JPH07196610A - Production of 5-chloro-2-oxyindole - Google Patents

Abstract

PURPOSE:To provide a process for obtaining high-purity 5-chloro-2-oxyindole economically and safely in high yield. CONSTITUTION:The first step of reaction of 5-chloroisatin with hydrazine hydrate in a lower alcohol solvent is followed by the second step of reaction of the product with an alkali metal hydroxide, where during and/or after the process, the reaction mixture is concentrated and neutralized with a mineral acid, while the lower alcohol still remains in the mixture.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing 5-chloro-2-oxindole which is useful as an intermediate for anti-inflammatory agents. More specifically, 5-chloroisatin and hydrazine hydrate are reacted in a lower alcohol solvent and then reacted with a hydroxide of an alkali metal to give 5-chloro-2.
-A method for industrially producing oxindole.

[0002]

2. Description of the Related Art 5-chloroisatin is reacted with hydrazine hydrate in an ethanol solvent to give an intermediate 5-chloro-3.
-Hydrazino-2-oxindole was isolated and treated with sodium ethoxide in an ethanol solvent to give 5
However, it is known that -chloro-2-oxindole can be synthesized (Japanese Patent Application No. 3-42270). However, in order to isolate 5-chloro-2-oxindole by this method, the process is long and complicated. However, there is a problem that the yield is as low as about 50%.

[0003]

DISCLOSURE OF THE INVENTION In order to improve this point, the present invention simplifies the process and provides high yield and high purity.
It is intended to provide a method for producing chloro-2-oxindole.

[0004]

[Means for Solving the Problems] In order to solve the above-mentioned object, as a result of intensive studies by the present inventors, in the first step, 5-chloroisatin and hydrazine hydrate were reacted in a lower alcohol solvent, and then, It is characterized in that it is reacted with a hydroxide of an alkali metal in two steps, and at that time and / or after that, the reaction solution is concentrated so that lower alcohols are present in the reaction solution and neutralized with a mineral acid. The present invention has been reached by finding that 5-chloro-2-oxide is produced industrially advantageously.

The lower alcohols used as the reaction solvent in the present invention are preferably methanol, ethanol, propyl alcohol and isopropyl alcohol.

The amount of lower alcohols used as a solvent is 6 to 60 parts by weight, preferably 8 to 24 parts by weight, relative to the starting material 5-chloroisatin.

When the amount of the lower alcohols used is small, the reaction liquid temporarily becomes a slurry when the hydroxide of the alkali metal is added after the reaction with hydrazine,
This is not preferable because the reaction solution becomes poorly stirred.

When the amount of the lower alcohol used is large, a large amount of the alcohol is used during the reaction with the alkali metal hydroxide or after the reaction until the amount of the alcohol used is within an appropriate range. Is required to be distilled out of the reaction system, which is not advantageous.

The amount of hydrazine hydrate used is preferably 1 to 2 times the molar amount of 5-chloroisatin.

The reaction time and reaction temperature with hydrazine hydrate vary depending on the type of alcohol solvent used, but it is preferable to take 2 to 6 hours at the temperature at which the alcohol is refluxed.

The alkali metal hydroxide or its aqueous solution is preferably sodium hydroxide or potassium hydroxide.

From the viewpoint of the yield of the desired product, it is preferable to use a hydroxide of an alkali metal as a solid, but in view of industrial ease of use, an aqueous solution of a hydroxide of an alkali metal is used. You can use it.

In that case, the concentration of the aqueous solution of the alkali metal hydroxide is preferably 30 to 50%.

The amount of the alkali metal hydroxide used is preferably 1 to 3 times mol of the starting 5-chloroisatin.

The reaction of the alkali metal with the hydroxide is carried out at a temperature at which the reaction system is refluxed, preferably for 20 minutes to 3 hours.

Before neutralizing the reaction solution, it is necessary to distill a part of the alcohol out of the reaction system until an appropriate amount of the alcohol used in the reaction solution remains.

As a method for adjusting the amount of the alcohol used in the reaction solution to an appropriate range, a part of the alcohol is distilled out of the reaction system during the reaction with the hydroxide of an alkali metal or its aqueous solution. It is advantageous to do so, but it can be distilled out of the reaction system after reacting with a hydroxide of an alkali metal or its aqueous solution. Is
The alcohol in the reaction solution is preferably 6 to 18 parts by weight with respect to the raw material 5-chloroisatin.

When the amount of the alcohol present in the reaction solution is large, the purity of 5-chloro-2-oxindole is high, but the yield is lowered, and when the amount of the alcohol present in the reaction solution is small, the amount of the alcohol is 5 The yield of -chloro-2-oxindole increases, but the purity decreases.

When the reaction liquid from which the solvent has been removed becomes a slurry, it is preferable to add a small amount of water to form a uniform solution and then neutralize it.

The neutralization is a mineral acid, preferably hydrochloric acid or sulfuric acid. The mineral acid used at that time is preferably a 1 to 3 normal aqueous solution. The amount of the mineral acid used is preferably excessively added until the pH of the reaction solution after neutralization is in the acidic region, and more preferably PH2 or less.

The reaction solution after neutralization is filtered off, the solid is washed with sufficient water, then with a lower alcohol, and then dried under reduced pressure to give 5-chloro-2-oxindole as a target product. It can be isolated.

The amount of washing in the case of washing with lower alcohol is preferably 1 to 5 with respect to the raw material 5-chloroisatin.
It is a weight part, and it is advantageous to use the same alcohol as the reaction solvent for the type of lower alcohol.

The product thus obtained has such a purity that it can be sufficiently used for the reaction in the subsequent steps in the synthesis of medicines and agricultural chemicals, but if necessary, it may be subjected to recrystallization, chromatography or the like. It can be further purified by a usual organic chemistry technique.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

[0025]

【Example】

Example 1. 200 equipped with stirrer, thermometer, reflux head
4.5-g 5-chloroisatin in a 4-ml four-necked flask
(0.025 mol) and 80 ml of ethanol were added, and 1.75 g (0.035 mol) of hydrazine hydrate at room temperature with stirring.
mol) was added and the reaction was refluxed at about 80 ° C. for 3.5 hours. Then, the reaction solution was cooled to 70 ° C., 6.0 g of 50% aqueous sodium hydroxide solution was added, and the reaction solution was stirred and refluxed for 45 minutes. During this period, 40 ml of ethanol was distilled off.

The reaction solution is cooled to 20 ° C. or below, and 20 m of water is added.
1 was added, and 2N-hydrochloric acid was added to neutralize the pH of the reaction solution. The reaction solution was filtered, the solid was washed with 30 ml of water, and further washed with 8 ml of ethanol. The obtained solid was vacuum dried at 60 ° C. to obtain 3.56 g (yield 84.5%) of 5-chloro-2-oxindole having a purity of 99.5%. Further, ethanol was distilled off from the combined solution of the filtrate and the washing solution, the concentrated solution was cooled and then filtered, and the solid matter was washed with 5 m of water.
After washing with 1 and 3 ml of ethanol and vacuum drying at 60 ° C., 0.41 g of 5-chloro-2-oxindole having a purity of 88.6% was obtained.

Example 2. After reacting in the same procedure as in Example 1, 0.40 g of 5-chloro-2-oxindole recovered from the filtrate in Example 1 was added to the reaction solution before being neutralized with 2N-hydrochloric acid.

Then, a solid substance was isolated by the same procedure as in Example 1. As a result, 5-chloro-2- having a purity of 99.4%
3.93 g (yield 93.2%) of oxindole was obtained.
A solid substance was isolated from the reaction filtrate by the same procedure as in Example 1 to obtain 0.40 g of 5-chloro-2-oxindole having a purity of 87.9%.

Example 3. After reacting in the same procedure as in Example 1 and adding 6.0 g of 50% -caustic soda aqueous solution,
The reaction was carried out under reflux for 45 minutes without distilling ethanol off.
After that, the same procedure as in Example 1 was performed, and the purity was 99.7%.
3.02 g of 5-chloro-2-oxindole (yield 7
1.5%) was obtained.

Example 4. The reaction was performed in the same manner as in Example 1 except that the reaction solvent was changed to iso-propanol, and 5-chloro-2-oxindole 3.2 having a purity of 99.3% was used.
1 g (yield 76.1%) was obtained.

Example 5. The reaction was performed in the same procedure as in Example 1 except that the reaction solvent was changed to methanol, and the purity was 99.0.
% 4-chloro-2-oxindole (3.44 g, yield 81.4%) was obtained.

Example 6. Reaction was carried out by the same procedure as in Example 1 except that 3.0 g of solid caustic soda was used in place of 50% -caustic soda, and 3.66 g of 5-chloro-2-oxindole having a purity of 99.6%. (Yield 87.0%) was obtained.

Comparative Example 1. In a 300 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 5-chloroisatin 1
8.16 g (0.10 mol) and 160 ml of ethanol
Hydrazine hydrate 7.51 g (0.15 m
ol) was added, and the reaction solution was stirred and refluxed at about 80 ° C. for 3.5 hours. The reaction solution was cooled to 20 ° C or lower and filtered, and the obtained solid was washed with 20 ml of ethanol, and then the solid was heated to 60 ° C.
Dried under vacuum at. 5-chloro-2-oxindole 17.
70 g were obtained.

Comparative Example 2. In a 200 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 5.10 g (0.075 mol) of sodium ethoxide and 55 ml of ethanol were added.
After adding 4.89 g (0.025 mol) of the above-mentioned 5-chloro-2-oxindole at room temperature, the reaction solution was heated and refluxed with stirring at about 80 ° C. for 30 minutes. Next, the reaction solution is concentrated under reduced pressure, and water is added to the solution while cooling the concentrated solution.
The mixture was neutralized by adding 0 ml and then 2N-hydrochloric acid.

The reaction solution was filtered, the solid was washed with 30 ml of water, dried under vacuum at 60 ° C. and recrystallized with 50 ml of ethanol. As a result, 2.40 g of 5-chloro-2-oxindole having a purity of 99.6% was obtained. (Yield 51.6%) was obtained.

Comparative Example 3. Into a 200 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 14.47 g (0.075 mol) of 28% sodium methoxide and 35 ml of ethanol were put, and 5-chloro-2 synthesized in Comparative Example 1 was used.
After adding 4.89 g (0.025 mol) of oxindole, the reaction was carried out in the same procedure as in Comparative Example 1 and recrystallized from ethanol, and then 5-chloro-having a purity of 99.5%.
2.38 g of 2-oxindole (yield 51.1) was obtained.

[0037]

As described above, the present invention is
In producing 5-chloro-2-oxindole using chloroisatin as a raw material, 5-chloroitisan and hydrazine hydrate are reacted in a lower alcohol solvent in the first step, and then water of alkali metal is used in the second step. The reaction liquid is reacted with an oxide, and / or after that, the reaction liquid is concentrated and treated with a mineral acid in the presence of 6 to 18 parts by weight relative to the starting material 5-chloroisatin using lower alcohols in the reaction liquid. It is a method for industrially producing 5-chloro-2-oxindole by neutralizing, and according to the present invention, 5-chloro-2-oxindole is produced in a high yield, high purity, economically and safely by a method which is economical and safe. -2-Oxindole has the advantage that it can be obtained.

Claims (6)

[Claims] 1. In the first step, 5-chloroisatin and hydrazine hydrate are reacted in a lower alcohol solvent, and then in the second step, the reaction product is reacted with a hydroxide of an alkali metal. Alternatively, a method for producing 5-chloro-2-oxindole, which comprises concentrating the reaction solution, allowing lower alcohols to be present in the reaction solution, and neutralizing with a mineral acid. 2. The lower alcohols are methanol, ethanol, propyl alcohol, and isopropyl alcohol, and the amount used is 6 to 5 parts per 1 part of 5-chloroisatin.
The method for producing 5-chloro-2-oxindole according to claim 1, which is 60 parts by weight. 3. The method for producing 5-chloro-2-oxindole according to claim 1, wherein the amount of the lower alcohol present during neutralization is 6 to 18 parts by weight per 1 part of 5-chloroisatin. 4. The method according to claim 1, wherein the hydroxide of alkali metal is sodium hydroxide or potassium hydroxide.
Method for producing chloro-2-oxindole. 5. The concentration of alkali metal hydroxide is 30%.
The method for producing 5-chloro-2-oxindole according to claim 1, which is used as the above aqueous solution. 6. The method for producing 5-chloro-2-oxindole according to claim 1, wherein the mineral acid is hydrochloric acid or sulfuric acid.