JP2541882B2 - Method for producing anthranilic acids - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing anthranilic acid useful as a synthetic raw material for medicines, agricultural chemicals, dyes and the like.

[0002]

2. Description of the Related Art As an industrial method for producing anthranilic acid, a method is known in which phthalimide obtained from phthalic anhydride and ammonia is reacted with sodium hypochlorite and sodium hydroxide. It is difficult to apply to various anthranilic acids having a substituent on the aromatic nucleus.

As a method for synthesizing an anthranilic acid having a substituent in the nucleus, for example, 4-chloroanthranilic acid, 2-nitro-4-chlorotoluene is used as a starting material and reduced to give 2-amino-4-chlorotoluene. Then, a method of undergoing several steps of reaction of acetylation of amino group, oxidation of methyl group, and hydrolysis (deacetylation) is described in 1946, Journal of American Chemical Society, Volume 68, 1285. ~ Introduced on page 1288. However, in this method, since the number of steps is large, it is difficult to inexpensively obtain a high quality target compound.

On the other hand, a method of synthesizing anthranilic acid by orthohalogenobenzoic acid as a raw material and ammonolyzing this in ammonia water is already known, but few reports have been made. For example, in an old German patent (DRP, 145604, 1902) of Hoechst, anthranilic acid is synthesized from 2-chlorobenzoic acid in ammonia water at 125 ° C using copper powder as a catalyst. However, even after removing excess ammonia from this reaction mixture and subjecting it to acid precipitation with mineral acid as it is, the obtained 4-chloroanthranilic acid contains a large amount of a copper compound insoluble in water or an organic solvent. Therefore, it is colored from gray-purple to yellow-green and its purity is low.

The cause of this is that in the ammonolysis of these orthohalogenobenzoic acids, the metallic copper or the copper-containing catalyst used as a catalyst remains dissolved in the reaction mixture after the reaction in the form of a copper-ammonium complex compound, and a part of it remains. This is considered to form a stable chelate complex compound with anthranilic acid which is a reaction product. As a method of removing the catalyst dissolved as a copper ammonium complex compound, treatment with an aqueous solution of alkali hydroxide to precipitate and separate as copper oxide, treatment with an alkali sulfide or alkali hydrosulfide to separate and precipitate as copper sulfide, and ion It is possible to separate copper by adsorbing copper on the exchange resin, but in the method of or, since the alkali hydroxide or alkali sulfide aqueous solution itself dissolves copper oxide or copper sulfide, it completely precipitates as copper oxide or copper sulfide, This method is not practical because it has a drawback that it cannot be separated, and the method also has a drawback that a large amount of ion exchange resin is required and operations such as desorption and regeneration are complicated.

Further, as a method for synthesizing 4-chloroanthranilic acid from 2,4-dichlorobenzoic acid as a raw material,
The partial ammonolysis method in ammonia water is Samant (S
amant) [Samant, Ber., 75B, 1008 (19
42)]. In a more recent report, Yakhontov
Et al. Are trying to synthesize by the same route [Yakhontov, LNe
Tal. Khim.- Farm. Zh., 21 (1), 38-49 (1987)]. Samanto uses 0-valent metallic copper alone as a catalyst and reacts it in 37% ammonia water at 120 ° C. for 4 hours. Yacomto et al. Also used 126-129 as a catalyst using copper acetate, which is a divalent copper compound. The reaction is carried out at 0 ° C for 10 hours. However, as a result of the inventors repeating each method, both methods have low reaction conversion rates and a large amount of unreacted 2,4-dichlorobenzoic acid remains, so that the quality of the isolated product deteriorates. It was confirmed. It is not easy to purify by removing unreacted raw materials mixed in the product without impairing the yield, which deviates from the original purpose of obtaining 4-chloroanthranilic acid at low cost. Further, in both methods, since the reaction temperature and pressure are relatively high, there is a drawback in that the rate of side reaction to be hydroxylated other than the original amination reaction and the rate of thermal decomposition of the product is increased. It is not preferable because the material and the specifications of the device are greatly restricted.

[0007]

SUMMARY OF THE INVENTION Therefore, the object of the present invention is to provide a new route, which is different from the routes conventionally used industrially, for ammonolysis of orthohalogenobenzoates in a one-step reaction to give the corresponding anthranil. An object of the present invention is to provide a method for producing acids at low cost, efficiently and in high yield.

[0008]

Means for Solving the Problems The inventors of the present invention have surprisingly studied as a result of ammonolysis of such conventional orthohalogenobenzoic acids to synthesize the corresponding anthranilic acids, and as a result, unexpectedly Also has an oxidation state of 0
It was found that cuprous, which is located between the valent metal copper and cupric, is extremely effective as a catalyst for synthesizing the corresponding anthranilic acid from orthohalogenobenzoic acids, and the present invention is based on this finding. It came to eggplant.

That is, the present invention has the general formula (I)

Embedded image (In the formula, Y is a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, an alkoxy group, an acetoxy group, a nitro group,
It represents an amino group, a sulfo group, a carboxyl group, a trifluoromethyl group, or an aryl group, and Y may be the same or different from each other. n shows the integer of 1-4.
M is selected from a hydrogen atom, an ammonium group, an alkali metal atom, or an alkaline earth metal atom. ) In producing the anthranilic acid represented by the general formula (II)

Embedded image (In the formula, X represents a halogen atom selected from chlorine, bromine, and iodine, and Y, n, and M have the same meanings as described above.) In the presence of a cuprous-containing catalyst. The present invention provides a method for producing anthranilic acids, which comprises reacting in aqueous ammonia under heating.

Hereinafter, the present invention will be described specifically. The orthohalogenobenzoic acid used as a starting material in the method of the present invention is a compound represented by the general formula (II),
Specifically, 2-chlorobenzoic acid, 2-bromobenzoic acid,
2-iodobenzoic acid, 2,3-dichlorobenzoic acid, 2,
4-dichlorobenzoic acid, 2,5-dichlorobenzoic acid,
2,6-dichlorobenzoic acid, 2-chloro-4-fluorobenzoic acid, 2-chloro-6-fluorobenzoic acid, 2-chloro-4,5-difluorobenzoic acid, 2,4-dichloro-5-fluorobenzoic acid Acid, 2,3,4-trichlorobenzoic acid, 2,3,5-trichlorobenzoic acid, 2,4,5-
Trichlorobenzoic acid, 2,4,6-trichlorobenzoic acid, 2,3,4,5-tetrachlorobenzoic acid, 2-chloro-4-methylbenzoic acid, 2-chloro-5-methylbenzoic acid, 2-chloro -6-Methylbenzoic acid, 2-chloro-
3-hydroxybenzoic acid, 2-chloro-4-hydroxybenzoic acid, 2-chloro-3-nitrobenzoic acid, 2-chloro-4-nitrobenzoic acid, 2-chloro-5-nitrobenzoic acid, 4-amino- 2-chlorobenzoic acid, 5-amino-
2-chlorobenzoic acid, chloroterephthalic acid, 4-chloroisophthalic acid, 3,4-dichlorophthalic acid, 5-chlorotrimellitic acid, 2-chloro-4-trifluoromethylbenzoic acid, 1-chloro-2-naphthoate Acid, 3-chloro-
2-naphthoic acid and the like are exemplified, and these may be not only free acids but also ammonium salts, alkali metal salts such as K and Na, and alkaline earth metal salts such as Mg and Ca.

The ammonolysis reaction in the present invention is
It is carried out in ammonia water using a pressure-resistant reaction container and also serving as a reaction solvent. The concentration of aqueous ammonia is preferably 1
It is 0 to 50 wt%, more preferably 20 to 35 wt%.
If the concentration of ammonia becomes too low, the proportion of salicylic acid derivatives by-produced will increase and the pH will decrease,
It adversely affects the corrosion resistance of the reaction vessel material. If the concentration becomes too high, the by-products of diphenylamine dicarboxylic acid type derivatives will increase, and industrially the pressure during the reaction will become extremely high, which will limit the specifications of the reactor, and when recovering and reusing ammonia water. Will be at a disadvantage.

The amount of ammonia used is preferably 3 to 40 times mol, more preferably 6 to 25 times mol, relative to 1 mol of orthohalogenobenzoic acid. If the amount is less than this, stirring becomes difficult and the corrosion of the apparatus may increase. Further, even if it is used in a larger amount than necessary, the reaction result does not improve and the production efficiency only decreases.

The cuprous-containing catalyst used in the method of the present invention is, for example, a copper compound in the oxidation state of cuprous, and specifically, cuprous oxide, cuprous chloride, cuprous bromide. , Cuprous iodide, copper thiocyanate or copper cyanide. Further, the present invention uses any combination of zero-valent metallic copper and a copper compound in the oxidation state of cupric acid, and as shown by the following formula, an equivalent mixture of metallic copper and cupric compound reacts. It may be the case that the cuprous oxide may exist in a substantially oxidized state due to the disproportionation reaction of the ionic valence. Cu + Cu ²⁺ → 2Cu ⁺

Copper compounds in the oxidation state of cupric used in combination with zero-valent copper metal (oxides, hydroxides, fluorides, chlorides, bromides, iodides, acetates, carbonates,
(One or more selected from perchlorates, nitrates, phosphates and sulfates), specifically, cupric oxide, cupric hydroxide, cupric fluoride, cupric chloride Copper, cupric bromide, cupric iodide, ammonium cupric chloride, copper acetylacetonate, copper borofluoride, copper formate, copper acetate, copper citrate, copper oxalate, copper stearate, copper carbonate, Examples include copper perchlorate, copper nitrate, copper phosphate, copper pyrophosphate, copper sulfate and the like. One or more of these copper compounds are used together with metallic copper. The metallic copper may be added in the form of powder, shaving, or any other shape. Of these,
Copper compounds in the oxidation state of copper metal and cuprous metal are easily oxidized by oxygen in the air in ammonia water and converted to copper ammonium complex compounds in the oxidation state of cupric acid, which reduces the catalytic action. When the catalyst is added to the reaction vessel, it is essential to quickly purge the air with an inert gas such as nitrogen.

The amount of the cuprous-containing catalyst used in the present invention is 1 mol of orthohalogenobenzoic acid as a raw material.
It is 0.001 to 1.0 gram atom, preferably 0.02 to 0.3 gram atom in terms of copper atom. As described above, it is usually used as a cuprous compound, but a zero-valent metallic copper and a cupric compound may be used in combination. In this case, the metallic copper and the cupric compound do not necessarily have to be in the same amount, and if one of them is in the above-mentioned catalytic amount range as cuprous due to the disproportionation of the valence, either one becomes excessive. Good. If the amount of cuprous copper is less than this, the reaction rate becomes slow and unreacted raw materials remain. Further, if it is used in a larger amount than necessary, the catalyst removal operation in the post-treatment becomes complicated, which is not preferable.

The reaction temperature is preferably 50 to 160 ° C, more preferably 70 to 120 ° C. If the reaction temperature is too low, the reaction rate will be slow, and if it is too high, the rate of by-products of salicylic acid derivatives and the thermal decomposition (decarboxylation) of the target substance will increase, resulting in a decrease in yield and quality. There are problems and restrictions in terms of.

In the method of the present invention, it is preferable to treat the catalyst contained in the reaction solution after the completion of the reaction and recover it as metallic copper. As a method therefor, a. The reaction mixture containing the copper-containing catalyst is treated with a dithionite salt, for example, hydrosulfite (Na ₂ S ₂ O ₄ ) to deposit metallic copper, which is then separated to remove anthranilic acids from the reaction solution. A method of isolating, b. A reaction mixture containing a copper-containing catalyst is treated with any one of hydrazine compounds selected from hydrazine, hydrazine hydrate, and neutral hydrazine sulfate to precipitate metallic copper, and then the reaction solution is removed and separated from the reaction solution. There is a method for isolating anthranilic acids.

[0018] dithionite salt or as in this way reducing agent
Others can be reduced a copper compound to metallic copper by the addition of hydrazine compounds. The amount of these reducing agents used is 0.1 to 10 mol, preferably 0.5 to 2 mol, per 1 gram atom of copper in the catalyst. This amount corresponds to 0.0001 to 10 mol with respect to 1 mol of orthohalogenobenzoic acid as a raw material. If the amount of the reducing agent is less than this, the reduction becomes insufficient, and a copper compound is mixed in the product to deteriorate the quality. Increasing the amount of reducing agent beyond this is uneconomical and causes problems in wastewater treatment. Preferably, nitrite or hydrid
The amount of radine compound used is the orthohalogenobenzoic scent of the raw material.
The amount is 0.001 to 2 mol with respect to 1 mol of the acid.

The reducing agent used in the present invention may be added after the reaction is completed, after most of the ammonia is once discharged and recovered from the reaction mixture, or may be added before the operation of recovering ammonia. Further, it may be added together with a caustic alkali which is usually used for decomposing the ammonium salt formed in the reaction. Usually, the reaction mixture is treated with a reducing agent while avoiding contact with air, and stirred at a temperature range of room temperature to 100 ° C. for several minutes to several tens of hours to deposit metallic copper. At this time, it is preferable to set the temperature to 80 to 100 ° C. and sufficiently remove the dissolved ammonia under normal pressure or reduced pressure.
Further, as described above, the addition of caustic alkali is preferable in order to decompose the ammonium salt and completely discharge the ammonia. The caustic alkali is usually used in an amount of 1 to 3 mol with respect to 1 mol of orthohalogenobenzoic acid as a raw material.

When the deposited metallic copper is separated by a method such as filtration or decantation, a normally pale yellow transparent solution containing an alkali metal salt of anthranilic acid is obtained. When this is treated with a mineral acid, white to light tan anthranilic acids are isolated in a high yield of 90 to 95%.

Industrial Applicability According to the method of the present invention, desired anthranilic acids can be obtained in high purity and high yield by only one-step reaction of ammonolysis in the presence of cuprous catalyst.
According to the present invention, the temperature is lower than the conventional one and the pressure is 80 to 100 ° C.
The reaction can be completed within a few hours even under mild conditions of ^{3 to} 6 kg / cm ² G, and the proportion of side reactions can be suppressed, so that high-purity anthranilic acid can be synthesized inexpensively and in good yield. In addition, since the reaction temperature and the pressure during the reaction are significantly reduced, the facility conditions relating to the corrosion resistance and pressure resistance of the reaction vessel can be relaxed, which is suitable for industrial implementation. Furthermore, by treating the reaction liquid with a specific reducing agent after completion of the reaction, it becomes possible to efficiently separate the copper compound. Thus, anthranilic acids can be synthesized from orthohalogenobenzoic acid with high purity and high yield.

[0021]

The present invention will be described in more detail based on the following examples.

EXAMPLE 1 190 g (2.79 mol) of 25% ammonia water and 30.0 g (0.157 mol) of 2,4-dichlorobenzoic acid were charged into a 300 ml stainless pressure reaction vessel and stirred to prepare milk. It dissolved until it became cloudy. 1.55 g (0.0157 mol) of cuprous chloride as a catalyst was added thereto, and the reaction vessel was sealed. After purging the internal air with nitrogen, 100 ℃
The mixture was stirred for 6 hours and reacted. Internal pressure during reaction is 4.9-
It was 4.3 kg / cm ² G.

After cooling to ambient temperature, the reaction mixture was withdrawn by opening the reaction vessel under a nitrogen blanket. The reaction mixture was analyzed by high performance liquid chromatography (internal standard method using o-hydroxydiphenyl as an internal standard substance) to give the following analytical values, the reaction conversion rate was 100%, and the selectivity of 4-chloroanthranilic acid was 96. It was 0.2%. 4-chloroanthranilic acid 0.1510 mol 4-chlorosalicylic acid 0.0028 mol 2,4-dichlorobenzoic acid Not detected

After the dissolved ammonia and catalyst were removed from the reaction mixture thus obtained, it was subjected to acid precipitation treatment with a mineral acid to obtain 25.8 g of 4-chloroanthranilic acid having a purity of 98.6%. Further, recrystallization from a mixed solvent of alcohol and water yielded 24.1 g of 4-chloroanthranilic acid having a purity of 99.7% as white needle crystals. 2,4
-The yield based on dichlorobenzoic acid was 89.4%.

Comparative Examples 1 to 4 4-Chloroanthranilic acid was synthesized under the same reaction conditions as in Example 1 except that the catalyst was changed to a metallic copper or cupric compound alone. The results are shown in Table 1.

[0026]

[Table 1]

Example 2 190 g of 25% aqueous ammonia was placed in the same reaction vessel as in Example 1.
(2.79 mol) and 2,3-dichlorobenzoic acid 30.
0 g (0.157 mol) was charged and stirred, and dissolved until it became an emulsion. 1.12 g of cuprous oxide as a catalyst
(0.00783 mol) was added and the reaction vessel was sealed.
After purging air with nitrogen, the mixture was stirred at 110 ° C. for 6 hours. The internal pressure during the reaction was 6.8 to 6.5 kg / cm ² G.

When the reaction mixture was analyzed in the same manner as in Example 1, the following analytical values were given, and the reaction conversion rate was 99.8%, 3
The selectivity for chloroanthranilic acid was 97.4%. 3-chloroanthranilic acid 0.1529 mol 3-chlorosalicylic acid 0.0012 mol 2,3-dichlorobenzoic acid 0.0003 mol

Example 3 170% 20% aqueous ammonia was placed in the same reaction vessel as in Example 1.
g (2.00 mol) and 2-chlorobenzoic acid 37.6
(0.240 mol) was added and stirred to dissolve. To this, 1.19 g (0.012 mol) of cuprous chloride was added, the reaction vessel was sealed, and nitrogen was purged of air. The mixture was reacted by stirring at 85 ° C for 6 hours. Internal pressure during the reaction is 3.0-2.6kg
It was / cm ² G.

When the reaction mixture was analyzed in the same manner as in Example 1, the following analytical values were given, and the reaction conversion rate was 100% and the anthranilic acid selectivity was 97.2%. Anthranilic acid 0.2333 mol Salicylic acid 0.0012 mol Orthochlorobenzoic acid Not detected

Example 4 150 g of 25% ammonia water in the same reaction vessel as in Example 1
(2.20 mol) and cuprous iodide 1.43 g (0.0
(0751 mol) was added, the reaction vessel was sealed, and then air was purged with nitrogen. While stirring, 90 g of an aqueous K salt solution of 2,4-dichlorobenzoic acid (30.0 g of 2,4-dichlorobenzoic acid, 17.5 g of 50% KOH aqueous solution and 4 parts of water) was added.
2.5 g was mixed and melted by heating at 85 ° C.) was pressed with nitrogen. The mixture was stirred at 90 ° C for 8 hours. The internal pressure during the reaction was 3.4 to 3.2 kg / cm ² G.

When the reaction mixture was analyzed in the same manner as in Example 1, the following analytical values were given, and the reaction conversion rate was 99.9%, 4
The selectivity for -chloroanthranilic acid was 95.9%. 4-chloroanthranilic acid 0.1505 mol 4-chlorosalicylic acid 0.0034 mol 2,4-dichlorobenzoic acid 0.00016 mol

Example 5 25% aqueous ammonia and 2,4-dichlorobenzoic acid were added as in Example 1, and 0.500 g of metallic copper was used as a catalyst.
(0.00787 mol), cupric oxide 0.562 g
A combination of (0.00707 mol) was used, and after nitrogen purging, the mixture was stirred at 100 ° C. for 6 hours to be reacted. Analysis of the reaction mixture as in Example 1 gave the following analytical values:
The reaction conversion was 99.9% and the selectivity of 4-chloroanthranilic acid was 96.3%.

Examples 6 to 11 In accordance with Examples 1 to 5, 300 ml of the reaction solution was charged with the composition shown in Table 2 and the reaction was carried out under the reaction conditions shown in Table 2 to obtain Examples 6 to 11. . The results are shown in Table 3 together with Examples 1 to 5.

[0035]

[Table 2]

[0036]

[Table 3]

Example 12 3.4 g (0.016) of sodium hydrosulfite (content 85%) were added to the reaction mixture finally obtained in Example 1.
32 g (0.3 mol) and 48% sodium hydroxide solution (0.3
8 mol) was added, and heated to 100 ° C. while avoiding contact with air to discharge excess ammonia. After cooling to room temperature under a nitrogen blanket, precipitated copper compounds such as metallic copper were filtered off. The filterability was very good.

Water was added to make the total amount 250 g, 35%
Acidified with hydrochloric acid until pH becomes 5 to 6, filtered, washed with water, and dried to obtain purity 98.6%, copper content (as Cu, hereinafter the same) 15 ppm, and white powder 4-chloroanthranilic acid 25.8 g. Was given. Further, when recrystallized with a mixed solvent of alcohol and water, 4-4.1 g of 4-chloroanthranilic acid having a purity of 99.7% and a copper content (as Cu, the same applies hereinafter) of 6 ppm was obtained as white needle crystals. The yield based on 2,4-dichlorobenzoic acid was 89.4%.

Example 13 Example 13 was repeated except that the sodium hydrosulfite used in Example 12 was changed to 8.0 g (0.16 mol) of humanradine monohydrate. Purity 9
23.9 g (yield 88.7%) of 4-chloroanthranilic acid of 9.6%, a copper content of 8 ppm and white needle crystals were obtained.

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Claims (7)

(57) [Claims] 1. A compound represented by the general formula (I): (In the formula, Y is a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, an alkoxy group, an acetoxy group, a nitro group,
It represents an amino group, a sulfo group, a carboxyl group, a trifluoromethyl group, or an aryl group, and Y may be the same or different from each other. n shows the integer of 1-4.
M is selected from a hydrogen atom, an ammonium group, an alkali metal atom, or an alkaline earth metal atom. In producing the anthranilic acid represented by the formula (1) , a compound represented by the general formula (II): (In the formula, X represents a halogen atom selected from chlorine, bromine, and iodine, and Y, n, and M have the same meanings as described above.) In the presence of a cuprous-containing catalyst. A method for producing anthranilic acids, which comprises reacting in aqueous ammonia with heating. 2. The process according to claim 1, wherein the cuprous-containing catalyst is a copper oxide, chloride, bromide, iodide, thiocyanate or cyanide in the cuprous oxide oxidation state. 3. The cuprous-containing catalyst uses a combination of a zero-valent metallic copper and a copper compound in the oxidation state of cupric, and causes the disproportionation of the valence to substantially bring the cuprous oxide into the oxidation state. Yes, claim 1
The described method. 4. The amount of the cuprous-containing catalyst used in terms of copper atoms is 0.001 with respect to 1 mol of orthohalogenobenzoic acid.
The method of claim 1, wherein the method is ~ 1 gram atom. 5. An anthranilic acid is isolated from a reaction solution obtained by treating a reaction mixture containing a cuprous-containing catalyst with dithionite to precipitate metallic copper and then removing and separating the metallic copper. A method for producing the described anthranilic acids. 6. A reaction mixture containing a cuprous-containing catalyst is treated with any hydrazine compound selected from hydrazine, hydrazine hydrate and hydrazine neutral sulphate to deposit metallic copper, which is then deposited. The method for producing anthranilic acids according to claim 1, wherein the anthranilic acids are isolated from the reaction solution separated and removed. 7. The method according to claim 5, wherein the amount of the nithionite salt or the hydrazine compound used is 0.001 to 2 mol per mol of the orthohalogenobenzoic acid as a raw material.