JPS60228457A - Method of purification of 4-hydroxyindole - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a remedy for circulatory organs, etc. simply in high yield in high purity, by reacting a crude 4-hydroxyindole with a base to form a base, extracting it in water, hydrolyzing optionally with an acid, removing an impurity. CONSTITUTION:A 4-oxotetrahydroindole (4-OI for short) [e.g., compound shown by the formula I (R<1>-R<6> are H, or hydrocarbon residue) or compound shown by the formula II] is removed from a crude 4-hydroxyindole (4-HI for short) containing 4-OI as an impurity. In the operation, the crude 4-HI is reacted with a base (e.g., NaOH, KOH, etc.) to form a salt of 4-HI, etc., the salt extracted in water, and the salt is optionally hydrolyzed with an acid (e.g., HCl, H2SO4, etc.), so that 4-HI is purified.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to 4-hydroxyindoles (hereinafter referred to as 4-HI
It is written as (Prior art) 4- (Prior art) HI is known to be useful as a synthetic intermediate for the cardiovascular treatment drug "pindolol" and its analogs.

Conventionally, as a method for producing 4-HI, 4-OIt
- It is known to use intermediates and then oxidize them.

In this method, the crude 4-II obtained by the reaction contains a considerable amount of unreacted raw materials and by-products as impurities, and must be purified in the final step. Recrystallization methods, adsorption methods, and the like have been adopted as purification methods, but the yield in the purification step is only about 60% at most, and the yield decreases further when trying to increase the purity. A method has also been proposed in which purified j94-HI is obtained by distilling crude 4-HI under reduced pressure at a temperature of 100°C or higher and lower than the melting point of 4-OI (Japanese Patent Application Laid-open No. 13566/1982). In the case of this method, high yield and purity can be obtained if the distillation operation time is short (for example, within 30 minutes), but if the distillation operation time is extended (for example, tf 1 hour or more), the thermal deterioration of 4-HI occurs. However, it has been difficult to carry out the process on an industrial scale due to the disadvantages that the production of high-boiling compounds is significant and the yield is also significantly reduced.

(Problems to be Solved by the Invention) Therefore, the present inventors conducted intensive studies to eliminate such drawbacks of the conventional technology, and as a result, focused on the difference in chemical structure between 4-OI and 4-HI, and found that 4- ) It has been found that a method of extracting IIi salt in water is suitable, and the present invention has been completed.

(Means for Solving All Problems) Thus, according to the present invention, when removing 4-oxotetrahydroindole gold from crude 4-hydroxyindoles containing 4-oxotetrahydroindole as impurities, the crude 4-hydroxyindoles are A 4-hydroxyindole characterized by reacting an indole with a base to form a salt of 4-hydroxyindole, extracting several groups in water, and hydrolyzing several groups with an acid as necessary. Kinds of purification methods are provided.

The 4-HI crude product to be treated in the present invention has the main component of 4-HIi represented by the following general formula (1), and contains 4-HIi represented by the following general formula (II) as an impurity. It is.

[In the formula, R1, R2, R5, R4, R5 and R6 each represent a hydrogen atom or a hydrocarbon residue. ] The hydrocarbon group usually has carbon atoms of 20 or less, preferably 10 or less; specific examples thereof include methyl, ethyl, n-propyl, 1so-propyl, n-butylene, 1
Alkyl groups such as so-butyl, amyl, hexyl, heptyl, octyl, stearyl, cycloalkyl groups such as cyclopropyl, cyclopentyl, cyclohexyl, methylcyclohexyl, phenyl, tolyl, xylyl, p
Examples include aryl groups such as -methylphenyl, and aralkyl groups such as p-methyl and benzyl.

The base used in the present invention may be any base that can form a water-soluble salt of 4-HI, and specific examples thereof include:
Inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate,
Examples include amines such as ammonia, pyridine, triethylamine, and methyldiethylamine. Among these, it is advantageous to use alkali metal hydroxides or carbonates from the viewpoint of handling or economy.

The amount of base used can be selected as appropriate, but the amount of 4-HI in crude 4-HI
Usually 0.8 to 2 equivalents, preferably 1 to 1 equivalent to HI
．． There is no particular problem in using an excess of ash or base within the range of 5 equivalents, but it is meaningless.

In the present invention, a water-soluble salt is formed by reacting a crude 4-HI containing 4-OI'i with a base.

The procedure of this reaction is not particularly limited, and examples include a method of adding an aqueous solution of a base to a 4-HI crude product, a method of adding an aqueous solution of a base to a 4-H
A method of adding a base after dissolving or suspending the 4-HI crude product in water, a method of adding the 4-HI crude product to an aqueous solution of the base, etc. can be adopted.

The reaction conditions can be selected as appropriate, and the reaction temperature is usually
The temperature is 0 to 80°C, preferably 5 to 50°C, and the amount of water used is usually 2 to 10% of the 4-HI in the 4-HI crude product.
0 times by weight, preferably 4 to 25 times by weight.

By this treatment, 4-HI is extracted into water in the form of a water-soluble salt, and impurities that are insoluble in water and 4-OI with low solubility are efficiently removed. For example, separating the aqueous layer and solid molecules, F
After separation, water is distilled off to obtain highly pure 4-HI.
salt can be isolated.

Also, organic solvents with low solubility in water, such as Hough 1L
)-ol, n-amyl alcohol, 1ao-7-myl alcohol, n-hexanol, n-hetethanol, cyclohexanol, etc. to further improve impurity removal efficiency by extracting impurities into an organic solvent. be able to.

The salt extracted in water is hydrolyzed with acid as necessary, and 4
-It can also be recovered in HIO form. Specific examples of the acid used include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, butyric acid, propionic acid, and oxalic acid. There are no particular restrictions on the recovery of 4-HI; for example, 4-H precipitated by distilling off water, cooling, etc.
A method of separating IiF and a method of extraction using an organic solvent can be adopted.

(Effects of the Invention) Thus, according to the method of the present invention, highly purified 4-HI' can be obtained in a higher yield with simpler operations than in the conventional method.

The present invention will be explained in more detail with reference to Examples below. Note that parts and parts in the examples are based on the weight of the hook without any breaks.

Example 1 24.0 parts of 4-HI crude product (4-hydroxyindole 83.3q6.4-oxo-4,5,6,7-titrahydroindole 12.5%, other high-boiling impurities 4,
2%) was added with 100 parts of a 6% sodium hydroxide aqueous solution at room temperature, stirred for 1 hour, and left to stand for 30 minutes to extract the Na salt of 1-hydroxyindole into water. Next, insoluble matter was separated, and water was distilled off from the filtrate under reduced pressure. 50 parts of acetone was added to the residue after water was distilled off, and 1
After stirring between portions, the solid was filtered through a kW filter and washed with a small amount of a7ton, yielding 21.2 parts of a crystalline solid. As a result of elemental analysis and infrared absorption spectrum analysis, the crystal is 4-
It was confirmed that hydroxyindole was NatJ (NatJ).The yield based on the number of moles of 4-hydroxyindole in the crude 4-HI material was 91.1. 4-oxo-4,5,6,7-titra contained in the salt was suspended in tetrahydrofuran, several groups were extracted from the F side, and the p solution was analyzed by gas chromatography and high performance liquid phase chromatography. Hydroindole and other impurities were 0.2% and 0.1% or less, respectively. Example 2 4-HI 24.0 parts of crude H (4-hydroxyindole 82.9%, 4-oxo-4 , 5,6,7-titrahydroindole 12.1%, other high boiling point impurities 5,0
%) at room temperature, add 6% sodium hydroxide aqueous solution 10
0 part was added and stirred for 1 hour. Next, 50 parts of n-amyl alcohol was added, and after stirring for 30 minutes, the organic layer was allowed to stand still and separated. To the separated aqueous layer, another 50 parts of n-amyl alcohol was added and the same operation was performed to obtain sodium 4-hydroxyindole. The salts were extracted into water. A 10% aqueous solution of hydrochloric acid was added dropwise to about 100 parts of the aqueous solution obtained in this way at room temperature to hydrolyze the salt, and then 50 parts of the main fish were distilled off under reduced pressure, and further cooled to 5°C to crystallize. was precipitated.

Next, the crystals t-F were separated, and the crystals were washed with a small amount of water and dried to obtain 17.2 parts of crystals. This crystal was analyzed by elemental analysis and NMR, and was confirmed to be 4-hydroxyindole.

Its melting point was 97-99°C. The recovery rate of 4-hydroxyindole is 4-H! In the crude product, it was 86% based on 4-hydroxyindole.

Patent applicant: Zeon Corporation

Claims (1)

[Claims] 1. When removing 4-oxotetrahydroindole from crude 4-hydroxyindoles containing 4-oxotetrahydroindole as an impurity, the crude 4-oxotetrahydroindole
- After reacting hydroxyindoles with a base to form a salt of 4-hydroxyindoles, several groups are extracted into water, and if necessary, some groups are hydrolyzed with an acid. Hydroxyindoles purification method 0