JPH0784406B2 - Process for producing 2- (substituted aryl) propionic acid or ester - Google Patents

Description

TECHNICAL FIELD The present invention relates to 2- (substituted aryl) propionic acid esters and / or 2- (, which are useful as intermediates in the field of pharmaceuticals and organic synthetic fields including pharmaceuticals. It relates to a method for producing a substituted aryl) propionic acid. These 2- (substituted aryl) propionic acid esters and / or 2- (substituted aryl) propionic acids contain many substances useful as pharmaceuticals having an antiphlogistic / analgesic effect. More specifically, when the substituted aryl ethylene is reacted with carbon monoxide and water and / or alcohol to produce a carboxylic acid ester and / or a carboxylic acid,
The present invention relates to a novel method for increasing the selectivity of a target substance by allowing a specific metal salt to coexist.

[Prior Art and Problems to be Solved by the Present Invention] Conventionally, as a method of carbonylating a substituted arylethylene in the presence of a palladium catalyst to obtain 2- (substituted aryl) propionic acid, for example, British Patent No. 156523
No. 5, Patent Publication No. 52-97930 and the like have been proposed.

Generally, in the carbonylation of a terminal olefin, in addition to a 2- (substituted aryl) form in which a carbonyl group is introduced to a carbon atom at the α-position with respect to an intended aryl group, A by-product of the 3- (substituted aryl) form having a carbonyl group introduced was unavoidable. Conventionally useful and preferred 2- (substituted aryl) in the art.
A method of increasing the selectivity to the body has been desired. That is, 2-
In terms of the molar ratio of the (substituted aryl) form (α) / 3- (substituted aryl) form (β), efforts are being made to increase the ratio of α / β.

As a method for achieving this object, in addition to the specific method proposed above, a method of generally adding hydrochloric acid is also performed. However, corrosion of the apparatus, loss due to polymerization of substituted arylethylene, acid It was not always a preferable method because of by-product of ether by a catalyst.

The present inventors have made it possible to prevent
The inventors have completed the present invention by finding that the ratio of the 3- (substituted aryl) form to the-(substituted aryl) form can be improved.

Furthermore, the method of the present invention can be expressed as a flow sheet as follows.

[Means for Solving the Problem] That is, the present invention provides a salt of at least one metal selected from Cu and Zn in an amount of 0.05 to 1.5 with respect to one atom of palladium metal.
Coexisting at a ratio of atoms, substituted aryl ethylene in the presence of a palladium carbonylation catalyst, carbon monoxide,
Provided is a method for producing 2- (substituted aryl) propionic acid, which comprises hydroesterifying by reacting with water and / or lower alcohol and optionally hydrolyzing, and is useful and preferable 2- (substituted aryl). ) It relates to a method for efficiently producing a body.

The substituted aryl ethylene of the present invention includes, in addition to styrene, alkylstyrenes such as methylstyrene, ethylstyrene, dimethylstyrene, propylstyrene, butylstyrene, etc., diphenyl group, phenoxyphenyl group, alkoxynaphthyl group, and benzoylphenyl group. And substituted aryl ethylenes. Any of these substituted aryl ethylenes can be used as long as they are produced by a conventionally known method. As a specific example of the manufacturing method, Industrial and Engineering Chemistry, Vol.46, No.4,6
52 (1954), Journal of Chemical and Engineering Data, Vol.9, No.
1,104 (1964), I & EC Product Resarch and Development, Vol.3, No.1,
16 (1964), U.S. Pat.Nos. 2,420,689, 2,422,318,2,864,872, 2,954,41
No. 3 and No. 3,025,330 have been proposed, and any substituted aryl ethylene produced by these methods can be used.

2- (Substituted aryl) obtained by the specific method of the present invention
Propionic acid includes α- (3-isobutylphenyl) propionic acid, α- (3-diphenylyl) propionic acid,
α- (3-phenoxyphenyl) propionic acid, α-
(3-Alkoxynaphthyl) propionic acid, α- (3-
Examples thereof include benzoylphenyl) propionic acid.

The compound which is reacted with the substituted aryl ethylene in the process of the present invention together with carbon monoxide is water, a lower alcohol or a mixture thereof.

In the method of the present invention, 2- (substituted aryl) propionic acid can be directly produced as a free carboxylic acid when reacted with carbon monoxide using water.

Also, when a lower alcohol is reacted with carbon monoxide, 2- (substituted aryl) propionic acid is produced as an alkyl ester of the alcohol used.

This ester can be easily converted into a free carboxylic acid by hydrolysis according to a conventionally known method, if necessary. These lower alcohols have 1 to 4 carbon atoms
Is an aliphatic alcohol having a lower alkyl group. Specific examples of these are methanol, ethanol, n-
Propanol, isopropanol, n-butanol, se
Such as c-butanol, isobutanol and tert-butanol. These can be used alone or as a mixture of two or more kinds of alcohols. The type can be appropriately selected depending on the substituted aryl ethylene to be reacted. The alcohol may be used in an excess amount with respect to the substituted aryl ethylene, but a molar ratio of up to 5 relative to 1 of the substituted aryl ethylene is sufficient.

Hydroesterification using alcohol generally produces both normal isomers and isomeric isomers as ester isomers. When these isomers need to be separated and purified by distillation, for example, the type of alcohol used may be appropriately selected so that the physical constants between the isomers such as boiling point and melting point differ.

The hydroesterification catalyst of the present invention has palladium as an active center, and an active metal having an acid value of 0 to the highest acid value can be used. These catalysts include trivalent phosphorus compounds, π-allyl groups, amines, nitriles, oximes,
A complex containing olefin, hydrogen or carbon monoxide as a ligand can also be used.

Specific examples of these complexes include a bistriphenylphosphine dichloro complex, a bistributylphosphine dichloro complex, a bistricyclohexylphosphine dichloro complex, a π-allyltriphenylphosphine dichloro complex,
Triphenylphosphine piperidine dichloro complex, bisbenzonitrile dichloro complex, biscyclohexyl oxime dichloro complex, 1,5,9-cyclododecatriene-dichloro complex, bistriphenylphosphine dicarbonyl complex, bistriphenylphosphine acetate complex, bistriphenylphosphinedinite Rate complex, bistriphenylphosphine sulfate complex, tetrakistriphenylphosphine complex and chlorocarbonylbistriphenylphosphine complex having carbon monoxide as a part of the ligand, hydridocarbonyltristriphenylphosphine complex, bischlorotetracarbonyl complex, di Carbonyl acetylacetonate complex etc. can be mentioned.

Further, a compound capable of forming the above complex in the reaction system can also be used.

That is, a method in which a compound that can serve as a ligand for palladium as an active center, that is, phosphine, a nitrile, an allyl compound, an amine, an oxime, an olefin, or carbon monoxide is simultaneously present in the reaction system may be used.

Examples of the phosphine include, for example, triphenylphosphine, tritolylphosphine, tributylphosphine,
Tricyclohexylphosphine, triethylphosphine, etc .; Nitriles, for example, benzonitrile, acrylonitrile, propionitrile, benzylnitrile group; Allyl compounds, for example, allyl chloride, allyl alcohol, etc .; Amines, for example, benzylamine, Pyridine, piperazine, tri-n-butylamine and the like; oximes such as cyclohexyl oxime, acetoxime and benzaldoxime; and olefins such as 1,5-cyclooctadiene and 1,5,9-
Examples thereof include cyclododecatriene.

The metal salt to be allowed to coexist in the hydroesterification reaction of the present invention is a salt of at least one metal selected from Cu and Zn, which is an inorganic acid salt such as a halogen salt, a sulfate salt, a nitrate salt or a phosphate salt, and an acetate salt. It may be a salt of a lower carboxylic acid such as These salts may be anhydrous salts or crystalline hydrated salts. Furthermore, these may be used alone or in the form of a mixture. These metal salts preferably coexist at an atomic ratio of 0.05 to 1.5 with respect to one atom of palladium. If the atomic ratio is less than 0.05, the effect of adding the metal salt will not be obtained. That is, there is no effect of improving the above-mentioned α / β ratio (i / n ratio). In addition, when the atomic ratio exceeds 1.5, the metal salt itself exhibits another catalytic activity, the loss due to the polymerization of the substituted arylethylene as a raw material becomes remarkable, or the catalytic activity of palladium is suppressed, which is preferable. Absent.

Specific metal salts of the present invention include CuCl ₂ , ZnCl ₂ and Cu.
_{(NO 3) 2, Cu (} OCOCH 3) 2 and the like.

The amount of palladium, which is the active center of the hydroesterification catalyst, was 0.0001 per mol of the substituted aryl ethylene.
Is 0.5 mol, preferably 0.0005 to 0.1 mol. The amount of the compound that can serve as a ligand is 0.8 to 10 mol, preferably 1 to 4 mol, per 1 atom of palladium.

The hydroesterification reaction is carried out at a reaction temperature of 40 to 200 ° C, preferably 50 to 180 ° C. If the reaction temperature is below 40 ° C,
The reaction rate becomes remarkably slow and it cannot be practically carried out. Further, if the temperature exceeds 200 ° C., side reactions such as polymerization and decomposition of the palladium carbonylation catalyst occur, which is not preferable.

The reaction pressure can be appropriately selected as long as it is 5 Kg / cm ² or more. 5 kg / c
If it is less than m ² , the reaction becomes so slow that it cannot be practically carried out. Further, the higher the pressure is, the faster the reaction proceeds, which is preferable. However, too high pressure naturally has a limit in terms of the production apparatus, such that the pressure resistance of the reactor must be extremely high.
Therefore, a pressure of 500 Kg / cm ² or less is practically sufficient.

The carbonylation reaction may be carried out until no pressure decrease due to absorption of carbon monoxide is observed, and a reaction time of 4 to 20 hours is usually sufficient.

The carbon monoxide to be supplied may be supplied alone. However, gases such as nitrogen, helium, argon, methane, and ethane which are inert to the carbonylation reaction may coexist.

In the carbonylation of the present invention, generally, a sufficiently favorable result can be obtained in a solvent-free state, but a solvent inert to carbonylation can be used for the purpose of removing heat of reaction. As a solvent inert to carbonylation, ether,
Examples thereof include polar solvents such as ketone and alcohol, and nonpolar solvents such as paraffin, cycloparaffin, and aromatic hydrocarbon.

When reacted with alcohol, 2- (substituted aryl) propionic acid is obtained in the form of alcohol ester. To convert this to a carboxylic acid form, if necessary, for example, heating with an aqueous alkali solution for hydrolysis, acidification with a suitable acid to convert it into a free carboxylic acid, and further converting the carboxylic acid into a solvent, etc. Extract and separate with.

After the reaction is completed, the desired 2- (substituted aryl) propionic acid is obtained by recrystallization or the like.

[Effects of the Invention] According to the method of the present invention, it is preferable in practical use.
(Substituted aryl) propionic acid can be produced efficiently with good selectivity.

[Examples] The present invention will be described in more detail with reference to Examples below.

Example 1-Hydroesterification of styrene-In a pressure vessel equipped with a stirrer and having a capacity of 200 ml, 42 g of styrene (0.4 mol), 0.071 g of PdCl ₂ (0.4 mmol), 0.2133 g.
Of triphenylphosphine (0.8 mmol), 20 g of methanol (0.6 mol) and CuCl ₂ in the amounts shown below were charged, and the pressure was maintained at 75 Kg / cm ^{2 with} carbon monoxide, and the pressure was maintained. 10 at a temperature of 90 ° C with stirring under pressure
Reacted for hours. After completion of the reaction, the mixture was cooled, and then surplus carbon monoxide was released, and the obtained reaction product was analyzed by gas chromatogram to obtain the yield of α-phenylpropionic acid methyl ester, and the selectivity of α- to β-position. The molar ratio of the scaffolds was calculated. The results are shown below.

The reaction products obtained in Experimental Examples 1 to 5 were collected together by precision distillation at a distillation temperature of 98 ° C. at a pressure of 12 mmHg to 22 mmHg.
Α-Phenylpropionic acid methyl ester (recovery rate 86%, purity 98.7%) was obtained as a fraction at 119 ° C.

Example 2-Hydroesterification of butylstyrene-Similar to Example 1, in a pressure vessel equipped with a stirrer and having a volume of 200 ml, 83 g of p-isobutylstyrene (0.4 mol), 0.07
1 g of PdCl ₂ (0.4 mmol), 0.2133 g of triphenylphosphine (0.8 mmol), 20 g of methanol (0.6 mol) and ZnCl ₂ in the respective amounts shown below were added, and the pressure was adjusted to 75 Kg / cm ^{2 with} carbon monoxide. Pressurized and kept under pressure. The mixture was reacted under pressure at 90 ° C. for 10 hours with stirring. After cooling after completion of the reaction, the reaction product obtained by releasing excess carbon monoxide was analyzed by a gas chromatogram,
The molar ratio of α-position to β-position was calculated as yield and selectivity. The results are shown below.

The reaction products obtained in Experimental Examples 6 to 10 were collected and subjected to precision distillation at a distillation temperature of 120 ° C. to 1 at a pressure of 3 mmHg to 5 mmHg.
Α- (p-Isobutylphenyl) propionic acid methyl ester (recovery rate 89%, purity 98.6%) was obtained as a fraction at 29 ° C.

Example 3-Hydroesterification of butylstyrene-In the same manner as in Example 2, for the metal Pd atom shown below.
Hydroatomization of α-isobutylstyrene was carried out by adding an amount of 0.5 atomic ratio to palladium with respect to the catalyst. Similarly, the yield and the selectivity were obtained.

Example 5-Hydrolysis-Hydrolysis was carried out using 110 g of the α- (p-isobutylphenyl) propionic acid methyl ester fraction obtained by distillation in Example 2.

To a reactor having a reflux condenser and a stirrer with a capacity of 1 liter, 170 g of a 10% aqueous solution of sodium hydroxide in a ester was added, and the mixture was gradually heated with stirring and kept at 80 to 95 ° C. for 3 hours for reaction. After completion of the reaction, the mixture was cooled to room temperature and acidified by adding 35% hydrochloric acid. 300 g of toluene were added to the reaction mixture, which was cloudy due to the product liberated as carboxylic acid, to extract the carboxylic acid. After extraction, toluene is separated by distillation to obtain pale yellow α- (p-isobutylphenyl) propionic acid 99
g (mp 73.0 ° C-74.5 ° C) were obtained.

The pale yellow crystals were recrystallized from n-hexane to give white crystals having a melting point of 75.0 ° C to 75.5 ° C. This product also showed the same melting point in the mixed melting point test with the standard sample.

Example 6 and Comparative Experimental Example 5-Palladium Complex-Catalyzed Hydroesterification-In place of PdCl _{2 in} Example 2, Experimental Example 8, dichloropalladium bistriphenylphosphine (281 mg, 0.4 mmol) was used, and Example 2 The butylstyrene was hydroesterified in the same manner as in. The yield of α-isobutylphenylpropionic acid methyl ester was 97.6%, and the α / β ratio was 44.5.

Further, in the above experiment, hydroesterification was performed without adding ZnCl ₂ , the yield of the ester was 91.4%,
The α / β ratio was 13.8.

Example 7 and Comparative Experimental Example-Hydroesterification with Propyl Alcohol and Butyl Alcohol-In Example 2 and Experimental Example 8, isopropyl alcohol and sec-butyl alcohol were used in place of methyl alcohol for hydroesterification. Further, in each case, an experiment was carried out for a system in which ZnCl ₂ was not added. The results are shown below.

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Claims (3)

[Claims] 1. In the presence of a palladium-based carbonylation catalyst, 0.05 to 1.5 atoms of Cu are added to 1 atom of palladium metal.
And a salt of at least one metal selected from Zn and co-existent, and the substituted arylethylene is reacted with carbon monoxide and water and / or a lower alcohol, and is optionally hydrolyzed. A method for producing a (substituted aryl) propionic acid or ester. 2. The 2- (substituted aryl) propionic acid according to claim 1, wherein p-isobutylstyrene is reacted as the substituted arylethylene to produce α- (3-isobutylphenyl) propionic acid, or Method for producing ester. 3. The method for producing 2- (substituted aryl) propionic acid or ester according to claim 1, wherein the metal salt is a halogen salt.