JPS6312869B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing indole-3-acetic acid. More specifically, it relates to a method for producing indole-3-acetic acid, which is itself a plant growth regulating substance and is useful as a raw material for various agricultural chemicals and pharmaceuticals, in one step from inexpensive and easily available raw materials. be.

Various methods have been known to produce indole-3-acetic acid, including (1) a method in which indole is used as a raw material and the desired side chain is bonded to the 3-position; (2) a method in which phenylhydrazine is used as a raw material; There are two main methods: one uses Fischer's indole synthesis method. Method (1) requires expensive raw materials;
The steps are complicated, and the method (2) generally has a low yield, making the reaction operation complicated. In addition, as method (2), phenylhydrazine is condensed with β-formylpropionate in the presence of a mineral acid in an aqueous solvent, and the ester is hydrolyzed at the same time as cyclization to obtain the compound ( (Japanese Patent Publication No. 44-32780), but β-formylpropionate is difficult to obtain industrially in large quantities, and is unstable in acidic aqueous solutions, resulting in the formation of various condensates during long-term storage. When this is formed and used to react with phenylhydrazine, it has the disadvantage that an oily substance is produced as a by-product, reducing the yield and purity of the desired indole-3-acetic acid.

Therefore, in order to eliminate such drawbacks, the present inventors
As a result of various studies, it is expressed by the following formula. 3,9-bis(2-carboxyethyl)-2,
4,8,10-tetraoxaspiro[5,5]undecane (hereinafter simply abbreviated as CATU) is industrially available, does not decompose at all even when stored in an acidic aqueous solution for a long time, and furthermore, CATU Although it is almost insoluble in water, it was discovered that it is easily hydrolyzed under certain conditions, leading to the completion of the present invention.

That is, the present invention uses phenylhydrazine and
This method is characterized by reacting CATU so that the reaction solution is always kept acidic, and is a method for producing indole-3-acetic acid with high purity and high yield in one step. The reaction is estimated to proceed according to the following equation.

In order to explain the method of the present invention in more detail, one embodiment thereof is shown. First, phenylhydrazine is dissolved in its strong acid salt or acidic aqueous solvent,
A solution of CATU dispersed in water or an acidic aqueous solvent is added to this, and this mixture is then reacted while being heated and stirred. When the reaction solution is cooled, the desired indole-3-acetic acid will crystallize. By collecting these crystals, washing them with water and drying them, a highly pure product can be obtained.

CATU used in the present invention is a compound that can be easily and inexpensively synthesized by spiroacetalizing β-cyanopropionaldehyde obtained by the oxo method of acrylonitrile with pentaerythritol and then hydrolyzing the cyano group. .

A solvent is used in carrying out the present invention, and generally water is the most suitable reaction solvent, but a mixture of hydrophilic polar solvents such as ethanol, propyl alcohol, and acetic acid may also be used. I can do it. When alcohols are mixed with water to be used as a reaction solvent, it is preferable to contain 30 vol% or more of water in order to prevent indole-3-acetic acid from being esterified.

The reaction is carried out by adding phenylhydrazine and a substance that keeps the reaction system acidic in a solvent, and heating at 75°C or
120°C, preferably at the reflux temperature of the solvent used,
CATU is suspended in the reaction solvent and added dropwise,
The process progresses easily by stirring at the same temperature for 0.5 to 8 hours.

Substances that keep the reaction system acidic include hydrochloric acid, sulfuric acid,
Inorganic acids such as phosphoric acid and polyphosphoric acid, organic acids such as p-toluenesulfonic acid and polystyrene sulfonic acid, or Lewis acids such as zinc chloride can be used; It can also be used as an acid salt. When using these strong acid salts of phenylhydrazine, the reaction system can be kept acidic even without adding acid, but it is generally preferable to add an excess of acid to phenylhydrazine.
In this case, it is desirable that the acid concentration in the reaction system be 2.0 normal or less; if a higher concentration of acid is used, the product will be unstable and decomposition will occur.

The amount of phenylhydrazine used in the present invention is
It is preferable to use at least twice the molar amount of CATU.
When the amount is less than this, a large amount of CATU decomposition products and condensates tend to be produced as by-products, and the reaction proceeds favorably even when a large excess of phenylhydrazine is used.

As mentioned above, while CATU is an extremely stable substance and easy to handle, it decomposes under certain conditions and undergoes cyclocondensation with phenylhydrazine, producing indole-3-acetic acid with high purity and high yield. The fact that it can be obtained at such a high rate can be said to be a completely new manufacturing method that has never been seen before.

Hereinafter, the present invention will be explained in detail with reference to Examples.

Example 1 Phenylhydrazine hydrochloride 5.78g (40mmole)
Dissolve CATU in 100ml of water by heating, and when it reaches 98℃ while stirring, add 3.04g (10mmole) of CATU to 50ml of water.
ml of the solution was added dropwise over 1 hour. After the dropwise addition was completed, the reaction was carried out at reflux temperature for 6 hours. Thereafter, the reaction solution was cooled with ice and crystallized to obtain 2.62 g of indole-3-acetic acid (theoretical yield: 74.7%) as a white powder crystal. The melting point of this product was 167-170°C.

Example 2 30ml of 1.0N sulfuric acid was diluted with 70ml of water, and 3.24g (30mmole) of phenylhydrazine was added and dissolved.
3.04 g of CATU (10
mmole) dispersed in 50 ml of 0.1N sulfuric acid aqueous solution was added dropwise over 1 hour. After the dropwise addition was completed, the mixture was heated under reflux for 4 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain 2.78 g of indole-3-acetic acid (theoretical yield: 79.3%).

Example 3 Phenylhydrazine hydrochloride 5.78g (40mmole)
was heated and dissolved in 100 ml of 0.1 N aqueous hydrochloric acid solution, and while refluxing, a solution of 3.04 g (10 mmole) of CATU dispersed in 100 ml of 0.1 N aqueous hydrochloric acid solution was added dropwise over 1.5 hours, and the mixture was allowed to react at reflux temperature for 3 hours. After the reaction is complete,
The same treatment as in Example 1 was carried out to obtain 2.94 g (theoretical yield: 83.8%) of indole-3-acetic acid.

Example 4 Phenylhydrazine hydrochloride 2.89g (20mmole)
When the reaction was carried out in the same manner as in Example 3, 1.87 g (theoretical yield: 57%) of indole-3-acetic acid was obtained.

Example 5 p-Toluenesulfonic acid monohydrate in 100 ml of water
Dissolve 6.31g and add 3.24g of phenylhydrazine to this.
g (30 mmole) was added, heated and stirred, and when the reflux temperature was reached, it was dispersed in 50 ml of water.
3.04 g (10 mmole) of CATU was added dropwise over 45 minutes.
After further refluxing for 6 hours, the mixture was crystallized under ice cooling to obtain 2.18 g of indole-3-acetic acid (theoretical yield: 62.2%).

Example 6 85 in place of p-toluenesulfonic acid in Example 5
The reaction was carried out in the same manner as in Example 5 except that 5.76 g of phosphoric acid with a concentration of 1.23 g of indole-3-acetic acid was used.
(Theoretical yield: 35%).

Example 7 Except for dropping a solution of 3.04 g (10 mmole) of CATU dispersed in 50 ml of n-propyl alcohol.
The reaction was carried out in the same manner as in Example 1. After the reaction is complete, the solvent is completely removed under reduced pressure, and the resulting solid residue is
50 ml of water was added to dissolve, and the mixture was crystallized under ice cooling to obtain 1.58 g of indole-3-acetic acid (theoretical yield: 45%).

Example 8 The reaction was carried out in the same manner as in Example 1, except that a solution of 6.08 g (20 mmole) of CATU dispersed in 50 ml of acetic acid was added dropwise. After the reaction was completed, the reaction solution was concentrated under reduced pressure to approximately 50 ml and crystallized, yielding 3.29 g of indole-3-acetic acid.
(Theoretical yield: 47%).

Claims (1)

[Claims] 1 3,9-bis(2-carboxyethyl)-2,
A method for producing indole-3-acetic acid, which comprises reacting 4,8,10-tetraoxaspiro[5,5]undecane and phenylhydrazine under acidic conditions.