JPS61151170A - Indole purification method - Google Patents

Abstract

PURPOSE:Crude indole is brought into contact with a solvent by liquid-liquid contact or solid-liquid contact to extract indole, purified indole crystal is precipitated and separated from the prepared indole solution, and the remaining solution is repeatedly used as an extraction solvent. CONSTITUTION:In purifying crude indole by recrystallization method, the crude indole is subjected to liquid-liquid or solid-liquid contact with a paraffinic solvent such as hexane, heptane, etc., or naphthenic solvent such as cyclohexane, methylcyclohexane, etc., at 40-70 deg.C to extract indole, an indole solution is obtained by separation method, precipitation method, etc., and purified indole crystal is precipitated from the solution by cooling method, concentration method, etc. The solution from which the crystal is separated dissolves indole in saturated solubility and it is used as an extraction solvent so almost all of crude indole to be extracted in the following time can be precipitated as crystal.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to a method for purifying indole.

(Prior art and its problems) Indole is a compound that has been known for a long time and has a melting point of 53° C. and forms white scale-like crystals, and has been traditionally used as a raw material for the synthesis of tryptophan, which is one of the essential amino acids, and as a flavoring material. In particular, since tryptophan has recently been attracting attention as a "third amino acid," inexpensive mass production methods for the raw material indole are attracting attention and being studied.

The present inventors investigated a method for separating and purifying refined indole from a reaction product in a method for producing indole by subjecting aniline and ethylene glycol to a gas phase contact reaction in the presence of a catalyst. The reaction product contained by-reactants in addition to the excess aniline and the target product indole, and the commonly known lid method was used as the first-stage separation method. The batch was closed under reduced pressure, but the indole part contained many types of side-reactants with boiling points close to each other, albeit in small quantities.
However, it was not possible to obtain a high-purity product with a purity of 9 cm or higher. Therefore, a recrystallization method was adopted as the second-stage separation method. When selecting a solvent for recrystallization, we used the solubility of indole in the solvent as a criterion, and investigated using a single or mixed solvent with a solubility of 5% by weight or less at room temperature, and found that it was a side reaction product. Despite the fact that indole derivatives have a good solubility in these solvents, they show affinity for indole crystals with similar properties when precipitating indole crystals, and the expected purification value cannot be obtained even after washing the adhering liquid. It was found that this impedes the improvement of purity.

A prior art similar to the above can be found in JP-A No. 57-134462, but in this invention, methyl indoles are cited as purity improvement inhibitors, and the content of methyl indoles is reduced to 4% by weight or less before recrystallization. Discloses that there is a need.

(Means for Solving the Problems) Under such circumstances, the present inventors have completed the present invention as a result of intensive study on a recrystallization method that has a wider range of applications and has a good indole recovery rate. .

That is, the present invention provides: 1) When crude indole is purified by a recrystallization method, indole is extracted by bringing the crude indole into liquid or solid-liquid contact with a solvent, the obtained indole solution is separated, and then the indole is purified by a recrystallization method. 2) A method for purifying indole, characterized by precipitating and separating sheath indole crystals from a solution; and 2) a method for purifying indole, characterized by repeatedly using a liquid from which purified indole crystals are separated as a crude indole extraction solvent. .

The crude indole referred to in the present invention does not need to be particularly limited in its production method, and may be anything that contains an indole derivative as an impurity and has indole as its main component, such as a synthetic reaction solution, an indole reservoir in the lid, or an extraction. There are extracts whose main component is indole separated by the method.

The concentration of indole in the crude indole referred to in the present invention is 60 to 99% by weight, preferably 80 to 98% by weight, and the concentration of the indole derivative contained is 20% by weight or less, preferably 10% by weight or less.

Regarding the solvent used in the method of the present invention, the solubility of indole in the solvent is 5% by weight at room temperature, considering the recovery rate (yield) in recrystallization and the washing process of separated crystals, which is a usual method in the recrystallization method. It is preferable to select from the following: Looking at the solubility of indole in a single solvent, preferable conditions for the above conditions include paraffinic solvents such as hexane, heptane, and octane, and naphthenic solvents such as cyclohexane and methylcyclohexane. It can be used because it meets the above conditions. On the other hand, aromatic solvents such as benzene and toluene,
Alcohols such as methanol, ethanol and isopropyl alcohol, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, and ethyl ether
1. Ethers such as 4-dioxane and tetrahydrofuran have a large solubility in indole and are not suitable for use alone, but alcohols, ketones, and ethers that are compatible with water, which only slightly dissolve indole, By selecting and selecting the mixing ratio, it is possible to obtain an indole solubility preferable for the present invention in a mixed system with water, and it can be used. The boundary conditions for bringing the crude indole into liquid or solid-liquid contact with the solvent include, for example, the melting point of indole is 53°C in terms of temperature, but the melting point may drop in the coexistence of a solvent, so the temperature should be adjusted. At the boundary, indole changes from solid to liquid, and the melting point depression becomes even greater depending on the impurity concentration of the crude indole, and a boundary condition may be reached at a temperature of 15° C. or more below the melting point.

The ratio of crude indole and solvent used in the method of the present invention is such that at the temperature when the crude indole and solvent are brought into liquid-liquid or solid-liquid contact, an amount of crude indole equal to or greater than the amount of indole to be extracted into the solvent is prepared in advance. Generally, the crude indole excess is 5% by weight or more, preferably 10% by weight or more. In this way, by charging crude indole in an amount greater than the extraction amount and leaving a portion of it as a solid or liquid, it is possible to leave an indole derivative in the indole that has a stronger affinity than the solvent, and it is possible to dissolve the crude indole in the solvent. The concentration of the dissolved indole derivative in the solvent can be kept low compared to the above, which is advantageous when separating refined indole by precipitation. Furthermore, when the filtrate from which refined indole is precipitated and separated is repeatedly used as an extraction solvent for crude indole, it also functions to control the impurity concentration in the repeatedly used solvent due to equilibrium due to the distribution ratio of the indole derivative between the crude indole phase and the solvent phase. It will be advantageous for Ashi. Because indole derivatives accumulate in the crude indole phase after extraction, it is necessary to extract some or all of it and purify it, but industrially, indole purification processes such as lid parts are usually performed before and after the recrystallization process. Therefore, by returning it to that process, economical purification can be performed.

The temperature at which the crude indole and the solvent are brought into liquid or solid-liquid contact in the method of the present invention is usually 40 to 70°C, and after bringing the crude indole and the solvent into liquid or solid-liquid contact, the crude indole phase As a method for separating indole from the solvent phase extracted, it is usual to use a filtration method or a precipitation method in the case of solid-liquid contact, and a liquid separation method in the case of liquid-liquid contact.

Methods for precipitating refined indole crystals from the indole solution extracted by the method of the present invention include the usual cooling method, concentration method, etc., but the cooling method is preferable in order to suppress contamination with impurities. In addition, a filtration method is usually used to separate the precipitated fine indole crystals, but the fine indole crystals have a scaly shape and a high liquid content, and the liquid filtration is difficult due to clogging with the crystals. It is easy to cause defects, and even if the crystals are washed after separation, it is difficult to obtain a sufficient effect, so consideration must be given to the operation.

In the present invention, the above-mentioned separated solution of refined indole crystals can be repeatedly used as an extraction solvent from crude indole, but since indole is dissolved in the separated solution at a saturation solubility under the conditions for precipitation of refined indole crystals, the next extraction will be Since most of it can be precipitated as crystals, it is very advantageous in terms of recovery rate (yield).

(Example) Hereinafter, the present invention will be specifically explained with reference to Examples.

In addition, in the following examples, all "chi" and "part" are based on weight. Indole and impurities were analyzed by gas chromatography.

Reference Example An indole synthesis reaction solution obtained by subjecting aniline and ethylene glycol to a gas phase contact reaction in the presence of a known catalyst was used. In addition, the indole lid of the synthetic solution has a theoretical plate number of 19.
The experiment was carried out using a batch-type lid tower with multiple stages under the following conditions.

Aniline distillation tank: Top pressure: 9 to 12 Hg Top temperature: 6
1-74℃ Reflux ratio 0.2 Indole distillation tank: Top pressure 7-1101nrILH
Column top temperature 124-136°C Reflux ratio 4.0 Example 1 Indole distillation tank (
Crude indole) was recrystallized from n-hexane in the following manner. The analytical values of the crude indole used and the purified indole obtained by recrystallization are summarized in Table 1.

(Experiment 1) When 25 parts of crude indole and 200 parts of n-hexane were mixed in 500 Erlenmeyer flasks and heated in a water bath at 40°C, part of the crude indole became liquid and a state of two-liquid separation occurred. . The n-hexane layer was transferred to another container by decantation, allowed to cool to room temperature, and then cooled to 5° C., and the precipitated crystals were filtered. The crystals were washed twice using 20 parts of n-hexane cooled to 5 DEG C., and dried by leaving them in a desiccator overnight at room temperature under reduced pressure. In addition, n
- After separating the hexane layer by decantation, the crude indole remaining in the Erlenmeyer flask was repeatedly used in Experiments 2 to 5 below.

(Experiments 2 to 5) Washing liquid was added to the filtrate obtained by filtering refined indole to make 200 parts, and 20 parts of crude indole was added to this and heated in a 40°C water bath as in Experiment 1 while mixing.
A fine indole crystal was obtained by repeating the same method. Experiment 5
After the completion of the reaction, the crude indole remaining in the Erlenmeyer flask was analyzed and the purity of the indole was 86%.

Example 2 Recrystallization from methylcyclohexane was performed using the same crude indole used in Example 1 in the following manner. The results are summarized in Table 2.

(Experiment 6) When 25 parts of crude indole and 200 parts of methylcyclohexane were mixed in a SOOMG Erlenmeyer flask and heated in a water bath at 60°C, a part of the crude indole became liquid, resulting in a two-liquid separation state. Transfer the methylcyclohexane layer to another container by decantation and leave to cool to room temperature.
It was cooled to ℃ and the precipitated crystals were filtered. The crystals were washed twice using 20 parts of methylcyclohexane cooled to 1 DEG C., and dried by leaving them in a desiccator overnight at room temperature under reduced pressure. Incidentally, after separating the methylcyclohexane layer by decantation, the crude indole remaining in the Erlenmeyer flask was repeatedly used in experiments 7 to 1 below.

(Experiments 7 to 10) Washing liquid was added to the filtrate obtained by filtering refined indole to make 200 parts, and 20 parts of crude indole was added to this and heated in a water bath at 30°C as in Experiment 6 while mixing.
A fine indole crystal was obtained by repeating the same method. Experiment 1
When the crude indole remaining in the Erlenmeyer flask was analyzed after the completion of the reaction, the purity of indole was 81%. This confirmed that impurities were concentrated in the crude indole layer during decantation.

Example 3 25 parts of the same crude indole used in Example 1 and 200 parts of an aqueous ethanol solution were mixed in a 500 mJ Erlenmeyer flask and heated in a water bath at 45°C. Part of the crude indole became liquid and 200 parts of the ethanol aqueous solution was mixed. A state of liquid separation has occurred. The ethanol aqueous solution layer was transferred to another container by decantation, allowed to cool to room temperature, and then cooled to 5° C., and the precipitated crystals were filtered.

To wash the crystals, use 20 parts each of an aqueous ethanol solution cooled to 5°C twice, and dry them at room temperature in a desiccator.
The mixture was left to stand under reduced pressure overnight. By the way, #1. The ethanol aqueous solution contained 35% ethanol. The purity of the obtained fine indole crystals was 994%.

Example 4 Using the same crude indole as used in Example 1, recrystallization from methylcyclohexane was performed in the following manner. The results are summarized in Table 6.

(Experiment 11) 500ml of 18 parts of crude indole and 200 parts of methylcyclohexane! When the mixture was mixed in an Erlenmeyer flask and heated in a water bath at 30°C, the crude indole was completely dissolved to form a homogeneous solution. This solution was left to cool to room temperature and then cooled to 1° C., and the precipitated crystals were filtered. Cleaning of crystals at 1℃
20 parts each of methylcyclohexane that had been cooled to
It was used twice and dried by leaving it in a desiccator at room temperature under reduced pressure overnight.

(Experiments 12 to 15) Washing liquid was added to the filtrate obtained by filtering refined indole to make 200 parts, and 18 parts of crude indole was added to this and heated in a water bath at 60°C as in Experiment 6 while mixing. A method similar to Experiment 6 was repeated to obtain fine indole crystals.

(Effect of the invention) By carrying out the method of the present invention, it becomes possible to easily separate the indole derivative in the side reaction product, which was difficult to separate in the past, to a higher concentration. It is useful in the technical field to which the present invention pertains, not only because it can contribute to energy saving in the process, but also because the recrystallization solvent can be used repeatedly, resulting in energy savings and improved recovery rate (yield). It's a method.

Claims (1)

[Claims] 1) When crude indole is purified by a recrystallization method, indole is extracted by bringing the crude indole into liquid or solid-liquid contact with a solvent, and after separating the obtained indole solution, A method for purifying indole, which is characterized by precipitating and separating refined indole crystals from a solution. 2) The method according to claim 1, wherein the crude indole extraction solvent is a liquid obtained by separating precipitated refined indole crystals.