JPH08225525A - Production of oxyindoles - Google Patents

Abstract

PURPOSE: To obtain oxyindoles of a high purity in a high yield by one pot without passing through troublesome steps using a specific halogenophenylacetic acid as a starting raw material. CONSTITUTION: (A) A 2-halogenophenylacetic acid of formula I [X1 is Cl or Br; Z is H, a halogen, an alkyl or an alkoxy; R is H, an alkyl or an alkoxy; M1 is H, ammonium or an alkali metal; (n1 ) is 1 to 4] or its salt is reacted with (C) ammonia in the presence of (B) a copper salt catalyst (e.g. cuprous chloride) and a mixture of the produced (D) 2-aminophenylacetic acid or its salt with oxyindoles of formula II is heated in the presence of an acid catalyst so as to cyclize the component D to provide the objective compound. Furthermore, the component A is heated in an aqueous solution of the component C to aminate the component A and a series of operations ranging from amination to ring closing is preferably carried out while blocking air or in the presence of an inert gas.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing oxindoles useful as a synthetic raw material for agricultural chemicals, pharmaceuticals and the like.

[0002]

BACKGROUND OF THE INVENTION Many phenyl nucleus-substituted indole derivatives are known to have biochemical effects.
It is used for medicines. Various methods have been proposed as methods for producing oxindole and chloro-substituted indole, which are synthetic raw materials at that time.

For example, a method of synthesizing ω-chloroacetanilide or a nuclear chloro-substituted product thereof from aniline or a chloro-substituted product thereof and chloroacetyl chloride and heating the mixture at 220 to 230 ° C. in the presence of aluminum chloride to effect ring closure ( For example, RA Abramovitch
et al.), J. Chem. Soc., 1954 , 1697 to 1704 or JP-A-6-184108), or a method of catalytically reducing 2-nitrophenylacetic acid or its ester to perform reductive ring closure (for example, G. Hahn et
al.), Chem. Ber., 74 , 500-519 (1941) or TV RajanBabu et al., J. Org. Chem.,
51 , 1704-1712 (1986)) and the like have been proposed. But,
In the former method, the ring is closed at a high temperature of 220 ° C. or higher in the presence of aluminum chloride, so that the reactor is greatly restricted. In the latter case, it is difficult to say that 2-nitrophenylacetic acid as a raw material is suitable for industrial use.

Alternatively, a method for producing oxindole by ammonolysis of 2-chlorophenylacetic acid in aqueous ammonia in the presence of a copper catalyst and simultaneously ring closure (Alexander B. Neill, J. A.
mer. Chem. Soc., 75 , 1508, (1953)) is known, but in this method, 2-chlorophenylacetic acid as a raw material is relatively easy to obtain, and oxindole can be produced in one step. However, the reaction temperature is 1
Since it is a relatively high temperature of 55 to 165 ° C, there are problems such as restrictions on the material of the reactor and a low yield of 34 to 43%.

As a method for improving the above-mentioned ammonolysis method, a method has been proposed in which 2-halogenophenylacetic acid ester is used as a starting material and an amination reaction and a ring-closing reaction are carried out in aqueous ammonia in the presence of a copper salt ( Japanese Patent Publication No. 62-28133). In this method,
It is expected that the halogenophenyl acetic acid ester undergoes ammonolysis through the corresponding acid amide in the reaction system. According to the example, oxindole was produced from the raw material 2-chlorophenylacetic acid methyl ester in a yield of 78%.
Although the yield is higher than the method carried out by Nail, the reaction temperature is as high as 190 ° C., and further ammonia gas is enclosed until the pressure reaches 10 kg / cm ² G before heating, There is a problem that the time pressure increases significantly. Therefore, this method is also largely restricted by the material of the reaction vessel and the specifications of the apparatus when it is industrially carried out. Furthermore, there are problems that the cost is disadvantageous because an ester is used as a raw material, and that separation of alcohol and by-product, which is a by-product when ammonia is recovered after the reaction, becomes complicated.

Generally, when amination of a halide in aqueous ammonia is carried out, the ammonium halide produced as a by-product during the reaction lowers the pH of the reaction solution. It is known that the reaction temperature should be lowered to suppress this (for example, by PH Groggins, Unit Processes in Organic Synt.
hesis, International Student Edition, pp. 388-39
7), published by McGraw-Hill). When such a reaction is industrially carried out, stainless steel is generally used as the material of the reaction vessel, but at this time, lowering the reaction temperature prevents corrosion of the reaction vessel by suppressing the pH decrease. In addition, it is very significant in terms of easing the pressure resistance of the device due to the decrease in reaction pressure.

[0007]

SUMMARY OF THE INVENTION Therefore, the object of the present invention is to obtain oxindoles with high purity and high yield from a relatively easily available raw material by a method that does not require complicated steps and has few restrictions on the reactor. It is to provide a method for industrially manufacturing at a rate.

[0008]

As a result of intensive studies in view of the above problems, the present inventors have found that when the 2-position of 2-halogenophenylacetic acid or a salt thereof is substituted with an amino group, the reaction temperature is higher than that of the conventional reaction temperature. When the amination reaction is carried out under a high selectivity with a large decrease, in the reaction product, in addition to the corresponding oxindoles, the precursor 2-aminophenylacetic acid or its salt is usually present. It was confirmed that a large amount of was mixed. After removing the catalyst and excess ammonia from this reaction product, the residual 2-aminophenylacetic acid or a salt thereof was converted into oxindoles by ring closure by heating in the presence of an acid catalyst, resulting in high purity and high yield. It was found that oxindoles can be obtained, and the present invention has been completed based on this finding. That is, the present invention provides (1) Formula (I)

[0009]

Embedded image

(In the formula, X ₁ represents a chlorine atom or a bromine atom, Z represents a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, R represents a hydrogen atom, an alkyl group or an alkoxy group, and M ₁ represents Represents a hydrogen atom, an ammonium group or an alkali metal, X ₁ and Z may be the same or different, and n ₁ represents an integer of ₁ to 4)
2-halogenophenylacetic acid or a salt thereof (hereinafter, simply referred to as 2-halogenophenylacetic acid in the general description of the invention) is reacted with ammonia in the presence of a copper salt catalyst,
The formed 2-aminophenylacetic acid or a salt thereof and the formula (II)
To heat the mixture with the oxindole represented by the formula (1) in the presence of an acid catalyst to ring-close 2-aminophenylacetic acid or a salt thereof (hereinafter, simply referred to as 2-aminophenylacetic acid in the general description of the invention). Characteristic formula (II)

[0011]

[Chemical 4]

(In the formula, Z, R and n ₁ have the same meaning as in formula (I).) A method for producing oxindoles, (2) Amination is carried out by heating in aqueous ammonia (1). ) The method for producing oxindoles according to item 1), and (3) the series of operations from amination to completion of ring closure are carried out under air exclusion or in the presence of an inert gas (1) or (2). The present invention provides a method for manufacturing a class of products.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The phenyl group and / or methylene group of 2-halogenophenylacetic acid used as a starting material in the process for producing oxindoles in the present invention is a bulky compound which does not inhibit an amination reaction and a subsequent ring closure reaction. It may be substituted with a non-highly substituted group. Preferably, Z is a hydrogen atom, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom), an alkyl group or an alkoxy group,
R is a hydrogen atom, an alkyl group or an alkoxy group. This compound, 2-halogenophenylacetic acid, may be a free acid, an ammonium salt, or an alkali metal salt such as potassium or sodium, and preferably a free acid.

Further, the 2-halogenophenylacetic acid used in the present invention is preferably a compound represented by the following formula (III), specifically 2-chlorophenylacetic acid and 2-chlorophenylacetic acid.
Bromophenylacetic acid, 2,3-dichlorophenylacetic acid,
2,4-dichlorophenylacetic acid, 2,5-dichlorophenylacetic acid, 2,6-dichlorophenylacetic acid, 2-chloro-4-fluorophenylacetic acid, 2-chloro-5-fluorophenylacetic acid, 2-chloro-6-fluorophenylacetic acid , 2-chloro-5-bromophenylacetic acid, 2,4,5
-Trichlorophenylacetic acid, particularly preferably 2-chlorophenylacetic acid, 2,4-dichlorophenylacetic acid, 2,5-dichlorophenylacetic acid, 2-chloro-5-
Bromophenylacetic acid. Oxindoles of formula (IV) are obtained from the compound of formula (III). Formula (III)

[0015]

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(In the formula, X represents a chlorine atom or a bromine atom, Y represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, and M represents a hydrogen atom, an ammonium group or an alkali metal. X and Y represent They may be the same or different from each other, and n represents an integer of 1 to 4.) Formula (IV)

[0017]

[Chemical 6]

(In the formula, Y and n have the same meanings as in formula (III).) Preferably, the amination reaction in the present invention is carried out in an ammonia water which also serves as a reaction solvent, using a pressure resistant reaction vessel. . Ammonia water concentration is preferably 10 to 50 wt
%, More preferably 20 to 35 wt%. If the concentration of ammonia is too low, the proportion of 2-hydroxyphenylacetic acid, which is a hydrolysis product, as a by-product is increased, and the pH in the reaction system is lowered, which adversely affects the corrosion resistance of the reaction vessel. If the concentration of ammonia is too high,
Since the pressure during the reaction becomes extremely high, the specifications of the reaction device may be restricted, and the ammonia water may be disadvantageous for recovery and reuse. The amount of ammonia used is preferably 3 to 45 times mol, more preferably 6 to 3 times, with respect to 1 mol of 2-halogenophenylacetic acid represented by the formula (I).
It is 5 times the molar amount. If the amount of ammonia used is too small, stirring may become difficult and the corrosion of the reactor may increase. If the amount is too large, the reaction result does not improve and the production efficiency decreases.

The reaction temperature of the amination reaction of the present invention is 70 to
The temperature is 140 ° C, preferably 90 to 120 ° C, more preferably 100 to 110 ° C. If the reaction temperature is too low, the reaction rate will be slow, and if it is too high, the yield and quality will decrease due to an increase in the amount of by-products of coloring or tar-like impurities, and there will be restrictions on the corrosion resistance and pressure resistance of the reactor. May occur. The reaction pressure depends on the concentration of ammonia water, the reaction temperature, etc., but is usually 5 to 8 kg / cm ² G. The reaction time is usually preferably 1 to 30 hours, more preferably 14 to 24 hours.

A copper salt can be used as a catalyst for the amination reaction of the method for producing oxindoles of the present invention,
Specifically, monovalent copper salts such as cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cupric chloride, cupric hydroxide, cupric oxide, There may be mentioned divalent copper salts such as copper sulfate, and cuprous chloride, due to reaction activity and selectivity.
More preferred are monovalent copper salts such as cuprous bromide, cuprous iodide, and cuprous oxide. The amount of the catalyst used is 0.001 to 1 mol of 2-halogenophenylacetic acid represented by the formula (I) in terms of copper atom in both monovalent and divalent copper salts.
It is 1.0 gram atom, preferably 0.05 to 0.3 gram atom. If the amount of the catalyst is too small, the reaction rate becomes slow and a large amount of unreacted raw material remains. On the other hand, if the amount is too large, the catalyst removal operation in the post-treatment becomes complicated, which is not preferable.

By the above reaction, the conversion rate of the starting material reaches 93 to 100%. The amination reaction of the present invention allows the conversion reaction in which the halogen atom at the 2-position of the phenyl group of 2-halogenophenylacetic acid is replaced with an amino group. When the conversion reaches 90% or more, preferably 95% or more, the first stage reaction is terminated. At this time, oxindole is formed, but it is not preferable to react the generated 2-aminophenylacetic acid for a long time until all of the generated 2-aminophenylacetic acid is converted, because it causes thermal decomposition of 2-aminophenylacetic acid and an increase in coloring impurities.

The product thus obtained usually contains, in addition to the corresponding oxindoles, a large amount of its precursor, 2-aminophenylacetic acid, and its composition is usually 2-aminophenyl. Oxindole is in the range of 20 to 70 mol%, preferably 30 to 60 mol%, based on the total amount of acetic acid and oxindole. After removing the copper salt catalyst and excess ammonia from the reaction product, an acid catalyst is added to the oxyindoles to be rapidly ring-closed by heating the 2-aminophenylacetic acid to obtain oxindoles in high yield and high purity. be able to.

Removal of the copper salt catalyst and excess ammonia is
It can be carried out by an ordinary method such as distilling ammonia after treating the resin with a suitable chelating resin to separate the resin which becomes a copper complex. At this time, in order to decompose the ammonium salt formed in the amination reaction to form free ammonia,
In addition, in order to suppress the thermal decomposition of 2-aminophenylacetic acid, alkali hydroxide is added to make it alkaline, preferably pH 10 or higher. After removal of the copper salt catalyst and excess ammonia, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
Alternatively, an organic acid such as p-toluenesulfonic acid or methanesulfonic acid is added to adjust the acidity, preferably pH 2 to 5, more preferably pH 2 to 3, and the mixed 2-aminophenylacetic acid is heat-closed to oxindole. Be similar. When the pH is lower than 2 and close to 1, 2-aminophenylacetic acid is easily decomposed, which is not preferable. The heating temperature for ring closure is preferably 30 to 100 ° C., and 50 to
80 ° C. is more preferable. If the heating temperature is too high 2-
Aminophenylacetic acid is easily decomposed, which is not preferable. The heating time is several minutes to several hours, preferably 30 minutes to 3 hours. The conversion of 2-aminophenylacetic acid to oxindoles can be confirmed by analyzing this reaction product by high performance liquid chromatography or the like. In addition, at the time of heating for ring closure, it may be possible to carry out in the state of an aqueous solution as it is, such as unsubstituted oxindole having high solubility in water, but crystals are precipitated in chloro-substituted oxindoles having low solubility. It may become an aqueous slurry. In such a case, in order to accelerate the ring-closing reaction, water may be added, or a lower alcohol such as methanol or ethanol, or an inert solvent such as acetonitrile may be added, if necessary.

After the ring-closing reaction, an alkaline aqueous solution is added to make the reaction product containing oxindoles weakly alkaline,
The unreacted raw material and the phenolic impurities may be changed to alkali metal salts, which may be easily removed in the subsequent crystallization. Thereafter, the crystals can be cooled to precipitate crystals of oxindole, and the crystals can be taken out by adding operations such as filtration, washing with water, and drying. The color of the product may be improved by adding an activated carbon treatment operation before crystallization or adding a suitable solvent such as toluene or xylene during crystallization. In the method for producing oxindoles of the present invention, it is preferable to carry out a series of operations from amination to completion of ring closure under air exclusion or in the presence of an inert gas such as nitrogen, helium or argon.

[0025]

According to the present invention, it is relatively easy to obtain 2
-By using halogenophenylacetic acid as a starting material, oxindoles can be industrially produced in a single pot with high purity and high yield without complicated steps. Further, in the method for producing oxindoles of the present invention, since the amination is performed at a temperature significantly lower than that of the conventional method, it is possible to suppress the decrease in the pH of the reaction solution, and to prevent the corrosion, the pressure resistance, and other specifications of the reaction apparatus. There is an excellent effect that the restriction of 1 can be relaxed.

[0026]

The present invention will be described in more detail based on the following examples, but the invention is not intended to be limited thereto. The melting points in the examples were measured using an FP-62 type automatic melting point measuring device (manufactured by Mettler).

Example 1 (Synthesis of oxindole) In a stainless steel autoclave having a volume of 3 liters, 427 g (2.50 mol) of 2-chlorophenylacetic acid, 2040 g (30.0 mol) of 25% aqueous ammonia and cuprous chloride as a catalyst. 25.0 g (0.25 mol) was added and the mixture was sealed. After purging the internal air with nitrogen,
The reaction was allowed to stir for a period of time. The internal pressure during the reaction was 6.8 to 5.6.
It was kg / cm ² G. After the reaction, cool to 30 ° C,
The amination reaction mixture was removed under a blanket of nitrogen. When the reaction mixture was analyzed by high performance liquid chromatography, the conversion of 2-chlorophenylacetic acid was 95.6%,
Oxindole is 33.4 mol% and its precursor is 2-
Aminophenylacetic acid was produced in an amount of 56.7 mol%, and the total yield of oxindole and 2-aminophenylacetic acid was 90.1%. In addition, 5.2% of 2-hydroxyphenylacetic acid was by-produced.

To the reaction product thus obtained, 416 g of a 48% sodium hydroxide aqueous solution was added. After removing dissolved ammonia and catalyst, about 330 g of 35% hydrochloric acid
Is added at 65 to 70 ° C. until the pH becomes 2, and 1 at the same temperature
After stirring for 2 hours, the remaining 2-aminophenylacetic acid was closed to give oxindole. Then, add 10% sodium hydroxide aqueous solution to adjust the pH to 8 and powder activated carbon 2.5 g.
Was added, and the mixture was decolorized at 90 to 95 ° C and filtered by heating. Toluene (500 g) was added and cooled to room temperature for crystallization. The precipitated crystals were filtered, washed with water and dried to obtain 260 g (yield 78.1%) of white crystals of oxindole. Purity 99.0%, m.p. p. 125.5 ° C

Example 2 (Synthesis of 6-chlorooxindole) 226 g (1.10 mol) of 2,4-dichlorophenylacetic acid in a 3 liter stainless steel autoclave, 30%
2300 g (40.5 mol) of aqueous ammonia and 21.8 g (0.22 mol) of cuprous chloride as a catalyst were added and the mixture was sealed. After purging the internal air with nitrogen, 2 at 100 ° C
The mixture was stirred and reacted for 2 hours. The internal pressure during the reaction was 8.2 to 7.
It was 5 kg / cm ² G. After the reaction, the temperature was cooled to 30 ° C., and the amination reaction mixture was taken out. To this was added 184 g of 48% aqueous sodium hydroxide solution. After removing the dissolved ammonia and catalyst, analysis by high performance liquid chromatography revealed that the conversion of 2,4-dichlorophenylacetic acid was 98.7% and the yield of 6-chlorooxindole was 62.5%. In addition, about 20% of 2-amino-4-chlorophenylacetic acid was by-produced. After water was added to the reaction product to make the total amount 4000 g, about 140 g of 85% phosphoric acid was added at 75 to 80 ° C. until the pH reached 3, to precipitate crystals. Further, the mixture was stirred at the same temperature for 2 hours and the remaining 2-amino-4-chlorophenylacetic acid was closed to give 6-chlorooxindole.

The slurry thus obtained was adjusted to pH 8 by adding 10% aqueous sodium hydroxide solution, cooled to room temperature, filtered, washed with water and dried to give 137 g of 6-chlorooxindole as pale yellow crystals (yield 74. 3%) was obtained. m. p. 192.4 ° C

This product was dissolved in 10 to 15 times the amount of methanol under heating, treated with activated carbon and recrystallized to obtain 6-chlorooxindole as white crystals. m. p. 198.6 ° C. ¹ H-NMR (DMSO-d ₆ + CDCl ₃ ) δppm 3.43 (s, 1H, CH ₂ ), 6.85
7.27 (m, 3H), 10.46 (s, br, D ₂ O
Exchangeable 1H, CONH), IR (KBr, cm ^-1 ) 3148, 3036, 1698, 1618, 1487,
1457, 1332, 1302, 933, 822, 56
1

Example 3 50.0 g (0.50 mol) of double cuprous chloride as a catalyst
The processes up to the amination reaction were carried out in the same manner as in Example 1 except for the above. After the reaction, the reaction mixture was analyzed by high performance liquid chromatography to find that the conversion of 2-chlorophenylacetic acid was 99.3% and that of oxindole was 37.8.
%, Its precursor 2-aminophenylacetic acid 54.0%
The total yield of oxindole and 2-aminophenylacetic acid was 91.8%. Besides 2-
Hydroxyphenylacetic acid was produced by 7.1%. In the same manner as in Example 1, 48% sodium hydroxide was added to this reaction product, and then the dissolved ammonia and catalyst were removed. Subsequently, the mixture was cooled to room temperature without ring-closing treatment, and the precipitated crystals were filtered, washed with water, and dried to obtain 114 g of light brown oxindole (yield 34.2%). Purity 98.6%, m.p. p. 125.2 ° C. Further, about 310 g of 50% sulfuric acid is added to the filtrate to adjust the pH to 2
Then, the resulting 2-aminophenylacetic acid was ring-closed to give oxindole.
Then add 10% sodium hydroxide to bring the pH to 8,
Crystallization was performed by cooling to room temperature. The precipitated crystals were filtered, washed with water and dried to give 153 g of light brown oxindole (yield 4
5.9%) was obtained. Purity 98.6%, m.p. p. 125.2 ° C. The total yield of oxindole was 80.1%.

COMPARATIVE EXAMPLE 1 Except that the heat ring-closing treatment with the addition of 35% hydrochloric acid was not carried out,
Processing was carried out in the same manner as in Example 1. The oxindole yield was 40%.

COMPARATIVE EXAMPLE 2 427 g (2.50 mol) of 2-chlorophenylacetic acid as a raw material was mixed with 462 g (2.5
The treatment was carried out in the same manner as in Example 1 except that the amount was changed to 0 mol). The conversion of methyl 2-chlorophenylacetate after the amination reaction was 100%, but it contained 33 mol% of 2-chlorophenylacetamide. The yield of oxindole contained in the reaction solution after the completion of the heat-ring closure operation by adding 35% hydrochloric acid was 46.3%.

Comparative Example 3 Treatment was carried out in the same manner as in Example 1 except that 21.8 g (0.22 mol) of cuprous chloride as a catalyst was replaced with 14.0 g (0.22 gram atom) of copper powder. . The raw material recovery rate after the amination reaction was 99% or more, and the total yield of oxindole and 2-aminophenylacetic acid was less than 1%.

Claims (3)

[Claims] 1. Formula (I): (In the formula, X ₁ represents a chlorine atom or a bromine atom, Z represents a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, R represents a hydrogen atom, an alkyl group or an alkoxy group, M ₁ represents a hydrogen atom, An ammonium group or an alkali metal, X ₁ and Z may be the same or different, and n ₁ represents an integer of ₁ to 4) and the presence of a copper salt catalyst in 2-halogenophenylacetic acid or a salt thereof. Then, a mixture of 2-aminophenylacetic acid or a salt thereof and the oxindole represented by the formula (II) is heated in the presence of an acid catalyst to react 2-aminophenylacetic acid or a salt thereof with lower ammonia. Formula (II) characterized by ring closure (In the formula, Z, R and n ₁ have the same meanings as in formula (I).) A method for producing oxindoles. 2. The method for producing oxindoles according to claim 1, wherein the amination is carried out by heating in aqueous ammonia. 3. The method for producing oxindoles according to claim 1 or 2, wherein a series of operations from amination to completion of ring closure are carried out under air exclusion or in the presence of an inert gas.