JP3099929B2 - Purification method of 2-methyl-3-aminobenzotrifluoride - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to the production of 2-methyl-3-aminobenzotrifluoride from an isomer mixture of 2-methyl-3-aminobenzotrifluoride and 2-methyl-5-aminobenzotrifluoride. The present invention relates to a purification method for selectively separating and recovering. 2-Methyl-3-aminobenzotrifluoride is useful as an intermediate in the manufacture of an anti-inflammatory analgesic flunixin as described in, for example, U.S. Patent Nos. 3,891,761 and 3,839,344.

[0002]

2. Description of the Related Art A compound in which an aromatic ring hydrogen is substituted by an amino group is usually produced by nitrating a corresponding aromatic compound and then reducing the nitro group. The reaction product varies depending on the type of the substituent. It is often obtained as a mixture of various positional isomers. Since such substances are mainly used as intermediates of pharmaceuticals / pesticides or functional materials, they are generally not used as a mixture and only need to separate specific isomers. The body may be separated by rectification as described in JP-A-57-139043. But,
Where applicable, this method is preferred because it is technically established, but the isomers often have close boiling points to each other and may not be economically feasible when obtaining high-purity products. . Therefore, the separation of isomers of a compound having an amino group is described in, for example, JP-A-60-9224.
No. 7, a method for separating toluidine isomers using X-type and Y-type zeolites, and a method for separating dialkylaniline isomers using a titanium oxide-containing solid adsorbent described in JP-A-58-57346. Separation methods and the like have been proposed.

[0003]

It is anticipated that 2-methyl-3-aminobenzotrifluoride will be prepared by a process that nitrates the corresponding 2-methylbenzotrifluoride and then reduces the nitro group. However, the reaction product in the nitration reaction involves a considerable amount of the isomer 2-methyl-5-nitrobenzotrifluoride in addition to 2-methyl-3-nitrobenzotrifluoride, followed by the formation of the subsequent reduction reaction. Since the product is also obtained as a mixture of the corresponding isomers, the production method cannot be established unless this separation and purification is performed efficiently.

The boiling points of 2-methyl-3-aminobenzotrifluoride and 2-methyl-5-aminobenzotrifluoride are 135-136 ° C. (85-86 mmH, respectively).
g) Since it is relatively close to 136 to 137 ° C (85 to 86 mmHg), separation by distillation is substantially difficult. In addition, in the method by adsorption separation, it is difficult to prepare an adsorbent,
There is a problem in industrially performing the adsorption operation because it is complicated.

[0005]

Means for Solving the Problems The present inventors have studied a separation method that can replace the above-mentioned distillation method and adsorption method.
The salts formed between -methyl-3-aminobenzotrifluoride and 2-methyl-5-aminobenzotrifluoride with certain organic acids are found to have significantly different solubilities in certain solvents; The present invention has been completed.

That is, the present invention provides substantially 2-methyl-
A mixture of 3-aminobenzotrifluoride and 2-methyl-5-aminobenzotrifluoride is brought into contact with an organic acid in the presence of water or an organic solvent to precipitate and separate insoluble components, and the solution A method for purifying 2-methyl-3-aminobenzotrifluoride, characterized in that 2-methyl-3-aminobenzotrifluoride is taken out as a single substance by adding a substance.

[0007] Substantially 2-methyl-3-aminobenzotrifluoride and 2-methyl-5 to which the method of the present invention is applied.
A mixture consisting of aminobenzotrifluoride (hereinafter, referred to as
It is called "isomer mixture". ) Does not limit the process through which it is obtained, for example,
An aminobenzotrifluoride isomer mixture obtained by nitrating 2-methylbenzotrifluoride with a mixed acid of nitric acid and sulfuric acid and then reducing the nitro group with hydrogen can be exemplified. This mixture is usually 2-methyl-3
20 to 40 mol% of aminobenzotrifluoride and 2
-Methyl-5-aminobenzotrifluoride is 60 to 8
0 mol%. Further, the method of the present invention can be applied to the case where a small amount of other compounds coexist besides these isomers without departing from the gist of the present invention. Other compounds can include, for example, unreacted raw materials or by-products in nitration or reduction reactions.
Therefore, the method of the present invention can be applied to a solution obtained by subjecting the reaction solution obtained in the reduction reaction step to a post-treatment step such as filtration, washing, and drying, or further removing other compounds by distillation or the like in advance. It can also be applied to a mixture of 2-methyl-3-aminobenzotrifluoride and 2-methyl-5-aminobenzotrifluoride.

In one embodiment of the method of the present invention, a solution comprising water or an organic solvent in which an organic acid is dissolved is prepared in a reactor equipped with a stirrer, and a mixture of isomers is gradually injected into the solution. , A solid is precipitated from the solution, and the solid is removed by filtration.The resulting solution is neutralized by adding a basic substance, and the solvent is distilled off. This is a method of obtaining solid 2-methyl-3-aminobenzotrifluoride by crystallization.

The organic acid used in the present invention is preferably a dicarboxylic acid or a polyvalent carboxylic acid, and two carboxyl groups are located at the cis position or the ortho position of the aromatic ring with respect to the double bond, or at least two at the same time. It is necessary that the carboxyl groups of can be close to each other. Such examples include, for example, aliphatic unsaturated dicarboxylic acids such as maleic acid and citraconic acid, aromatic polycarboxylic acids such as o-phthalic acid and pyromellitic acid, and HOOC-R-COOH.
(R is an alkylene group.)
Succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, methylmalonic acid,
And aliphatic saturated dicarboxylic acids such as dimethylmalonic acid. Of these dicarboxylic acids or polycarboxylic acids, maleic acid, malonic acid and o-phthalic acid are preferred, and maleic acid is a particularly preferred example. The amount of organic acid required is at least 2
-Methyl-5-aminobenzotrifluoride is the amount required to form a salt, and excess organic acid reduces the solubility of the salt of 2-methyl-3-aminobenzotrifluoride in the solvent. To precipitate as a solid, which is not preferable. Therefore, the amount of the organic acid is 1 to 3 times, preferably 1 to 2 times the molar amount of 2-methyl-5-aminobenzotrifluoride.

In order to sufficiently promote the reaction between the organic acid and the isomer mixture, the reaction temperature is about -20 to 80 ° C.
0-50 ° C is preferred. If the temperature is lower than −20 ° C., the reaction is slow and takes a long time. If the temperature is higher than 80 ° C., an apparatus for selecting a solvent and preventing the evaporation of the solvent is required, which is not preferable. At the end of the reaction, the temperature of the solution is reduced to about -20 to promote the precipitation of the salt of 2-methyl-5-aminobenzotrifluoride.
Preferably, the temperature is lowered to -20 ° C, more preferably to about 0-5 ° C. The reaction time depends on the reaction temperature, but may be generally about 10 minutes to 5 hours, more preferably 30 minutes to 2 hours.

The reaction between the isomer mixture of the present invention and an organic acid is 2
The reaction may be carried out in a solvent in which a salt of -methyl-5-aminobenzotrifluoride is hardly soluble and a salt of 2-methyl-3-aminobenzotrifluoride is easily soluble.
Examples include ethyl acetate, butyl acetate, methanol, ethanol, isopropanol, n-hexane, methylene chloride, chloroform, and chlorofluorocarbon solvents. Although the amount of the solvent depends on the type of the solvent, 2-methyl-5-
It is preferable to select the aminobenzotrifluoride salt to such an extent that the salt is precipitated with high purity, and usually an amount of 50 to 500 g of the isomer mixture per liter of the solvent is appropriate.

In the solvent after the salt of 2-methyl-5-aminobenzotrifluoride was separated by filtration, 2-methyl-3-aminobenzotrifluoride or its salt increased its isomer ratio in the solvent. Since the organic acid forms a salt with the basic substance when the basic substance is added to the solution, the salt is removed by washing with water and / or solvent extraction. To give 2-methyl-3-aminobenzotrifluoride. As the basic substance, hydroxides, carbonates, hydrogencarbonates and the like of alkali metals or alkaline earth metals, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, Sodium bicarbonate and the like can be mentioned.
The amount of the basic substance to be used is preferably 2 to 3 times by mole (1 to 1.5 times by mole in the case of calcium hydroxide), and preferably 2 to 2.2 times by mole relative to the salt of aminomethylbenzotrifluorolide. 1.1 mole times). This neutralization reaction is performed at about 0 to 40 ° C, preferably about 0 to 10 ° C. There is no particular advantage in performing the reaction at about 0 ° C. or lower, and at 40 ° C. or higher, a side reaction may occur, which is not preferable. A non-water-soluble solvent can be used for the solvent extraction, and examples thereof include ethyl acetate, butyl acetate, n-hexane, n-heptane, methylene chloride, chloroform, and a fluorocarbon solvent.

The salt of 2-methyl-3-aminobenzotrifluoride with a basic substance of an organic acid can be further purified by recrystallization with a non-polar solvent such as n-hexane, n-heptane or the like. The recrystallization temperature is not particularly limited, but is about -40 to 30C, and more preferably about 0 to 5C. If the temperature is lower than -40 ° C, the operation is difficult. If the temperature is higher than 30 ° C, the solvent volatilizes remarkably. The mother liquor in the recrystallization is preferably used repeatedly from the viewpoint of improving the yield.

Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

[0015]

【Example】

Preparation Example 1 In a 300 ml four-necked round bottom flask equipped with a thermometer, a stirrer, a Dimroth condenser, and a 500 ml dropping funnel, 2-methylbenzotrifluoride 32 having a purity of 99.8% was placed.
After 0.0 g (2.0 mol) was charged and stirring was started and the temperature of the reaction solution was lowered to 30 ° C. or lower, 138.6 g (2.2 mol) of fuming nitric acid and 392.0 g of concentrated sulfuric acid were previously prepared.
(4.0 mol) was added, and the mixed acid was dropped from a dropping funnel charged with the mixed acid prepared. The mixed acid was added dropwise over 1 hour while maintaining the reaction temperature at 60 ° C.
After the addition of the mixed acid, the reaction was continued for 3 hours while maintaining the temperature at 60 ° C., and then the stirring was stopped and analyzed.
At this time, the purity of 2-methyl-3-nitrobenzotrifluoride and 2-methyl-5-nitrobenzotrifluoride were 26.6% and 72.7%, respectively. Then, the mixture was transferred to a separating funnel of 1000 ml, the mixed acid phase was separated, washed with 500 ml of water, washed with 500 ml of a saturated aqueous solution of sodium hydrogen carbonate, and further washed with 500 ml of water.
l. Magnesium sulfate was added to the separated organic phase and dried, and magnesium sulfate was removed by filtration under reduced pressure to obtain 394.6 g of a nitrated mixture.

Preparation Example 2 The nitrated mixture obtained in Preparation Example 1 was placed in a 500 ml SUS-316 autoclave equipped with a stirrer.
0 g (2.0 mol) and 4.1 g (1.0% by weight) of a 5% -Pd / carbon-supported catalyst were charged. Replace the inside of the container with hydrogen, raise the temperature to 80 ° C in an oil bath, and reduce the hydrogen pressure to 5K.
When the stirring was started while maintaining the pressure at g / cm ² , the absorption of hydrogen started. After 8 hours, the heating and stirring were stopped, and after cooling, analysis revealed that the conversion of the nitrated mixture was 99.9%. After the reaction, the catalyst was removed by filtration under reduced pressure, and the mixture was transferred to a 1,000-ml separating funnel, separated into an aqueous phase and washed with 500-ml water. Magnesium sulfate is added to the separated organic phase and dried,
When magnesium sulfate was removed by filtration under reduced pressure, 332.7 g of a reduced product was obtained. The reduced products, 2-methyl-3-aminobenzotrifluoride and 2-methyl-5-
The content of aminobenzotrifluoride is 26.
6% and 72.7%. The yield at this time is 9
It was 5.1%.

Example 1 o-phthalic acid 1 was placed in a 300 ml Erlenmeyer flask made of glass.
1.6 g (0.1 mol) and 120 ml of ethanol were charged, and the mixture of isomers of Preparation Example 2 (2-methyl-3-aminobenzotrifluoride / 2-methyl-5-based on the area ratio of gas chromatograph) was stirred and stirred. Aminobenzotrifluoride isomer ratio 26.6 / 72.7) 17.5 g
(0.10 mol) was added dropwise while maintaining the solution temperature at about 40 ° C., and then stirring was continued for 30 minutes, and further stirred at about 0 ° C. for 30 minutes. After completion of the reaction, a solution obtained by filtering a white solid from the reaction solution was neutralized with a 10% by weight sodium hydroxide solution, extracted with 70 g of chloroform, and the solvent was distilled off under reduced pressure using an evaporator to give a purity of 81.9% by weight. 5.6 g of 2-methyl-3-aminobenzotrifluoride was obtained.

Example 2 Malonic acid 10.4 was placed in a 100 ml glass Erlenmeyer flask.
g (0.1 mol) and 30 ml of isopropanol were charged, and the mixture of isomers of Preparation Example 2 (2-methyl-3-aminobenzotrifluoride / 2-methyl-5-aminobenzo according to the area ratio of gas chromatograph) was stirred and stirred. Isomeric ratio of trifluoride 26.6 / 72.7) 17.5 g
(0.10 mol) was added dropwise while maintaining the solution temperature at about 40 ° C., and then stirring was continued for 30 minutes, and further stirred at about 0 ° C. for 30 minutes. After completion of the reaction, a solution obtained by filtering a white solid from the reaction solution was neutralized with a 10% by weight sodium hydroxide solution, extracted with 70 g of chloroform, and the solvent was distilled off under reduced pressure using an evaporator to give a purity of 76.4% by weight. 5.8 g of 2-methyl-3-aminobenzotrifluoride was obtained.

EXAMPLE 3 92.9 g of maleic acid (0.80 g) was placed in a 2 liter glass flask equipped with a stirrer, condenser, thermometer and dropping funnel.
Mol) and 1 liter of ethyl acetate, and while stirring, an isomer mixture (2-methyl-3-based on the area ratio of gas chromatograph) produced by the same method as in Preparation Examples 1 and 2.
Aminobenzotrifluoride / 2-methyl-5-aminobenzotrifluoride isomer ratio 25.1 / 74.5)
175.2 g (1.00 mol) was added dropwise while maintaining the solution temperature at about 40 ° C., and then stirring was continued for 1 hour.
Stirred at C for 1 hour. After completion of the reaction, a solution obtained by filtering a white solid from the reaction solution was neutralized with a 15% by weight sodium hydroxide solution, washed with water, and ethyl acetate was distilled off under reduced pressure using an evaporator to obtain an oily substance. 9 g (purity, 90.7% by weight) were obtained. N-hexane 9
After adding 7.8 g and recrystallizing at about 0 ° C, 2-methyl-3-aminobenzotrifluoride having a purity of 99.7% by weight was obtained.
5.9 g were obtained.

Comparative Example 11.6 fumaric acid was placed in a 300 ml Erlenmeyer flask made of glass.
g (0.1 mol) and 200 ml of ethanol were charged, and the mixture of isomers of Preparation Example 2 (2-methyl-3-aminobenzotrifluoride / 2-methyl-5-aminobenzo according to gas chromatographic area ratio) was stirred and stirred. 17.5 g (0.1 of isomer ratio of trifluoride 26.6 / 72.7)
(0 mol) was added dropwise while maintaining the solution temperature at about 40 ° C., and thereafter stirring was continued for 30 minutes, and further stirred at about 0 ° C. for 30 minutes. After completion of the reaction, a solution obtained by filtering a white solid from the reaction solution was neutralized with a 10% by weight sodium hydroxide solution, extracted with 70 g of chloroform, and the solvent was distilled off under reduced pressure using an evaporator to obtain 17.0 g of an isomer mixture. was gotten. The mixture of isomers is determined by the area ratio of gas chromatograph.
Isomer ratio of methyl-3-aminobenzotrifluoride / 2-methyl-5-aminobenzotrifluoride is 26.9.
/72.3, which was almost the same as the raw material used for separation.

[0021]

According to the method of the present invention, 2-methyl-3
-From a mixture of aminobenzotrifluoride and 2-methyl-5-aminobenzotrifluoride from 2-methyl-3-
It has the effect that aminobenzotrifluoride can be produced with high purity.

(56) References JP-A-60-92247 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 211/52 C07C 209/86 CA (STN) REGISTRY ( STN)

Claims (5)

(57) [Claims] A mixture of substantially 2-methyl-3-aminobenzotrifluoride and 2-methyl-5-aminobenzotrifluoride in the presence of water or an organic solvent in the following manner (A), (B): A method for purifying 2-methyl-3-aminobenzotrifluoride, comprising contacting with one or more organic acids selected from the group (C). (A) Aliphatic saturated dicarboxylic acid. (B) an aliphatic unsaturated dicarboxylic acid in which two carboxyl groups are at the cis position. (C) An aromatic polycarboxylic acid in which two carboxyl groups are at the ortho position. 2. A mixture comprising substantially 2-methyl-3-aminobenzotrifluoride and 2-methyl-5-aminobenzotrifluoride in the presence of water or an organic solvent in the following manner (A), (B): (C) adding a basic substance to a solution obtained by contacting with one or more kinds of organic acids selected from the group to precipitate and separate insolubles, and adding a basic substance to the solution. Purification method of fluoride. (A) Aliphatic saturated dicarboxylic acid. (B) an aliphatic unsaturated dicarboxylic acid in which two carboxyl groups are at the cis position. (C) An aromatic polycarboxylic acid in which two carboxyl groups are at the ortho position. 3. The method for purifying 2-methyl-3-aminobenzotrifluoride according to claim 1, wherein the organic acid is at least one selected from maleic acid, o-phthalic acid and malonic acid. 4. The organic solvent according to claim 1, wherein the organic solvent is at least one selected from the group consisting of ethyl acetate, butyl acetate, methanol, ethanol, isopropanol, n-hexane, methylene chloride, chloroform and a fluorocarbon solvent. Methyl-
A method for purifying 3-aminobenzotrifluoride. 5. The method for purifying 2-methyl-3-aminobenzotrifluoride according to claim 2, wherein the basic substance is at least one selected from sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.