0.1 mole) of α-bromopropionic acid and 40 ml of toluene are cooled to 10 10 ° C and a solution of 50 ml of 2 M methylmagnesium bromide in tetrahydrofuran / toluene (1: 1). is then added slowly, keeping the temperature at 10-20 ° C during the addition, which lasts 15-20 minutes. The reaction mixture is then stirred at 5 ° C for an additional 20 minutes to prepare a 1.1 M solution 15 of the complex.

By proceeding in a similar manner, the mixed magnesium-halide complex can be prepared using tetrahydrofuran as the sole solvent.

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Methylmagnesium bromide can also be substituted with other G r in g nard reagents such as methylmagnesium chloride, ispropylmagnesium chloride, phenylmagnesium chloride and the like at concentrations varying from approx. 1 to approx. 4 M.

25

The mixed magnesium chloride complex of α-bromopropionic acid (prepared as described above using 3 M CH 3 MgCl in tetrahydrofuran) was isolated in crystalline form as its tetrahydrofuran monoetherate after distillation of tetrahydrofuran from a tetrahydrofuran solution and analyzed: m.p. 147-155 ° C, infrared spectrum (KBr) 1625, 1450, 1420, 1372, 1291, 1200, 1070, 1030, 988 and 890 cm -1, nuclear magnetic resonance spectrum (D20) delta 1.8 (multiplet, 7) 3.7 (multiplied, 4) and 4.35 parts per million (quartet, J = 7). Elemental analysis calculated for C7H12BrClMg03: Mg 8.57%, Cl 12.49%.

Found: Mg 8.63%, Cl 12.97%.

DK 156898 B

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Method of freezing 3

Preparation of aryl magnesium bromides 0.025 mol of aryl bromide is dissolved in tetrahydrofuran (18 ml). This solution is added to an excess of magnesium metal (3 g, 0.02 mol) and tetrahydrofuran (7 ml) under a nitrogen atmosphere. The temperature is kept at 50-60 ° C with cooling during the addition period of 10-15 minutes. The reaction mixture is then freed of 10 magnesium excess and transferred to a pure container under nitrogen and stored at 10 ° C to obtain a 1.0 M Grignard reagent. Grignard reagents prepared in this way were prepared in 2- (6-methoxynaphthyl) magnesium bromide 4- (4'-fluorobiphenyl) magnesium bromide 1- (4-isopropylphenyl) magnesium bromide 1- (4-isobutylphenyl) magnesium bromide 1 - (4-methylphenyl) magnesium umbromide.

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Preparation Method 4 A. Preparation of the mixed magnesium halogenide complex of g-bromopropionic acid 25 α-bromopropionic acid (3.8 g, 0.025 mol) is dissolved in tetrahydrofuran (8 ml) and the solution is cooled to -10 ° C. To this solution, 3 M methylmagnesium chloride in tetrahydrofuran (8 ml) is added over a 15 minute period while maintaining the temperature between -10 ° C and 0 ° C. This gives a 1.1 molar readout of the complex which is stored at 0 ° C or below until used.

By replacing 3 M methylmagnesium chloride with 1 M methylmagnesium bromide, the corresponding magnesium bromide complex can similarly be prepared.

DK 156898 B

9 B · Preparation of the magnesium salt of α-bromopropionic acid α-bromopropionic acid (3.8 g, 0.025 mol) is dissolved in methanol (6 ml) and the solution is cooled to -10 ° C. To this is added a 0.5 M 5 magnesium methoxide in methanol solution (25 ml) over a 10 minute period while keeping the temperature at 11 ° C -10 ° C and 0 ° C. Methanol is then removed under reduced pressure to give the solid site, sonicated in vacuo at 50 ° C for 12 hours to prepare the terre magnesium salt (4.1 g, 0.0125 mol, 97.2¾ pure). This site is read into 18 ml of tetrahydrofuran for the coupling reaction.

Example 1 15 A. The solution of complex from Preparation Method 2 is slowly added to the Grignard solution from Preparation Method 1, keeping the temperature at 15-20 ° C during the addition, which lasts from 10 to 15 minutes. The reaction mixture is allowed to reach room temperature and stirred for 2 hours. The reaction mixture is then cooled in an ice bath and a solution of 20 ml of cold N hydrochloric acid and 150 ml of water is added. After stirring for 5 minutes, the two-phase system is filtered and the filter cake is washed with 55 ml of toluene and 50 ml of water. The organic phase is extracted with 10¾ potassium hydroxide solution (2 x 150ml) and the combined 25 basic extracts are washed with toluene (30ml) and neutralized with 12N hydrochloric acid to pH 1. The white solid 2- (6-methoxy) The 2-naphthylpropionic acid is filtered in vacuo and terred at 55 ° C in vacuo to give 15.2 g (66%), mp 149.5-153.5 ° C.

B. After filtration, the organic phase may alternatively be extracted with 10% potassium hydroxide solution (2 x 150 ml), washed with toluene (30 ml) and filtered. 15 ml of methanol and 12 ml of toluene are added, then sufficient 12N hydrochloric acid is added to adjust the pH to between 4 and 5. The resulting slurry is then heated to reflux for 1 hour, cooled and filtered. The precipitate is washed with water (20 ml), toluene (2 x 3 ml) and hexane (2 x 3 ml) and terred at 55 ° C

. DK 156898B

In vacuo to produce 15.0 g (65.1%) of product, mp 154.5155 ° C.

Example 2 67 ml of a 1.5 M solution of the mixed magnesium chloride complex of α-bromopropionic acid in tetrahydrofuran (prepared using 3 M methylmagnesium chloride) is slowly added to a spiked (10 ° C) solution of 1.5 M 2 - (6-methoxy-naphthyl) magnesium bromide in tetrahydrofuran (67 ml) at a rate such that the temperature is kept at 55 ° C or below. The resulting slurry is stirred at 50 ° C for 1 hour and then heated to reflux, with 30-40% of the tetrahydrofuran being allowed to distill off. The reaction mixture is cooled to 50 ° C, 30 ml of toluene is added and the reaction mixture is rapidly cooled with aqueous hydrochloric acid and worked up as described in Example 18 to prepare 2- (6-methoxy-2-naphthyl) propionic acid, m.p. 157 ° C, in a yield of 73%.

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Example 3 A. The magnesium salt of α-bromopropionic acid, i.e.

[CH3CH (Br) C00] 2Mg was prepared by reacting the acid with 25 1/2 molar equivalent of magnesium carbonate followed by drying the salt at 60 ° C in vacuo. Replacement of the mixed magnesium chloride complex used in Example 2 with this site resulted in a yield of 34.7%.

B. The salt from Section A was also prepared using 1/2. molar equivalent of magnesium methoxide, removing methanol as an azeotrope. Use of the salt in the method of Example 2 gave a product yield of 43.0%.

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DK 156898 B

11

Example 4

Example 3A was repeated except that 1/2 molar equivalent of anhydrous magnesium chloride was added to the magnesium salt during the coupling reaction. A product yield of 5.1¾ was obtained.

Example 5

The procedure of Example 3B was repeated except that equimolar amounts of α-bromopropionic acid and magnesium methoxide were used. The product yield was 35.1¾.

Example 6 Comparative Coupling Reactions Using Mixed Magnesium Halide Complexes and Mg

Scaling coupling reactions (according to the scale given below) were carried out using both the mixed magnesium chloride complex of α-bromopropionic acid (prepared according to Preparation Method 4A) or the magnesium salt of α-Bromopropionic acid (prepared according to Preparation Method 4B) with the corresponding Grignard reagent ( manufactured according to method of manufacture 3). The procedure (illustrated on a 0.025 mol scale) was as follows: The 1.0 M solution of arylmagnesium bromide is cooled to 10 ° C and the solution of either the magnesium salt or the magnesium chloride complex in tetrahydrofuran is added over a 5 minute period, while keeping the temperature between 10 ° C and 55 ° C. The reaction mixture is then stirred at 25-30 ° C for 2 hours. The reaction mixture is then cooled to 10 ° C and a solution of 12 N hydrochloric acid (10 ml) and water (50 ml) is added. Toluene (50 ml) is added thereto and the aqueous phase is separated and discarded.

35 The organic phase is extracted two yarns with 10¾ potassium hydroxide (50 ml). The basic extracts are combined and neutralized with hydrochloric acid to produce a precipitate, which is filtered and tarred at 50 ° C. The results are given in the following table:

12 DK 156898 B

X O) m JJ o \ ° o \ o o \ ° o \ ° o \ °

• H jJ O CO 10 CD

4J ^ o \ ° · CO CM LD CN

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000 eu a s ® cd o *, · fi CO 04 Î-J -fi, CO CD fi CO CD -0 1

σ 'oo (UC CUC

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lai 0U'§1 ° «J" ü g II

.3 G X N HO Γ0 -fi HO U fi Φ fi G G fi H Φ ^, Sa

M S eu H ^ 4 Ο I P -P 0) W

y fi fi i co ° & g ι Φ λ 53 S -P -P co H -H co Spoo u s

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H H T - O * »CO t '·· CO Γ' CN CO O O

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U CNOl CO i — I O CO COH LOLC) CNLO

dp Ch ["- - h <^ co ^ cn * - in m ^ al I-1 I-1 a) çd fi • fi <u fl S1 c1 Ç ·. ç ·" s d> d,> d> eu g g s g s g

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fi S Λ δ δ, Û & ^ 4¾ 04¾ Æ Tj rfi 'Ci 04¾ 04¾

H g -Η (0 -H CÇrH CÇrH rjHIH ^ S

tM SL @ & o! qo rOu o! 8 S 8 Y R * s £ * δ Ή fi Ή fi O fi py h ^ ΊεΊβΊ Blal & §

a (U -fi (U H îfi H HH CO -fi CD H

f 8 f 8 -8 8 ΐ 8 V 8 so γ & f & γ & y | y | <N g * 4 g 4 * | j H g H g al

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S CD eu Sn fi nj {d Θ {U tn {U fi g H eu fi,, Ύ d, (U ^ 4 I HH O Q H d H § "fi ^ ^ ^ m in

g, 3 3 S SS S

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DK 156898 B

13

From the above, it appears that in each case a higher yield (about twice as large) of a more pure product of the mixed magnesium chloride complex was obtained.

Comparable results can similarly be obtained with the preparation of the following 2-aryl propionic acids: 2- (4-isobutylphenyl) propionic acid, 2- (4-methylphenyl) propanoic acid.

10

If the above process is interrupted, rapid aqueous acid cooling and the solvent removed in vacuo, the coupled magnesium halide complexes, ArylCH (CH 3 CO 100 MgX or etherates thereof) can be isolated.

15

The mixed magnesium chloride complex of 2- (6-methoxy-2-naphthyl) propionic acid and its tetrahydrofuran mono etherate (98.1% purity) gives the following properties: Melting point 113 ° C (decomposition), infrared spectrum (KBr disk) 1600, 1450, 1410, 1260, 1210, 1155, 1025, 923, 885, 850, 805 and 750 cm -1, Nuclear Magnetic Resonance Spectrum (DMSO-dg) delta (TMS) 1.4 (doublet, 2H), 1.9 (multiplet, 4H ), 3.6 (multiplet, 5H), 3.9 (singlet, 3H), 7.5 (multiplet, 6H) 25 parts per million.

Similarly, the mixed magnesium chloride complexes (tetrahydro uranium monoetherates) of the precipitating 2-aryl propionic acids with precipitating physical constants have been isolated: 2-aryl-propionic acid physical constants 2- (4-methylphenyl) - mp: 70-79 ° C (dec) ; ir (KBr propionic acid disk): 3400, 1630, 1585, 1512, 1458, 1420, 1365, 1285, 1070, 35 815, 790, 730 cm -1 NMR (DMSO-dg) Ô (TMS): 1.3 (doublet, 3H), 1.8 (multiplet, 4H), 2.3 (singlet, 3H), 3.6

Claims (10)

A process for the preparation of a 2-arylpropionic acid wherein aryl is selected from the group consisting of 6-methoxy-2-naphthyl, 4-alkylphenyl and 4'-fluoro-4-biphenyl, by reacting a solution of an aryl magnesium bromide, wherein the aryl group is as defined above, with a solution of a magnesium compound of α-bromopropionic acid in an aprotic organic solvent medium comprising an ether, and acidification of the resulting product, characterized in that as magnesium compound of α-bromopropionic acid uses a complex of the formula CH3-CH (Br) C00MgX, where X is chlorine or bromine. Process according to claim 1, characterized in that said solvent medium comprises tetrahydrofuran. 30 A method according to claim 1, characterized in that the reaction is carried out at a temperature between approx. 10 and 60 ° C. Method according to Claim 1, characterized in that said arylmagnesium bromide solution is between approx. 0.5 and 2.0 molar, and said complex solution is between ca. 1.0 and 2.0 molar. DK 156898 B Process according to claim 1, characterized in that said 2-arylpropionic acid is 2- (6-methoxy-2-naphthyl) propionic acid. Process according to claim 1, characterized in that said 2-arylpropionic acid is 2- (41-fluoro-4-biphenyl) propionic acid. Process according to claim 1, characterized in that said 2-arylpropionic acid is 2- (4-isopropylphenyl) propionic acid. Process according to claim 1, characterized in that said 2-arylpropionic acid is 2- (4-isobutylphenyl) propionic acid. A process according to claim 1 for the preparation of 2- (6-methoxy-2-naphthyl) propionic acid by reacting an approximately 0.5 to 2.0 molar solution of 2- (6-methoxynaphthyl) magnesium bromide in tetrahydrofuran with a solution of a magnesium compound of α-bromopropionic acid in an aprotic organic solvent medium comprising an ether, and stirring of the resulting product, characterized in that as a magnesium compound of α-bromopropionic acid, about 1.0 -2.0 molar solution of a mixed magnesium chloride or bromide complex of α-bromopropionic acid in tetrahydrofuran. Process according to claim 9, characterized in that the reaction is carried out at a temperature between approx. 10 and 60 ° C. 30 35