JP2001122857A - Production of indole-3-carboxylic acids - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an economical production process for indole-3-carboxylic acids from indole-3-aldehydes in no need of environmentally troublesome potassium permanganate or expensive silver oxide. SOLUTION: Indole-3-aldehydes are oxidized with molecular oxygen in the presence of an alkali metal hydroxide in an organic solvent to produce the objective indole-3-carboxylic acids.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing indole-3-carboxylic acids widely used as a raw material for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art Conventionally, as an industrial production method of indole-3-carboxylic acid, a method of oxidizing indole-3-aldehyde with potassium permanganate (G, L., Arm. Khim. Z
h., 29, 1062, (1976)) and a method of oxidizing indole-3-aldehyde with silver oxide or silver oxide and oxygen in an aqueous alkali solution (Japanese Patent Application Laid-Open No. 1-96168).
Etc. are known. The former method has environmental problems in that potassium permanganate is used as an oxidizing agent and manganese dioxide is produced as a by-product, so that special handling and treatment are required, and the yield is 65%. % Is not satisfactory.

Although the latter method using silver oxide is a relatively good method, the initial cost is high because a large amount of expensive silver oxide is used, and foaming is severe when oxygen is blown, thereby increasing the substrate concentration. However, there were problems such as poor productivity, high cost of silver oxide regeneration, and the like, and it was not always a satisfactory method.

[0004] For this reason, the present inventors have previously proposed a method of using hydrogen peroxide instead of blowing oxygen (JP-A-11-180953) as an improvement method of the latter. According to this proposal, there is a great advantage that the amount of silver oxide used can be reduced to about 1/2, but the problem of silver oxide regeneration has not been solved yet.

[0005]

SUMMARY OF THE INVENTION Accordingly, the present inventors
Oxidation of indole-3-aldehydes to indole-
In producing 3-carboxylic acids, investigations were made to find a new oxidation method that does not have the drawbacks of these conventional methods. As a result, they have found that the method described below can produce the desired product without these disadvantages and at low cost, and have reached the present invention. Accordingly, an object of the present invention is to provide a novel industrially useful method for producing indole-3-carboxylic acids.

[0006]

That is, the present invention provides an indole-3-aldehyde which is oxidized with molecular oxygen in the presence of an alkali metal hydroxide in an organic solvent. This is a method for producing carboxylic acids. According to the present invention, indole-3-carboxylic acids can be produced cleanly and inexpensively without using potassium permanganate, which is an environmental problem, and without using expensive silver oxide. .

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Indole used in the present invention
The 3-aldehydes are indole-3-aldehydes represented by the following general formula (1) and homologs thereof.

[0008]

Embedded image (In the formula, R ₁ , R ₂ , and R ₃ are each hydrogen, and have 1 to 1 carbon atoms.
4 alkyl groups, halogens such as chlorine, bromine and iodine, and acyl groups having 1 to 4 carbon atoms. )

More specifically, in addition to indole-3-aldehyde, N-methylindole-3-aldehyde,
Representative examples include N-alkyl-substituted products such as N-ethylindole-3-aldehyde and nuclear alkyl-substituted products such as 5-methylindole-3-aldehyde. Such indole-3-aldehydes can be easily synthesized by a known method, or may be synthesized by any method. For example, by reacting indole with phosphorus oxychloride and dimethylformamide, indole-3 can be obtained in high yield.
Aldehydes can be obtained (Org. Syn. 39 , 3
0). In addition, by reacting similarly from N-methylindole, almost quantitatively N-methylindole-
3-aldehyde can be obtained.

The organic solvent used in the present invention is not particularly limited as long as it is not an acidic solvent which reacts with an alkali metal hydroxide, but a relatively high boiling hydrocarbon such as xylene, methylnaphthalene or methylbiphenyl. , Quinoline, heterocyclic aromatic compounds such as isoquinoline,
It is desirable to use an aprotic polar solvent such as dimethylformamide or dimethylsulfoxide.
The amount of the organic solvent used is determined based on the flowability of the raw material indole-3-aldehydes, the alkali metal hydroxide and the product indole-3-carboxylic acid, based on the total weight of the raw materials and the alkali metal hydroxide. , 2 to 20 times by weight.

The alkali metal hydroxide used in the present invention includes potassium hydroxide, sodium hydroxide, lithium hydroxide and the like, but is not particularly limited, but potassium hydroxide, sodium hydroxide, or Mixtures of these are desirable. There is no particular limitation on the shape and size of these alkali metal hydroxides, and flake products that are generally available can be used as they are. Further, in order to improve dispersibility, it is also possible to use by pulverizing in advance.

The amount of the alkali metal hydroxide used is preferably in the range of 1 to 20 mol, particularly 2 to 10 mol, per mol of the raw material indole-3-aldehyde. That is, if the amount used is too small, the conversion rate of the starting aldehyde becomes low, and the yield decreases. Also, if the amount used is excessive, there is no longer any effect on the yield improvement, and there is no economic advantage.

In the present invention, molecular oxygen is used as an oxidizing agent. If it contains molecular oxygen, not only pure oxygen but also air and combustion waste gas can be used. It is also possible to use oxygen generated by dropping hydrogen peroxide. Usually, it is preferable to use inexpensive and easily available air.

The reaction of the present invention is carried out by reacting an organic solvent with indole-
This is carried out by dispersing an alkali metal hydroxide in a mixture of 3-aldehydes and introducing molecular oxygen into the mixture. The reactor is not particularly limited as long as the raw material indole-3-aldehydes, alkali metal hydroxide and molecular oxygen can be sufficiently mixed, and for example, a stirring tank or a bubble column can be used. Also, as the reaction format,
Any system such as a batch system, a semi-batch system, and a continuous system may be employed.

The reaction temperature is 60 to 250 ° C., preferably 8
The range is from 0 to 200 ° C. If the temperature is lower than 60 ° C., the reaction rate is extremely low, which is not industrial. Also 25
If the temperature exceeds 0 ° C., the formation of heavy by-products becomes remarkable, and the yield decreases, which is not preferable. The reaction pressure is not particularly limited, and may be any pressure that keeps the organic solvent in a liquid state.

The reaction time varies depending on the type and amount of the solvent and the alkali metal hydroxide used, the reaction temperature, the reaction pressure and the like, but is usually in the range of 1 to 30 hours.

There is no particular limitation on the method of recovering the target substance after the completion of the oxidation reaction, and the method may be appropriately selected from methods such as concentration, filtration, extraction and the like depending on the physical properties of the target substance to be obtained. However, after the oxidation reaction, the indole-3-carboxylic acid, which is the target product, forms an alkali metal salt, and may be collected by neutralizing with an acid if necessary. The used organic solvent can be recovered by distillation if necessary and used repeatedly.

[0018]

The present invention will be described below in detail with reference to examples.

Example 1 In a 200 ml flask, 7.25 g (0.05 mol) of indole-3-aldehyde,
After charging 23.6 g (0.40 mol) of 95% potassium hydroxide and 75 g of xylene, the mixture was heated to 120 ° C. with stirring,
Air was blown at 35 ml / min for 4 hours. After the completion of the reaction, 50 ml of water was added to dissolve the reaction product, followed by liquid separation. Hydrochloric acid was added to the obtained aqueous layer to adjust the pH to 4.5. The precipitated cake was collected by filtration, rinsed with water and dried to obtain 7.4 g of indole-3-carboxylic acid. The purity of the obtained indole-3-carboxylic acid is 94.4.
%, And the yield was 83.8 mol%.

Example 2 The same operation as in Example 1 was performed, except that the solvent was changed from xylene to methylnaphthalene. The purity of the recovered indole-3-carboxylic acid is 9
6.8% and the yield was 85.3 mol%.

Example 3 In Example 2, indole-3-aldehyde was replaced with an equimolar amount of N-methylindole-
The same operation as in Example 2 was performed except for changing to 3-aldehyde. The purity of N-methylindole-3-carboxylic acid was 90.9%, and the yield was 83.3 mol%.

Comparative Example 1 The reaction was carried out in the same manner as in Example 1 except that potassium hydroxide was changed to an equimolar amount of potassium carbonate, but no desired product was obtained.

Comparative Example 2 The same operation as in Example 1 was carried out except that water was used instead of xylene as the solvent in Example 1, and the reaction temperature was changed to 80 ° C., but the desired product was obtained at all. Did not.

[0024]

According to the present invention, it is possible to produce indole-3-carboxylic acids at low cost without using an oxidizing agent which causes environmental problems and without using expensive silver oxide. Can be.

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[Procedure amendment]

[Submission date] October 27, 1999 (1999.10.
27)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Name of invention

[Correction method] Change

[Correction contents]

Method for producing indole over 3-carboxylic acid compounds [Title of the Invention]

Claims (1)

[Claims] 1. A method for producing indole-3-carboxylic acids, comprising oxidizing indole-3-aldehydes with molecular oxygen in an organic solvent in the presence of an alkali metal hydroxide.