JP5225525B2 - Method for producing an indole derivative containing no aromatic amine compound as an impurity - Google Patents

Description

Technical field to which the invention belongs

  The present invention relates to a method for decomposing and removing harmful aromatic amine compounds contained as by-products in the production of indole derivatives mainly used as intermediates for pharmaceuticals and synthetic dyes.

  As a method for synthesizing an indole derivative, a Fischer indole synthesis method using an aromatic hydrazine compound and a ketone compound as raw materials is used. This method is a very general synthesis method described in textbooks of organic chemistry. In this method, an aromatic hydrazone is formed by condensation of an aromatic hydrazine and an aldehyde or ketone, and a cyclization reaction is performed using a Lewis acid such as zinc chloride or a protonic acid catalyst such as sulfuric acid.

Problems to be solved by the invention

The aromatic hydrazine used as a raw material contains a slight amount of harmful aromatic amine compound, and this aromatic amine remains in the indole derivative product. For example, in the synthesis of a bentindol derivative, a raw material containing naphthylamine, which is a carcinogenic substance and a substance prohibited from the production of the Anhe Law, is used. In a general production-purification method, this naphthylamine remains in the bentindol derivative product. End up. In addition, in the synthesis of 7-methoxyindole derivatives, o-anisidine, which is a publicly announced material for the Anhe Law, will remain.
Naturally, it is not desirable that harmful substances are mixed in chemical products on the market, and even if the harmfulness is not a problem, it is always required to reduce the impurity content as much as possible. Therefore, development of a method for removing the remaining aromatic amine by some method has been desired.

Means for solving the problem

  As a result of intensive studies to solve such problems, the present inventors added sodium nitrite according to the amount of the aromatic amine compound contained in the reaction solution after the reaction of the indole derivative by the Fischer method. The present inventors have found a method of decomposing an aromatic amine compound into a harmless one by forming an aromatic amine with a diazo compound and then setting the temperature at which the diazo compound decomposes. According to this method, it is possible to produce an indole derivative product which does not contain an aromatic amine as an impurity by a method that is easy to industrialize without significantly changing the production process.

  In addition, for indole derivative products containing aromatic amine compounds as impurities produced by ordinary methods, this indole derivative is made into an acidic solution, and sodium nitrite is added according to the amount of the aromatic amine compound to add aromatic amine. The present inventors have found a method for decomposing an aromatic amine compound to be harmless by forming a diazo compound and then setting the temperature at which the diazo compound decomposes.

  The present invention is described in detail below. The synthesis of indole derivatives by the Fischer indole synthesis method is performed under acidic conditions using various solvents such as water, alcohol, ether, ketone, and adding mineral acid or Lewis acid.

  After the indole synthesis reaction, the content of the aromatic amine compound to be decomposed and removed present in the reaction solution is determined.

  The temperature of the reaction solution is adjusted in the range of −20 ° C. to 20 ° C., preferably 0 ° C. to 5 ° C. 1-10 times equivalent with respect to the aromatic amine compound of decomposition | disassembly object here, Preferably 1-2 times equivalent sodium nitrite is dripped as aqueous solution. After completion of the dropwise addition, the temperature of the solution is raised to a temperature at which the diazo compound decomposes, specifically 20 ° C to 50 ° C. By the above operation, the aromatic amine compound is once diazotized and then denitrogenated and decomposed by heating to convert it into a harmless compound.

  The solution after passing through the diazotization to decomposition steps is subjected to an ordinary treatment method and the target indole compound is taken out.

  When the impurity aromatic amine compound contained in the indole derivative taken out as crystals is decomposed and removed, the following treatment is performed.

  The content of the aromatic amine compound which is present in the indole derivative and which is desired to be decomposed and removed is determined.

  The indole derivative is dissolved in water or an alcohol derivative to which a mineral acid or an organic acid is added to form an acid solution, and the liquid temperature is adjusted in the range of -20 ° C to 20 ° C, preferably 0 ° C to 5 ° C. 1-10 times equivalent with respect to the aromatic amine compound of decomposition | disassembly object here, Preferably 1-2 times equivalent sodium nitrite is dripped as aqueous solution. After completion of the dropwise addition, the temperature of the solution is raised to a temperature at which the diazo compound decomposes, specifically 20 ° C to 50 ° C. By the above operation, the aromatic amine compound is once diazotized and then denitrogenated and decomposed by heating to convert it into a harmless compound.

  From the solution after the diazotization to decomposition step, the desired indole derivative is taken out by a general method such as concentration or extraction after neutralization.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

[Example 1]
Synthesis of 1,1,2-trimethyl-benz [e] indolenine
According to the method described in Chemishe Berichte Vol.38 p266-, 2-naphthylhydrazine was synthesized from 2-hydroxy-1-naphthoic acid and hydrazine hydrate. The 2-naphthylhydrazine synthesized by this method was confirmed to contain 2.4% by weight of 2-naphthylamine by gas chromatography / internal standard determination.

  To 840 ml of ethanol, 108 g of 2-naphthylhydrazine containing 2-naphthylamine, 92 g of methyl isopropyl ketone, 69 g of 35% hydrochloric acid and 92 g of concentrated sulfuric acid were added, and refluxed for 2 hours. Here, when 2-naphthylamine in the reaction solution was quantified, the presence of 0.9 g was confirmed. Next, ethanol was distilled off under reduced pressure, and 500 ml of water was added. This aqueous solution was cooled to 0 ° C., and a solution obtained by dissolving 0.9 g of sodium nitrite (2 times equivalent to 2-naphthylamine content in the reaction solution) in 2 ml of water was added dropwise. After completion of the dropwise addition, the solution was returned to room temperature, and an aqueous sodium hydroxide solution was added to adjust pH = 9. Thereafter, extraction was performed using 750 ml of ethyl acetate, and the ethyl acetate solution was concentrated under reduced pressure to obtain 80 g of the desired 1,1,2-trimethyl-benz [e] indolenine.

  In the gas chromatographic analysis of 1,1,2-trimethyl-benz [e] indolenine obtained by this method, 2-naphthylamine was not detected.

[Target Example 1]
The same raw materials as in Example 1 were used, and the synthesis was performed under the same conditions except that no sodium nitrite aqueous solution was added. As a result, 80 g of 1,1,2-trimethyl-benz [e] indolenine was obtained. As a result of quantitative analysis by gas chromatography of 1,1,2-trimethyl-benz [e] indolenine obtained by this method, 1% by weight of 2-naphthylamine was contained.

[Example 2]
500 ml of water and 27.5 g of 35% hydrochloric acid were added to 50 g of 1,1,2-trimethyl-benz [e] indolenine containing 1% by weight of 2-naphthylamine obtained in Target Example 1 to obtain an acidic aqueous solution. . This aqueous solution was cooled to 0 ° C., and a solution obtained by dissolving 0.5 g of sodium nitrite (2 times equivalent to 2-naphthylamine content) in 2 ml of water was added dropwise. After completion of the dropwise addition, the solution was returned to room temperature, and an aqueous sodium hydroxide solution was added to adjust pH = 9. Thereafter, extraction was performed using 500 ml of ethyl acetate, and the ethyl acetate solution was concentrated under reduced pressure to obtain 48 g of the desired 1,1,2-trimethyl-benz [e] indolenine.

  In the gas chromatographic analysis of 1,1,2-trimethyl-benz [e] indolenine obtained by this method, 2-naphthylamine was not detected.

Effect of the invention

  As described above, an indole derivative in which an aromatic amine compound remains as an impurity is obtained as a product in a normal production method, whereas an indole derivative that does not contain an aromatic amine compound as an impurity is industrialized by the method of the present invention. It can be manufactured by suitable means.

Claims (4)

Sodium nitrite is added to the reaction solution after synthesis of the indole derivative in which the aromatic amine compound remains to form the aromatic amine compound as a diazonium salt, and the solution is heated to 20 ° C. to 50 ° C., which is the temperature at which the diazo compound decomposes. A method for decomposing and removing the aromatic amine compound by raising the temperature, wherein the temperature of the solution to which sodium nitrite is added is -20 ° C to 20 ° C.
A temperature at which an indole derivative in which an aromatic amine compound remains is dissolved in a solvent to which a mineral acid or an organic acid is added, sodium nitrite is added to form the aromatic amine compound as a diazonium salt, and the diazo compound decomposes the solution. A method of decomposing and removing the aromatic amine compound by raising the temperature to 20 ° C. to 50 ° C., wherein the temperature of the solution to which sodium nitrite is added is −20 ° C. to 20 ° C.
The method according to claim 1 or 2, wherein the aromatic amine compound is a harmful compound having mutagenicity or carcinogenicity.
Indole derivatives, 1,1,2-trimethyl - Benz [e] The method according to any one of claims 1 to 3 which is indolenine.