CH640500A5 - Magnesium halide complexes of 2-arylpropionic acids, and their preparation - Google Patents

Abstract

Compounds of the formula aryl CH(CH3)COOMgX, in which aryl denotes 6-methoxy-2-naphthyl, 4-alkylphenyl or 4'-fluoro-4-biphenyl, and X denotes chlorine or bromine, and their etherates, are described. They are prepared by treating a solution of the corresponding arylmagnesium bromide with the solution of a complex of the formula CH3CH(Br)COOMgX in an aprotic solvent containing an ether. The compounds are important intermediates in the synthesis of known 2-arylpropionic acids of therapeutic importance.

Description

The present invention now provides an important intermediate in the manufacture 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 plays an essential role in 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 certain 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. Any mention of 2-arylpropionic acids in the present application refers to the racemic form of these compounds.

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, Ca.Yl and Mgy2 salt of a-bromopropionic 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 represents chlorine or bromine. In fact, a direct comparison of the magnesium salt of a-bromopropionic acid (prepared by both methods described in US Pat. No. 3,959,364) with the new complex thereof shows a significantly increased yield of the end products obtained (about a 2-fold difference), which is shown in the following examples is illustrated in more detail. It is a further advantage of the coupling process according to the invention that its yields are not influenced to the extent by the production of the organic magnesium halide complex as the yields of the coupling process according to US Pat. No. 3,959,364 are influenced by the production process of the salt of 2-bromopropionic acid (see U.S. Patent 3,959,364, column 3, lines 10 and 11).

The invention thus relates to magnesium halide complexes of 2-arylpropionic acids of the formula ArylCH (CH3) COOMgX, in which aryl is selected from 6-methoxy-2-naphthyl, 4-alkylphenyl and 4'-fluoro-4-biphenyl and X is chlorine or bromine, and the etherates of these compounds, especially their tetrahydrofuran monoetherates.

According to the invention, magnesium halide complexes of such 2-arylpropionic acids can be produced in which the aryl part is as follows: 6-methoxy-2-naphthyl, 4-alkylphenyl, where “alkyl” preferably refers to straight and branched chain saturated hydrocarbon groups with 1-4 C- Refers to atoms, e.g. 4-methylphenyl, 4-iso-propylphenyl and 4-isobutylphenyl; and 4'-fluoro-4-bi-phenyl.

According to the invention, the compounds are prepared by mixing a solution of an aryl magnesium bromide with a solution of a complex of the formula CH3CH (Br) -COOMgX, in which X represents chlorine or bromine, in ei2

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an aprotic organic solvent medium comprising an ether.

The invention is explained in more detail below.

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 1-12 C atoms or arylmagnesium Grigard compounds with 6-9 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. Methyl magnesium chloride and methyl magnesium are particularly preferred and are readily available, and they are bromide are, lead to the formation of gaseous methane that escapes from the reaction mixture and does not interfere with the reaction or workup. It has surprisingly been found that the addition of one of the Gri-gnard reagents mentioned above to a-erompropionic acid leads mainly to the formation of the complex mentioned above. 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 comprise other aprotic solvents 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 1-4M, preferably about 2-3M. A final complex solution for use in the direct coupling stage is about 1-2M, preferably about 1.0-1.5M. The temperature of the complex formation step is usually maintained between about -20 and + 30 ° C, preferably between about -10 and + 20 ° C.

According to the invention, the coupling itself takes place 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 0.5-2M, especially about 1.0M.

The coupling process itself can be carried out over a temperature range of about 0-100 ° C, preferably between about 10-60 ° C. It is especially convenient to gradually lower the temperature during the Addi640 500

tion stage to rise to about 40-60 ° C, whereupon one goes back to room temperature until the desired amount 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: 1.1-1.1: 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 to about 20 hours, in particular about 1-5 hours.

In order to be able to determine the yield of the coupling reaction, it is advisable to treat the solution containing the aryl magnesium halide complex with an acid and to isolate and quantify the 2-aryl propionic acid itself.

The method according to the invention can be carried out easily and expediently on a large scale.

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 cm3 of tetrahydrofuran with heating. This solution was then added to 3 g (0.12 mol) of excess metallic magnesium, 15 cm3 of toluene and 15 cm3 of tetrahydrofuran under a nitrogen atmosphere within 10-15 minutes. The reaction mixture was then cooled and stirred at 25-30 ° C. for a further hour. The reaction mixture was transferred from the excess magnesium to 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.

Trial 2

Mixed magnesium halide complex of a-bromo-propionic 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 cm3 of 2M methylmagnesium bromide in 1: 1 was slowly Tetrahydrofuran / toluene was added keeping the temperature at 10-20 ° C for 15-20 minutes during the addition period. Then the reaction mixture was stirred for a further 20 minutes to form a 1.1m solution of the complex at 5 ° C.

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

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640 500

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 1-4M.

The mixed magnesium chloride complex of a-bromopropionic 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 "1; NMR (D20) 5 1.6 (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 cm 3 of tetrahydrofuran under a nitrogen atmosphere. The temperature was maintained at 50-60 ° C during the 10-15 minute addition period by cooling. 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 4

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 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 a-bromopropionic acid

3.8 g (0.025 mol) of a-bromopropionic acid was dissolved in 6 cm 3 of methanol and the solution was cooled to -10 ° C. 0.5M magnesium methoxide in methanol solution (25 cm 3) was added over the course of 10 minutes, the temperature being kept at -10 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% has been. This salt was dissolved in 19 cm 3 of tetrahydrofuran for the coupling reaction.

example 1

The solution of the complex from experiment 2 was slowly added to the Grignard solution from experiment 1, the

Temperature was maintained at 15-20 ° C for 10-15 minutes during the addition period. The reaction mixture was allowed to warm to room temperature and then stirred for 2 hours. It was then cooled in an ice bath.

The procedure for determining the yield of the coupling reaction was as follows.

A) A solution of 20 cm3 of 12N hydrochloric acid and 150 cm3 of water was added to the reaction solution. After stirring for 5 minutes, the two-phase system was filtered and the filter cake was washed with 55 cm 3 of toluene and 50 cm 3 of water. The organic phase was extracted twice with 150 cm 3 of 10% potassium hydroxide solution 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 149.5-153 , 5 ° C was obtained.

20 B) After filtering, the organic phase can also be extracted twice with 150 cm 3 of 10% potassium hydroxide solution, washed with 30 cm 3 of toluene and filtered. 15 cm3 of methanol and 12 cm3 of toluene and then sufficient 12N hydrochloric acid were added to bring the pH to 25 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., whereby 15.0 g (65.1%) of 30 product with a melting point of 154.5-155 ° C was obtained.

Example 2

67 cm3 of a 1.5M solution of the mixed magnesium chloride complex of a-bromopropionic acid in 35 tetrahydrofuran (produced using 3M methylmagnesium chloride) slowly became a solution of 1.5M 2- (6-methoxynaphthyl) cooled to 10 ° C. Magnesium bromide in tetrahydrofuran (67 cm3) was added at such a rate that the temperature was kept at 40 55 ° C or below. The resulting slurry was stirred at 50 ° C for 1 hour and then heated to reflux, allowing 30-40% of the tetrahydrofuran to be distilled off. The reaction mixture was cooled to 50 ° C. and 30 cm 3 of toluene were added. 45 To determine the yield, the reaction mixture was quenched with aqueous hydrochloric acid as in Example 1B and worked up, yielding 2- (6-methoxy-2-naphthyl) propionic acid with a melting point of 156-157 ° C. in 73% yield .

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Example 3

A) The magnesium salt of a-bromopropionic acid, i.e. [CH3CH (Br) COO] 2Mg, was prepared by reacting the acid with a molar equivalent of magnesium carbonate,

ss whereupon 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 used

60 of 1A molar equivalent of magnesium methoxide was produced, with methanol being removed as an azeotrope. Use of the salt in the procedure of Example 2 provided the product in 43.0% yield.

6S

Example 4

Example 3A was repeated, but Vi molar equivalent of anhydrous magnesium chloride

magnesium salt was added before the coupling reaction. A 5.1% yield of product was obtained.

Example 5

Example 38 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 ^ 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 0.025 mole reaction) was as follows:

5,640,500

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 within 5 minutes, keeping the temperature at 10-55 ° C. Then the reaction mixture was stirred at 25-30 ° C for 2 hours and cooled to 10 ° C.

To determine the coupling yield, a solution of 10 cm312n hydrochloric acid and 50 cm3 water was added. After adding 50 cm3 of toluene, the aqueous phase was separated off 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.

The results are shown in the following table:

Mgy2 salt or% yield of comments

MgCl complex crude product (g)

Approach 1 Aryl Grignard reagent

Mol

0.12 2- (6-Metlioxynaphthyl) -

magnesium bromide 0.12 2- (6-methoxynaphthyl) -

magnesium bromide 0.025 4- (4'-fluorobiphenyl) -

magnesium bromide 0.025 4- (4'-fluorobiphenyl) -

magnesium bromide 0.05 l- (4-isopropylphenyl) -

magnesium bromide 0.05 l- (4-isopropylphenyl) -

magnesium bromide

MgCl

72.9

(20.1)

Mg, /,

43.0

(11.9)

MgCl

60.6

(3.7

Mg, / 2

28.6

(1.75)

MgCl

55.2

(5.3)

Mg (4th

52.0

(5.0)

actual

Yield%

Product purity 96.0% 70

Product purity 86.8% 37.4

M.p. 136-142 ° C ^ 60 NMR2

M. 130-138 ° C 3 <28

NMR2 ^ 55 F. 58-64 ° C

Product to about 50% ^ 26 pure according to NM R oil

1 using stoichiometric amounts of the reactants

2 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.

Similarly, comparable results can be obtained in the preparation of the magnesium halide complexes of the following 2-arylpropionic acids: 2- (4-isobutylphenyl) propionic acid 2- (4-methylphenyl) propionic acid.

If, in the process according to the invention, the solvent is removed in vacuo after coupling, the coupled magnesium halide complexes, ie. H.

ArylCH (CH3) COOMgX or their etherates.

The mixed magnesium chloride complex of 2- (6-meth-45 oxy-2-naphthyl) propionic acid shows as its tetrahydrofuran monoetherate (purity 98.1%) the following properties:

F. 113 ° C (and dec.); IR (KBr disk) 1600, 1450, 1410, 1260, 1210, 1155, 1025, 923, 855, 850, 805 and 750 cm-1; see NMR (DMSO-d6) 5 (TMS) 1.4 (Düblet, 2H), 1.8 (Multiplet, 4H), 3.6 (Multiplet, 5H), 3.9 (Singlet, 3H), 7.5 (Multiplet, 6H) ppm.

Claims (8)

640 500 PATENT CLAIMS 1. ArylCH (CH3) COOMgX or an etherate thereof, in which aryl is selected from 6-methoxy-2-naphthyl, 4-alkylphenyl and 4'-fluoro-4-biphenyl and X represents chlorine or bromine. 2. As the compound of claim 1, that compound in which aryl is 6-methoxy-2-naphthyl and X is chlorine. 3. As a compound according to claim 1, the tetrahydrofuran monoetherate of the compound according to claim 1. 4. A process for the preparation of the compound according to claim 1, characterized in that a solution of an aryl magnesium bromide with a solution of a complex of the formula CH3CH (Br) COOMgX, in which X represents chlorine or bromine, in an acratic organic solvent medium, the one Ether embraces, displaces. 5. The method according to claim 4, characterized in that the solvent medium comprises tetrahydrofuran. 6. The method according to claims 4 and 5, characterized in that the reaction is carried out at a temperature of 10-60 ° C. 7. The method according to claims 4 to 6, characterized in that the aryl magnesium bromide solution is 0.5-2.0 molar and the solution of the complex is 1.0-2.0 molar. 8. The method according to claim 4, characterized in that a 0.5-2.0 molar solution of 2- (6-methoxy-naphthyl) magnesium bromide in tetrahydrofuran with a 1.0-2.0 molar solution of an organic complex from a-bromopropionic acid and magnesium chloride or bromide in tetrahydrofuran at a temperature of 0-100 ° C. One of the most commonly used synthetic methods to prepare arylalkanoic acids has been to couple an organometallic aryl reagent with a haloalkanoic acid derivative, such as a haloalkanoic acid ester. This process 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 acid of the formula CH3CH (X) COM where X is bromine and M is OLi, ONa, 0 (Mg), / 2 or 0 (Ca) ./ 2 (see 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. B. the preparation of a salt of halopropionic acid in aprotic solvent medium, which must be used for the coupling reaction, which leads to poor results in large-scale production. 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.