KR20220033151A - Method for preparing high purity mesotrione - Google Patents

Abstract

The present invention relates to a method for preparing high purity mesotrione. The method for preparing high purity mesotrione includes a synthesis step of synthesizing a crude mesotrione product from 4-methylsulfonyl-2-nitrobenzoic acid, cyclohexane-1,3-dione, and N,N'-dicyclohexyl carbodiimide; and a removing step of removing dicyclohexyl urea from the synthesized crude mesotrione product using a basic material.

Description

Method for producing high-purity mesotrione {METHOD FOR PREPARING HIGH PURITY MESOTRIONE}

The present invention relates to a method for preparing high-purity mesotrione.

Mesotrione (2-(4-methylsulfonyl-2-nitrobenzoyl)cyclohexane-1,3-dione) represented by the following formula (1) is a triketone compound, and HPPD of crop growth in agriculture and weed management Used as an inhibitory herbicide.

[Formula 1]

For example, Patent Document WO2016-197900 A1 discloses a method for preparing mesotrione represented by Chemical Formula 1 according to the following series of Schemes A-1 to A-3.

[Scheme A-1]

[Scheme A-2]

[Scheme A-3]

However, when preparing mesotrione according to the conventional method as described above, since three or more stepwise synthesis reactions are required, the time required for the process is long, high-temperature reflux reaction conditions are required, the reaction yield is low, and the synthesis reaction is difficult. There is a problem in that a large amount of acid waste is generated as a by-product.

WO 2016-197900 A1 US 2016-0355472 A1

One embodiment of the present invention is to provide a method for producing high-purity mesotrione.

One embodiment of the present invention is

a synthesis step of synthesizing a crude mesotrione product from 4-methylsulfonyl-2-nitrobenzoic acid, cyclohexane-1,3-dione and N,N'-dicyclohexylcarbodiimide; and

It provides a method for producing high-purity mesotrione comprising a removal step of removing dicyclohexylurea using a basic material from the synthesized crude mesotrione product.

Another embodiment of the present invention is

The synthesis step is

a reaction step of reacting 4-methylsulfonyl-2-nitrobenzoic acid, cyclohexane-1,3-dione and N,N'-dicyclohexylcarbodiimide;

A stirring step of stirring the product in the reaction step with cyanide; and

It provides a method for producing high-purity mesotrione, comprising an obtaining step of obtaining a crude mesotrione product from the stirred solution in the stirring step.

Another exemplary embodiment of the present invention provides a method for producing high-purity mesotrione, wherein at least one of the synthesis step and the removal step is made in a temperature range of 15° C. to 30° C., respectively.

Another exemplary embodiment of the present invention provides a method for producing high-purity mesotrione in which the reaction step, the stirring step and the obtaining step of the synthesis step consist of a one-pot reaction.

According to the manufacturing method of high-purity mesotrione according to an exemplary embodiment of the present invention, high-purity mesotrione can be manufactured according to a one-pot reaction instead of the conventional three-step or more stepwise synthesis reaction.

According to the manufacturing method of high-purity mesotrione according to an exemplary embodiment of the present invention, it is possible to simplify the manufacturing process of high-purity mesotrione and reduce the time required for the process.

According to the manufacturing method of high purity mesotrione according to an exemplary embodiment of the present invention, it is possible to increase the final yield of mesotrione.

According to the method for producing high-purity mesotrione according to an exemplary embodiment of the present invention, mesotrione can be obtained with high purity.

According to the method for producing high-purity mesotrione according to an exemplary embodiment of the present invention, it is possible to prevent the generation of a large amount of acid waste, which is a by-product of the conventional mesotrione synthesis reaction.

According to the method for producing high-purity mesotrione according to an exemplary embodiment of the present invention, high-purity mesotrione can be prepared according to a one-pot reaction in a temperature range of 15° C. to 30° C. without high temperature or reflux conditions.

Hereinafter, the present invention will be described in more detail.

In the present invention, when a part "includes" a certain component, this means that other components may be further included, rather than excluding other components, unless otherwise stated.

In the present invention, "filtration" means a method of separating a liquid and a solid mixed material using a difference in particle size, for example, filtration by a filter having physical pores or gaps as a known method can be done, but is not limited thereto.

In the present invention, "one-pot reaction" refers to a reaction product of the next step in one reactor without purifying the intermediate product of each step in the middle when a target compound is synthesized by two or more reaction processes. It means a method of reacting by adding

In the present invention, the content of the solvent is not particularly limited, except when the content is specifically specified in each step, a sufficient content to dissolve the reactants is used.

An exemplary embodiment of the present invention is 4-methylsulfonyl-2-nitrobenzoic acid (4-(MethylSulfonyl)-2-NitroBenzoic Acid), cyclohexane-1,3-dione (CycloHexane-1,3-Dione) and N, A synthesis step of synthesizing a crude mesotrione product from N'-dicyclohexylcarbodiimide (N,N'-DiCyclohexylCarbodiimide); and a removal step of removing dicyclohexylurea from the synthesized crude mesotrione using a basic material.

An exemplary embodiment of the present invention provides a method for preparing high-purity mesotrione by using N,N′-dicyclohexylcarbodiimide, which is one of the reactants in the synthesis step, instead of thionyl chloride (SOCl ₂ ). According to the prior art, when thionyl chloride is used in the preparation of mesotrione, a large amount of acid waste (eg, hydrogen chloride, etc.) is generated as a reaction by-product. According to an embodiment of the present invention, N instead of thionyl chloride By using ,N'-dicyclohexylcarbodiimide, it is possible to prevent the formation of reaction by-products. Specifically, it is possible to prevent a large amount of hydrogen chloride (HCl) from being generated to adversely affect the environment or safety.

In one embodiment, the synthesis step is 4-methylsulfonyl-2-nitrobenzoic acid (4-(MethylSulfonyl)-2-NitroBenzoic Acid), cyclohexane-1,3-dione (CycloHexane-1,3-Dione) and a reaction step of reacting N,N'-dicyclohexylcarbodiimide (N,N'-DiCyclohexylCarbodiimide); A stirring step of stirring the product in the reaction step with cyanide; and obtaining a crude mesotrione product from the stirred solution in the stirring step.

In one embodiment, the reaction step may be performed in a solvent. At this time, the solvent is acetonitrile (Acetonitrile), 1,2-dichloroethane (1,2-Dichloroethane), toluene (Toluene), ethyl acetate (Ethyl acetate), 1,4-dioxane (1,4-Dioxane) It may be one or more solvents selected from the group consisting of. Preferably, the solvent may be acetonitrile.

In one embodiment, the equivalent ratio of 4-methylsulfonyl-2-nitrobenzoic acid and cyclohexane-1,3-dione in the reaction step is 1:1 to 3:1, or 1:1 to 1:3. and preferably 1:1.

In one embodiment, the equivalent ratio of 4-methylsulfonyl-2-nitrobenzoic acid and N,N'-dicyclohexylcarbodiimide in the reaction step is 1:1 to 3:1, or 1:1 to 1: 3, preferably 1:1.

In one embodiment, the equivalent ratio of cyclohexane-1,3-dione and N,N'-dicyclohexylcarbodiimide in the reaction step is 1:1 to 3:1, or 1:1 to 1:3 days and preferably 1:1.

In one embodiment, the reaction step may include adding 4-methylsulfonyl-2-nitrobenzoic acid, cyclohexane-1,3-dione and N,N'-dicyclohexylcarbodiimide to a solvent. can

In an exemplary embodiment, the reaction step may include adding 4-methylsulfonyl-2-nitrobenzoic acid, cyclohexanedione and dicyclohexylcarbodiimide to a solvent. At this time, the step of adding 4-methylsulfonyl-2-nitrobenzoic acid, cyclohexanedione and dicyclohexylcarbodiimide to the solvent is 4-methylsulfonyl-2-nitrobenzoic acid, cyclohexanedione, and dicyclohexylcarrone. The bodyimide may be added to the solvent, or the solvent may be added to 4-methylsulfonyl-2-nitrobenzoic acid, cyclohexanedione and dicyclohexylcarbodiimide. The addition method may be, for example, dropwise, but is not limited thereto.

In one embodiment, the reaction step may include an additional stirring step of further stirring in a temperature range of 15 °C to 30 °C. At this time, additional stirring is 1 hour to 4 hours; Alternatively, it may be made for 1.5 hours to 3 hours, and preferably for 2 hours to 2.5 hours.

In one embodiment, the cyanide of the stirring step is sodium cyanide (NaCN), potassium cyanide (KCN), calcium cyanide (Ca(CN) ₂ ), zinc cyanide (Zn(CN) ₂ ), It may be copper cyanide (CuCN), but is not limited thereto. Preferably, the cyanide in the stirring step may be sodium cyanide.

In one embodiment, the cyanide is an aqueous solution of 5% to 20% cyanide in terms of mole%; Alternatively, it may be an aqueous solution of 5% to 15% cyanide, preferably an aqueous solution of cyanide of 10%. For example, the cyanide included in the stirring step may be a 10% sodium cyanide aqueous solution in terms of mole %.

In one embodiment, the stirring step may be stirred by further including a base. The base may be included through the step of being added to the product in the reaction step. In addition, the base may specifically be triethylamine (Triethylamine), potassium carbonate (K ₂ CO ₃ ), sodium carbonate (Na ₂ CO ₃ ), etc., but is not limited thereto. For example, the equivalent ratio of triethylamine and cyclohexane-1,3-dione included in the stirring step may be 1:1 to 3:1, or 1:1 to 1:3, preferably 1: It may be 1.15, but is not limited thereto. Alternatively, the equivalent ratio of triethylamine and N,N'-dicyclohexylcarbodiimide included in the stirring step may be 1:1 to 3:1, or 1:1 to 1:3, preferably 1: It may be 1.15, but is not limited thereto.

In one embodiment, the stirring step may be made in a temperature range of 15 ℃ to 30 ℃. At this time, stirring is 1 hour to 4 hours; Alternatively, it may be made for 1.5 hours to 3 hours, and preferably for 2 hours to 3 hours.

In one embodiment, the obtaining step may include removing impurities generated in the reaction step or the stirring step. In this case, the impurity is an arbitrary impurity generated in the reaction step or the stirring step, and may be, for example, dicyclohexylurea. In the step of removing impurities, impurities generated in the reaction step or stirring step may be removed through filtration using a filtering medium, and a glass filter may be used as the filtering medium, but limited thereto doesn't happen

In one embodiment, the obtaining step may include a precipitation step of precipitating a solid using the first acid from the solution stirred in the stirring step. In this case, in the precipitation step, impurities may be removed through the impurity removal step and a solid may be precipitated from a filtrate obtained by using a solubility difference according to pH.

In one embodiment, the first acid may be an acidic material. Specifically, the first acid may be hydrogen chloride (HCl), nitric acid (HNO ₃ ), or sulfuric acid (H ₂ SO ₄ ), and an aqueous solution thereof, but is not limited thereto. For example, an aqueous hydrogen chloride solution having a concentration of 2N may be added to the filtrate. At this time, the first acid may be added until the pH of the filtrate is in the range of 1.5 to 3.5, preferably 2 to 3.

In one embodiment, in the obtaining step, the first acid is added to the solution stirred in the stirring step, and then at a temperature range of 15°C to 30°C for 0.5 hours to 2 hours, preferably 1 hour to 1.5 hours A solid can be precipitated by stirring during the time.

In the solid obtained in the obtaining step, dicyclohexyl urea, which is secondary produced when mesotrione is synthesized according to an exemplary embodiment of the present invention, remains, and in order to obtain high-purity mesotrione, residual dicyclohexyl It is necessary to remove the urea.

An exemplary embodiment of the present invention includes the step of removing dicyclohexylurea using a basic material from the synthesized crude mesotrione product.

In one embodiment, the basic material may include at least one selected from the group consisting of inorganic bases such as sodium hydroxide, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, but is not limited thereto. In another embodiment, the basic material may include at least one of sodium hydroxide and sodium methoxide. Preferably, the basic material may be sodium hydroxide.

In one embodiment, the equivalent ratio of the crude mesotrione synthesized in the synthesis step and the basic material used in the removal step may be 1:1 to 1:2, preferably 1:1.2.

In one embodiment, the removing step may be performed in an organic solvent. In this case, the organic solvent used in the removal step may be ethanol, methanol, isopropyl alcohol, acetonitrile, acetone, etc., but is not limited thereto. In one embodiment, the organic solvent used in the removing step may be preferably ethanol or methanol.

In one embodiment, the step of removing dicyclohexylurea using a basic material from the crude mesotrione product synthesized in the synthesis step is a method of separating mesotrione and dicyclohexylurea using a solubility difference. Available. Specifically, separation may proceed using the difference in solubility of mestrione and dicyclohexylurea in a solution in which the basic material is dissolved. Dicyclohexylurea is dissolved in a solution in which the basic substance is dissolved, but mesotrione is not dissolved in a solution in which the basic substance is dissolved, so dicyclohexylurea, which is an impurity, is dissolved in a solution in which the basic substance is dissolved. The difference can be used to remove it in the removal step. Accordingly, high-purity mesotrione having a small content of dicyclohexylurea can be obtained.

In one embodiment, the step of removing dicyclohexylurea using a basic material from the crude mesotrione product synthesized in the synthesis step includes: adding the synthesized crude mesotrione product and the basic material to a solvent; and stirring the synthesized crude mesotrione product and the solvent into which the basic material is added.

In one embodiment, in the step of adding the synthesized crude mesotrione product and the basic material to the solvent, the synthesized crude mesotrione product and the basic material may be simultaneously added to the solvent. In another embodiment, the synthesized crude mesotrione may be added to the solvent before the basic material. In another embodiment, the basic material may be added to the solvent before the synthesized crude mesotrione product. Furthermore, the order of input of the synthesized crude mesotrione product and the basic material is not limited to the above embodiments, and may be arbitrarily changed by a person having average knowledge in the art.

In an exemplary embodiment, the step of stirring the synthesized crude mesotrione product and the solvent in which the basic material is added may be performed at a temperature range of 15°C to 30°C. At this time, the stirring is 2 hours to 5 hours; Alternatively, it may be made for 2 to 4 hours, and preferably from 3 to 3.5 hours. As described above, by stirring the synthesized crude mesotrione product and the solvent in which the basic material is added, high-purity mesotrione from which dicyclohexylurea has been removed can be obtained from the crude mesotrione product.

In an exemplary embodiment, in the mesotrione from which the dicyclohexylurea is removed from the crude mesotrione product using the basic material, the dicyclohexylurea content in the mesotrione may be 500 ppm or less. In another exemplary embodiment, in the mesotrione from which the dicyclohexylurea has been removed from the crude mesotrione product using the basic material, the content of dicyclohexylurea in the mesotrione may be 100 ppm or less. In another exemplary embodiment, in the mesotrione from which the dicyclohexylurea has been removed from the crude mesotrione product using the basic material, the dicyclohexylurea content in the mesotrione may be 50 ppm or less. In another exemplary embodiment, in the mesotrione from which the dicyclohexylurea has been removed from the crude mesotrione product using the basic material, the dicyclohexylurea content in the mesotrione may be 30 ppm or less. In a preferred embodiment of the present invention, in the mesotrione from which the dicyclohexylurea has been removed from the crude mesotrione product using the basic material, the dicyclohexylurea content in the mesotrione may be 100 ppm or less, but limited thereto it is not going to be

In one embodiment, dicyclohexylurea is removed in the removing step and the obtained mesotrione may be in the form of mesotrione enolate.

In one embodiment, at least one of the synthesizing step and the removing step may be performed at room temperature, respectively. At this time, since the room temperature may be in a temperature range of 15°C to 30°C, in other words, at least one of the synthesis step and the removal step may be performed in a temperature range of 15°C to 30°C, respectively. Accordingly, the synthesis step and removal step, and any of the reaction step, stirring step, and obtaining step that may be included in the synthesis step may not raise the temperature to 100° C. or higher, and the process of refluxing the heated material also can be omitted.

In one embodiment, the reaction step, the stirring step, and the obtaining step of the synthesis step may be continuously made in a one-pot reaction in one reactor. Compared to the method for producing mesotrione through three or more stepwise synthesis according to the prior art, the method for producing mesotrione according to an exemplary embodiment of the present invention follows a one-pot reaction, thereby simplifying the manufacturing process, the process can reduce the time required for

Hereinafter, examples and experimental examples will be given to describe the present invention in detail. However, the Examples and Experimental Examples according to the present invention may be modified in various other forms, and the scope of the present invention is not to be construed as being limited to the Examples and Experimental Examples described below. Examples and experimental examples of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

<Example 1>

(1) Synthesis of crude mesotrione product

2g of MSNBA, DCC 1.05eq, and CHD 1.05eq were added to 10 mL of ACN (acetonitrile) and stirred at room temperature for 2 hours. Then, NaCN 10mol% 40mg and TEA (triethylamine) 1.2eq were added and stirred for 2 hours. Then, DCU (1,3-dicyclohexylurea, dicyclohexylurea) was isolated through filtration. At this time, the reaction conversion rate of the crude mesotrione product obtained by separating DCU through the filtration is 94.47%.

(2) Dicyclohexylurea Removal

The crude mesotrione product obtained in the step of synthesizing the crude mesotrione product was stirred at room temperature for 3 hours after adding 1.2eq of NaOH and 6 mL (3V/W) of ethanol. The solid produced at this time was obtained through filtration.

Then, 6 mL of distilled water (3V/W) and 2N HCl were added to the separated and secured solid to a pH of 2-3, followed by stirring for 1 hour to precipitate a solid. The solid was obtained through filtration.

Through this, mesotrione of high purity of 99.74% was obtained, and the concentration of dicyclohexylurea in the obtained mesotrione was 25 ppm. (Yield: 84.7%)

<Examples 2 to 5>

(1) the step of synthesizing the crude mesotrione product, and (2) Dicyclohexylurea Removal

In Examples 2 to 5, the solvent in the dicyclohexylurea removal step was tested under the solvent conditions shown in Table 1 below, and the same experiment as in Example 1 was performed except for the solvent conditions shown in Table 1 below. The results shown in Table 1 below (residual amount (ppm) of dicyclohexylurea in mesotrione from which dicyclohexylurea has been removed) were confirmed.

<Experimental Examples 1 to 4>

(1) Synthesis of crude mesotrione product

The crude mesotrione product was synthesized in the same manner as in Example 1 of the description of the present invention.

(2) Dicyclohexylurea Removal

As a result of measuring the concentration of dicyclohexylurea in the crude mesotrione product obtained in the step of synthesizing the crude mesotrione product, the concentration of dicyclohexylurea remaining in the crude mesotrione product is 2300 ppm. Accordingly, as Experimental Examples 1 to 4, NaOH 1.2eq and 6mL (3V/W) of each solvent of Experimental Examples 1 to 4 in Table 1 were added, followed by stirring at room temperature for 3 hours. Then, water 6mL (3V/W) and 2N HCl were added to the separated and secured solid to a pH of 2-3, followed by stirring for 1 hour to precipitate a solid. The solid was obtained through filtration. At this time, the produced solid was obtained through filtration, and the results (residual amount (ppm) of dicyclohexylurea in mesotrione from which dicyclohexylurea was removed (ppm)) were confirmed as shown in Table 1 below.

menstruum Residual amount of dicyclohexylurea (ppm) Example 1 ethanol 25 Example 2 methanol 2 Example 3 isopropyl alcohol 70 Example 4 acetone 80 Example 5 acetonitrile 90 Experimental Example 1 Distilled water 5500 Experimental Example 2 dichloroethylene 690 Experimental Example 3 toluene 1800 Experimental Example 4 methyl t-butyl ether 1400

The method for preparing mesotrione according to an exemplary embodiment of the present invention can obtain mesotrione through fewer steps compared to the existing production method, and can also obtain high-purity mesotrione, and at room temperature without an additional heating process can proceed from In addition, the high-purity mesotrione can be obtained in a high yield.

Specifically, in the case of Examples 1 and 2 in which ethanol and methanol were used as solvents, respectively, the purity of the finally obtained mesotrione was 99.74% and 99.88%, respectively, to obtain mesotrione of high purity of 99.5% or more, In the case of Examples 3 to 5 in which the concentration of dicyclohexylurea in mesotrione is 100 ppm or less, particularly 30 ppm or less, and isopropyl alcohol, acetone and acetonitrile are used as solvents, respectively, dicyclohexyl urea in the obtained mesotrione Concentrations of 70ppm, 80ppm and 90ppm, respectively, were all 100ppm or less, to obtain mesotrione of high purity. In particular, in the case of Example 1 in which ethanol was used as a solvent, the finally obtained high-purity mesotrione yield was 84.7%, so that high-purity mesotrione having a purity of 99.5% or more was obtained in high yield.

On the other hand, in the case of Experimental Examples 1 to 4, the concentration of dicyclohexylurea in the obtained mesotrione was all 690 ppm or more. Therefore, high-purity mesotrione cannot be prepared by the method for preparing mesotrione according to Experimental Examples 1 to 4, and in order to obtain high-purity mesotrione of the degree obtained by the Examples of the present invention, an additional purification process I need this.

Claims (8)

a synthesis step of synthesizing a crude mesotrione product from 4-methylsulfonyl-2-nitrobenzoic acid, cyclohexane-1,3-dione and N,N'-dicyclohexylcarbodiimide; and
A method for producing high purity mesotrione, comprising a removing step of removing dicyclohexylurea from the synthesized crude mesotrione product using a basic material. The method according to claim 1, wherein the synthesis step
a reaction step of reacting 4-methylsulfonyl-2-nitrobenzoic acid, cyclohexane-1,3-dione and N,N'-dicyclohexylcarbodiimide;
A stirring step of stirring the product in the reaction step with cyanide; and
A method for producing high-purity mesotrione, comprising an obtaining step of obtaining a crude mesotrione product from the stirred solution in the stirring step. The method according to claim 1, wherein at least one of the synthesizing step and the removing step is made in a temperature range of 15 °C to 30 °C, respectively. The method according to claim 1, wherein the reaction step, the stirring step, and the obtaining step of the synthesis step are made of a one-pot reaction. The method according to claim 1,
The basic material is sodium hydroxide, sodium methoxide, sodium ethoxide, potassium carbonate, the method for producing a high-purity mesotrione comprising at least one selected from the group consisting of sodium carbonate. The method according to claim 1,
The removing step is a method for producing high purity mesotrione is carried out in an organic solvent. The method according to claim 1,
Mesotrione from which dicyclohexylurea has been removed in the removing step is a method for producing high-purity mesotrione in the form of mesotrione enolate. The method according to claim 1,
A method for producing a high-purity mesotrione in which the dicyclohexylurea content is 100 ppm or less in the mesotrione from which the dicyclohexylurea has been removed.