JPH06184108A - Production of 5-chlorooxyindole - Google Patents

Abstract

PURPOSE:To readily obtain in high yield 5-chlorooxyindole from p-chloro-omega- chloroacetanilide readily obtainable from p-chloroaniline. CONSTITUTION:In producing 5-chlorooxyindole by subjecting p-chloro-omega- chloroacetanilide to ring closure in the presence of aluminum chloride by Friedel-Crafts reaction, three times as much aluminum chloride as p-chloro-omega- chloroacetanilide by mols is used to produce 5-chlorooxyindole.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 5-chlorooxindole by ring closure of p-chloro-ω-chloroacetanilide by Friedel-Crafts reaction.

[0002]

2. Description of the Prior Art 5-Chlorooxindole is a synthetic intermediate for a cardiac drug or a drug having a pharmacological effect of stopping the progression of rheumatism, and its production method is, for example, a method by Robin D. Clark et al. (Synthesis, 871, 1991), Thomas A. Fogli
Method by a et al. (J. Org. Chem. 33 (12), 4440, 1968),
Method by Bryan B. Molloy et al. (US Patent 388223
6) and the method by AE Kellie et al. (J. Chem. Soc. 3
809, 1956) etc. are known.

[0003]

However, the above-mentioned methods (1) to (3) have the drawbacks that the raw materials or reagents are expensive, or that multiple steps are required, and none of these methods are industrially satisfactory. . The only method is a method using a compound that is easily and cheaply available as a raw material, but the method described in the literature has a drawback of low yield. That is, in the literature, there was no change when p-chloro-ω-chloroacetanilide was reacted with aluminum chloride at 225 ° C, and only a slight yield of 5-chloro when reacted with aluminum chloride at 250 ° C. It is stated that oxindole cannot be obtained.

[0004]

SUMMARY OF THE INVENTION The present inventors have proposed to solve the problem of low yield in this method by using Fr.
As a result of intensive studies on the reaction conditions of the iedel-Crafts reaction, it was found that the target product can be obtained in a high yield by reacting p-chloro-ω-chloroacetanilide with 3 times or more moles of aluminum chloride. At the same time, various studies were added to complete the present invention.

That is, the present invention uses p-chloro-ω-chloroacetanilide with Friedel-Cr using aluminum chloride.
In producing 5-chlorooxindole by subjecting it to afts reaction and ring closure, it is characterized by using 3 times or more moles of aluminum chloride with respect to p-chloro-ω-chloroacetanilide.

That is, as is clear from the description of Comparative Examples below, the reaction does not proceed with the use of 1.5 times the molar amount of aluminum chloride with respect to p-chloro-ω-chloroacetanilide, and p-chloro-ω- It was possible to obtain the desired 5-chlorooxindole in an industrially meaningful yield for the first time by using aluminum chloride in an amount of 3 times the molar amount of chloroacetanilide (Example 1).

The p-chloro-ω-chloroacetanilide used in the present invention can be obtained more easily than the reaction of p-chloroaniline with chloroacetyl chloride, and it is not necessary to purify the reaction product before use. The amount of aluminum chloride used is at least 3 times, and usually about 3 to 8 times the mol of p-chloro-ω-chloroacetanilide. It is preferably used in an amount of about 5 to 6 times.

The reaction temperature is usually 180 to 250 ° C, preferably 220 to 230 ° C. The reaction time is usually about 2 to 5 hours. After the reaction, the target product can be taken out by a conventional method, for example, by adding a protic solvent such as water and then performing operations such as filtration, liquid separation and extraction. The target product taken out can be further purified by performing operations such as recrystallization and various chromatographies.

[0009]

According to the method of the present invention, 5-chlorooxindole can be easily obtained from p-chloro-ω-chloroacetanilide in a high yield.

[0010]

The present invention will be described in more detail based on the following examples, but the invention is not intended to be limited to these examples.

Example 1 1.4 g of p-chloroaniline was dissolved in 25 ml of dichloromethane and 1.2 g of triethylamine was added. The mixture was cooled to 0 ° C. and 1.4 g of chloroacetyl chloride was added dropwise with stirring. After completion of dropping, the mixture was stirred at room temperature for 1 hour. After that, dichloromethane was removed by concentration under reduced pressure, an aqueous sodium hydroxide solution was added to the precipitated solid, and the mixture was extracted with ethyl acetate. The oil layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude p-chloro-ω-chloroacetanilide. To the obtained crude p-chloro-ω-chloroacetanilide, 4.5 g of aluminum chloride was added and mixed well. The mixture was heated at 230 ° C. for 4 hours. After cooling, water and methanol were added. After removing methanol by concentration under reduced pressure, the mixture was extracted with ethyl acetate. The oil layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and 0.58 g
To give 5-chlorooxindole. The yield based on p-chloroaniline was 32%.

Example 2 1.4 g of p-chloroaniline was dissolved in 25 ml of dichloromethane and 1.2 g of triethylamine was added. The mixture was cooled to 0 ° C. and 1.4 g of chloroacetyl chloride was added dropwise with stirring. After completion of dropping, the mixture was stirred at room temperature for 1 hour. After that, dichloromethane was removed by concentration under reduced pressure, an aqueous sodium hydroxide solution was added to the precipitated solid, and the mixture was extracted with ethyl acetate. The oil layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude p-chloro-ω-chloroacetanilide. To the obtained crude p-chloro-ω-chloroacetanilide, 7.5 g of aluminum chloride was added and mixed well. The mixture was heated at 230 ° C. for 4 hours. After cooling, water and methanol were added. After removing methanol by concentration under reduced pressure, the mixture was extracted with ethyl acetate. The oil layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 1.3 g of 5-chlorooxindole. The yield based on p-chloroaniline was 71%.

Example 3 30 g of p-chloroaniline was dissolved in 300 ml of dichloromethane and 26 g of triethylamine was added. The mixture was cooled to 0 ° C. and 29 g of chloroacetyl chloride was added dropwise with stirring. After completion of dropping, the mixture was stirred at room temperature for 1 hour. After that, dichloromethane was removed by concentration under reduced pressure, an aqueous sodium hydroxide solution was added to the precipitated solid, and the mixture was extracted with ethyl acetate. The oil layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude p-chloro-ω-chloroacetanilide. To the obtained crude p-chloro-ω-chloroacetanilide, 157 g of aluminum chloride was added and mixed well. The mixture was heated at 230 ° C. for 4 hours. After that, the liquid mixture was added to ice water without cooling, and the mixture was allowed to stand for 1 hour, and then the solid was filtered off. To this solid was added 500 ml of ethyl acetate and the mixture was filtered while hot. The filtrate was concentrated under reduced pressure, and extracted with ethyl acetate to give 2
After recrystallization, 24 g of 5-chlorooxindole was obtained. The yield based on p-chloroaniline was 61%.

Example 4 100 g of p-chloro-ω-chloroacetanilide 3
After adding 30 g of aluminum chloride and mixing well, 23
It heated at 0 degreeC and reacted for 4 hours. After allowing to cool, water and methanol were added, and methanol was removed by concentration under reduced pressure. After extraction with ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, 66
g of 5-chlorooxindole was obtained. p-chloro-
The yield based on ω-chloroacetanilide was 80%.

Comparative Example 1 1.4 g of p-chloroaniline was dissolved in 25 ml of dichloromethane and 1.2 g of triethylamine was added. The mixture was cooled to 0 ° C. and 1.4 g of chloroacetyl chloride was added dropwise with stirring. After completion of dropping, the mixture was stirred at room temperature for 1 hour. After that, dichloromethane was removed by concentration under reduced pressure, an aqueous sodium hydroxide solution was added to the precipitated solid, and the mixture was extracted with ethyl acetate. The oil layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude p-chloro-ω-chloroacetanilide. To the obtained crude p-chloro-ω-chloroacetanilide, 2.3 g of aluminum chloride was added and mixed well. The mixture was heated at 230 ° C. for 4 hours. However, the reaction did not proceed and the desired product could not be obtained.

Claims (1)

[Claims] 1. When 5-chlorooxindole is produced by subjecting p-chloro-ω-chloroacetanilide to a ring closure reaction in the presence of aluminum chloride, a 3-fold molar amount relative to p-chloro-ω-chloroacetanilide is used. A method for producing 5-chlorooxindole, which comprises using the above aluminum chloride.