JPH09169725A - Production of 4-hydroxyindole - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain 4-hydroxyindole which is useful as a synthetic raw material for an antiarrhythmic drug from readily available raw materials without using any expensive chemical reactor. SOLUTION: The addition reaction of formaldehyde or its polymer to 2,6- dinitrotoluene is carried out at -20 to +100 deg.C in a solvent in the presence of a basic catalyst to form 2-(2,6-dinitrophenyl)ethanol nonelectrolytically. Then, the reaction mixture is, without purification, mixed with an amine to deactivate unreacting formaldehyde or the like, subjected to reductive treatment to give 2-(2,6-diaminophenyl)ethanol. This product is heat-treated in the presence of an acid catalyst and the product, 4-hydroxy-2,3-dihydroxyindole is further dehydrogeneted to give the objective 4-hydroxyindole.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 4-hydroxyindole (hereinafter abbreviated as 4-HI). 4-HI is useful as a raw material for the synthesis of pindolol and other 4-substituted indole drugs, which are widely used as antiarrhythmic agents and antihypertensive agents.

[0002]

2. Description of the Related Art 4-HI is currently cyclohexane-1,3
It has been synthesized from 4-dione by dehydrogenation of 4-oxo-4,5,6,7-tetrahydroindole [JP-A-54-19
971 publication, JP-A-60-146870 publication, JP-A-4-2082
62, J. Org. Chem., 36, 1232 (1971), etc.], but this method has problems that the intermediate is extremely unstable and that the yield is low.

Regarding the synthesis of 4-HI, 4-aminoindole (hereinafter abbreviated as 4-AI) is also used in the literature.
[Chem. Pharm. Bull., 29 , 3145 (1981), JP-A-63-216861], hydrogenation of 2-cyanomethyl-3-alkoxynitrobenzene (JP-A-55-76859, JP A large number of methods such as hydrogenation of 2-nitro-6-substituted methoxy-β-dialkylaminostyrene (JP-A-57-99568) have been investigated. However, all of these methods have problems that it is difficult to obtain (or synthesize) the starting material and the yield of the target product is low.

Tanaka et al., Bull. Chem. Soc. Jpn., 62, 374.
2 (1989), 2,6-dinitrotoluene (hereinafter, 2,6-
Paraformaldehyde was added to DNT) under electrolysis conditions to produce 2- (2,6-dinitrophenyl) ethanol (hereinafter abbreviated as DNE), which was isolated and purified, and then in the presence of Raney nickel. It is reduced to induce 2- (2,6-diaminophenyl) ethanol (hereinafter abbreviated as DAE), and then this DAE is treated with 70% phosphoric acid at 220 ° C. for one-stage acid treatment or 30% sulfuric acid. After heating in water to 170 ° C., the resulting intermediate product (4-aminoindoline = 4
-Amino-2,3-dihydroindole, below 4-A
(Abbreviated as DI) is heated to 220 ° C in 30% phosphoric acid 2
4-hydroxyindoline (alias: 4
-Hydroxy-2,3-dihydroindole) (hereinafter 4-
HDI) is generated and 4-HDI is dehydrogenated to obtain 4-HI. Japanese Patent Application Laid-Open No. 1-168667 by the same inventor (author) also discloses 2,6-DNT.
A similar procedure as above for the syntheses from to HDI is briefly described, omitting the reaction conditions.

However, this method requires an electrolytic equipment for the addition reaction of paraformaldehyde, which makes the equipment complicated and expensive, and unreacted paraformaldehyde participates in the reaction in the subsequent step and lowers the yield. Therefore, there is a problem that the yield of the final target product is remarkably low and an isolation and purification step is required. Furthermore, the DN generated after the end of the first step
Separating and purifying E from 2,6-DNT is particularly
Since 2,6-DNT is a highly explosive compound, it is economically unfavorable in terms of safety problems and complicated operation.

[0006]

SUMMARY OF THE INVENTION The object of the present invention is to provide a raw material which can be easily obtained or synthesized without using expensive reaction equipment such as electrolysis equipment, and can be safely and simply produced with high yield. It is to provide a method for producing HI. Specifically, it is to achieve the above object by using 2,6-DNT as a raw material.

[0007]

The present inventors have found that 2,6-D
Focusing on the fact that NT is readily available as a commercial product, the inventors have made earnest studies to achieve the above object by using this as a raw material. As a result, in the presence of a basic catalyst, formaldehyde (or its polymer) can be effectively added chemically to 2,6-DNT under certain reaction conditions (ie, non-electrolytically). It is possible to synthesize DNE in a high yield, and even if the reaction solution is directly subjected to reduction treatment without separating DNE from this reaction solution, if unreacted formaldehyde is inactivated by addition of an amine before reduction, the reduction product Two
-(2,6-diaminophenyl) ethanol (DAE) can be obtained in a high yield, and DAE can be obtained via DNE in good yield with a safe and simple operation, which is described in the above-mentioned paper by Tanaka et al. In the same manner as in the method, by inducing 4-HDI by one-step or two-step acid treatment and then dehydrogenating,
The inventors have reached the present invention by knowing that the desired 4-HI can be obtained in high yield.

Thus, the method of the present invention comprises the following steps (a)
To 4- (d) 4-hydroxyindole (4-HI)
It is a manufacturing method of. (a) Formaldehyde or a polymer thereof is subjected to an addition reaction with 2,6-dinitrotoluene in a solvent in the presence of a basic catalyst at a reaction temperature of −20 ° C. to + 100 ° C. to non-electrolytically react with 2-6-dinitrotoluene.
Step of generating (2,6-dinitrophenyl) ethanol (DNE), (b) Unreacted by adding amine to the reaction solution obtained in step (a) without isolation of unreacted products or products. After inactivating the formaldehyde or its polymer, the reaction solution is subjected to reduction treatment to give 2- (2,6-diaminophenyl) ethanol (DA
E), (c) heat treating the product of step (b) in the presence of an acid catalyst to give 4-hydroxy-2,3-dihydroindole (4-HD
I), a step of (d) dehydrogenating the product of step (c) to give 4-hydroxyindole (4-HI).

In a preferred embodiment, in step (a),
The basic catalyst is a quaternary ammonium hydroxide compound,
Formaldehyde or its polymer is added to 2,6-dinitrotoluene in a molar ratio of 0.5 to
Use 2.0 times the amount. The product of step (b) is preferably separated from the reaction mixture by distillation and then subjected to step (c).

The step (c) uses phosphoric acid as an acid catalyst,
When the heating temperature is 100 to 250 ° C., 4-HDI can be produced from DAE by one-step acid treatment. Alternatively, step (c) can be carried out by a two-step acid treatment as follows. (c-1) The product of step (b) is heat treated in the presence of an acid catalyst to give 4-amino-2,3-dihydroindole (4-AD
I) is produced, and (c-2) this product is preferably separated by distillation and then heat treated in the presence of an acid catalyst to obtain 4
-Generate HDI. In the case of this two-step acid treatment, (c-
The heating temperature in 1) is preferably 80 to 200 ° C., and the acid treatment conditions in (c-2) are preferably the same as the one-step acid treatment.

It is also preferable to carry out step (d) after separating the product of step (c) by distillation.

The reaction formula of the method comprising the above steps of the present invention is shown below.

[0013]

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[0014]

BEST MODE FOR CARRYING OUT THE INVENTION Throughout all steps of the production method of the present invention, the most expensive substance, which is concerned about handling safety (explosion, ignition due to heating or chemical decomposition), is used as a starting material.
-DNT. Therefore, in a series of reactions, 2,6-
Maintaining a high yield per DNT and construction of a highly safe reaction process are particularly important issues.

First, the chemical reaction of addition of formaldehyde to 2,6-DNT to the 2,6-DNT in the step (a) by a basic catalyst has not been reported, and therefore detailed investigations have been made. as a result,
Unlike the formaldehyde addition to nitrotoluene that is usually performed, in the case of formaldehyde addition to 2,6-DNT, the raw material has two nitro groups, so the reactivity is high and the reaction solution is likely to become heavier. However, when the reaction solution containing the produced DNE is used as it is, it is difficult for the catalytic hydrogenation (reduction) reaction of the nitro group to proceed in the next step (b), and it is found that severe reaction conditions are required. It was

In this case, before the reduction treatment in step (b),
As a countermeasure, it is possible to separate DNE from the reaction solution in advance. Also, by reducing the amount of formaldehyde added, the reaction is performed while suppressing the formation of heavier substances, and
In order to increase the yield per 2,6-DNT, it is possible to recover unreacted 2,6-DNT from the reaction solution. However, it is difficult to recover DNE and 2,6-DNT from the reaction solution because it is dangerous. From this, while suppressing the heaviness,
The reaction conditions with good yield per 2,6-DNT used were investigated.

The reaction component used in the addition reaction of step (a) may be either formaldehyde itself or a polymer of formaldehyde which produces formaldehyde under the reaction conditions, such as trioxane or paraformaldehyde. Amount of formaldehyde or its polymer used
(For polymers, the amount converted to the amount of formaldehyde, that is, the amount based on formaldehyde, the same applies below) is 2,6
The molar ratio to -DNT is preferably 0.5 to 2 times. If the amount is too small, the yield per 2,6-DNT used will decrease, and if it is too large, the yield will decrease due to the heaviness.

As the basic catalyst, alkali metal, alkali metal alcoholate, 1,8-diazabicyclo [5.4.0]
Undecene-7, a quaternary ammonium hydroxide compound, an anion exchange resin and the like can be used. The type of catalyst is determined by the combination with the reactivity of the starting nitro compound, but in the case of 2,6-DNT, it was found that a quaternary ammonium hydroxide compound is suitable from the viewpoint of reaction control. The amount of the basic catalyst used is 0.01 to 0.5 times, preferably 0.05 to 0.3 times the molar ratio of formaldehyde. In the case of anion exchange resin, it is desirable to use it in the range of 50 to 500 g per mol of formaldehyde.

As the reaction solvent in the step (a), an aprotic polar solvent exerts an excellent effect. Examples of suitable reaction solvents include alcohols, dimethyl sulfoxide, dimethyl sulfone, dimethylformamide, dimethylacetamide, THF (tetrahydrofuran), HMPA (hexamethylphosphoramide), sulfolane, N-methyl-2.
-Pyrrolidone and the like can be exemplified. As will be described later, a solvent that can also be used as a solvent for the reduction reaction in the next step (b) is desirable.

It has been found that the reaction temperature has a decisive influence on the yield. That is, particularly when a quaternary ammonium hydroxide compound is used as the basic catalyst, the reaction is preferably carried out in the temperature range of -20 ° C or higher and + 100 ° C or lower, preferably +10 to 60 ° C. If the temperature is high, heavier
The yield also decreases, and if it is too low, the reaction becomes difficult to proceed and the reaction takes time. The reaction time is usually several minutes to about one day. The reaction pressure is not particularly limited and is usually atmospheric pressure,
It is also possible to react under reduced pressure or increased pressure.

After completion of the reaction, the catalyst is removed out of the system, or the catalyst is deactivated by neutralization (eg, addition of an organic acid such as acetic acid, a mineral acid, or an acidic salt thereof). The reaction can be stopped. However, for example, using a quaternary ammonium hydroxide compound as a catalyst and the amount of formaldehyde or its polymer used relative to 2,6-DNT
It was found that if the molar ratio is within the range of 0.5 to 2.0 times, side reactions such as heaviness hardly occur without stopping the reaction. When using other basic catalysts,
It suffices to find a condition in which such a heaviness does not easily occur.
By preventing the catalyst from becoming heavier in this way, the reaction solution is directly used in the subsequent reduction step without deactivating the catalyst.
Can be used in (b).

However, if unreacted formaldehyde or its polymer remains in the reaction solution, as shown in the following reaction formula, it is first reacted with an amino acid in the reduction step (b) to produce N.
-Methyl compound, which is finally converted to 1-methyl-4-hydroxyindole through steps (c) and (d). It was clarified that these by-products are difficult to separate in the reaction process in the middle, which leads to a decrease in the purity and yield of the product 4-HI.

[0023]

Embedded image

Therefore, it is very desirable to remove or inactivate unreacted formaldehyde or its polymer from the reaction solution. As a result of studying the simple method, when an amine was added to the reaction solution and reacted with formaldehyde or its polymer, the reactivity of formaldehyde was lost (that is, inactivated) in the subsequent steps, and formaldehyde was found to be product quality. It has been found that it is possible to avoid affecting the reaction process in the middle of the process.

As the amine, in addition to aliphatic amine and aromatic amine, hydroxylamine, hydrazine and the like can be used. Further, molecular compounds such as inorganic or organic salts or hydrates of these amines are also effective. Among these, hydrazine and its molecular compound are particularly preferred because they do not need to be removed after the reaction.

The amount of amine added varies depending on the type of amine. For example, when using hydrazine, the molar ratio to unreacted formaldehyde or its polymer is 0.5 to
An amount of 2.0 times is preferable. The temperature condition at this time is not particularly limited, and amine may be added to the reaction liquid immediately after the end of step (a). After addition of the amine, the reaction solution can be directly subjected to the reduction step.

Therefore, according to the invention, in step (b):
After the amine is added to the reaction solution as described above without separating unreacted products or DNE of the product from the reaction solution containing DNE obtained in the formaldehyde addition reaction of step (a), the step (b) Is performed to produce DAE in which the nitro group is reduced to an amino group. If desired, a part or all of the catalyst and the solvent may be removed before and after the addition of the amine, and when the solvent is removed, a solvent suitable for the step (b) such as alcohol may be added if necessary. However, as described above, removal of the solvent is not desirable in consideration of safety and ease of operation.

The reduction treatment in step (b) can be carried out by any conventionally known technique which can be used for reductive amination of an aromatic nitro compound. For example, many methods such as iron powder reduction, reduction with metal and acid, catalytic hydrogenation with nickel catalyst or noble metal catalyst can be applied. Of these, catalytic hydrogenation is preferable from the viewpoint of reaction operation and economy. The conditions for catalytic hydrogenation may be the same as in the conventional case, and for example, catalytic hydrogenation can be carried out at a temperature of 50 to 150 ° C. and a hydrogen pressure of 5 to 100 kg / cm ² G.

In step (c), DAE produced in the reduction reaction in step (b) is treated with acid to obtain 4-HDI. 4 obtained
-Dehydrogenation of HDI in step (d) yields the desired 4-H
I is obtained.

The acid treatment in step (c) may be carried out on the reaction mixture obtained by removing the solvent and the catalyst from the reaction solution obtained in step (b), if necessary. However, according to this method, the purity of 4-HI finally obtained after dehydrogenation is low, the yield is necessarily low, and its purification is also difficult. As a result of studying this point, it was found that it can be solved by distilling and separating DAE from the reaction mixture obtained in the step (b).

Therefore, in order to obtain high-purity 4-HI in high yield, the product DA is obtained from the reaction mixture obtained in step (b).
It is preferred to separate E by distillation and to carry out step (c) with the DAE thus separated. However, as will be described later, when the acid treatment is carried out in two steps, the same effect can be obtained even by separating 4-ADI obtained as an intermediate product by distillation. Therefore, the reaction mixture of step (b) was directly subjected to the first step of the two-step acid treatment of step (c) without distillation, and the reaction mixture obtained by the acid treatment of the first step was distilled to obtain 4-ADI.
May be separated and subjected to a second stage acid treatment.

Vacuum distillation is desirable as the DAE distillation separation condition, and the pressure is 100 mmHg or less, preferably 50 mmHg or less, more preferably 5 mmHg or less. Distillation of DAE
It is preferable to perform the treatment at 250 ° C. or less within 5 hours. If distillation can be carried out under these conditions, it is possible to suppress a decrease in yield due to the decomposition of DAE, the addition of heavy substances, and the like.

In the acid treatment (heating in the presence of an acid catalyst) of DAE in the step (c), dehydration reaction first proceeds to ring closure and 4-ADI is produced, and then hydrolysis reaction occurs 4 Generated by HDI. That is, if the reaction conditions (type of acid catalyst and reaction temperature) are severe, hydrolysis will proceed, and if the reaction conditions are mild, the dehydration reaction will stop. Therefore, when the reaction conditions of acid treatment are mild and the reaction has stopped at the dehydration stage (4-ADI was produced), acid treatment is continued under more severe reaction conditions to hydrolyze 4-ADI. ,
Obtain 4-HDI. That is, the acid treatment is performed in two steps. On the other hand, if the reaction conditions of acid treatment are severe, DAE can be induced to 4-HDI by one-step acid treatment.

From the reaction mixture obtained in step (b) DAE
When the acid treatment in step (c) is performed after distilling and separating
Performing the one-step acid treatment is advantageous because a highly purified target product can be obtained in a high yield in a simplified process. On the other hand, when the reaction mixture of step (b) is directly used in step (c) without performing this distillation separation, a two-step acid treatment is carried out, and the reaction mixture is treated after the completion of the first-step acid treatment. By distilling and separating 4-ADI which is an intermediate product, and then subjecting this to the acid treatment of the second stage, a high-purity target product can be obtained in high yield.

As the acid catalyst, mineral acids such as sulfuric acid, hydrochloric acid, nitric acid and phosphoric acid, and solid acids such as zeolite (silica-alumina) can be used. The amount of the acid catalyst used with respect to DAE is 0.1 to 50 times as much as the molar ratio for the mineral acid and the weight ratio for the solid acid.
0.01 to 0.2 times is preferable. In order to convert DAE into 4-HDI by one-step acid treatment, it is preferable to use phosphoric acid as an acid catalyst. With other acid catalysts, the reaction is stopped by dehydration and further hydrolyzed with phosphoric acid.
(That is, two-step acid treatment) is often required.

Water is required for the hydrolysis reaction. Therefore, the second step in the case of one-step acid treatment or two-step acid treatment
In the case of (hydrolysis), it is desirable that water is present in the reaction system in a weight ratio of about 3 to 50 times that of DAE as a solvent. In addition to water, a water-miscible organic solvent inert to the reaction may coexist. Further, in the first step (dehydration) in the case of the two-step acid treatment, the use of a solvent is not essential, but when used, it can be selected from water and an inert organic solvent.

The heating temperature of the acid treatment is 100 to 250 ° C., preferably 130 to 200 ° C. in the one-stage acid treatment or the second-stage acid treatment for the purpose of producing 4-HDI. . On the other hand, in the first stage of the two-step acid treatment for the purpose of producing 4-ADI, the heating temperature of the acid treatment is 80 to 200.
C., preferably 100 to 150.degree. In any case, it is usually sufficient that the heating time is about 1 to 50 hours.
When the heating temperature is high and the heating time is long, it is advantageous for the production of 4-HDI. On the contrary, when the heating temperature is low and the heating time is short,
-Advantageous for the production of ADI. Therefore, for example, even if phosphoric acid is used as an acid catalyst, the reaction is dehydrated (that is, 4-ADI is produced) depending on the heating temperature, heating time, and phosphoric acid concentration.
4-HDI in one step as it may stop at
If it is desired to generate the above, it is necessary to select these reaction conditions so that the hydrolysis reaction occurs after dehydration.

When the acid treatment is carried out in two steps, after completion of the reaction (dehydration reaction) in the first step, pretreatment such as neutralization is carried out if necessary, and then extraction or the like is carried out. The intermediate product 4-ADI is separated. If desired, the resulting reaction mixture may be distilled to separate 4-ADI, as described above. This distillative separation is preferably carried out especially when the reaction mixture in step (b) is not distilled off. At this time, the distillation separation condition of 4-ADI is also preferably distillation under the same reduced pressure condition as described above. This vacuum distillation is preferably carried out at a temperature of 200 ° C. or lower within 5 hours.

After completion of the one-step or two-step acid treatment in step (c), after performing a pretreatment such as neutralization, if necessary,
4-HDI is separated by an operation such as extraction, and this is dehydrogenated in step (d) to give 4-HI. This dehydrogenation reaction
It can be carried out in the presence of a catalyst containing a noble metal such as palladium, platinum or ruthenium according to a conventional method. The catalyst may be either a noble metal supported catalyst or a complex catalyst, but usually a noble metal is supported on a carrier such as activated carbon or alumina,
A relatively inexpensive supported catalyst is sufficiently effective. The amount of the catalyst used is preferably 0.01 to 0.2 times the weight of 4-HDI. The solvent is not essential, but alcohols, aromatic hydrocarbons, alicyclic hydrocarbons, etc. can be used, and the reaction is carried out in the presence or absence of a hydrogen acceptor such as a nitro compound or a carbonyl compound. The amount of solvent used is 4
A suitable weight ratio to HDI is 0.1 to 50 times. The reaction temperature may be 80 to 250 ° C, but is usually carried out at the reflux temperature of the solvent. A reaction time of about 1 to 30 hours is usually sufficient. The reaction atmosphere is preferably an inert atmosphere such as a nitrogen atmosphere.

However, it was found that 4,5,6,7-tetrahydro-4-oxindole was by-produced considerably in the conventional dehydrogenation method. As a result of investigating the cause, it was found that 4,5,6,7-tetrahydro-4-oxindole was a large by-product under conditions where the catalyst could easily store hydrogen. It was found to be effective to boil the solvent added with and to add 4-HDI little by little to this. For example, 2-
Using ethylhexanol as a solvent, 2% by weight of 5% platinum / carbon as a catalyst is added to this solvent as a catalyst, and 4-HDI is added at a rate of 200 g / kg · Hr per unit amount of solvent under boiling conditions. The total amount of 4-HDI added is 0.02 to 0.5 times, preferably 0.05 to 0.2 times the weight of the solvent. If the addition amount is small, the economical efficiency is deteriorated, and if the addition amount is too large, the yield is likely to decrease due to side reactions.

From the reaction solution obtained in step (d), the desired product, 4-HI, is usually practiced in the field of chemical synthesis such as crystallization method, acid precipitation method, extraction method and distillation method. It can be separated and purified by a method.

[0042]

The present invention will be described below in detail with reference to examples. In the examples, analysis was performed by gas chromatography. In addition,% in the examples is% by weight unless otherwise specified.

(Synthesis of DNE) Examples 1 to 4 and Comparative Examples 1 to 3 As shown in Table 1, 2,6-DNT was dissolved in a reaction solvent,
A basic catalyst and paraformaldehyde were added to the obtained solution and reacted at a predetermined reaction temperature for a predetermined time, and then the DNE concentration in the reaction solution was measured. Table 1 shows the solvents and catalysts used, the reaction conditions and the results.

[0044]

[Table 1]

(Synthesis of DAE) Comparative Example 4 The reaction solution obtained in Example 1 was placed in a stainless steel autoclave.
(DNE 40.9% and unreacted paraformaldehyde 2.8% in dimethylformamide) was charged together with 10g of 5% Pd carbon powder (50% water containing product) and heated at 90 ° C. under hydrogen pressure of 20 kg / cm ² G. The reduction was performed. The reaction was stopped when the hydrogen absorption was stopped, the catalyst was filtered off, and DAE in the reaction solution was quantified. The weight of the reaction solution was 134.7 g, and the DAE concentration was 23.5%. The reduction yield of DNE to DAE is 80 mol%, DAE
6% of the N-methyl compound was contained.

Example 5 After adding 6.3 g of hydrazine monohydrate to the reaction solution obtained in Example 1, catalytic reduction was carried out in the presence of 5% Pd carbon powder by the same operation as in Comparative Example 4 to carry out the reaction. 141.0 g of liquid was obtained. The DAE concentration of this reaction solution was 27.0%, and DAE to DA
The reduction yield to E was 96 mol%, and the N-methyl form of DAE was not detected.

Example 6 Example 5 was repeated, except that the reaction solution obtained after catalytic reduction was distilled as follows. First, 100 mmHg from the reaction solution
After distilling off the solvent dimethylformamide under reduced pressure of
DAE was separated by distillation with the degree of vacuum reduced to 5 mmHg. At this time, the top temperature was 200 ° C, the bottom temperature was 210 ° C, and the distillation time was 180 ° C.
Minutes. The DAE fraction obtained was 39.7 g.
The purity was 91.1% and the distillation yield was 95 mol%.

(Synthesis of 4-HDI: One-Step Acid Treatment) Comparative Example 5 From the reaction solution obtained in Comparative Example 4, dimethylformamide as a solvent was distilled off under reduced pressure to obtain 30 g of crude DAE (purity: 67.0).
%) In a glass autoclave with a volume of 1 liter together with 200 g of a 50% phosphoric acid aqueous solution.
Reaction was performed at 24 ° C. for 24 hours. After cooling, the reaction solution was neutralized and extracted with 230 ml of methyl isobutyl ketone. The solvent of the obtained organic layer was distilled off to give 19.5 g of 4-HDI (purity 75%, yield
82 mol%).

Example 7 30 g of crude DAE (purity 72.8%) after distilling off the solvent dimethylformamide from the reaction solution obtained in Example 5 by vacuum distillation
Was placed in a glass autoclave with a volume of 1 liter together with 200 g of a 50% phosphoric acid aqueous solution at 180 ° C under a nitrogen atmosphere.
The reaction was performed for 24 hours. The obtained reaction liquid was treated in the same manner as in Comparative Example 5 to obtain 20.1 g of 4-HDI (purity 82.0%, yield 85 mol%).

Example 8 Using 30 g of the DAE fraction obtained in Example 6, a reaction was carried out in the same manner as in Example 7, and then the reaction solution was treated in the same manner as in Comparative Example 5 to obtain 44.0 g of 4-HDI. (Purity 93.0%, Yield 92 mol%)
I got

(Synthesis of 4-HDI: Two-step acid treatment) Example 9 30 g of crude DAE (purity 72.8%) after distilling off the solvent dimethylformamide from the reaction solution obtained in Example 5 by vacuum distillation
Was placed in a glass autoclave with a volume of 1 liter together with 300 g of a 30% aqueous solution of sulfuric acid and reacted at 150 ° C. for 10 hours. After cooling, the reaction solution is neutralized and methyl isobutyl ketone is added.
Extracted with 330 ml. The solvent of the obtained organic layer was distilled off,
22.1 g of 4-ADI (purity 80%, yield 92 mol%) was obtained.

22.1 g of 4-ADI thus obtained was distilled at 3 mmHg. At this time, the tower top temperature was 137 ° C and the tower bottom temperature was 153 ° C.
The temperature and the distillation time were 180 minutes. 4-A by this distillation
A DI fraction of 17.7 g (purity 97.0%, distillation yield 97.2 mol%) was obtained. Using 47.7 g of this 4-ADI fraction, the second stage acid treatment was carried out in the presence of a phosphoric acid catalyst in the same manner as in Example 7, and the reaction solution was treated in the same manner as in Comparative Example 5. as a result,
18.1 g of 4-HDI (purity 92.5%, yield 97 mol% based on 4-ADI fraction, 86.7% based on crude DAE) were obtained.

(Synthesis of 4-HI) Comparative Example 6 4-HDI obtained in Comparative Example 5 (19.5 g), 2-ethylhexanol (190 g), and 5% Pd carbon powder (50% hydrous product).
0.5 g was placed in a reactor and refluxed for 5 hours under a nitrogen atmosphere to carry out a dehydrogenation reaction. The conversion rate of 4-HDI was 100%. The reaction solution was filtered off, the solvent 2-ethylhexanol was distilled off from the filtrate under reduced pressure of 100 mmHg, and then 4-HI was distilled at a reduced pressure of 3 mmHg. The tower top temperature at this time is
The temperature of the bottom was 138 ° C, the temperature of the bottom was 152 ° C, and the distillation time was 180 minutes. The obtained 4-HI fraction was 12.7 g, and 4-HI purity was 9
5.1%, the yield from 4-HDI was 84 mol%. The bottom residue of the distillation contained 1.5 g of 4,5,6,7-tetrahydro-4-oxindole.

Example 10 24.0 g of 4-HDI obtained in Example 8, 230 g of 2-ethylhexanol, and 5% Pd carbon powder (50% hydrous product).
7 g was placed in a reactor and refluxed for 5 hours under a nitrogen atmosphere to carry out a dehydrogenation reaction. The conversion rate of 4-HDI was 100%. After cooling, the catalyst was filtered off and 2-ethylhexanol was added.
After distilling off at a reduced pressure of 100 mmHg, the reduced pressure was adjusted to 3 mmHg and 4-HI was distilled in the same manner as in Comparative Example 6. 4 obtained
The -HI fraction was 18.9 g, the purity was 99.0%, and the yield from 4-HDI was 85 mol%. 4,5, in the bottom residue of the distillation,
This contained 2.23 g of 6,7-tetrahydro-4-oxindole.

Example 11 Reaction and treatment were carried out in the same manner as in Example 10 except that cyclohexyl acetate was used instead of 2-ethylhexanol. The obtained 4-HI fraction was 18.2 g, the purity was 98.8%, and the yield from 4-HDI was 82 mol%. In the bottom residue of the distillation
4,5,6,7-tetrahydro-4-oxindole is 2.9
g was included.

Example 12 18.1 g of 4-HDI obtained in Example 9, 170 g of 2-ethylhexanol, and 5% Pd carbon powder (50% hydrous product).
5 g was placed in a reactor and refluxed for 5 hours under a nitrogen atmosphere to carry out a dehydrogenation reaction. The conversion rate of 4-HDI was 100%. After cooling, the catalyst was filtered off and 2-ethylhexanol was added.
After distilling off at a reduced pressure of 100 mmHg, the reduced pressure was adjusted to 3 mmHg and 4-HI was distilled in the same manner as in Comparative Example 6. 4 obtained
The -HI fraction was 14.2 g, the purity was 99.2%, and the yield from 4-HDI was 85.3 mol%. 4, in the bottom residue of the distillation
1.7 g of 5,6,7-tetrahydro-4-oxindole
Was included.

Example 13 50 g of 2-ethylhexanol and 5% Pt carbon powder (50
% Water-containing product) 2.0 g was put in the reactor and refluxed under a nitrogen atmosphere. 24.0 g of 4-HDI obtained in Example 8 was added to this reflux liquid.
Was dissolved in 330 g of 2-ethylhexanol,
Dropwise at a rate of g / Hr. After completion of the dropping, the reflux was continued for another 3 hours to convert 4-HDI to 100%. After cooling the reaction solution, the catalyst was filtered off, 2-ethylhexanol was distilled off under reduced pressure of 100 mmHg, and the degree of reduced pressure was changed to 3 mmHg and 4-H.
I was distilled. At this time, the tower top temperature was 138 ° C and the tower bottom temperature was
The distillation time was 147 ° C and the distillation time was 180 minutes. 4-HI obtained
The fraction was 20.6 g, the 4-HI purity was 99.1%, and the yield from 4-HDI was 93 mol%. 4, in the bottom residue of the distillation
It contained 0.4 g of 5,6,7-tetrahydro-4-oxindole.

Table 2 shows the synthesis results of DNE to 4-HI exemplified above. As can be seen from Table 2, when the reaction solution obtained by the synthesis of DNE was used as a raw material, as shown in Comparative Example, when this reaction solution was used as it was, the yield and purity of DAE significantly decreased, and As a result, the reaction performance after that was not good. On the other hand, according to the present invention, when amine was added to the reaction solution obtained by the synthesis of DNE to inactivate unreacted paraformaldehyde, the yield and purity of DAE were remarkably improved. It is also found that in the subsequent reaction, when DAE or 4-ADI is separated by distillation in advance and then used in the reaction, the yield and purity of 4-HI are finally improved.

[0059]

[Table 2]

[0060]

Industrial Applicability According to the present invention, 2,6-
It is possible to safely produce 4-HI from DNT as a raw material in a high yield with a simple operation without using expensive reaction equipment such as electrolysis equipment. Especially from 2,6-DNT to DNE
Since it can be produced without making the reaction system heavy, the obtained reaction solution can be used as it is in the next reduction step by simply adding an amine thereto. As a result, the unreacted 2,6-DNT was removed and the produced DNE
This avoids work that may cause explosion, such as separation, and is very advantageous in terms of safety and process simplification.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor, Kouichi Takeda, Kamijima, Kashima City, Ibaraki Prefecture, Sumitomo Chemical Co., Ltd., Research Institute (72) Inventor, Keiichi Yokota, Kashima City, Ibaraki Prefecture, Hikari No. 3, Sumitomo Chemical Co., Ltd. In the laboratory

Claims (7)

[Claims] 1. A method for producing 4-hydroxyindole comprising the following steps (a) to (d): (a) Formaldehyde or a polymer thereof is subjected to an addition reaction with 2,6-dinitrotoluene in a solvent in the presence of a basic catalyst at a reaction temperature of −20 ° C. to + 100 ° C. to non-electrolytically react with 2-6-dinitrotoluene.
(2,6-dinitrophenyl) step of producing ethanol, (b) to the reaction solution obtained in step (a), without isolation of unreacted products or products, amine was added to react unreacted formaldehyde or its After inactivating the polymer, the reaction solution is subjected to reduction treatment to produce 2- (2,6-diaminophenyl) ethanol, (c) the product of step (b) is added in the presence of an acid catalyst. Heat treatment to produce 4-hydroxy-2,3-dihydroindole, (d) dehydrogenating the product of step (c) to give 4-hydroxyindole. 2. In the step (a), the basic catalyst is a quaternary ammonium hydroxide compound, and formaldehyde or a polymer thereof is used in an amount of 0.5 to 2.0 times as much as the molar ratio of formaldehyde to 2,6-dinitrotoluene. To do
The method of claim 1. 3. A process according to claim 1 or 2, wherein the product of step (b) is separated by distillation before step (c) is carried out. 4. In the step (c), the acid catalyst is phosphoric acid, the heating temperature is 100 to 250 ° C.
Generate hydroxy-2,3-dihydroindole,
A method according to any one of claims 1 to 3. 5. The step (c), (c-1) the heat treatment of the product of the step (b) in the presence of an acid catalyst to produce 4-amino-2,3-dihydroindole, -2) This is further heat treated in the presence of an acid catalyst to
Generate hydroxy-2,3-dihydroindole,
The method according to claim 1, wherein the method is performed in two steps. 6. The heating temperature in (c-1) is 80 to 200 ° C., and the produced 4-amino-2,3-dihydroindole is separated by distillation, and then this is converted into phosphoric acid in (c-2). The method according to claim 5, wherein the heat treatment is carried out at a temperature of 100 to 250 ° C as an acid catalyst. 7. The method according to claim 1, wherein step (d) is carried out by gradually adding 4-hydroxy-2,3-dihydroindole to a boiling solvent containing a noble metal-containing catalyst. The method described.