CH640499A5 - Process for preparing a 2-arylpropionic acid - Google Patents

Abstract

Useful 2-arylpropionic acids are prepared, as antiinflammatory agents, by direct reaction of arylmagnesium bromides with an organic complex consisting of magnesium chloride or bromide and alpha-bromopropionic acid, and then acidification of the reaction product. The aryl moiety is selected from 6-methoxy-2-naphthyl, 4-alkylphenyl and 4'-fluoro-4-biphenyl. The reaction is carried out in an aprotic organic solvent which contains an ether.

Description

The present invention now relates to the preparation of known, valuable, anti-inflammatory agents, namely 2-arylpropionic acids, such as 2- (6-methoxy-2-naphthyl) propionic acid, which is described in U.S. Patent 3,904,682 . The present invention thus relates to a new process for the production of these valuable therapeutic agents.

In particular, the present invention is directed to a direct coupling process by which a particular aryl magnesium bromide is coupled with an organic magnesium halide complex of a-bromopropionic acid in high yield to form the corresponding 2-aryl-propionic acid. Each mention of 2-aryl-propionic acids in the present application refers to the racemic form of these compounds.

According to the invention, 2-arylpropionic acids can be prepared in which the aryl part is as follows:

6-methoxy-2-naphthyl, i.e. 2- (6-methoxy-2-naphthyl) propionic acid; 4-alkylphenyl, where "alkyl" preferably refers to straight and branched chain saturated hydrocarbon groups with 1 to 4 carbon atoms, e.g. B. 2- (4-methylphenyl) propionic acid, 2- (4-isopropylphenyl) propionic acid and 2- (4-isobutylphenyl) propionic acid; and 4'-fluoro-4-biphenyl, i.e. 2- (4'-fluoro-4-biphenyl) propion-45 acid.

As mentioned, the known US Pat. No. 3,959,364 describes the preparation of arylalkanoic acids by direct coupling of an Aryl-Grignard reagent with the Na, Li, Cai / 2 and Mg./2 salt of a-bromo-propionic acid.

It has now surprisingly been found that an improved coupling reaction is achieved if an organic magnesium halide complex of a-bromopropionic acid is used instead of the salts mentioned above, i.e. a compound of the formula CH3CH (Br) COOMgX, in which X is chlorine or bromine. In fact, a direct comparison of the magnesium salt of a-bromopropionic acid (prepared by both processes described in US Pat. No. 3,959,364) with the new complex thereof shows a significantly increased yield of the end-6o products obtained (about a 2-fold difference), which is illustrated in more detail in the following examples. It is a further advantage of the coupling process according to the invention that its yields are not influenced by the production of the organic magnesium halide complex to the same extent as the yields of the coupling process according to US Pat. No. 3,959,364 by the production process of the salt of 2-bromopropionic acid are influenced (cf. US Pat. No. 3,959,364, column 3, lines 10 to 11).

The organic magnesium halide complex of a-bromopropionic acid can be prepared by treating the free acid with a suitable Grignard reagent. Although the nature of the hydrocarbon portion of the Grignard reagent is not critical, it is preferred that the free hydrocarbon formed in the reaction of the a-bromopropionic acid with the Grignard reagent not interfere with the coupling step or processing. Therefore, Grignard reagents are particularly useful which are derived from hydrocarbons which are gaseous or liquid at the reaction temperature, e.g. Alkylmagnesium Grignard compounds with 1 to 12 C atoms or arylmagnesium Grignard compounds with 6 to 9 C atoms. Special Grignard 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 etc. etc. are, lead to the formation of gaseous methane, which escapes from the reaction mixture and does not interfere with the reaction or workup. Surprisingly, it was found that the addition of one of the above-mentioned Grignard reagents to a-bromopropionic acid mainly leads to the formation of the above-mentioned complex. The addition of the Grignard reagent over the carbonyl portion of the carboxylic acid - a reaction that is normally expected on a large scale - appears to be minimal, even when a molar excess of the Grignard reagent is used.

The organic magnesium halide complex is normally prepared in an aprotic solvent medium consisting of an ether, such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, di (n-butyl) ether, etc. The solvent medium can use other aprotic solvents include, such as aromatic hydrocarbons, e.g. Benzene or toluene. A preferred solvent medium for complex preparation is tetrahydrofuran. Although the order of addition of the reagents is not particularly critical, it is usually preferred to add the Grignard reagent to the a-bromopropionic acid. The Grignard reagent in the solution is preferably about IM to 4M, preferably about 2M to about 3M. A final complex solution for use in the direct coupling stage is about 1 to 2M, preferably about 1.0 to 1.5M. The temperature of the complex formation step is normally maintained between about -20 ° and + 30 ° C, preferably between about -10 ° and + 20 ° C.

The coupling itself is carried out according to the invention by contacting a solution of the organic magnesium halide complex of a-bromopropionic acid with the arylmagnesium bromide in a preferably anhydrous aprotic, organic solvent medium which comprises an ether. Suitable solvent media for the reaction include organic ethers mixed with aromatic hydrocarbons as mentioned above for the complex formation step. A particularly preferred solvent medium for the coupling is tetrahydrofuran. The aryl magnesium bromide solution is preferably 0.5 to 2M, especially about 1.0M.

The coupling process itself can be carried out over a temperature range of about 0 to 100 ° C, preferably between about 10 and 60 ° C. It is particularly convenient to let the temperature rise gradually to about 40 to 60 ° C during the addition step, whereupon

640 499

one goes back to room temperature until the desired level of reaction is reached.

Although the coupling can be carried out using the reagents in different ratios to one another, approximately equimolar amounts of organic magnesium halide complex and aryl-Grignard reagent are preferably used. Preferred ratios are from about 0.9: 1.1 to 1.1: 0.9 complex: Grignard reagent.

The reaction can be carried out in any customary manner by suitably touching the two reactants in the solvent medium. However, it is particularly preferred to add the organic magnesium halide complex to the Grignard reagent and to keep the two reactants in an intimate mixture until the desired reaction has practically ended.

The time required for this reaction is of course influenced by the particular choice of the reactants, solvents and the reaction temperature and set by the person skilled in the art for the optimal formation of the desired product. However, this reaction time is usually between about 10 minutes and about 20 hours, in particular between about 1 and 5 hours.

When the coupling has progressed to the desired end, the reaction mixture containing the coupled arylCH (CH3) COOMgX complex is treated with a preferably dilute acid, preferably a dilute aqueous mineral acid, such as hydrochloric or sulfuric acid, in the manner customary for Grignard reactions. The free 2-arylpropionic acid can then be isolated and purified from the reaction mixture thus treated in a conventional manner, e.g. by extraction with aqueous alkali (for example 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 is either extracted into an organic solvent or purified directly in a conventional manner can be, e.g. by washing and / or recrystallization.

Optionally, the crude reaction product can be converted directly into a pharmaceutically acceptable derivative of the carboxylic acid, e.g. a salt, ester or amide, converted or separated into the optical isomers.

The process according to the invention can be carried out easily and expediently on a large scale and provides yields of purified product between 50 and 75%.

The following examples illustrate the present invention without restricting it.

Trial 1

Preparation of 2- (6-methoxynaphthyl) magnesium bromide, 23.7 g (0.1 mol) of 2-bromo-6-methoxynaphthalene were dissolved in 30 cm3 of toluene and 40 ccm of tetrahydrofuran with heating. This solution was then added to 3 g (0.12 mol) of excess metallic magnesium, 15 cm 3 of toluene and 15 cc of tetrahydrofuran under a nitrogen atmosphere within 10 to 15 minutes. The reaction mixture was then cooled and stirred at 25 to 30 ° C. for a further hour. The reaction mixture was transferred from the excess magnesium into a clean, dry vessel under nitrogen and stored at 10 ° C to form a 1.0M Grignard reagent.

Similarly, the Grignard reagent can be prepared using tetrahydrofuran as the sole solvent.

Furthermore, by using less solvent, a more concentrated Grignard reagent, e.g. of 1.5M.

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Trial 2

Mixed magnesium halide complex of a-bromopropionic acid 15.3 g (0.1 mol) of a-bromopropionic acid and 40 cm3 of toluene were cooled to 10 ° C., then a solution of 50 ccm of 2M methylmagnesium bromide in 1: 1 tetrahydrofuran / toluene was slowly added added, the temperature being maintained at 10 to 20 ° C. during the addition period from 15 to 20 minutes. The reaction mixture was then stirred at 5 ° C for a further 20 minutes to form a 1.1M solution of the complex.

Similarly, the mixed magnesium halide complex can be prepared with tetrahydrofuran as the sole solvent.

Furthermore, methyl magnesium bromide can be replaced by other Grignard reagents such as methyl magnesium chloride, iso-propyl magnesium chloride, phenyl magnesium chloride, etc., in concentrations between about 1 to 4M.

The mixed magnesium chloride complex of a-bromo-propionic acid (as prepared above using 3M CH3MgCl in tetrahydrofuran) was isolated in crystalline form as tetrahydrofuran monoetherate after distilling off the tetrahydrofuran from a tetrahydrofuran solution and showed the following analysis: mp 147-155 ° C; IR (KBr) 1625, 1450, 1420, 1372, 1291, 1200, 1070, 1030, 988 and 890 cm - ^ NMR (D20) 5 1.8 (multiplet, 7) 3.7 (multiplet, 4) and 4, 35 ppm (quartet; J = 7). Elemental analysis for C7H12BrClMg03

calc .: Mg 8.57 Cl 12.49%

found: Mg 8.63 Cl 12.97%.

Trial 3

Manufacture of aryl magnesium bromides. 0.025 mol of aryl bromide was dissolved in 18 cm 3 of tetrahydrofuran. This solution was then added to 3 g (0.02 mol) of excess metallic magnesium and 7 cc tetrahydrofuran under a nitrogen atmosphere. The temperature was maintained for 10 to 15 minutes by cooling to 50 to 60 ° C during the addition period. Then the reaction mixture of excess magnesium was transferred to a clean, dry vessel under nitrogen and stored at 10 ° C to form a 1.0M Grignard reagent. The following Grignard reagents were prepared in this way:

2- (6-methoxynaphthyl) magnesium bromide 4- (4'-fluorobiphenyl) magnesium bromide l- (4-isopropylphenyl) magnesium bromide l- (4-isobutylphenyl) magnesium bromide 1 - (4-methylphenyl) magnesium bromide.

Trial A

A. Preparation of the Mixed Magnesium Halide Complex of a-Bromopropionic Acid.

3.8 g (0.025 mol) of a-bromopropionic acid were dissolved in 8 cm 3 of tetrahydrofuran and the solution was cooled to -10 ° C. To this solution was added 3M methylmagnesium chloride in tetrahydrofuran (8 cm3) over 15 minutes, keeping the temperature at -10 ° C to 0 ° C. This gave a 1.1M molar solution of the complex which was stored at 0 ° C or below until use.

The corresponding magnesium bromide complex was obtained by using IM methylmagnesium bromide instead of 3M methylmagnesium chloride.

B. Preparation of the Magnesium Salt of α-Bromopropionic Acid 3.8 g (0.025 mol) of α-bromopropionic acid was dissolved in 6 cm3 of methanol and the solution cooled to -10 ° C. 0.5M magnesium methoxide in methanol solution (25 cc) was added within 10 minutes,

keeping the temperature at -10 ° C to 0 ° C. Then the methanol was removed under reduced pressure to give the solid salt, which was dried under vacuum at 50 ° C for 12 hours to form 4.1 g (0.0125 mol) of the dry magnesium salt in a purity of 97.2% . This salt was dissolved in 19 cm3 of tetrahydrofuran for the coupling reaction.

example 1

A. The solution of the complex from experiment 2 was slowly added to the Grignard solution from experiment 1, the temperature being kept at 15 to 20 ° C. during the addition period from 10 to 15 minutes. The reaction mixture was allowed to warm to room temperature and then stirred for 2 hours. It was then cooled in an ice bath and a solution of 20 ccm 12N hydrochloric acid and 150 cm3 water was added. After stirring for 5 minutes, the two-phase system was filtered and the filter kitchen was washed with 55 cc toluene and 50 ccm water. The organic phase was extracted twice with 150 cm 3 of 10% potassium hydroxide solution each and the combined basic extracts were washed with 30 cm 3 of toluene and neutralized to pH 1 with 12N hydrochloric acid. The white solid 2- (6-methoxy-2-naphthyl) propionic acid was filtered under vacuum and dried under vacuum at 55 ° C to give 15.2 g (66%) yield with a melting point of 149.5 to 153 , 5 ° C was obtained.

B. After filtering, the organic phase can also be extracted twice with 150 cm3 of 10% potassium hydroxide solution, washed with 30 cm3 of toluene and filtered. 15 cm3 of methanol and 12 cm3 of toluene and then sufficient I2N hydrochloric acid were added to bring the pH to 4-5. The resulting slurry was refluxed for 1 hour, cooled and filtered. The precipitate was washed with 20 cm3 of water, twice with 3 cm3 of toluene and twice with 3 cm3 of hexane and dried under vacuum at 55 ° C, giving 15.0 g (65.1%) of product with an mp of 154 , 5 to 155 ° C was obtained.

Example 2

67 cc of a 1.5M solution of the mixed magnesium chloride complex of a-bromopropionic acid in tetrahydrofuran (made using 3M methylmagnesium chloride) slowly became a solution of 1.5M 2- (6-methoxynaphthyl) magnesium bromide cooled to 10 ° C added in tetrahydrofuran (67 cc) at such a rate that the temperature was maintained at 55 ° C or below. The resulting slurry was stirred at 50 ° C for 1 hour and then heated to reflux, allowing 30 to 40% of the tetrahydrofuran to be distilled off. The reaction mixture was cooled to 50 ° C, 30 cc of toluene was added, and the reaction mixture was quenched with aqueous hydrochloric acid as in Example 1B and worked up to give 2- (6-methoxy-2-naphthyl) propionic acid with an F. obtained from 156 to 157 ° C in 73% yield.

Example 3

A. The magnesium salt of a-bromopropionic acid, i.e. [CH3CH (Br) COO] 2Mg was prepared by reacting the acid with V2 molar equivalent of magnesium carbonate and the salt was dried at 60 ° C under vacuum.

If the mixed magnesium chloride complex used in Example 2 was replaced by this salt, the product was obtained in a 34.7% yield.

B. The salt from Part A was also made using Vimolar equivalent of magnesium methoxide, with methanol being removed as an azeotrope. The use

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Formation of the salt in the procedure of Example 2 gave the product in 43.0% yield.

Example 4

Example 3A was repeated except that 'Amolar equivalent of anhydrous magnesium chloride was added to the magnesium salt before the coupling reaction. A 5.1% yield of product was obtained.

Example 5

Example 3B was repeated using equimolar amounts of a-bromopropionic acid and magnesium methoxide. The yield of the product was 35.1%.

Example 6

Comparative coupling reactions using mixed magnesium halide complexes and Mg./z salts.

The following coupling reactions to the extent specified below were carried out both with the mixed magnesium chloride complex of a-bromopropionic acid (prepared according to test 4A) and with the magnesium salt of a-bromopropionic acid (prepared according to test 4B) with the corresponding Grignard reagent (prepared according to test 3) . The procedure (shown for a 5 0.025 mole reaction) was as follows:

The 1.0M solution of aryl magnesium bromide was cooled to 10 ° C and either the magnesium salt or the magnesium chloride complex in tetrahydrofuran was added to the solution over 5 minutes, keeping the temperature at 10 to 55 ° C. The reaction mixture was then stirred at 25 to 30 ° C. for 2 hours, cooled to 10 ° C. and a solution of 10 cm 3 of 12N hydrochloric acid and 50 cm 3 of water was added. After adding 50 cm3 of toluene, the aqueous phase was separated and discarded. The organic phase was extracted twice with 50 cm 3 of 10% potassium hydroxide. The basic extracts were combined and neutralized with hydrochloric acid to form a precipitate which was filtered off and dried at 50 ° C.

20 The results are shown in the following table:

Approach * Mol

Aryl Grignard reagent

Mgw2 salt or MgCl complex

% Educ. of raw product (g)

Actual remarks

Yield%

0.12

2- (6-methoxynaphthyl) -

MgCl

72.9 (20.1)

Product purity

96.0%

70

magnesium bromide

0.12

2- (6-methoxynaphthyl) -

Mgi / 2

43.0 (11.9)

Product purity

86.8%

37.4

0.025

4- (4'-fluorobiphenyl) -

MgCl

60.6 (3.7)

F.136-142 ° C

~ 60

magnesium bromide

NMR **

0.025

4- (4'-fluorobiphenyl) -

Mg1 / 2

28.6 (1.75)

F. 130-138 ° C

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<28

0.05

1 - (4-isopropylphenyl) -

MgCl

55.2 (5.3)

NMR **

^ 55

magnesium bromide

F.58-64 ° C

0.05

1 - (4-isopropylphenyl) -

Mg1 / 2

52.0 (5.0)

50% product

purely

^ 26

magnesium bromide

according to NRM oil

* using stoichiometric amounts of reactants ** matches authentic sample

As can be seen, a higher yield (about 2 times more) of a purer product was obtained in each case from the mixed magnesium chloride complex.

In a similar way, comparable results can be achieved in the preparation of the following 2-arylpropionic acids:

2- (4-isobutylphenyl) propionic acid 2- (4-methylphenyl) propionic acid.

If the above process is stopped before quenching with the aqueous acid and the solvent is removed under vacuum, the coupled magnesium halide complexes, i.e. ArylCH (CH3) COOMgX or their etherates.

The organic magnesium chloride complex of 2- (6-methoxy-2-naphthyl) propionic acid shows as its tetrahydrofuran monoetherate (purity 98.1%) the following properties:

F. 113 ° C (dec.); IR (KBr disk) 1600, 1450, 1410, 1260, 1210, 1155, 1025.923, 885, 850, 805 and 750 cnT1; NMR (DMSO-d6) Ô (TMS) 1.4 (Düblet, 2H), 1.8 (Multiplet, 4H), 3.6 (Multiplet, 5H), 3.9 (Singlet, 3H>, 7.5 ( Multiplet, 6H) ppm.

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Claims (8)

640 499 PATENT CLAIMS 1. A process for the preparation of a 2-arylpropionic acid, the aryl part being selected from 6-methoxy-naphthyl, 4-alkylphenyl and 4'-fluoro-4-biphenyl, characterized in that a) a solution of an aryl magnesium bromide with a solution a complex CH3CH (Br) COOMgX, in which X stands for chlorine or bromine, in an aprotic organic solvent medium which brings an ether into contact and b) the reaction mixture from a) is treated with an acid. 2. The method according to claim 1, characterized in that the solvent medium comprises tetrahydrofuran. 3. The method according to claim 1 and 2, characterized in that step a) takes place at a temperature of 10 to 60 ° C. 4. The method according to any one of claims 1 to 3, characterized in that the aryl magnesium bromide solution is from 0.5 to 2.0 molar and the complex solution from 1.0 to 2.0 molar. 5. The method according to any one of claims 1 to 4, characterized in that 2- (6-methoxy-2-naphthyl) propionic acid, 2- (4'-fluoro-4-biphenyl) propionic acid, 2- (4th -Isopropyl-phenyl) -propionic acid or 2- (4-isobutylphenyl) -propionic acid is produced. 6. The method according to claim 1 for the preparation of 2- (6-methoxy-2-naphthyl) propionic acid, characterized in that a) a from 0.5 to 2.0 molar solution of 2- (6-methoxynaphthyl) - contacting magnesium bromide in tetrahydrofuran with a 1.0 to 2.0 molar solution of a mixed complex of a-bromopropionic acid and magnesium chloride or bromide in tetrahydrofuran at a temperature of 0 to 100 ° C. and b) the reaction mixture from stage a ) treated with acid. 7. Application of the method according to claim 1 to complexes of the formula CH3CH (Br) COOMgX, in which X represents chlorine or bromine, which is prepared by treating α-bromopropionic acid with a Grignard reagent in an aprotic, organic solvent comprising an ether are are. 8. Use according to claim 7, characterized in that the Grignard reagent is methyl magnesium chloride or methyl magnesium bromide. One of the most commonly used synthetic methods for the production of arylalkanoic acids has been the coupling of an organometallic aryl reagent with a haloalkanoic acid derivative, such as a haloalkanoic acid ester. This method has proven to be particularly important for the production of the valuable anti-inflammatory agent 2- (6-methoxy-2-naphthyl) propionic acid. For the preparation of these compounds, in particular couplings with an α-halogenopropionic acid ester and 2- (6-methoxynaphthyl) copper (US Pat. No. 3,658,863), zinc (US Pat. No. 3,663,584) and cadmium (US Pat. No. 3,658,858 and 3,694,476) was used. A disadvantage of these methods was that the organometallic reagent used for coupling has to be prepared from the corresponding Grignard reagent, which therefore requires an additional chemical reaction, additional reactants, etc. DOS 2 145 650 describes the direct coupling of aryl magnesium halides with potassium 2-iodopropionate. Recently US Pat. No. 3,959,364 has shown that improved direct coupling can be achieved by reacting an Aryl-Grignard reagent with the lithium, sodium, magnesium or calcium salts of 2-bromopropionic acids of the formula CH3CH (X) COM can achieve, where X is bromine and M is Oli, ONa, 0 (Mg) .A or 0 (Ca), / 2 (cf. Table II of US Pat. No. 3,959,364). However, it has been found that the preparation of 2-arylpropionic acids, in particular the valuable 2- (6-methoxy-2-naphthyl) propionic acid, suffers from numerous disadvantages by this process, such as e.g. the production of a salt of halopropionic acid in the aprotic solvent medium, which must be used for the coupling reaction, which leads to poor results in large-scale production. i5 A coupling process using an Aryl-Grignard reagent and a suitable halogen propionic acid derivative would therefore be extremely valuable, which provides the desired 2-aryl propionic acids in a simple manner and with a reproducible high yield and purity and is easily applicable to large-scale production.