JPS6038343A - Production of phenylacetic acid derivative - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as agricultural chemicals, etc., from easily available raw material, with small steps and simple operation, in high yield, by reacting a benzaldehyde derivative having strong electron donative group with CO and water, etc. in the presence of a Pd catalyst and a specific cocatalyst. CONSTITUTION:The phenylacetic acid derivative of formula II having strong electron donative group is produced by carbonylating the benzaldehyde deriva- tive of formula I [R<1> is alkoxy, aryloxy, OH or amine (strong electron donative group); R<2> and R<3> are H, alkyl, aryl, halogen or R<1>] with CO and the compound of formula R<4>-OH (R<4> is H, alkyl or aryl)preferably in a solvent using a Pd catalyst such as PdCl2 (pph3)2, etc. and a cocatalyst comprising an acidic compound such as HCl, p-toluenesulfonic acid, etc. in the presence of a metal choloride such as NaCl, at 40-150 deg.C and 10-200kg/cm<2> pressure. USE:Agricultural chemicals, perfumes and their intermediates.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing phenylacetic acid derivatives having a strong electron-donating group, which are extremely useful as medicines, agricultural chemicals, fragrances, and intermediates thereof.

More specifically, the present invention involves reacting a benzaldehyde derivative having a strong electron-donating group with carbon monoxide, water, alcohols, or phenols in the presence of hydrogen chloride or an acidic compound and a metal chloride using a palladium catalyst and a cocatalyst. The present invention relates to a method for producing phenylacetic acid derivatives. Note that the strong electron donating group herein means an alkoxy group, an aryloxy group, a hydroxy group, or an amino group.

Background of the Invention The following methods are known for producing phenylacetic acids from benzaldehydes.

(1) JP-A-52-136,133 discloses 0 to 20 moles of benzaldehyde obtained by oxidizing toluene and 80 to 10 moles of benzyl acetate or benzyl gropionate.
Oxygenated products containing 0 mol % of catalysts for group metals and
- It is described that phenylacetic acid is produced by contacting a gaseous mixture containing carbon monoxide in the presence of a rogen promoter, and specifically, in Example 6, the presence of a catalyst consisting of rhodium oxide and iodine is described. Kōchi - Phenyl acetic acid is obtained from benzaldehyde using a mixed gas of carbon oxide and hydrogen and water. However, the yield of phenylacetic acid is not high and there are many by-products.

The publication does not contain any description of benzaldehyde having a substituent, and in particular, there is no suggestion whatsoever of benzaldehyde having a strong electron-donating group.

(2) Japanese Patent Application Laid-Open No. 53-56,633 discloses that precious metals V1 of group Ⅰ of the periodic table, or compounds of these metals, and chlorine, iodine, or halogen compounds thereof in the presence of a catalyst, describes a method for producing acetic acid by reacting an aromatic aldehyde, carbon oxide and water. In Example 26, p-methoxy-phenylacetic acid was produced, but the yield was as low as 24%. Even unsubstituted phenylacetic acid requires the addition of additional silver or silver compounds to obtain satisfactory yields, complicating product fractionation and catalyst recovery.

(3) JP-A-56-75.452 discloses that aryl acetic acid is produced by reacting an aromatic aldehyde, carbon oxide, and water in the presence of a catalyst consisting of rhodium or a rhodium compound and hydrogen iodide. The method is described. As a substituent of phenylacetic acid, an alkoxy group is included, but in the examples, phenylacetic acid and 4-
It is limited to methylphenylacetic acid, and does not apply to phenylacetic acid having strong electron-donating substituents. According to additional tests conducted by the present inventors, the yield was low for producing phenylacetic acid having a strong electron-donating substituent, and no satisfactory results were obtained. (See Comparative Example 1) By these known methods, phenylacetic acids can be produced in good yield from benzaldehydes having an alkoxy group, phenoxy group, hydroxy group or amino group as a substituent, which are useful as intermediates for pharmaceuticals and agricultural chemicals. I couldn't do that.

SUMMARY OF THE INVENTION As a result of various intensive studies to overcome the above-mentioned drawbacks of conventionally known methods, the present inventors have succeeded in producing the corresponding phenylacetic acid in good yield from benzaldehyde having a strong electron-donating substituent. ◎ That is, the present invention is a benzaldehyde derivative represented by the following formula (wherein R1 represents an alkoxy group, an aryloxy group, a hydroxy group, or an amino group, and R2 and R3 are independently represents hydrogen, an alkyl group, an aryl group, an alkoxy group, an arylokita group, a hydroxy group, a halogen, or an ζ) group. ) and -carbon oxide, water, alcohols or phenols as a palladium catalyst and a co-catalyst 5- The following reaction is carried out in the presence of hydrogen chloride or an acidic compound and a metal chloride. A method for producing a phenylacetic acid derivative represented by the formula.

(In the formula, R1, R2%- and R3 represent the same meanings as above, and 1 (4 represents hydrogen, an alkyl group, or an aryl group). Based on the new knowledge that aqueous chloride or an acidic compound and a metal chloride are used as a palladium catalyst and a cocatalyst for the carbonylation of benzaldehyde, which has a strong electron-donating group selected from a group or an amino group. As a result, they succeeded in producing the corresponding phenyl acetic acid in an extremely high yield.

That is, according to the method of the present invention, easily available raw materials are used,
Phenyl acetic acid derivatives can be produced with good yield through a small number of steps and simple operations. Specifically, it is extremely effective as a method for producing 4-hydroxyphenylacetic acid or its ester, which is useful as a modifier for penicillin or cephalosporin.

3. Detailed Description of the Invention (1) Benzaldehyde Derivative The benzaldehyde derivative represented by ②m of the present invention has at least one strong electron donating group selected from an alkoxy group, an aryloxy group, a hydroxy group, or an amine group in benzene. It is characterized by having it on a ring.

The alkoxy group for R1 in formula m preferably has 1 to 10 carbon atoms, such as methoxy group, ethoxy group, propoxy group, butoxy group, octyloxy group, and the like. The aryloxy group for R1 preferably has 6 to 15 carbon atoms, and may have a substituent such as aryl nialkoxy, halogen, or phenoxy, such as phenoxy, tolyloxy, methoxyphenoxy,
Examples include chlorphenoxy group and phenylphenoxy group. 1-1 amino group is an alkyl group having 1 to 4 carbon atoms,
Phenyl &, 6- or halogen-substituted phenyl groups may be substituted, for example, amino group, dimethylamino group,
Examples include diethylamine group, ethylmethylamino group, dichlorophenylamino group, and diphenylamino group.

The alkyl group for R2 and RS preferably has 1 to 10 carbon atoms, and includes, for example, a methyl group, ethyl group, propyl group, butyl group, octyl group, cyclopentyl group, and cyclohexyl group. The aryl group for R'' and R3 is preferably one having carbon #Ii6 to 15, and may be substituted with an alkoxy group, a phenoxy group, or a halocarbon group, such as a phenyl group, a tolyl group, a methoxyphenyl group, a phenoxyphenyl group, Chlorphenyl group, biphenylyl group, etc. R2 and 1 (alkoxy group, aryloxy group and amino group in 3 are R1
It is similar to the one mentioned above. The halogen for R'' and R3 is preferably chlorine or bromine.

Examples of these benzaldehyde derivatives include 4
-Methoxybenzaldehyde, 2-methoxybenzaldehyde, 4-hydroxybenzaldehyde, 2-hydroxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, 3-chloro-4-hydroxybenzaldehyde, 3.4.5-) Rimethoxybenzaldehyde, 3- Hydroxy-4-phenylbenzaldehyde, 4-dimethylaminobenzaldehyde and 2-((
Examples include 2,6-dichlorophenyl)aminocobenzaldehyde.

(2) Water, Alcohols, and Phenols In the present invention, when water is used, carboxylic acids are produced, and when alcohols or phenols are used, corresponding carboxylic esters are produced. Furthermore, when water and alcohols or water and phenols are used together, a mixture of carboxylic acid and its ester is produced.

These water, alcohols, or phenols can be collectively represented by the following general formula [11] O9-R'-OtIll[l [wherein R4 represents hydrogen, an argyl group, or an aryl group]. ] The alkyl group is preferably a chain, branched or cyclic group having 1 to 10 carbon atoms, and may be substituted with an aromatic group, such as a methyl group, ethyl group, propyl group,
Butyl group, cyclopentyl group, hexyl group, cyclohexyl group, heptyl group, octyl group, fuchlorooctyl group,
Examples include nonyl group, decyl group, and benzyl group.

The aryl group preferably has 6 to 5 carbon atoms,
Examples include phenyl group, tolyl group, xylyl group, and the like. Further, these alkyl groups and aryl groups may have one or more hydroxyl groups. When an alcohol in which R4 is an alkyl group is used, the desired phenylacetic acid derivative can be produced with particularly good yield.

Examples of the compound represented by the above general formula rfl[1 include water, methanol, ethanol, glopanol, butanol, cyclohexanol, benzylalcohol, ethylene glycol, phenol, cresol, t-butylphenol, and catechol. It will be done.

(a) - Carbon oxide Carbon monoxide may be pure or may contain an inert gas that does not participate in the reaction, such as nitrogen or saturated hydrocarbons. It is also possible to use, as a source of carbon oxide, water gas which can be obtained industrially at low cost.

(4) Palladium catalyst The palladium catalyst used in the present invention contains 0 palladium.
Valid to divalent palladium complexes containing /S logen group atoms, trivalent phosphorus compounds, π-allyl groups, amines, nitriles, oximes, olefin carbon oxides, etc. as ligands are effective. It is. Specific examples include bistriphenylphosphine dichloropalladium, bistributylphosphine dichloropalladium, bistricyclohexylphosphine dichloropalladium, π-allyltriphenylphosphine chloropalladium, tri-phenylphosphine piperidine dichloropalladium, bisbenzonitrile dichloropalladium, and biscyclohexylphosphine dichloropalladium. Sanoxime dichloropalladium, 1.5.9-cyclododecatriene-dichloropalladium, bistriphenylphosphine dicarbonyl palladium, bistriphenylphosphine palladium acetate-1-, bistriphenylphosphine palladium cinitrate, bistriphenylphosphine palladium sulfate, tetrakistrif Examples include egorphosphine 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. Phosphins include, for example, triphenylphosphine, tritolylphosphine, tributylphosphine, tricycloheximylphosphine, triethylphosphine, etc. Nitriles include, for example, benzonitrile, loride, allyl alcohol, etc.; amines include, for example, benzylamine,
Pyridine, piperazine, tri-n-butylamine, etc.; oximes include cyclohexanoxime, acetoxime, benzaldooxime, etc.; olefins include 1,
Examples include 5-cyclooctadiene, 1,5,9-cyclododecatriene, and the like.

(5) Co-catalyst In the present invention, the presence of a co-catalyst consisting of hydrogen chloride or an acidic compound and a metal chloride is important.

The acidic compound referred to in the present invention. means inorganic acids such as sulfuric acid, phosphoric acid, and boric acid, and organic acids such as p-)toluenesulfonic acid, methanesulfonic acid, and acetic acid.

Examples of metal chlorides include sodium chloride, potassium chloride, and chlorinated steel.

Among these cocatalysts, hydrogen chloride is preferred, and when hydrogen chloride is used, there is no problem even if a metal chloride is present.

(6) Solvent The present invention can be carried out with or without a solvent. When using a solvent, hexane, heptane,
Benzene and toluene 4iL< are hydrocarbons such as xylene, ethers such as tetrahydrofuran, dioxane or dimethoxyethane, organic carbonic acids such as acetic acid or gropionic acid, ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or r-
Examples include esters such as butyrolactone or ethyl acetate. When producing carboxylic acid from benzaldehyde conductor, -carbon oxide, and water, it is advantageous to use hydrophilic solvents such as tetrahydrofuran, dioxane, acetone, and acetic acid. The amounts of reactants used are as follows.

1) Water, alcohols, phenols, and solvents 14- Water, alcohols, or phenols are required in an equimolar or more amount relative to the benzaldehyde derivative.
6 times the mole, preferably 1.1 to 4 times the mole is used.

When a solvent is used, it can be used in an amount of 0.5 to 20 times, preferably 1 to 5 times, the volume of the mixture of the benzaldehyde derivative and water, alcohol, or phenol.

2) The amount of palladium catalyst used varies depending on the reaction rate, but too much is not advantageous. Usually, the palladium complex and the palladium compound capable of forming the palladium complex are added in an amount of 10-' to 1 mol, preferably 10-3 to 1 mol of the benzyl alcohol derivative.
It is appropriate to use ~10-1 mol. When using a palladium compound, the compound that can be a ligand to be added at the same time is 0.8 to 10% per mole of the palladium compound.
It is appropriate to use moles, preferably 1 to 5 moles.

c) The amount of co-catalyst hydrogen chloride and acidic compound to be used varies depending on the reaction rate, but it is not advantageous to use too much, and it is usually 1 to 50 times θ per 1 mole of palladium atoms, preferably 10 to 4
It is 0 times the mole. The amount of the metal chloride used together with the acidic compound is preferably 1 to 50 times, and suitably 10 to 40 times, per mole of palladium atoms.

(8) Reaction conditions The reaction temperature is usually 40-150°C, preferably 70-150°C.
The temperature is 20°C. The reaction pressure can be selected from a wide range of 10 to 9/e+J or more, but from the viewpoint of reaction rate and economy, it is 10 to 200 Kg/Cd.

% is preferably 20 to 15 oKq/di.

(9) Phenyl acetic acid W1 derivative The phenylacetic acid derivative obtained by the method of the present invention as described above is represented by the general formula 1).

Examples of such phenylacetic acids include 4-methoxyphenylacetic acid, 4-methoxyphenylacetic acid 7L, and acetic acid:
c -fl, 2-methoxyphenylacetic acid, ethyl 2-methoxyphenylacetate, 4-hydroxyphenylacetic acid Fi
IC4-Ethyl hydroxyphenylacetate, isopropyl 4-hydroxyphenylacetate, 2-hydroxyphenylacetate L Ethyl 2-hydroxyphenylacetate, 3-chloro-4-hydroxy 7ethylhWR13-Rio4-
Methyl hydroxyphenylacetate, 3,4.5-trimethoxyphenylacetic acid, 3.4.5-) butyl trimethoxyphenylacetate, 4-dimethylaminophenyl acetate, 4-
Examples include ethyl dimethylaminophenyl acetate.

Next, the present invention will be specifically explained with reference to Examples.

Example 1 4-Hydroxybenzaldehyde s, nt (41,0 mm!) was placed in a 100-inch autoclave made of Hastelloy C.
), ethyl alcohol 9.5 f (200 mmg
), bistriphenylphosphine dichloropalladium 0
．． 29 f (0.41 mmot), concentrated hydrochloric acid 0.5 f
(4,9111mot) and dioxane 25f as a solvent were added and reacted with stirring at a carbon oxide pressure of 100 Kf/d and a reaction temperature of 110°C for 5 hours. After cooling for 90 minutes, the -17- carbon oxide was removed and the contents were taken. I put it out. After evaporating the solvent by 1 liter, 30 ml of ethyl ether was added.

After neutralization with saturated Na1 (COa water and then saturated Nact water), ethyl ether was distilled off from the organic layer under reduced pressure. Ethyl 4-hydroxyphenylacetate 6,Of was obtained from the residue by vacuum distillation.

Boiling point 151-155°C/151IImHg (yield 81.
3%) Example 2 4-Hydroxybenzaldehyde 5. Of (41,0mmo
), water 3.6 F (200 mmot), bistriphenylphosphine dichloropalladium 0.29 f (0,4
1mmo,/-), concentrated hydrochloric acid 0.59 (4,9mmo
) and dioxane 25f as a solvent, -
Carbon oxide [E power 150 Ky/cd, reaction temperature 110°C
The reaction was continued with stirring for 5 hours. After cooling, the -carbon oxide was removed and the contents were taken out. After distilling off the solvent under reduced pressure, 25 rnl of saturated NaHCOa water was added and the aqueous layer was separated, acidified with hydrochloric acid, the precipitated organic matter was extracted with ethyl ether, the ethyl ether layer was washed with water, and dried over 18-magnesium sulfate. Thereafter, ethyl ether was distilled off under reduced pressure, and the resulting crude crystals were recrystallized from water to obtain 2.6 tons of 4-hydroxyphenylacetic acid.

Condolences] 49 to 151°C (yield 41.7%) Examples 3 to 8 Table 1 shows the results of reactions carried out according to Examples 1 and 2.

(The following is a blank space) Comparative Examples 1 to 5 Table 2 shows the results of reactions conducted according to the examples. It is shown that palladium compounds are preferred for the present invention.

(Margin below)

Claims (1)

[Claims] A benzaldehyde derivative represented by the following formula (wherein,
R1 represents an alkoxy group, an aryloxy group, a hydroxy group or an ayne group, and R2 and R3 are independently,
Hydrogen chloride (representing hydrogen, alkyl group, aryl group, alkoxy group, aryloxy group, hydroxy group, halogen or amino group), -carbon oxide, water, alcohol or phenol as palladium catalyst and co-catalyst) Alternatively, a method for producing a phenylacetic acid derivative represented by the following formula, which comprises reacting it in the presence of an acidic compound and a metal chloride. (In the formula, R1, R2 and R3 have the same meanings as above, and R4 represents hydrogen, an alkyl group, or an aryl group.)