KR810000581B1 - Process for the preparation of 2-aryl-propionic acid by direct-coupling utilizing - Google Patents

Abstract

Three MeCHRCO2H R = 6-methoxy-2-maphthyl (I), 4-alkylpheny, 4-fluoro-4-biphenylyl were prepd. by mixing the corresponding RMGBr with a soln. of MeCHBrCO2MgX (X = Cl, Br) in an aprotic solvent contg. ether, treating this mixt. with acid. Thus, MeCHBrCO2MgCl (from the acid and MeMgcl) in THF was added to 6,2-MeOC10H6MgBr in THF at 10≰C so the temp. remained 55≰C and the mixt. stirred for 1 hr at 50≰C, then refluxed, and worked up with aq. HCL to give 73% I.

Description

Method for preparing 2-aryl-propionic acid by direct coupling method

The present invention relates to a process for the preparation of 2-aryl-propionic acid such as 2- (6-methoxy-2-naphthyl) -pyrionic acid useful as an anti-inflammatory agent.

In other words, the present invention relates to a method of directly coupling aryl magnesium bromide with a mixed magnesium halide complex of alpha-bromopyrionic acid to produce a high yield of corresponding 2-aryl-pyropionic acid. 2-aryl-pyropionic acid in the present specification and claims refers to the racemic form of the compound.

Examples of 2-aryl-pyropionic acid that can be prepared by the method include an aryl moiety having 6-methoxy-2-naphthyl, ie 2- (6-methoxy-2-naphthyl) pyropionic acid; 4-alkylphenyl, in which the alkyl is a straight and branched chain saturated hydrocarbon group having 1 to 4 carbon atoms, i.e. 2- (4-methylphenyl) -pyrionic acid, 2- (4-isopropylphenyl) pyrrionic acid and 2- (4-isobutylphenyl) pyrionic acid; And 4'-fluoro-4-biphenyl, that is, 2- (4'-fluoro-4-biphenyl) pyrrionic acid and the like.

A previous method for preparing arylalkanoic acid by directly coupling an aryl Grignard reagent with Na, Li, Ca1 / 2 and Mg1 / 2 salts of alpha-bromopyrionic acid is described in US Pat. No. 3,959,364.

The coupling reaction of the process uses a mixed magnesium halide complex of alpha-bromopyrionic acid instead of the salts mentioned above. (It has been found that X produces a substance of the structure CH ₃ CH (Br) cooMgx wherein chloro or bromo). Indeed, when comparing the magnesium salts of alpha-bromopyrionic acid (prepared in two methods described in US Pat. No. 3,959,364) and the novel complexes of this chapter, the yields of the resulting pyrophytic acid produced vary greatly. (About twice), the difference is described in more detail in this example. The yield of the material produced by the coupling method of US Pat. No. 3,959,364 is somewhat dependent on the preparation method of 2-bromopyrophyte salt, while the yield by this coupling method is influenced by the preparation method of the mixed magnesium halide complex. (See, US Patent No. 3,959,364, column 3, lines 10 and 11).

Mixed magnesium halide complexes of alpha-bromopyrionic acid are prepared by treating the free acid with an appropriate Grignard reagent. The nature of the hydrocarbon portion of the Grignard reagent is not critical and the free hydrocarbons produced by the reaction of alpha-bromopyrionic acid and Grignard reagents do not interfere with the coupling or reaction steps. Therefore, the Grignard reagent derived from hydrocarbon water in gaseous or liquid state at reaction temperature is particularly suitable as alkyl magnesium Grignard reagent of 1-12 carbon atoms or aryl magnesium Grignard reagent of 6-9 carbon atoms.

Specific Grignard reagents which may be used for this purpose include methyl chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, phenyl magnesium chloride and o-, m- or P-tolyl magnesium chloride. have. Methyl magnesium chloride and methyl magnesium bromide are particularly preferred because they are commercially available, inexpensive, and form methane gas from the reaction mixture, while not hindering the reaction. It has been found that addition of one of the Grignard reagents described above to alpha-bromopyrionic acid produces predominantly the complexes mentioned above. When the Grignard reagent was added to the carbonyl portion of the carboxylic acid, the reaction which was generally expected to proceed much appeared to proceed only a little even when using an excess molar Grignard reagent.

Mixed magnesium halide complexes are generally prepared in an aprotic solvent medium containing ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, di- (n-butyl) ether and the like.

The solvent medium may also contain other aprotic solvents such as aromatic hydrocarbons such as benzene or toluene. The preferred solvent medium for preparing the complex is tetrahydrofuran. Although the order of addition of reagents does not have to be followed exactly, it is generally a good idea to add Grignard reagents to alpha-bromopyrionic acid. The Grignard reagent in the solution is usually about 1-4M, most preferably about 2-3M. The final complex solution used in the direct coupling step is preferably about 1-2M, preferably about 1.0-1.5M. The temperature of the step of forming the complex is usually -20 ° C to + 30 ° C, preferably about -10 to + 20 ° C.

The coupling reaction proceeds by contacting the mixed magnesium halide complex of alpha-bromopyrionic acid with aryl magnesium bromide in anhydrous aprotic organic solvent medium. Suitable solvent media for the reaction include organic ethers and mixtures of aromatic hydrocarbons and organic ethers as mentioned in the complex formation step. Particularly preferred solvent medium for the coupling reaction is tetrahydrofuran. The aryl magnesium bromide solution is about 0.5-2M and most preferably about 1.0M.

The coupling reaction is carried out at a temperature in the range of 0 to 100 ° C., preferably at a temperature of 10-60 ° C. In the addition step, the temperature is slowly heated from 40 ° C. to 60 ° C. and cooled to ambient temperature until the reaction proceeds to the desired degree.

The coupling reaction proceeds using various ratios of reagents, and it is preferable to use an almost equimolar amount of the mixed magnesium halide complex and the aryl Grignard reagent. The most preferred ratio of complex to Grignard reagent is from 0.9: 1.1 to 1.1: 0.9.

The reaction is carried out by contacting two reagents in the solvent medium by methods known in the art. However, it is particularly desirable to add mixed magnesium halide complexes to Grignard reagents and to store them in analogous mixtures until the required reaction is complete.

The time required to run the desired reaction depends on the choice of reagent, solvent and reaction temperature and is adjusted to suitably produce the required product. In general, the reaction time is about 10 minutes to 20 hours, usually in the range of about 1-5 hours.

After the coupling reaction proceeds completely to the desired state, the reaction mixture containing the complex aryl CH (CH ₃ ) cooMgx coupled according to the known method of Grignard reagent is diluted with dilute acid, preferably hydrochloric acid or sulfuric acid. Cool with aqueous mine. At this time, the free 2-aryl-pyrrionic acid product is separated, extracted with aqueous alkali (aqueous sodium hydroxide or potassium hydroxide), the aqueous alkaline separation from the organic phase, and the aqueous alkaline phase is acidified to liberate a preferred acid. Purification from the cold reaction mixture, or optionally extraction with an organic solvent, or directly by routine methods such as washing and / or crystallization.

If desired, the crude reaction product is directly converted in the form of a pharmaceutically acceptable derivative of the carboxylic acid, ie, salts, esters or amides of the carboxylic acid, or optical isomers.

The process of the present invention can be produced in large quantities in an easy and convenient way, yielding purified products in about 50-75% yield.

The following examples are illustrative of the invention and do not limit the spirit or scope of the invention.

[Manufacturing Method 1]

Method for preparing 2- (6-methoxynaphthyl) magnesium bromide

23.7 g (0.1 mol) of 2-bromo-6-methoxynaphthalene is heated and dissolved in 30 ml of toluene and 40 ml of tetrahydrofuran. The solution is added under nitrogen atmosphere to 3 g (0.12 mol) of excess magnesium metal, 15 ml of toluene and 15 ml of tetrahydrofuran for 10-15 minutes. The reaction mixture is cooled and then stirred at 25-30 ° C. for 1 hour. The reaction mixture is transferred from excess magnesium to a ceiling and drying vessel under nitrogen and stored at 10 ° C. to obtain 1.0 mole of Grignard reagent.

According to a similar method as above, Grignard reagent can be prepared using tetrahydrofuran as a single solvent.

Similarly, less concentrated solvent can be used to prepare more concentrated Grignard reagents (about 1.5 moles).

[Manufacturing Method 2]

Mixed Magnesium Halide Complexes of Alpha-Bromopyropionic Acid

15.3 g (0.1 mole) of alpha-bromopyrionic acid and 40 ml of toluene were cooled to 10 ° C., and 50 ml of 2 mol of methylmagnesium bromide contained in tetrahydrofuran / toluene (1: 1) was heated to a temperature of 10-20 ° C. Add slowly for 15-20 minutes while maintaining. The reaction mixture is stirred at 5 ° C. for 20 minutes to obtain 1.1 mol of complex solution.

In a similar manner to the above, a mixed magnesium halide complex is prepared using tetrahydrofuran as a single solvent.

Similarly, instead of methyl magnesium bromide, Grignard reagents such as methyl chloride, isopropyl magnesium chloride, phenyl magnesium chloride and the like can be used in various concentrations of 1-4 moles.

A mixed magnesium complex of alpha-bromopyrionic acid (prepared using 3 moles of CH ₃ Mgcl of tetrahydrofuran as described above) is distilled tetrahydrofuran in tetrahydrofuran solution to form a crystalline form of tetrahydrofuran monoether salt. Separate.

Analysis result: melting point 147-155 ° C; Infrared (KBr) 1625, 1450, 1420, 1372, 1291, 1200, 1070, 1030, 988 and 890 cm ^-1 Nuclear Magnetic Resonance (D ₂ O) Delta 1.8 (Multiple, 7) 3.7 (Multiple, 4 ) And 4.35 ppm (quartet, J = 7)

Urea Analysis of C ₇ H ₁₂ BrClMgO ₃

Mg: 8.57% Cl: 12.49%

Urea Analysis of C ₇ H ₁₂ BrClMgO ₃

Mg: 8.63% l: 12.97%

[Manufacturing Method 3]

Method for preparing aryl magnesium bromide

0.025 moles of aryl bromide are dissolved in 18 ml of tetrahydrofuran. The solution is added to excess magnesium metal (3 g, 0.002 moles) under nitrogen atmosphere and 7 ml of tetrahydrofuran. The temperature is maintained at 50-60 ° C. while cooling for 10-15 minutes addition. The reaction mixture is transferred from excess magnesium to a clean, dry vessel under nitrogen atmosphere and stored at 10 ° C. to obtain 1.0 moles of Grignard reagent. In the same manner as described above, the following Grignard reagent was prepared.

2- (6-methoxynaphthyl) magnesium bromide

4- (4'-fluorobiphenyl) magnesium bromide

1- (4-isopropylphenyl) magnesium bromide

1- (4-isobutylphenyl) magnesium bromide

1- (4-methylphenyl) magnesium bromide

[Manufacturing Method 4]

A. Method for preparing mixed magnesium halide complex of alpha-bromopyrionic acid

3.8 g (0.025 mole) of alpha-bromopyrionic acid is dissolved in 8 ml of tetrahydrofuran and cooled to -10 ° C. 3 mol of methyl magnesium chloride dissolved in 8 ml of tetrahydrofuran is added for 15 minutes while maintaining the temperature at -10 ° to 0 ° C. Obtain 1.1 mol of the complex solution stored below 0 ° C until use.

Similarly, one mole of methyl magnesium bromide can be used instead of three moles of methyl chloride to produce the corresponding magnesium bromide complex.

B. Method for preparing magnesium salt of alpha-bromopyrionic acid

3.8 g (0.025 mol) of alpha-bromopyrionic acid are dissolved in 6 ml of methanol and cooled to -10 ° C. 0.5 mol of magnesium methoxide in 25 ml of methanol solution is added for 10 minutes while maintaining the temperature at -10 ° to 0 ° C. Methanol was removed under reduced pressure to form a solid salt, which was dried in a vacuum at 50 ° C. for 12 hours to obtain 4.1 g of dried magnesium salt (0.0125 mol, 97.2% purity).

The salt is dissolved in 19 ml of tetrahydrofuran and used for the coupling reaction.

Example 1

A. The solution of Preparation 2 is slowly added to the Grignard solution of Preparation 1 for 10-15 minutes while maintaining the temperature of 15-20 ° C. The reaction mixture is heated to room temperature and stirred for 2 hours. The reaction mixture is cooled in an ice bath and a 20 ml solution of 12N hydrochloric acid in 150 ml of water is added. Stir for 5 minutes and filter the two phase system, then wash the filtrate with 55 ml of toluene and 50 ml of water. The organic phase is extracted twice with 10% calcium hydroxide solution (150 ml), the mixed basal extract is washed with 30 ml of toluene and acidified with 12N hydrochloric acid to pH 1. Under vacuum, the white solid 2- (6-methoxy-2-naphthyl) pyrrionic acid was filtered off and dried in vacuo at 55 ° C. to give 15.2 g (66%). Melting Point 149.5-153.5 ℃

B. Alternatively, after filtration, the organic phase is extracted twice with 150 ml of 10% potassium hydroxide solution, washed with 30 ml of toluene and filtered. 15 ml of methanol and 12 ml of toluene are added and 12N hydrochloric acid is added so that the pH is about 4-5. The final slurry is heated to reflux for 1 hour, cooled and filtered. The precipitate is washed with 20 ml of water 1 time, 3 ml of toluene 2 times and 3 ml of hexane 2 times and dried in vacuo at 55 ° C. to give 15.0 g of product (65.1%).

Melting Point: 154.5-155 ℃

Example 2

67 ml (1.5 mol) of a mixed magnesium chloride complex solution of alpha-bromopionic acid in tetrahydrofuran (prepared using 3 mol of magnesium chloride) was prepared in 2- (6-meth) contained in tetrahydrofuran (67 ml). To 1.5 moles of methoxynaphthyl) magnesium bromide is added slowly, maintaining the temperature below 55 ° C. The final slurry is stirred at 50 ° C. for 1 hour and heated to reflux to distill 30-40% of tetrahydrofuran. The reaction mixture is cooled to 50 ° C., 30 ml of toluene is added and cooled with aqueous hydrochloric acid, followed by Example 1B to give 73% yield of 2- (6-methoxy-2-naphthyl) pyrionic acid. Melting Point 156-157 ℃

Example 3

A. A salt obtained by reacting an acid with gram molecules of magnesium carbonate per half is dried in a vacuum at 60 ° C. to prepare a magnesium salt of alpha-bromopyrionic acid of the structural formula CH ₃ CH (Br) Coo ₂ Mg. .

The salt was used in place of the mixed magnesium chloride complex used in Example 2 to obtain 34.7% yield of the product.

B. The salt of part A may be prepared using gram molecules of magnesium methoxide, methanol per gram, which is removed together with boiling materials. In the course of Example 2, the salt is used to give 43.0% yield of the product.

Example 4

The method of Example 3A was carried out as is, except that gram of anhydrous magnesium chloride per 1/2 was added to the magnesium salt prior to the coupling reaction to give a 5.1% yield of the product.

Example 5

Except for using the same molar amount of alpha-bromopyrionic acid and magnesium methoxide, the method of Example 3B was carried out as is to obtain a product in 35.1% yield.

Example 6

Comparison Using Mixed Magnesium Halide Complexes and Mg1 / 2 Salts

Coupling reaction

The following coupling reaction is carried out by mixing a magnesium chloride complex of alpha-bromopyrionic acid (prepared by preparation method 4A) or magnesium salt of alpha-bromopyroionic acid (prepared by preparation method 4B) and the corresponding Grignard reagent (preparation) Production method 3). The preparation method is as follows (example for the case of 0.025 mol):

The 1.0 mol aryl magnesium bromomide solution is cooled to 10 ° C. and a solution of magnesium salt or magnesium chloride complex dissolved in tetrahydrofuran is added for 5 minutes while maintaining the temperature of 10 ° C.-55 ° C. The reaction mixture is stirred at a temperature of 25-30 ° C. for 2 hours. The reaction mixture is cooled to 10 ° C. and 10 ml of 12N hydrochloric acid and 50 ml of water are added. 50 ml of toluene is added and the aqueous layer is separated off. The organic phase is extracted twice with 50 ml of 10% calcium hydroxide. The base extract is mixed and neutralized with hydrochloric acid to form a precipitate, filtered and dried to 50 ° C.

The results are shown in the chart below.

As a result of each of the above examples, it was found that a high yield (about 2 times) product having high purity can be obtained from the mixed magnesium chloride complex.

In a similar manner, 2-arylpyrropionic acid, such as 2- (4-isobutylphenyl) pyrrionic acid and 2- (4-methylphenyl) pyrionic acid, may be prepared to obtain similar results.

If the process is stopped before cooling with aqueous acid and removing the solvent in vacuo, the coupled magnesium halide complex, aryl CH— (CH ₃ ) COOMgX or ether salt of the material may be separated.

The mixed magnesium chloride complex of 2- (6-methoxy-2-naphthyl) pyrionic acid exhibits the following properties as tetrahydrofuran monoene salt (purity 98.1%).

Melting point 113 ° C. (10 ×); Infrared (KBr disc) 1600, 1450, 1410, 1260, 1210, 1155, 1025, 923, 885, 850, 805 and 750 cm ⁻¹ ; Hexagon Resonance (DMSO-d ₆ ) Delta (TMS) 1.4 Dual, 2H, 1.8 (Multiple, 4H), 3.6 (Multiple, 5H), 3.9 (Single, 3H), 7.5 (Multiple, 6H) ppm

Claims (1)

The aryl magnesium bromide solution is reacted with a complex solution of the structural formula CH ₃ CH- (Br) COOMgX in an aprotic organic solvent medium containing ether and the reaction mixture is cooled with an acid. (Aryl is selected from the group consisting of 6-methoxy-2-naphthyl, 4-alkylfetyl and 4'-fluoro-4-biphenyl and X is chlorine or bromine.)