JPH07233130A - Production of aminobenzoic alkyl ester - Google Patents

Abstract

PURPOSE:To obtain an alkyl aminobenzoate in high purity and yield by reaction of an aminobenzoic acid with an alcohol using a strongly acidic macroporous type cation exchange resin as an esterification catalyst to suppress N-alkyl derivative production. CONSTITUTION:This alkyl aminobenzoate of formula II (R is a 1-6C alkyl) can be obtained by reaction of an aminobenzoic acid of formula I (X is H, a halogen or nitro; n is 1-4) with a 1-6C alcohol in the presence of a strohngly acidic macroporous type cation exchange resin. The aminobenzoic acid of formula I is pref. anthranilic acid or 3-chloroanthranilic acid. The above-mentioned catalyst, the cation exchange resin, is prepared, for example, by introducing sulfonic acid group as functional group onto a resin having porous physical structure. This catalyst is highly effective for suppressing esp. N-alkyl derivative production. The alcohol mentioned above is pref. methanol, ethanol, 1-propanol or 1-butanol.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing aminobenzoic acid alkyl esters useful as synthetic raw materials for agricultural chemicals, pharmaceuticals, dyes and the like.

[0002]

2. Description of the Related Art Conventionally, as a method for producing an aminobenzoic acid ester, a method has been known in which a starting carboxylic acid is heated in an alcohol in the presence of hydrogen chloride (for example, in the synthesis of methyl 4-chloroanthranilate). , RE Lut
z et al. J. Am. Chem. Soc. , V
ol. 68, 1285-1287 (1946)). However, this method usually requires a large excess of alcohol and hydrogen chloride, and further requires special equipment for the introduction and detoxification of hydrogen chloride. Further, in this case, since the ester which is a reaction product exists in the form of a hydrochloride salt which is hardly soluble in alcohol, the content of the ester is particularly high when some aminobenzoic acid having a substituent in the aromatic nucleus is used as a raw material. However, there is a drawback that it becomes a highly viscous slurry and stirring becomes difficult.
As a method similar to the above, the present inventors carried out methyl esterification in a system of 4-chloroanthranilic acid and a large excess of methanol, using concentrated sulfuric acid or p-toluenesulfonic acid as a catalyst instead of hydrogen chloride as a catalyst. Attempts were made, but it was confirmed that the reaction rate was extremely slow if it was left as it was. In that case,
Reduce the proportion of methanol to increase the reaction rate,
When a reaction temperature is increased by adding a solvent such as toluene, the amount of methyl 2-methylamino-4-chlorobenzoate, which is an N-methyl derivative as a by-product, is reduced with respect to the desired methyl 4-chloroanthranilate. 2 in case of hydrogen catalyst
It was found that what was ˜3% was increased to 6 to 10%.

On the other hand, P. K. Kadaba reports an example of synthesizing methyl 4-chloroanthranilate using boron trifluoride etherate as a catalyst in the same carboxylic acid and alcohol system as described above (Pankaja).
K. Kadaba, J .; Pharm. Sci. , Vo
l. 63, no. 8, 1333-1335, (197
4)). This report does not describe the amount of N-methyl derivative as a by-product. When the present inventors repeated this method, in this method, the amount of methyl 2-methylamino-4-chlorobenzoate by-produced was about 3.5 as the content in the produced methyl 4-chloroanthranilate. %, It was confirmed that the desired ester production method was not satisfactory.

In addition, a method for producing an aromatic aminocarboxylic acid alkyl ester has been disclosed (Japanese Patent Laid-Open No. Sho 5).
7-15067). This is a method of reacting an aminocarboxylic acid salt with a dialkyl sulfuric acid in an aprotic solvent. According to this method, the above publication discloses a yield of 95.4%,
It is described that methyl 4-chloroanthranilate was synthesized with a relatively good result of the content of N-alkyl derivative being 1.4%. However, industrially, it is not always a desirable method from the viewpoint of handling highly toxic dialkyl sulfuric acid, recovering an aprotic solvent, and treating wastewater.

It is generally known that when an aminobenzoic acid is alkyl-esterified with an alcohol in the presence of an acid catalyst, a by-product of an N-alkyl derivative cannot be avoided. However, in applications such as pesticides and pharmaceuticals, a trace amount of N-alkyl derivative mixed in desired aminobenzoic acid alkyl ester may be a problem. Since this N-alkyl derivative has a boiling point extremely close to that of the desired ester, a rectification facility having a considerably high theoretical plate number is required to obtain a highly purified ester by finely purifying it by a distillation operation (for example, anthranilic acid). Vapor pressure data for methyl and methyl N-methylanthranilate are found in the Beilstein Handbook, which are close approximations). On the other hand, according to the experiments by the present inventors, removing the N-alkyl derivative by the crystallization operation was carried out because the melting point of the aminobenzoic acid alkyl ester was relatively low and there was no safe solvent. It turned out that practical application is actually difficult. Therefore, in order to obtain a high-purity aminobenzoic acid alkyl ester containing a small amount of N-alkyl derivative by the alkylesterification of aminobenzoic acid, it is desired to suppress the amount of by-products in the reaction stage as much as possible.

As another method for synthesizing the aminobenzoic acid alkyl ester, a method of catalytically reducing the corresponding nitrobenzoic acid alkyl ester can be considered. However, it may be very difficult to obtain nitrobenzoic acid having a halogen atom or a nitro group in the aromatic nucleus as the raw material.
Furthermore, in a benzoic acid ester having a plurality of nitro groups, it is not easy to selectively reduce only one of the nitro groups to an amino group. Fortunately, o-halobenzoic acids having a halogen atom or a nitro group in the aromatic nucleus are relatively easily available, and by ammonolysis of these,
Corresponding anthranilic acids can be synthesized (for example, JP-A-4-356449 and JP-A-5-255212).
issue). Therefore, a technique for alkyl-esterifying aminobenzoic acids, in particular, a method for suppressing the by-production of N-alkyl derivatives, which does not use special equipment or causes safety and health problems. Development is required.

[0007]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to produce a high-purity aminobenzoic acid alkyl ester of high purity, which is more efficient than the conventional method and has a small amount of N-alkyl derivative. To provide a method.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to solve the above-mentioned problems in producing aminobenzoic acid alkyl esters, and as a result, as a catalyst for esterification, a strongly acidic macromolecule was used. The present inventors have found that a porous cation exchange resin is extremely effective for suppressing N-alkyl derivatives, and have completed the present invention.

That is, the present invention provides (1) the general formula (I)

[0010]

[Chemical 3]

(In the formula, X represents a hydrogen atom, a halogen atom or a nitro group, n represents an integer of 1 to 4, n is 2,
When 3 and 4, a plurality of Xs may be the same or different. ) The aminobenzoic acid represented by the formula (1) is reacted with an alcohol having 1 to 6 carbon atoms in the presence of a strongly acidic macroporous cation exchange resin.

[0012]

[Chemical 4]

(Wherein X and n have the same meanings as described above, R represents an alkyl group having 1 to 6 carbon atoms), and a method for producing an aminobenzoic acid alkyl ester is provided. .

Next, the present invention will be described in detail. The aminobenzoic acid used as a raw material in the method of the present invention is a compound represented by the general formula (I),
In the formula, X represents a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.) or a nitro group, and n represents an integer of 1 to 4. When n is 2, 3, or 4, plural Xs may be the same or different from each other. Specific examples of the compound represented by the general formula (I) include anthranilic acid and 3
-, 4-, 5- or 6-chloroanthranilic acid, 3-,
4-, 5- or 6-fluoroanthranilic acid, 4- or 5-bromoanthranilic acid, 3,5-dichloroanthranilic acid, 4-bromo-5-chloroanthranilic acid, 4,
Anthranilic acids such as 5-difluoroanthranilic acid, 3-, 4- or 5-nitroanthranilic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, 3-amino-4-chlorobenzoic acid, 4-amino-2- Chlorobenzoic acid, 4-
Aminobenzoic acids such as amino-3-chlorobenzoic acid and 5-amino-2-chlorobenzoic acid are exemplified. Of these, anthranilic acids are preferable, and 3-chloroanthranilic acid is particularly preferable.

The strongly acidic macroporous cation exchange resin used as a catalyst for esterification in the method of the present invention is used for a catalyst in which, for example, a sulfonic acid group is introduced as a functional group onto a resin having a porous physical structure. An ion exchange resin, specifically, Amberlyst 15, 16, 35 (manufactured by Rohm and Haas or Organo), Diaion RCP160M, RCP170M (manufactured by Mitsubishi Kasei),
It is selected from Bayer catalysts K2641 and K2611 (manufactured by Bayer). Usually, it is preferable to use a dry resin having a water content of 3% or less as it is, but even a resin having a water content of 50 to 60% may be washed with raw alcohol or azeotropically dehydrated before adding raw alcohol. Depending on the method, water may be removed until the water content falls to several percent or less before use. The amount of the cation exchange resin used for the catalyst may be the desired yield, reaction time,
It is determined in consideration of the mixed state of the reaction contents and the cost of the catalyst, etc., but is usually 10 to 150 wt%, preferably 30 to 90 wt%, particularly preferably 30 wt% as a dry resin with respect to the raw material aminobenzoic acids. 40-80w
t%.

The alcohol is an alcohol containing all isomers having 1 to 6 carbon atoms, which corresponds to the alkyl group of the desired alkyl ester, of which 1 to 4 carbon atoms are included.
Are preferred, and examples thereof include methanol, ethanol, 1-propanol, and 1-butanol. As the reaction solvent, the above alcohol may be used alone as a solvent, but when an alcohol having a relatively low boiling point is used, it has a boiling point higher than that of the alcohol and is azeotroped with water in order to accelerate the reaction. Aromatic inert solvent,
For example, it is preferable to add an inert solvent selected from toluene, xylene, chlorobenzene, etc., and raise the reaction temperature to carry out. The reaction temperature is usually 65 to 130 ° C., which is the reflux temperature of the alcohol under atmospheric pressure, preferably 80 to 120 ° C., and particularly preferably 85 to 85 ° C.
It is 100 ° C. If the reaction temperature is low, the reaction rate will be remarkably reduced and the reaction time will be prolonged, while if it is high, problems will occur in the heat resistance of the catalyst. In the case of esterification with methanol or ethanol under atmospheric pressure, it is practically preferable to react in the above-mentioned inert solvent. On the other hand, when alcohol is used alone, the reaction may be carried out under a pressure exceeding atmospheric pressure in a pressure vessel in order to raise the reaction temperature. The amount of the inert solvent used when the method of the present invention is carried out under atmospheric pressure is usually 200 to 600 wt% with respect to 100 wt% of aminobenzoic acid as a raw material, and preferably 3
0 to 500 wt%, particularly preferably 350 to 4
It is 50 wt%. The amount of alcohol used when carrying out the method of the present invention under atmospheric pressure is usually 1 mol or more, preferably 1.5 to 3.5 mol, relative to 1 mol of aminobenzoic acid as a raw material, Particularly preferably 2.0 to
It is 3.0 mol. Furthermore, in order to increase the reflux temperature, the alcohol is not added all at once at the start of the reaction, but is first equimolar to the aminobenzoic acids,
It is preferable to supplement the remaining amount continuously or intermittently during the reaction. In the case of methanol having a low boiling point, even if the amount of methanol used is increased to more than 3 mol per 1 mol of aminobenzoic acid as a raw material, the reaction temperature will be lowered to less than 80 ° C., which has the opposite effect. Further, in the reaction in an inert solvent, not only in the reflux system, but also water produced during the reaction is azeotropically dehydrated and discharged out of the system, and at the same time, an amount of alcohol and an inert solvent corresponding to the distillate amount are replenished. The method is also effective. According to the method of the present invention, the reaction time is usually 10 to 40 hours, preferably 15 to 35 hours, particularly preferably 20 to 25 hours,
Aminobenzoic acid alkyl esters are obtained in a yield of 75-95%. The amount of the N-alkylaminobenzoic acid alkyl ester produced as a by-product can be set within the range of about 0.03 to 1.5%, and a high-purity aminobenzoic acid alkyl ester with a purity of 98.5% or more. The kind is easily obtained. The aminobenzoic acid alkyl ester can be isolated by a conventional method.

In the method of the present invention, when the reaction is carried out using an inert solvent such as toluene or xylene,
The dissolved ester can be isolated from the reaction solution as follows. That is, after completion of the reaction, the catalyst resin is filtered off, and then a dilute aqueous solution of sodium carbonate is added to adjust the pH of the aqueous layer to about 9 to 10, and unreacted aminobenzoic acid is extracted into the aqueous layer and recovered. After the organic layer containing the ester is washed with water, the solvent is distilled off under reduced pressure, and a crude ester having a purity of 98% or more is usually obtained as it is. Further, if necessary, the ester can be purified by a method such as distillation or recrystallization. In distillation, the amount of residual high boiling impurities is usually as small as 0.5% or less with respect to the amount of crude ester before distillation.

[0018]

INDUSTRIAL APPLICABILITY According to the method of the present invention, when alkyl-esterifying aminobenzoic acids, the N-alkyl derivative by-produced in the reaction can be significantly suppressed as compared with the conventional method. An acid alkyl ester can be synthesized, which is an industrially advantageous method. Further, by using a solid acid catalyst called a strongly acidic macroporous cation exchange resin as an esterification catalyst, the post-treatment operation for isolating a desired ester from the obtained reaction solution is also performed after the catalyst is separated. This is an efficient method as far as extracting unreacted raw materials with a weak alkaline solution. Furthermore, in the method of the present invention, since hydrogen chloride is not used, special hydrogen chloride introduction equipment or detoxification equipment is not used, and since dialkyl sulfuric acid is not used, safety and hygiene problems, solvent recovery and No problems such as wastewater treatment occur.

[0019]

The present invention will be described in more detail based on the following examples. Example 1 137.3 g (0.800 mol) of 3-chloroanthranilic acid, 112 g of dried amberlyst 15 and 500 g of xylene were added with 25.6 g (0.800 mol) of methanol.
Was added, and the mixture was heated and stirred at a reflux temperature of 87 to 93 ° C. After 4 hours, 8 hours and 12 hours from the start of the reaction, 8.54 g (0.267 mol) of methanol was added.
Each was added in three portions. The raw materials were dissolved in the reaction time of several tens of hours, and the heating was completed and cooled in 20 hours from the start of the reaction.

After separating the resin by filtration, it was washed twice with 100 g of xylene each time, and the washing liquid was combined with the filtrate. Further, the resin was washed off with 80 g of methanol three times. The obtained xylene solution and methanol washing solution were analyzed by high performance liquid chromatography (internal standard method using o-phenylphenol as an internal standard substance) to give the following analytical values, and yield of methyl 3-chloroanthranilate was obtained. Is 92.
It was 8%. Methyl 3-chloroanthranilate contained in xylene solution 0.690 mol 3-chloroanthranilic acid 0.019 mol Methyl 3-chloroanthranilate contained in methanol washing solution 0.052 mol 3-chloroanthranilic acid 0.038 Mol 100 g of 4% aqueous sodium carbonate solution in the xylene solution
Was added to adjust the pH of the aqueous layer to 9.5, 3-chloroanthranilic acid was extracted into the aqueous layer, then washed with water, xylene was distilled off under reduced pressure, and crude 3-chloroanthranilic acid colored light yellow was added. 127 g of methyl were obtained. When analyzed by capillary gas chromatography, the area ratio of methyl 3-chloroanthranilate / 2-methylmethyl 2-methylamino-3-chlorobenzoate was 99.96 / 0.036. 127 g of this crude ester was subjected to simple distillation under a distillation condition of 124-125 ° C./9 mmHg to obtain 115 g of white methyl 3-chloroanthranilate. The purity analysis value by capillary gas chromatography was 99.96 / 0.036 which was the same as that of the crude ester.

Comparative Example 1 10.0 g (0.0583 mol) of 3-chloroanthranilic acid was dissolved in 80 g of methanol, and hydrogen chloride was blown thereinto at a rate of about 0.2 liter / min for 5 hours while heating under reflux. As a result of neutralizing the excess hydrogen chloride and analyzing the reaction mixture, 3-
The yield of methyl chloroanthranilate was 70.1%, 3-
Methyl chloroanthranilate / 2-methylamino-3-
The area ratio of methyl chlorobenzoate is 97.87 / 2.13.
Met.

Example 2 27.45 g (0.160 mol) of 4-chloroanthranilic acid, Diaion RCP160M (52% hydrous product) 4
4.8 g and 100 g of xylene were heated to 110 ° C. to carry out azeotropic dehydration until water did not distill, and xylene in the distillate was returned to the system. Cool to 80 ° C. and methanol 5.1
3 g (0.160 mol) was added, and the mixture was heated and stirred at a reflux temperature of 83 to 93 ° C. After 7 hours and 15 hours, 2.56 g (0.080 mol) of methanol was added and reacted for a total of 24 hours. After cooling, the catalyst was filtered off, washed and the reaction mixture was analyzed. The yield of methyl 4-chloroanthranilate was 89.5%, methyl 4-chloroanthranilate / 2-methylamino-4-chlorobenzoic acid. The area ratio of methyl was 98.62 / 1.38.

Example 3 Diaion RCP160M (52%) in Example 2
(Water-containing product) 44.8 g of Bayer Catalyst K2641
The reaction was carried out in the same manner as in Example 2, except that the reaction time was changed to 11.2 g (water content: 2% or less) to 31 hours. When the reaction liquid was analyzed, the yield of methyl 4-chloroanthranilate was 85.8%, and the area ratio of methyl 4-chloroanthranilate / 2-methylamino-4-chlorobenzoate was 98.53 / 1. It was 47.

Comparative Example 2 4-chloroanthranilic acid 17.2 g (0.100 mol), methanol 64.1 g (2.00 mol) and boron trifluoride etherate (boron trifluoride ethyl ether complex) 28.4 g (0 (.200 mol) was heated and stirred at reflux temperature for 24 hours. After completion of the reaction, the catalyst in the reaction solution was neutralized with 5% aqueous sodium carbonate solution, and the reaction solution was analyzed. The yield of methyl 4-chloroanthranilate was 70.0%, methyl 4-chloroanthranilate / 2. The area ratio of methyl-methylamino-4-chlorobenzoate was 96.48 / 3.52.

Comparative Example 3 3-chloroanthranilic acid 17.2 g (0.100 mol), methanol 3.20 g (0.100 mol), toluene 165 g and p-toluenesulfonic acid monohydrate 2
8.6 g (0.150 mol) was heated and stirred at a reflux temperature of 85 to 91 ° C. for 30 hours, while 12.8 g of methanol was added.
(0.400 mol) was added portionwise. After completion of the reaction, the catalyst was neutralized and the reaction solution was analyzed. The yield of methyl 3-chloroanthranilate was 67.7%, and methyl 3-chloroanthranilate / 2-methylamino-3-chlorobenzoate methyl The area ratio was 88.2 / 111.8.

Example 4 4-chloroanthranilic acid 14.0 g (0.0816 mol), Amberlyst 15 dry product 11.5 g and 1-butanol 140 g (1.89 mol) were added at 112 to 114 ° C.
The mixture was heated and stirred at the reflux temperature of 24 hours. After completion of the reaction, the catalyst was filtered off, washed and the reaction solution was analyzed. The yield of n-butyl 4-chloroanthranilate was 95.2%, and n-butyl 4-chloroanthranilate / 2-butylamino- Four
-The area ratio of n-butyl chlorobenzoate is 98.76 /
It was 1.24.

Example 5 3,5-Dichloroanthranilic acid 20.6 g (0.10)
Mol), 11.2 g of dried amberlyst 15 and 100 g of toluene, and 4.63 g (0.
100 mol) was added and the mixture was heated with stirring at the reflux temperature for 36 hours. During this period, 9.28 g of 99.5% ethanol (0.2
(00 mol) was added in four portions, and azeotropic dehydration operation was further carried out to adjust the amount of distillate to 7.0 g. After the reaction was completed, the catalyst was separated by filtration, washed, and the reaction solution was analyzed. The yield of ethyl 3,5-dichloroanthranilate was 85.9%.
-Ethyl dichloroanthranilate / 2-ethylamino-
The area ratio of ethyl 3,5-dichlorobenzoate is 99.61.
It was /0.39.

EXAMPLE 6 14.6 g (0.0800 mol) of 4-nitroanthranilic acid was added to a 300 ml Hastelloy C autoclave.
Amberlyst 15 dry product 11.2g and methanol 1
Add 50 g (4.68 mol), 105 ° C., internal pressure 3-4
The mixture was heated and stirred at kg / cm ² G for 5 hours. After completion of the reaction, the mixture was cooled, the catalyst was filtered off, and the catalyst was washed with 150 ml of methanol. The filtrate and the washing solution were combined, and methanol was partially concentrated, and then cooled to room temperature. The precipitated crystals were filtered and dried to obtain methyl 4-nitroanthranilate as orange crystals in an amount of 11.4 g and an isolated yield of 72.6%. The purity of methyl 4-nitroanthranilate by capillary gas chromatography was 98.80%, and the methyl 2-methylamino-4-nitrobenzoate produced as a by-product was 1.2.
It was 0%.

EXAMPLE 7 11.2 g (0.0816 mol) of 4-aminobenzoic acid, 11.5 g of dried Amberlyst 15 and 140 g of methanol were placed in a 300 ml Hastelloy C autoclave.
(4.37 mol) was added, and the internal pressure was 2 kg / cm ^{2 at} 90 ° C.
G was heated and stirred for 7 hours. After completion of the reaction, the mixture was cooled, the catalyst was filtered off, and the catalyst was washed with 70 g of methanol. The filtrate and washings were combined and most of the methanol was concentrated. Toluene and 4% aqueous sodium carbonate solution were added to adjust the pH of the aqueous layer to 10
The ester was extracted with toluene, and the toluene layer was washed with water. When the obtained toluene solution is concentrated to dryness, 4
-Methyl aminobenzoate as a pale brown solid 9.29
g, isolated yield 75.3%. Purity of methyl 4-aminobenzoate by capillary gas chromatography was 98.88%, and methyl 4-methylaminobenzoate by-produced was 1.12%.

Claims (3)

[Claims] 1. A compound represented by the general formula (I): (In the formula, X represents a hydrogen atom, a halogen atom, or a nitro group, and n represents an integer of 1 to 4. When n is 2, 3, or 4, plural Xs may be the same or different. )
The aminobenzoic acid represented by formula (II) is characterized by reacting with an alcohol having 1 to 6 carbon atoms in the presence of a strongly acidic macroporous cation exchange resin. (In the formula, X and n have the same meanings as described above. R represents an alkyl group having 1 to 6 carbon atoms.) A method for producing an aminobenzoic acid alkyl ester. 2. The method according to claim 1, wherein the aminobenzoic acid represented by the general formula (I) is anthranilic acid. 3. The method according to claim 2, wherein the aminobenzoic acid represented by the general formula (I) is 3-chloroanthranilic acid.