JPS6045171B2 - Production method of α-(substituted aryl)propionic acid compound - Google Patents

Description

Detailed Description of the Invention [I] Background of the Invention The present invention relates to α-(substituted aryl)propionic acid and its precursor α-(
The present invention relates to a method for producing substituted aryl)propionate esters.

In the present invention, there are various types of compounds depending on the type of substituent of the "substituted aryl", and the compounds are named with attention to the substituent.

Conventionally, various methods have been proposed for synthesizing these compounds. For example, fenoprofen [α-(m
-phenoxyphenyl)propionic acid] is disclosed in French Patent No. 2015728 and JP-A-51-4136.
No., JP-A-51-16636 and JP-A-51-23
The method according to No. 235, and the method for synthesizing ketoprofen [α-(m-benzoylphenyl)propionic acid] include Japanese Patent Publication No. 19287-1987, Japanese Patent Publication No. 7024-1987, French Patent No. 2163875, Japanese Patent Publication No. 37028-1987, and Japanese Patent Publication No. 48-37028. The method for synthesizing flurpaiprofen [α-(2-fluoro-4-biphenylyl)propionic acid] is described in Japanese Patent Publication No. 44-25076, Japanese Patent Publication No. 45-283, German Patent Publication No. 45-283. National Patent No. 2241913
No., French Patent No. 15452m, JP-A-51-4136
The method disclosed in Japanese Patent Application Laid-Open No. 51-16636 is known. All of these methods involve a large number of steps and are often complicated, but the following methods are examples of methods that involve a relatively small number of steps. (1) Method for hydrolyzing α-(substituted aryl)probionitrile (2) Alternative method for reducing α-(substituted aryl)acrylic acid (3) α-(substituted aryl)
A method of oxidizing propionaldehyde or β-methyl-β-(substituted aryl)pyruvic acid.

However, even with these methods, it cannot be said that the synthesis of raw materials is easy, and in the case of (3), there is a concern that various by-products may be produced depending on the degree of oxidation reaction.

In view of these points, the present inventors developed a method for producing α-(4-isobutylphenyl)propionic acid, known as ibuprofen, by combining 4-isobutylstyrene with carbon monoxide in the presence of water or alcohol. A patent application filed in 1972 proposed a method of carbonylation through reaction.
No. 7787).

[Old Summary of the Invention 4f1 Abstract The present invention aims to provide a solution to the drawbacks of these known methods and attempts to achieve this aim by carbonylating substituted arylethylenes with carbon monoxide. .

1-1■1'151--(No1 Technique 3) Therefore, the method for producing α-(substituted aryl)propionic acid or its esters represented by the general formula 1 according to the present invention is based on the general formula R1-CH= The method is characterized in that a substituted arylethylene represented by C2 is reacted with carbon monoxide in the presence of a lower alcohol or water using a palladium-based catalyst.

(Here, R1 is > or ), and R° represents hydrogen or a lower alkyl group).

Also, according to one embodiment of the present invention, the substituted arylethylene used in the above method is a common S. ↓"↓"It is produced by dehydrating or hydrogen halogenating α- or β-substituted arylethyl alcohol or α- or β-monosubstituted arylethyl halide represented by 2 [where R1 is They have the same meanings as above, and one of X and Y represents hydrogen, and the other represents a hydroxyl group or a halogen group).

Two Effects According to a preferred embodiment of the invention, α- or β-(
substituted aryl) ethyl alcohol or α- or β
α-(Substituted aryl)propionic acid is synthesized using a -(substituted aryl)ethyl halide as a starting material and a dehydration or dehydrohalogenation step followed by a carbonylation step.

Compared to conventional methods, raw materials that are generally easier to synthesize are used, the number of steps is extremely small, and the compounds handled are simple and stable, resulting in fewer by-products and easy operation.

[■] Detailed Description of the Invention 1 Flow Sheet The reaction formula for the process of the present invention starting from substituted arylethyl alcohol or halide is as follows.

1 廿? ■ [In the formula, R1, R2, X. ．． Y is the same as shown above.
] Compounds represented by general formula (1) suitable as starting materials for synthesizing disubstituted arylethyl alcohol or halide-substituted arylethylene are α-(substituted aryl)ethyl alcohol, β-mono(substituted aryl)ethyl alcohol, α Mono(substituted aryl)ethyl halide and β-
(Substituted aryl)ethyl halide, and the halogen atoms of X and Y are chlorine, bromine, and iodine.

These compounds represented by the general formula (1) can be easily produced in the same manner as general methods for producing aralkyl alcohols and aralkyl halides.

That is, α-(substituted aryl)ethyl alcohol can be prepared, for example, by reduction of a substituted aryl methyl ketone or by reaction of the corresponding substituted arylmagnesium bromide with valaldehyde; or by subjecting the corresponding substituted aromatic compound to a Friedel-Crafts reaction with ethylene oxide to form β-hydroxyethylation.

α- or β-(substituted aryl)ethyl halides can be obtained by halogenating the corresponding alcohol with a halogenating agent, halogenating the corresponding substituted arylethane with a halogenating agent, or halogenating the corresponding substituted aromatic compound with balaldehyde. Produced by chloroethylation with hydrogen.

Specific examples of alpha- or beta (substituted aryl)ethyl alcohols or halides suitable for use in the present invention will be apparent from where R1 is as specified above (specific examples of halogen in the case of halides). are chlorine and bromine).

3 Dehydration or dehydrohalogenation step The step of obtaining substituted aryl ethylene (■) by dehydration or dehydrohalogenation of the compound of general formula (1) is the known dehydration of arylethyl alcohol and dehydrohalogenation of arylethyl halide. It can be carried out according to the method of

Some of the methods will be explained below using specific examples. These reactions proceed with good yield, produce few by-products, and the substituted arylethylene product is a stable compound.
Substituted aryl ethylene of sufficiently high purity can be obtained by purification to the extent of simple distillation, and can be used as a raw material for the next carbonylation step.

(1) Dehydration of α- or β-mono(substituted aryl)ethyl alcohol (a) Normal pressure liquid phase heating Using 1 to 20 mol, preferably 3 to 10 mol of dimethyl sulfoxide per 1 mol of the alcohol, polymerization The inhibitor is present from 0.1 to 30% by weight of the alcohol, preferably from 1 to 15%, and from 100 to 25% by weight of the alcohol.
Heating to 0°C1, preferably 130-190°C.

Examples of the polymerization inhibitor used include hydroquinone, m-dinitrobenzene, N-nitrosodiphenylamine, picric acid, and sodium sulfite.

(b) Reduced pressure liquid phase heating Presence of sulfuric acid compound as a dehydration accelerator It is normal to

As the sulfuric acid compound, sodium hydrogen sulfate, potassium hydrogen sulfate, potassium pyrosulfate, etc. are used.

The polymerization inhibitor used is the same as that described in method (a) above.

The reaction is carried out by adding 0.01 to 10%, preferably 0.1 to 5%, by weight of a sulfuric acid compound and 0.1 to 30%, preferably 1 to 15%, of a polymerization inhibitor to the alcohol. “Hgl preferably 20-400T!
Under reduced pressure of RlnHg, 100-280°C, preferably 1
It is heated to 95-250°C.

(C) Activated alumina that exhibits dehydration effect in vapor phase heating. Rui is exposed to caustic alkali under heating. Ru.

A layer of activated alumina or a caustic alkali such as sodium hydroxide or potassium hydroxide is heated and the alcohol is added thereto under reduced pressure or in the presence of a diluent gas such as nitrogen or carbon dioxide, or benzene, toluene, etc.! Passes with volatile solvents.

In the case of activated alumina, under a reduced pressure of 10 to 600 mHg, preferably 20 to 4007 mHg, or diluting gas of nitrogen or carbon dioxide at 1 to 40 mHg per mole of alcohol.
mol, preferably 5-20 mol of I, or when the alcohol is solid, a volatile solvent such as benzene, toluene, xylene, dioxane, etc. is added to 1 mol of the alcohol, preferably 0.01 mol to 10 mol, preferably 0. 120-400°C, preferably 150-3
Heating to 50°C is suitable.

In case of caustic alkali, 2-200T! RmHg, preferably under a reduced pressure of 5 to 10 hHg, or in the presence of a diluent gas of nitrogen or carbon dioxide in an amount of 1 to 40 mol, preferably 5 to 20 mol, per 1 mol of the alcohol, or when the alcohol is solid, benzene, toluene, xylene,
In the presence of a volatile solvent such as dioxane in an amount of 0.01 mol to 10 mol, preferably 0.1-5 mol, per mol of the alcohol, the temperature is 100 to 250°C, preferably 120 to 200°C.
It is appropriate to heat it to ℃.

(2) Dehydrohalogenation of α- or β-(substituted aryl)ethyl halide (a) Heating with a base Examples of bases used include pyridine, quinoline, piperidine, piperazine, aniline, N-N-dimethylaniline, etc. and inorganic bases such as sodium hydroxide and potassium hydroxide.

In the reaction, the amount of base is 0.8 to 1 mole of the halide.
Add 30 mol, preferably 1 to 15 mol, and heat at 0 to 260°C
, preferably at 20 to 220°C.

(b) Heating under reduced pressure with amine hydrochloride The amine hydrochloride used is the hydrochloride of secondary and tertiary amines, such as diamylamine hydrochloride, triamylamine hydrochloride, dihexylamine hydrochloride, trihexylamine Examples include hydrochloride and the like.

The reaction is carried out under reduced pressure of 20 to 760 mHg, preferably 50 to 20 mHg, or diluting gas of nitrogen or carbon dioxide at 1 to 40 mHg per mole of the halide.
mol, preferably 5-20 mol, or if the halide is solid, a volatile solvent such as benzene, toluene, xylene, dioxane, etc. per mol of the halide, from 0.01 mol to 10 mol, preferably 0. 150-300°C, preferably 170-27°C in the presence of .1-5 mol
It is carried out in the gas phase by passing the amine hydrochloride in the molten state heated to 0°C.

Substituted Aryl Ethylene The substituted aryl ethylene thus obtained is a compound represented by the above general formula (■).

Some specific examples are shown in the table below.

Compounds without literature names are believed to be new. This table also shows the names of α-(substituted aryl)propionic acids obtained by carbonylating this substituted arylethylene. 5 Carbonylation step (1) Raw materials and reaction conditions The step of carbonylating substituted aryl ethylene to produce α (substituted aryl) propionic acid ester (■) or α- (substituted aryl) propionic acid (■) This is done by reacting alcohol or water with carbon monoxide in the presence of a palladium-based catalyst.

As the palladium-based catalyst used, a palladium complex is suitable, and palladium has a valence of O to 2, a halogen group atom, a trivalent phosphorus compound, a π-allyl group, an amine,
Those containing nitrile, oxime, olefin, carbon monoxide, etc. as a ligand are effective.

Specific examples include bistriphenylphosphine dichloropalladium, bistributylphosphine dichloropalladium, bistricyclohexylphosphine dichloropalladium, 1'-allyltriphenylphosphine chloropalladium, triphenylphosphine piperidine dichloropalladium, bisbenzonitrile dichloropalladium, and biscyclohexyloxime. Dichloropalladium, 1.5
・9-cyclododecatriene-dichloropalladium, bistriphenylphosphine dicarbonylpalladium,
bistriphenylphosphine palladium acetate, bistriphenylphosphine palladium dinitrate,
bistriphenylphosphine palladium sulfate,
Examples include tetrakistriphenylphosphine palladium. Further, a compound capable of forming the above-mentioned palladium complex can also be used in the reaction system.

That is, this is a method in which a palladium salt, such as palladium oxide, palladium sulfate, or palladium chloride, and a compound that can serve as a ligand, such as a phosphine, nitrile, allyl compound, amine, oxime, olefin, or carbon monoxide, are simultaneously present in the reaction system. Examples of phosphine include triphenylphosphine, tritolynephosphine, tributylphosphine, tricyclohexylphosphine, triethylphosphine, etc.; examples of tolyles include benzonitrile, acrylonitrile, probionitrile, benzylnitrile; and examples of allyl compounds! Examples include allyl chloride and allyl alcohol; amines include benzylamine, pyridine, piperazine, and tri-n-butylamine; oximes include cyclohexyloxime, acetoxime, and benzaldoxime; and olefins include 1,5-cyclooctadiene. , 1.5●9-cyclododecatriene, and the like.

The alcohol used is a lower aliphatic alcohol having about 1 to 4 carbon atoms, such as methanol, ethanol, propanol, butanol, and the like.

Hydrogen chloride, boron trifluoride, etc. can be added to suppress side reactions of this reaction, to maintain the life of the palladium catalyst, and to further improve the reaction rate.

The amount of palladium complex and palladium compound used is 0.0001 to 0.5 per mole of substituted aryl ethylene.
mol, preferably 0.001 to 0.1 mol, and when a palladium compound is used, the amount of the compound that can be a ligand added is 0.8 to 10 mol per mol of the palladium compound.
mol, preferably 1 to 5 mol.

The alcohol and water do not function as a solvent together with the reaction raw materials, and the amount used is 0.5 to 5 parts by weight, preferably 1 to 2 parts by weight, based on the substituted aryl ethylene.

Note that alcohol and water can be considered as the main reaction raw materials, and other solvents can also serve as the solvent. That is,
Alcohol or water or an organic solvent miscible therewith (
For example, mixtures with benzene, toluene, hexane) can be used.

The amount of hydrogen chloride used as necessary is 1 to 20% by weight, preferably 2 to 15% by weight based on the alcohol or water.
% is appropriate.

The appropriate amount of boron trifluoride is 0.8 to 1 mole, preferably 1 to 7 times the mole of the palladium complex and palladium compound. The amount of carbon monoxide for carbonylation may be in excess of the substituted aryl ethylene and will vary depending on the size and form of the reactor.

2) Carbonylation operation The carbonylation reaction is carried out as follows.

(1) When using alcohol and adding hydrogen chloride, the reaction temperature is 40 to 150'C.
1 Preferably at a temperature of 60 to 140°C and a carbon monoxide pressure of 100 to
It is suitable to carry out the reaction at 8 (4) atmospheres, preferably 100 to 600 atmospheres.

When adding boron trifluoride, the reaction temperature is 40-12
0°C1 preferably 50-100°C, carbon monoxide pressure 10
It is appropriate to conduct the reaction at a pressure of 1 to 1 (a) pressure, preferably 20 to 1 pressure.

(2) When using water Since boron trifluoride decomposes when it comes into contact with water, it is preferable to add hydrogen chloride, and the reaction conditions (1)
This is the same as when using hydrogen chloride.

The ester (■) can be obtained by the method (1), and the acid (■) can be obtained by the method (2). Also, when a mixture of alcohol and water is used, a mixture of ester and acid is obtained.

The carbonylation reaction, which is carried out using the highly purified substituted aryl ethylene obtained in the previous step, ie, the dehydration or dehydrohalogenation step, also proceeds quantitatively,
α-(substituted aryl)propionate or α
-(Substituted aryl)propionic acid can be obtained with good selectivity and high purity.

Furthermore, since the ester is a stable substance, it can be easily purified by simple distillation or recrystallization.

(3) Conversion of the product The α-(substituted aryl)propionic acid ester obtained by carbonylation in alcohol can be easily converted into the final target α-(penta-substituted aryl) propionate by a conventional ester hydrolysis method. ) can be propionic acid.

That is, for example, it is refluxed with an aqueous sodium hydroxide solution, acidified, the precipitated acid is separated, and recrystallized with n-hexane, petroleum ether, or the like.

The resulting α-(substituted aryl)propionic acid has extremely high purity.

Examples 1 to 5 (1) 2-fluoro-4-vinylbiphenyl 3.59,
20ml of 10% aqueous hydrochloric acid solution, 0.2f of bistriphenylphosphine dichloropalladium, 20ml of benzene and 3T of N-nitrosodiphenylamine as a polymerization inhibitor.
119 was placed in an autoclave with an internal volume of 100 m1, carbon monoxide was press-fitted into 150 k91 c1t at room temperature, and 120
The reaction was allowed to take place at ℃ until no absorption of carbon monoxide was observed.

After cooling to room temperature, the benzene layer was separated and extracted with a 20% aqueous NaOH solution, then the extract was acidified with hydrochloric acid, and the precipitated solid was extracted with ether. After washing the ether layer with water, it was dried over magnesium sulfate, the ether was distilled off under reduced pressure, and the residue was recrystallized from hexane-toluene to obtain 3.5y of α-(2-fluoro-4-biphenylyl)propionic acid. . Yield 81 mol %, melting point 110-111 dC (2) The reaction was carried out in the same manner as in Example 1 except for the compounds shown in Table 2, carbon monoxide pressure, and reaction temperature.

The results were as shown in Table-1. Reference example 1 (1) 0.47y of lithium aluminum hydride in the reaction system
and 50 mt of anhydrous ether to make 150 mt of anhydrous ether.
7.0 y of 4-acetyl-3''-fluorobiphenyl dissolved in ml was added dropwise at such a rate that a gentle reflux continued.

After the addition was completed, the mixture was refluxed on a hot bath for 1 hour, and after cooling, 30 ml of water was added dropwise to the reaction system, and further 5 ml of 2% sulfuric acid was added dropwise.
The ether layer was separated, washed with water, and dried over magnesium sulfate. The ether was distilled off under reduced pressure, and the precipitated solid was recrystallized from hexane to obtain α-(3″-fluoro-4-biphenylyl)ethyl alcohol 6.1y. This is a new compound described at the end of the literature. Yield 84 mol%, melting point 62-
62.5 combined C nuclear magnetic resonance spectrum (CDCl3) δ(
Ppm) 1.67 (3H..d), 2.63 (1H.s
s), 4.92 (1H..q), 6.76-7.88 (
8H. ．． m) (2) 5.0 y of α-(3″-fluoro-4-biphenylyl)ethyl alcohol and 20 mg of N-nitrosodiphenylamine as a polymerization inhibitor were dissolved in 50 ml of dimethyl sulfoxide and reacted at 150° C. for 16 hours.

After cooling, 30 ml of ethyl acetate was added and washed with 300 ml of water to remove dimethyl sulfoxide, and then the ethyl acetate layer was separated. After drying the ethyl acetate layer over magnesium sulfate, ethyl acetate was distilled off under reduced pressure, and the residue was subjected to column chromatography. 3.3y of 3''-fluoro-4-vinylbiphenyl was obtained from the hexane/benzene (1:1) eluate. Yield: 72 mol%, melting point: 81-
81.5 C nuclear magnetic resonance spectrum (CDCl3) δP
pm5.28 (1H..dd), 5.77 (1H..d
d), 6.78 (1H.sdd), 6.91-7.82
(8HNm) Reference Example 2 (1) 2-fluoro-4-ethylbiphenyl 10f! was dissolved in 750 ml of carbon tetrachloride, 10y10.1y of N-bromosuccinimide benzoyl peroxide was added, and the mixture was heated under reflux for 1.5 hours.

After cooling, the solid matter was separated and carbon tetrachloride was distilled off from the solution [containing α-(2-fluoro-4-biphenylyl)ethyl bromide]. Add 500ml of ethyl alcohol to the residue.
1, 17y of potassium hydroxide was added thereto, and the mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was poured into 2.5 liters of water, extracted with benzene, and the benzene layer was washed with water and dried over magnesium sulfate. Benzene was distilled off under reduced pressure, and the residue was subjected to column chromatography. From the hexane eluate, 5.5y of 2-fluoro-4-vinylbiphenyl was obtained. Yield 56 mol%, refractive index n? ．． 51.6119 nuclear magnetic resonance spectrum (CCl4) δPpm5.29 (1H
．． ．． dd) 5.73 (1HNdd), 6.72 (1H
、． dd), 7.07-7.70 (8FI,.m) Reference Example 3 7.0y of α-(3-phenoxyphenyl)ethyl alcohol and 0.0y of m-dinitrobenzene as a polymerization inhibitor.
5y was dissolved in 250 mt of dimethyl sulfoxide, 16
The reaction was carried out at 0°C for 1 hour.

After cooling, add 250ml of dichloromethane to 660ml
After washing with water to remove dimethyl sulfoxide, the dichloromethane layer was separated. After drying the dichloromethane layer with magnesium sulfate, dichloromethane was distilled off under reduced pressure.
The residue was subjected to column chromatography. 4.75y of 3-phenoxystyrene was obtained from the hexane eluate. Yield 75%, NN1. 598O nuclear magnetic resonance spectrum (CDCl3) δPpm5.26
(1H..dd), 5.72 (1H,.dd), 6.6
7 (1H1dd), 6.75-7.52 (9H,.m)
Reference Example 4 α-(2.2″-difluoro-4-biphenylyl)ethyl alcohol 52y and 10 mg of quinhydrone as a polymerization inhibitor were dissolved in 100 ml of dimethyl sulfoxide and reacted at 170° C. for 1 hour.

After cooling, 50 ml of ethyl acetate was added, and the mixture was washed with 400 ml of water to remove dimethyl sulfoxide, and then the methyl acetate layer was separated. After drying the ethyl acetate layer over magnesium sulfate, ethyl acetate was distilled off under reduced pressure, and the residue was subjected to column chromatography. From the hexane elution part, 2●2
″-difluoro-4-vinylbiphenyl 3.3y was obtained. Yield: 90 mol% Nuclear magnetic resonance spectrum (CDCl3) δPpml.47
(3H., dd), 2.80 (1H..s), 4.90
(1H..q), 6.90-7.60 (7H,,m) Reference Example 5 3-Ethylbenzophenone 15y was dissolved in carbon tetrachloride 5
15y of N-bromosuccinimide and 0.1y of benzoyl peroxide were added thereto, and the mixture was heated under reflux for 1 hour.

After cooling, the solid matter was separated, and carbon tetrachloride was distilled off from the solution to obtain crude α-(3-benzoylphenyl)ethyl bromide. This was dissolved in 500 ml of ethyl alcohol, 20 y of potassium hydroxide was added, and the mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was poured into 2 liters of water, extracted with benzene, and the benzene layer was washed with water and dried over magnesium sulfate. Benzene was distilled off under reduced pressure, and the residue was subjected to column chromatography. From the hexane elution part, 3
-10.4y of vinylbenzophenone was obtained. Yield 70 mol%, refractive index n? =1.6174 nuclear magnetic resonance spectrum (CDCl3) δPpm5.3l (1H..dd), 5
．． 78 (1H1dd), 6.79 (1H1dd), 7.
36-8.01 (9H,.m) Example 6 (1) α-2-
Fluoro-4-biphenylyl)ethyl alcohol 200
Dissolve Da in 600 mL of 5% aqueous dioxane;
This solution is passed through a 30 mt bed of alumina heated to 0.degree. C. at a rate of 150 mt per hour with 710 ml of nitrogen per minute.

The outlet portion was cooled and the resulting liquid was concentrated to obtain crude 2-fluoro-4-vinylbiphenyl 182y. (2) 2-
Fluoro-4-vinylbiphenyl 182y 12% aqueous hydrochloric acid solution 43.0y1 Bistriphenylphosphine dichloropalladium 0.9y1 Triphenylphosphine 0.8f
and 640 ml of dioxane were placed in an autoclave with an internal volume of 2 liters, and cooled. 150k91cI of carbon monoxide
After heating to reach 110° C., carbon monoxide was further press-injected until the amount reached 200 kgIcIt, and the reaction was allowed to occur until no absorption of carbon monoxide was observed.

After cooling, the reaction solution was diluted with 10% sodium hydroxide aqueous solution 400
After washing the insoluble matter with chloroform, the aqueous layer was acidified with hydrochloric acid and extracted with ether. After washing the ether layer with water and drying with magnesium sulfate, the ether was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from hexane-toluene to obtain 233V of α-(2-fluoro-4-biphenyl)propionic acid. Yield 85 mol%, M. p. llO-1
11. Example 7) 3-vinylbenzophenone 5.0f
1 5.0 y of isopropyl alcohol 1 0.04 y of bistriphenylphosphine dichloropalladium and 20 ml of toluene were placed in an autoclave with an internal volume of 100 ml,
When cold, carbon monoxide is press-injected to 150 k9 nod, heated to 1
After reaching 10°C, add another 200 kg/cI of carbon monoxide.
The reaction was continued until no carbon monoxide absorption was observed.

After cooling, the reaction solution was washed with water, dried over magnesium sulfate, and distilled to give a boiling point of 169-170 C/0.1 Twt.
6.4q of α-(3-benzoylphenyl)propionic acid isopropyl ester of Hg was obtained. Yield: 90 mol% 2) 6.4 V of α-(3-benzoylphenyl)propionic acid isopropyl ester was heated under reflux for 3 hours with a mixture of 8 mt of water in which 2y sodium hydroxide was dissolved and 50 mt of isopropyl alcohol.

After cooling, the reaction solution was poured into a large amount of water, insoluble materials were removed by extraction with ether, and the aqueous layer was acidified with hydrochloric acid and extracted with ether.

Claims (1)

[Claims] 1. A substituted arylethylene represented by the general formula R^1-CH=CH_2 is carbonylated by reacting it with carbon monoxide in the presence of a lower alcohol or water using a palladium-based catalyst. A method for producing an α-(substituted aryl)propionic acid compound represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲ There are mathematical formulas, chemical formulas, tables, etc.▼, ▲mathematical formulas,
There are chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ where R^2 represents hydrogen or a lower alkyl group).