JP2003002864A - Method for producing oxocyclohexyl acetic acid and method for producing hydroxyiminocyclohexyl acetic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing oxocyclohexyl acetic acid with good productivity by catalytic hydrogenation of hydroxyphenyl acetic acid and a method for producing hydroxyiminocyclohexyl acetic acid with good productivity by reacting the oxocyclohexyl acetic acid produced by the above method with hydroxylamine. SOLUTION: In the production of the oxocyclohexyl acetic acid by reacting the hydroxyphenyl acetic acid with hydrogen in the presence of a hydrogenation catalyst in water solvent, the reaction is performed in the presence of a base. The hydroxyiminocyclohexyl acetic acid is produced by reacting the oxocyclohexyl acetic acid produced by the above method with the hydroxylamine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing oxocyclohexylacetic acid and hydroxyiminocyclohexylacetic acid, which are useful as, for example, pharmaceutical intermediates, and more particularly to a process for producing oxocyclohexylacetic acid by catalytic hydrogenation of hydroxyphenylacetic acid and oxocyclohexylacetic acid. It relates to a method for producing hydroxyiminocyclohexyl acetic acid by reacting cyclohexyl acetic acid with hydroxylamine.

[0002]

2. Description of the Related Art Conventionally, a method for catalytically hydrogenating hydroxyphenylacetic acid to produce oxocyclohexylacetic acid is known. For example, 4-hydroxyphenylacetic acid is reacted with hydrogen in the presence of a palladium catalyst in a water solvent. Four
A method for producing -oxocyclohexyl acetic acid is known (JP-A-56-92244). This method uses a large amount of water, which is a solvent. In addition, in JP-A-56-92244, when water is used as a reaction solvent when 4-hydroxyphenylacetic acid is catalytically hydrogenated to produce 4-oxocyclohexylacetic acid, alcohols, acetic acid, etc. It is described that the target product can be obtained in a better yield than when an organic solvent is used.

As a method for producing hydroxyiminocyclohexylacetic acid, for example, a method for producing 4-hydroxyiminocyclohexylacetic acid by oxidizing 4-aminocyclohexylacetic acid with hydrogen peroxide in the presence of a base and tungstic acid is known. (Russian patent 17742
No. 2, Zh. Vses. Khim. Obshchestva im. DI
Mendeleeva, 10, 711-2 (1965) etc.). The starting material 4-aminocyclohexylacetic acid used in this method can be produced by catalytic hydrogenation of 4-nitrophenylacetic acid (J. Med. Chem., 41, 760 (1998), etc.).

[0004]

However, in the above-mentioned conventional method for producing oxocyclohexyl acetic acid, since the amount of water used as a reaction solvent is large, the efficiency of the container is deteriorated and there is a problem in productivity. This is because, according to the findings of the present inventors, the solubility of hydroxyphenylacetic acid in water is small.

In order to obtain the starting material aminocyclohexylacetic acid used in the conventional method for producing hydroxyiminocyclohexylacetic acid, nitrophenylacetic acid is added to 10%.
It must be catalytically hydrogenated under a pressure as high as MPa (100 atm). In order to industrially carry out this catalytic hydrogenation of nitrophenyl acetic acid, the reaction equipment is required to have very high pressure resistance, and sufficient attention must be paid to safety.
There is a problem that the equipment cost becomes expensive. As described above, the conventional method for producing hydroxyiminocyclohexylacetic acid is not satisfactory as an industrial method in consideration of production of aminocyclohexylacetic acid as a raw material.

The present invention provides an industrial production method capable of producing oxocyclohexylacetic acid with high productivity by catalytic hydrogenation of hydroxyphenylacetic acid, and a high productivity by reacting oxocyclohexylacetic acid produced by the method with hydroxylamine. It is an object to provide a method capable of industrially producing hydroxyiminocyclohexyl acetic acid.

[0007]

Means for Solving the Problems The inventors of the present invention have made extensive studies to solve the above problems. As a result, when a base is present in the reaction system when reacting hydroxyphenylacetic acid with hydrogen in a water solvent in the presence of a hydrogenation catalyst, the solubility of hydroxyphenylacetic acid in water is improved, and the solvent It was found that the amount of water used can be reduced and oxocyclohexyl acetic acid can be produced in high yield. Further, they have found that hydroxyiminocyclohexylacetic acid can be easily produced with high productivity by reacting the oxocyclohexylacetic acid thus produced with hydroxylamine, and have completed the present invention.

That is, the present invention is characterized in that in the reaction of hydroxyphenylacetic acid with hydrogen in the presence of a hydrogenation catalyst in an aqueous solvent to produce oxocyclohexylacetic acid, the reaction is carried out in the presence of a base. It relates to a method for producing cyclohexyl acetic acid.

The present invention also comprises reacting oxocyclohexylacetic acid with hydroxylamine to produce hydroxyiminocyclohexylacetic acid by reacting hydroxyphenylacetic acid with hydrogen in the presence of a base and a hydrogenation catalyst in an aqueous solvent. The present invention relates to a method for producing hydroxyiminocyclohexylacetic acid, which comprises reacting oxocyclohexylacetic acid with hydroxylamine.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. Examples of the hydroxyphenylacetic acid used in the method for producing oxocyclohexylacetic acid of the present invention include 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid and 4-hydroxyphenylacetic acid, preferably 4
-Hydroxyphenylacetic acid. And according to the method of the present invention, it is possible to produce oxocyclohexyl acetic acid corresponding to the hydroxyphenyl acetic acid used in the reaction,
2-oxocyclohexylacetic acid, 3-oxocyclohexylacetic acid and 4-oxocyclohexylacetic acid can be prepared from the above-mentioned specific compounds of hydroxyphenylacetic acid.

In the method for producing oxocyclohexylacetic acid of the present invention, hydroxyphenylacetic acid is catalytically hydrogenated in the presence of a base in a water solvent. As the base, both an inorganic base and an organic base can be used, and as the inorganic base,
Examples thereof include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as potassium carbonate and sodium hydrogencarbonate, and the like, and organic secondary bases include aliphatic secondary amines such as dimethylamine, diethylamine, trimethylamine, and triethylamine. And aliphatic tertiary amines. A preferred base is an inorganic base. The amount of the base used is usually 0.1 to 10 mol, preferably 0.5 to 1.5 mol, per 1 mol of hydroxyphenylacetic acid.

As the catalyst for catalytic hydrogenation, well-known hydrogenation catalysts can be widely applied. Specifically, Raney catalysts such as Raney nickel and Raney cobalt, precious metal catalysts such as palladium catalysts, ruthenium catalysts and rhodium catalysts can be used. Is mentioned. A preferred hydrogenation catalyst is a noble metal catalyst, and specific examples thereof include a noble metal-supported catalyst in which a noble metal such as palladium, ruthenium, and rhodium is supported on a carrier such as carbon or alumina. Is 1 to 20% by weight, preferably 2 to 10% by weight. The amount of the catalyst used is usually 0.1 to 100% by weight, preferably 5 to 1 based on hydroxyphenylacetic acid.
It is 0% by weight.

Although water is usually used as the solvent, an organic solvent such as alcohol can be used in combination with water as long as the object of the present invention can be achieved. The amount of the solvent used is usually 1 to 20 parts by weight, preferably 2 to 15 parts by weight, relative to 1 part by weight of hydroxyphenylacetic acid.

The oxocyclohexyl acetic acid according to the present invention can be produced, for example, as follows.
A reactor is charged with hydroxyphenylacetic acid, a base, a hydrogenation catalyst and water, and the pressure is usually 0.1 to 5 MPa, preferably 0.5 to 5 while introducing hydrogen into the reactor while stirring.
The temperature is usually maintained at 25 to 200 ° C., preferably 100 to 120 ° C. at 2.0 MPa. After reacting until the theoretical amount of hydrogen is consumed, the reactor contents are cooled to stop the reaction.

In order to isolate oxocyclohexylacetic acid from the reaction mixture after completion of the reaction, for example, first, the reaction mixture obtained is filtered to remove the hydrogenation catalyst, and an acid equivalent to or more than the base used in the reaction is added. Is added to the filtrate to neutralize the base. Then, an organic solvent insoluble in water is added to the obtained mixture, and oxocyclohexylacetic acid is extracted with the organic solvent. Then, the solvent is distilled off from the obtained extract, and white crystals of oxocyclohexylacetic acid are obtained as a residue. As the organic solvent used for extraction, for example,
Examples thereof include esters such as ethyl acetate, ethers such as ethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as chloroform.

In the method for producing hydroxyiminocyclohexylacetic acid of the present invention, oxocyclohexylacetic acid produced by the above-mentioned method of the present invention is reacted with hydroxylamine. As a method for carrying out the reaction of oxocyclohexylacetic acid and hydroxylamine, for example, oxocyclohexylacetic acid is isolated from a reaction mixture after catalytic hydrogenation of hydroxyphenylacetic acid, and the isolated mixture of oxocyclohexylacetic acid, hydroxylamine and a solvent is stirred. Examples of the reaction method include a method of reacting while removing the hydrogenation catalyst from the reaction mixture after the catalytic hydrogenation of hydroxyphenylacetic acid, and optionally concentrating, and then adding an acid salt of hydroxylamine and reacting with stirring. It is not limited to these. The reaction temperature is usually 0-10.
It is 0 ° C, preferably 20 to 50 ° C.

When oxocyclohexylacetic acid is isolated from the reaction mixture after catalytic hydrogenation of hydroxyphenylacetic acid and the resulting mixture of oxocyclohexylacetic acid, hydroxylamine and solvent is reacted with stirring, examples of usable solvents include , In addition to the water-insoluble organic solvent used in extracting oxocyclohexylacetic acid from the reaction mixture after the catalytic hydrogenation of hydroxyphenylacetic acid, water, methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide Etc. The amount of the solvent used is usually 1 to 10 parts by weight with respect to 1 part by weight of oxocyclohexyl acetic acid. The amount of hydroxylamine used is usually 1 to 10 mol, preferably 1 to 1.5 mol, per 1 mol of oxocyclohexyl acetic acid.

When the hydrogenation catalyst is removed from the reaction mixture after the catalytic hydrogenation of hydroxyphenylacetic acid and, if desired, concentrated and then the hydroxylamine acid salt is added and reacted with stirring, the hydroxylamine acid salt is particularly limited. However, it is preferably hydroxylamine hydrochloride. The amount of the acid salt of hydroxylamine used is usually 1 to 10 mol, preferably 1 to 1.5 mol, based on 1 mol of hydroxyphenylacetic acid used for catalytic hydrogenation. The reaction temperature in this method is the same as that when using the above isolated oxocyclohexyl acetic acid.

To isolate hydroxyiminohexylacetic acid from the reaction mixture obtained after the above catalytic hydrogenation, for example, the hydroxyiminocyclohexylacetic acid produced by the above reaction precipitates as crystals in the reaction mixture, so that the reaction mixture The crystals are separated by filtration, and the obtained crystals may be washed, if desired, and dried.

According to the method for producing hydroxyiminocyclohexylacetic acid of the present invention, hydroxyiminocyclohexylacetic acid corresponding to oxocyclohexylacetic acid as a raw material can be produced. That is, from 2-oxocyclohexyl acetic acid to 2-
Hydroxyiminocyclohexylacetic acid is converted from 3-oxocyclohexylacetic acid to 3-hydroxyiminocyclohexylacetic acid and 4-oxocyclohexylacetic acid to 4-
Hydroxyiminocyclohexyl acetic acid can be produced.

[0021]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. Example 1 Preparation of 4-oxocyclohexyl acetic acid Potassium carbonate 1 in an autoclave with a volume of 500 ml
4 in a solution consisting of 4.5 g (0.1 mol) and 304 g of water
-Hydroxyphenylacetic acid 30.4 g (0.2 mol) was dissolved and 5 wt% Pd / C (water content: 54 wt%)
3.0 g was added. The obtained mixture was heated under stirring and maintained at 1.0 MPa and 110 ° C. while introducing hydrogen to carry out the reaction. When the theoretical amount of hydrogen was consumed, the reaction was stopped by cooling. The reaction time was about 2.5 hours. The obtained reaction mixture was filtered to remove the catalyst, and 100 g of 10 wt% hydrochloric acid was added to the filtrate to make it acidic, and 100 g of ethyl acetate was added to extract the mixture twice. Ethyl acetate was distilled off from the ethyl acetate extract under reduced pressure, and 30 g of 4-oxocyclohexylacetic acid as a residue (yield 96%)
Was obtained as a white solid.

Example 2 Production of 4-hydroxyiminocyclohexyl acetic acid After the reaction was carried out in the same manner as in Example 1, the resulting reaction mixture was filtered to remove the catalyst, and the filtrate was put under reduced pressure to 200 ml.
Concentrated to. After adding 20.9 g (0.3 mol) of hydroxylamine hydrochloride to the obtained concentrate, the mixture was stirred at room temperature for 1 hour for reaction. After completion of the reaction, the precipitated crystals were obtained and then dried to obtain 25.8 g (yield 75.4%) of 4-hydroxyiminocyclohexyl acetic acid as a white powder.

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Claims (5)

[Claims] 1. A method for producing oxocyclohexylacetic acid by reacting hydroxyphenylacetic acid with hydrogen in a water solvent in the presence of a hydrogenation catalyst, wherein the reaction is carried out in the presence of a base. Manufacturing method. 2. The hydroxyphenylacetic acid is 4-hydroxyphenylacetic acid and the oxocyclohexylacetic acid is 4.
-The method according to claim 1, which is oxocyclohexyl acetic acid. 3. An oxo produced by reacting hydroxyphenylacetic acid with hydrogen in the presence of a base and a hydrogenation catalyst in a water solvent in the production of hydroxyiminocyclohexylacetic acid by reacting oxocyclohexylacetic acid with hydroxylamine. A method for producing hydroxyiminocyclohexyl acetic acid, which comprises reacting cyclohexyl acetic acid with hydroxylamine. 4. The hydrogenation catalyst is removed from a reaction mixture containing oxocyclohexylacetic acid obtained by reacting hydroxyphenylacetic acid with hydrogen in a water solvent in the presence of a base and a hydrogenation catalyst to remove an acid salt of hydroxylamine. A method according to claim 3 additionally comprising reacting oxocyclohexyl acetic acid with hydroxylamine. 5. The hydroxyphenylacetic acid is 4-hydroxyphenylacetic acid, and the oxocyclohexylacetic acid is 4.
-Oxocyclohexylacetic acid, and the hydroxyiminocyclohexylacetic acid is 4-hydroxyiminocyclohexylacetic acid.