Method for preparing high purity methiozolin by using 1,3-difluoro-2-(((2-methylallyl)oxy)methyl) benzene as intermediate

Abstract

The present invention relates to a method for synthesizing, under conditions involving alkali metal and an organic solvent, methiozolin of chemical formula 1 by using N-hydroxy-3-methylthiophene-2-carbimidoyl chloride represented by chemical formula 3 and 1,3-difluoro-(((2-methylallyl)oxy)methyl) benzene represented by chemical formula 2. The method of the present invention enables methiozolin to be prepared with high efficiency and, after the reaction, enables methiozolin to be crystallized and purified to have high purity.

Description

Method for producing high-purity methiozolin using 1,3-difluoro-2-(((2-methylallyl)oxy)methyl)benzene as an intermediate

[0001] The present invention relates to a new industrial manufacturing method for producing [5-(2,6-difluorobenzyloxy)methyl-4,5-dihydro-5-methyl-3-(3-methylthiophen-2-yl)-isoxazole] (common name: methiozolin) represented by the following chemical formula 1 with high purity and high efficiency. The present invention relates to a method for industrially manufacturing high-purity methiozolin by using N-hydroxy-3-methylthiophene-2-carbimidoyl chloride represented by the chemical formula 3 and 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene represented by the chemical formula 2 as reaction raw materials according to the reaction scheme 1, reacting the mixture at 0 to 50°C using an alkali metal base in a single organic solvent, and then subjecting the resulting organic layer concentrate to a crystallization purification process.

[0002] [Reaction Formula 1]

[0003]

[0004] All of the prior art technologies for the production of [5-(2,6-difluorobenzyloxy)methyl-4,5-dihydro-5-methyl-3-(3-methylthiophen-2-yl)-isoxazole] (common name: methiozolin) used 5-methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl) methanol represented by chemical formula 4 in Scheme 2 and (2-(chloromethyl)-1,3-difluorobenzene or 2-(bromomethyl)-1,3-difluorobenzene) represented by chemical formula 5 as raw materials.

[0005] [Reaction Formula 2]

[0006]

[0007] In the previous literature [J. Agric. Food Chem. 2005, 53, 8639-8643], (5-methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl)methanol represented by chemical formula 4 and 2-(bromomethyl)-1,3-difluorobenzene represented by chemical formula 5 are used, and in the process of using sodium hydride as a reaction base, primary purification through column chromatography and secondary purification through hexane recrystallization are required, and anhydrous conditions and removal of mineral oil are required, making it unsuitable for mass production processes.

[0008] In the previous literature [Bulletin of the Koreac Chemical Society. 2012, Vol. 33, No. 1, 297-300], (5-methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl)methanol represented by chemical formula 4 and 2-(chloromethyl)-1,3-difluorobenzene represented by chemical formula 5 were used, and in the process using sodium hydroxide as a reaction base, primary purification through column chromatography using tetrahydrofuran and secondary purification through hexane recrystallization were required, resulting in a low yield and making it unsuitable for mass production.

[0009] Prior art documents US 6838416 B2 and US 7998902 B2 mention that [5-(2,6-difluorobenzyloxy)methyl-4,5-dihydro-5-methyl-3-(3-methylthiophen-2-yl)-isoxazole] (generic name: methiozolin), represented by chemical formula 1, is promising as a rice herbicide and a turf herbicide, but they emphasize that the purity of the target product should be as high as possible during mass production because toxicity or environmental problems may occur if impurities are included during the manufacturing process.

[0010] In the case of the above prior art, it is difficult to apply it to the industrial production method of methiozolin, but in the prior art US 2015158852A1, methiozolin is synthesized using (5-methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl)methanol represented by chemical formula 4 of reaction scheme 2 and (2-(chloromethyl)-1,3-difluorobenzene or 2-(bromomethyl)-1,3-difluorobenzene) represented by chemical formula 5 as intermediates, and the method of this document is sufficiently feasible for industrial application. However, there are several points to be improved in this manufacturing method, such as (i) the manufacturing period from the initial raw material is increased because (5-methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl)methanol represented by chemical formula 4 must be crystallized first to obtain it, (ii) when producing (2-(chloromethyl)-1,3-difluorobenzene or 2-(bromomethyl)-1,3-difluorobenzene) represented by chemical formula 5, toxic substances such as hydrochloric acid or hydrogen bromide are used, which may have a negative impact on workers and the off-site environment, and (iii) by reacting (5-methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl)methanol with (2-(chloromethyl)-1,3-difluorobenzene or 2-(bromomethyl)-1,3-difluorobenzene), The production of methiozolin requires the use of a phase transfer catalyst in water and an organic solvent. However, these phase transfer catalysts are generally expensive, and the primary recrystallization solvent used, high-purity n-heptane, is also expensive, increasing production costs. Furthermore, recrystallization is performed using a mixed solvent, making solvent recycling difficult.(iv) In this step, a by-product of chemical formula 8 is inevitably generated by reaction formula 3, and due to the generation of this by-product, an excess amount of (2-(chloromethyl)-1,3-difluorobenzene or 2-(bromomethyl)-1,3-difluorobenzene) is required to convert all of the (5-methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl)methanol into methiozolin, which becomes a factor in increasing the cost, and (v) there is a problem that the final yield of methiozolin is bound to decrease in the process of removing the by-product of chemical formula 8.

[0011] [Reaction Formula 3]

[0012]

[0013] The industrial production of methiozolin of the above chemical formula 1 requires a new production method that can improve the problems of (i) to (v).

[0014] Meanwhile, in Korean Patent Registration No. 1093102, the following reaction scheme 4 is disclosed as one of the synthesis methods of chemical formula 7, a phenylisoxazoline compound.

[0015] [Reaction Formula 4]

[0016]

[0017] However, there has been no disclosure of a manufacturing method according to the reaction scheme 1 of the present invention for manufacturing methiozolin using chemical formula 2 as an intermediate, which is industrially applicable and can significantly improve problems in existing industrial manufacturing methods.

[0018] The present invention was derived from the above-mentioned needs, and relates to a method for synthesizing methiozolin of chemical formula 1 using N-hydroxy-3-methylthiophene-2-carbimidoyl chloride represented by chemical formula 3 and 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene represented by chemical formula 2 under alkali metal and organic solvent conditions, and the method of the present invention can produce methiozolin with high efficiency, and completes the present invention by establishing conditions for crystallizing methiozolin after the reaction and purifying it with high purity.

[0019] In order to achieve the above object, the present invention comprises (1) a step of reacting N-hydroxy-3-methylthiophene-2-carbimidoyl chloride represented by chemical formula 3 and 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene represented by chemical formula 2 using a single organic solvent and an alkali metal base at a reaction temperature of 0 to 50°C according to the following reaction scheme 1; and

[0020] (2) A method for producing methiozolin (chemical formula 1) is provided, comprising a step of crystallizing the concentrate of the organic layer separated from the reaction solution after the reaction of the above step (1) in a mixed solvent of water / ethanol, water / isopropanol, or C1~C4 alcohol / n-heptane; or a single solvent of C1~C4 alcohol.

[0021] [Reaction Formula 1]

[0022]

[0023] In addition, the present invention provides a method for preparing a 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene compound, comprising the step of reacting a compound of the following chemical formula 9 with a compound of the following chemical formula 10 in the presence of a single organic solvent, a base, and a metal catalyst.

[0024] [Chemical Formula 9]

[0025]

[0026] [Chemical Formula 10]

[0027]

[0028] In addition, the present invention provides a use of a 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene compound represented by the following chemical formula 2 as an intermediate in the production of [5-(2,6-difluorobenzyloxy)methyl-4,5-dihydro-5-methyl-3-(3-methylthiophen-2-yl)-isoxazole] represented by the chemical formula 1.

[0029] [Chemical Formula 1]

[0030]

[0031] [Chemical Formula 2]

[0032]

[0033] The present invention relates to a method for producing high-purity methiozolin using 1,3-difluoro-2-(((2-methylallyl)oxy)methyl)benzene as an intermediate. By using 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene represented by chemical formula 2 as an intermediate, the step of producing chemical formula 4 from chemical formula 3 as disclosed in the following reaction scheme 5 can be omitted, and thus the recrystallization and drying processes can be omitted, thereby greatly saving the production time and cost of methiozolin and increasing the production efficiency.

[0034] In addition, since there is no need for a process to remove the byproduct of chemical formula 8 generated by commercializing chemical formula 5 when manufactured according to a conventional method, not only is the yield and purity of methiozolin increased, but the environmental and production cost burden can be reduced, and since an expensive catalyst is not used, it is an environmentally friendly manufacturing method that can reduce production costs.

[0035] Therefore, the manufacturing method of the present invention can reduce the manufacturing steps by utilizing chemical formula 2 as an intermediate as disclosed in Table 1 and Reaction Scheme 5, and thus can manufacture the compound of chemical formula 1 with high efficiency, and is therefore a manufacturing method that can be usefully used industrially.

[0036] [Reaction Formula 5]

[0037]

[0038] Number of days for production of each stage of synthesis: Day / batch / year 1) Existing process: 5 stages, 7 days, 37 days Improved process: 4 stages, 5 days, 52 days

[0039] 1) Calculated by assuming that year 1 is 260 days.

[0040] The present invention comprises (1) a step of reacting N-hydroxy-3-methylthiophene-2-carbimidoyl chloride represented by chemical formula 3 and 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene represented by chemical formula 2 using a single organic solvent and an alkali metal base at a reaction temperature of 0 to 50°C according to the following reaction scheme 1; and

[0041] (2) A method for producing methiozolin (chemical formula 1), comprising the step of crystallizing the concentrate of the organic layer separated from the reaction solution after the reaction of the above step (1) in a mixed solvent of water / ethanol, water / isopropanol, or C1~C4 alcohol / n-heptane; or a single solvent of C1~C4 alcohol;

[0042] [Reaction Formula 1]

[0043]

[0044] In the above step (1), a single organic solvent is used as the organic solvent, and the organic solvent is preferably one selected from among ethyl acetate, benzene, toluene, xylene, chlorobenzene, 1,2-dichloroethane, 1,2-dichloromethane, and dimethylformamide, more preferably toluene or ethyl acetate, but is not limited thereto.

[0045] The above alkali metal base is preferably one selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, and potassium bicarbonate, and the amount of base used is preferably 4 to 6 equivalents of the compound of chemical formula 3, but is not limited thereto.

[0046] The reaction temperature is preferably 10 to 50°C, more preferably 20 to 50°C, and even more preferably 25 to 30°C, which is a temperature at which yield and purity are excellent.

[0047] After the reaction in step (1), in step (2), the reaction solution is purified by removing by-products with water, cooling, drying and concentrating the separated organic layer, and the obtained concentrate is purified by crystallizing it in a solvent system of a single solvent of C1 to C4 alcohol; water / C1 to C4 alcohol; or C1 to C4 alcohol / (C5 to C7 aliphatic hydrocarbon or C6 to C7 aromatic); thereby obtaining (5-methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-yl)methanol in a simple and economical manner.

[0048] When crystallizing in a single solvent system, the C1 to C4 alcohol solvent used is preferably methanol, ethanol, propanol, isopropanol or n-butanol, and at this time, the amount of single solvent used is preferably 1 to 10 times the weight ratio of compound 3, but is not limited thereto.

[0049] The C1 to C4 alcohol solvent used for crystallization in a water / alcohol solvent system is methanol, ethanol, propanol, isopropanol or n-butanol, and the water / C1 to C4 alcohol ratio is preferably 1:10 to 5:5, and at this time, it is preferable to use 4 to 6 times the weight ratio of water to compound 3.

[0050] In the mixed solvent system of C1~ C4 alcohol / C6~ C7 aliphatic hydrocarbon, the hydrocarbons used for crystallization are n-pentane, n-hexane, and n-heptane, and the C1~ C4 alcohol solvents are methanol, ethanol, n-propane, isopropane, and n-butanol, etc. It is preferable to use a ratio of C1~ C4 alcohol and C6~ C7 aliphatic hydrocarbon of 5:5 to 10:1, and it is preferable to use an amount of alcohol 1 to 10 times the weight ratio of methiozolin before purification.

[0051] In the above step (2), the crystallization temperature is preferably -20 to 20°C, more preferably -5 to 10°C.

[0052] In the above step (2), the single solvent is preferably isopropanol or ethanol, and the mixed solvent is preferably water / isopropanol in a volume ratio of 1:10 to 5:5 or isopropanol / n-heptane in a volume ratio of 5:5 to 10:1, but is not limited thereto.

[0053] The organic solvent is ethyl acetate, the alkali metal base is sodium bicarbonate, the reaction temperature of step (1) is 20 to 50°C, and in step (2), it is most preferable to crystallize the organic layer concentrate using isopropanol, but is not limited thereto.

[0054] The compound of the above chemical formula 2 can be prepared by a preparation method including a step of reacting a compound of the following chemical formula 9 with a compound of the following chemical formula 10 in the presence of a single organic solvent, a base, and a metal catalyst.

[0055] [Chemical Formula 9]

[0056]

[0057] [Chemical Formula 10]

[0058]

[0059] In the preparation of the compound of the above chemical formula 2, the organic solvent is preferably one selected from toluene, 1,2-dichloromethane, 1,2-dichloroethane, acetonitrile, acetone, methyl ethyl ketone, and tetrahydrofuran, but is not limited thereto.

[0060] In the production of the compound of the above chemical formula 2, the metal catalyst is preferably one selected from among tetrabutylammonium sulfate, tetrabutylammonium iodide, and tetrabutylphosphonium bromide, but is not limited thereto.

[0061] In the preparation of the compound of the above chemical formula 2, the base is preferably one selected from potassium carbonate, sodium hydride, triethylamine, sodium carbonate, sodium bicarbonate, and sodium hydroxide, but is not limited thereto.

[0062] The compound of the above chemical formula 2 may be prepared by a method including a step of reacting the compound of the above chemical formula 9 with 1.2 to 1.5 equivalents of the compound of the above chemical formula 10 at 0 to 90°C in the presence of sodium hydroxide as a base and tetrabutylphosphonium bromide as a metal catalyst, without using an organic solvent as a reaction solution.

[0063] The purity of the synthesized methiozolin of the present invention is preferably 99% or higher, more preferably 99.0 to 99.9%, but is not limited thereto.

[0064] In addition, the present invention relates to a method for preparing a 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene compound, comprising a step of reacting a compound of the following chemical formula 9 with a compound of the following chemical formula 10 in the presence of a single organic solvent, a base, and a metal catalyst.

[0065] [Chemical Formula 9]

[0066]

[0067] [Chemical Formula 10]

[0068]

[0069] The organic solvent is preferably one selected from toluene, 1,2-dichloromethane, 1,2-dichloroethane, acetonitrile, acetone, methyl ethyl ketone, and tetrahydrofuran, but is not limited thereto.

[0070] The above metal catalyst is preferably one selected from among tetrabutylammonium sulfate, tetrabutylammonium iodide, and tetrabutylphosphonium bromide, but is not limited thereto.

[0071] The above base is preferably one selected from potassium carbonate, sodium hydride, triethylamine, sodium carbonate, sodium bicarbonate, and sodium hydroxide, but is not limited thereto.

[0072] In addition, the present invention relates to the use of a 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene compound represented by the following chemical formula 2 as an intermediate in the production of [5-(2,6-difluorobenzyloxy)methyl-4,5-dihydro-5-methyl-3-(3-methylthiophen-2-yl)-isoxazole] represented by the chemical formula 1.

[0073] [Chemical Formula 1]

[0074]

[0075] [Chemical Formula 2]

[0076]

[0077] The conditions of reaction scheme 1 of the present invention are different from the conditions of reaction scheme 4 disclosed in Korean Patent No. 1093102 in that, as summarized in Table 2 below, 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene represented by chemical formula 2 is commonly used, and the starting material, presence of a catalyst, and solvent conditions are different.

[0078]

[0079] The present invention relates to a manufacturing method for economically and efficiently synthesizing high-purity methiozolin under specific conditions, wherein the compound of formula 3 and the compound of formula 2 are reacted under conditions of maintaining a constant reaction temperature by selecting an optimal organic solvent and base, thereby obtaining formula 1 directly without the need for an intermediate product and purifying it through recrystallization using a selected solvent system. In performing the manufacturing method of the present invention for synthesizing methiozolin represented by formula 1 with high purity and high yield, the selection of the reaction solvent, base, and recrystallization solvent acts as a very important factor, and the present invention establishes a manufacturing method by optimizing these factors to minimize the additional products generated during the reaction.

[0080] The compound of chemical formula 13 used as a raw material in the present invention is a commercially available compound. It is preferable to use the compound of chemical formula 2 in an amount of 0.8 to 0.9 equivalents relative to the compound of chemical formula 3.

[0081] The present invention as described above will be specifically described in the following examples, but the present invention is not limited thereto.

[0082]

[0083] Reaction Example 1. Synthesis of 3-methylthiophene-2-carbaldehyde (Formula 12)

[0084] Diformamide (4.69 kg) was placed in a 50 ℓ glass reactor and cooled to 0 ℃. After that, phosphoryl chloride (3.24 kg) was added in three equal portions at 10-minute intervals and heated until the internal temperature reached 40 ℃. 3-Methylthiophene (0.985 kg) was added to the reaction solution, and when the internal temperature dropped below 45 ℃, 3-methylthiophene (0.985 g) was additionally added. After the addition was completed, the internal temperature was maintained at 50-55 ℃ and stirred for 15 hours. After the reaction was completed, ethyl acetate (2.9 kg) was added to the reaction solution, cooled to 0 ℃, and water (1.2 kg) was slowly added. After the addition of water was completed, additional water (12.87 kg) was slowly added when the internal temperature was below 10 ℃. At an internal temperature of 10℃, 25% sodium hydroxide (13.5 kg) was slowly added over 30 minutes, and care was taken to ensure that the internal temperature did not exceed 40℃. The reaction solution was stirred for 1 hour, allowed to settle, and after 30 minutes, the layers were separated, the dichloromethane layer was stored, and the aqueous layer was extracted with ethyl acetate (4.71 kg). The ethyl acetate stored in the reactor and extracted was concentrated under reduced pressure and used immediately in the next reaction.

[0085]

[0086] Reaction Example 2. Synthesis of 3-methylthiophene-2-carbaldehyde oxime (chemical formula 11)

[0087] In a 50-liter glass reactor, 3-methylthiophene-2-carbaldehyde (2.54 kg, 0.02 mol) was dissolved in methanol (1.39 kg) and water (7.15 kg), and hydroxylamine hydrochloride (1.54 kg, 0.022 mol) was added at room temperature. After 30 minutes, a solid was formed, and the mixture was stirred for an additional hour, cooled to 0°C, and 25% sodium hydroxide (3.38 kg, 0.021 mol) was added. The mixture was stirred at room temperature for 2 hours, and the temperature was lowered to 0 to 5°C. The formed solid was filtered and used immediately in the next reaction.

[0088]

[0089] Reaction Example 3. Synthesis of N-hydroxy-3-methylthiophene-2-carbimidoyl chloride (Formula 3)

[0090] 3-Methylthiophene-2-carbaldehyde oxime (2.84 kg) and dimethylformamide (5.68 kg) were added. While maintaining the internal temperature of the reactor at approximately -7 to -9°C, N-chlorosuccinimide (2.82 kg, 0.021 mol) was added in 10 equal portions at 1-hour intervals so that the temperature did not exceed -3 to 5°C, and stirred for 1 hour. When the reaction was complete, ethyl acetate (17.0 kg) was added to the reaction mixture, which was washed twice with water and then used in the next reaction.

[0091]

[0092] Reaction Example 4. 1,3-Difluoro-2-(((2-methylallyl)oxy)methyl)benzene (Formula 2)

[0093] In a 20ℓ glass reactor, (2,6-difluorophenyl)methanol (2.8kg, 0.019mol), 25% sodium hydroxide (9.34kg, 0.058mol), and tetrabutylphosphonium bromide (200g) were added and stirred for 30 minutes. 3-chloro-2-methylprop-1-ene (2.18kg, 0.023) was added and reacted at 90℃ for 4 hours. After the reaction was complete, toluene (1.68kg) was added and the organic layer was concentrated. The concentrated organic layer was distilled to obtain the target compound.

[0094]

[0095] Example 1. Synthesis of 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene (chemical formula 2)

[0096] In a 20ℓ organic reactor, (2,6-difluorophenyl)methanol (2.8kg, 0.019mol), 25% sodium hydroxide (9.34kg, 0.058mol), and tetrabutylphosphonium bromide (200g) were stirred for 30 minutes, then 3-chloro-2-methylprop-1-ene (2.18kg, 0.023) was added and reacted at 90℃ for 4 hours. After the reaction was complete, toluene (1.68kg) was added, and the organic layer was concentrated. The concentrated organic layer was distilled to obtain the target compound.

[0097]

[0098] Example 2. Synthesis of [5-(2,6-difluorobenzyloxy)methyl-4,5-dihydro-5-methyl-3-(3-methylthiophen-2-yl)-isoxazole] (Chemical Formula 1)

[0099] In a 50-liter glass reactor, 1,3-difluoro-2-(((2-methylallyl)oxy)methyl)benzene (3.53 kg, 0.02 mol) and sodium bicarbonate (21.21 kg, 0.12 mol) were placed, N-hydroxy-3-methylthiophene-2-carbimidoyl chloride dissolved in ethyl acetate (17.0 kg) was added, and the mixture was stirred at room temperature (25-30°C) for 12 hours. After the reaction was complete, the organic layer was washed twice with water and concentrated under reduced pressure. After concentration was complete, isopropanol (11.8 kg) was added, completely dissolved at 70°C, and slowly cooled to room temperature. After crystals were formed, the mixture was cooled to 0-5°C and stirred for 2 hours. The produced solid was filtered to obtain an ivory-colored solid, which was the target compound (yield: 72%, purity: 99.5%).

[0100]

Claims

1. (1) A step of reacting N-hydroxy-3-methylthiophene-2-carbimidoyl chloride represented by chemical formula 3 and 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene represented by chemical formula 2 using a single organic solvent and an alkali metal base at a reaction temperature of 0 to 50°C according to the following reaction scheme 1; and (2) A method for producing methiozolin (chemical formula 1), comprising the step of crystallizing the concentrate of the organic layer separated from the reaction solution after the reaction of the step (1) in a mixed solvent of water / ethanol, water / isopropanol, or C1 to C4 alcohol / n-heptane; or a single solvent of C1 to C4 alcohol; [Reaction Formula 1] 2. A method for producing methiozolin, characterized in that in the step (1), the organic solvent is any one selected from ethyl acetate, benzene, toluene, xylene, chlorobenzene, 1,2-dichloroethane, 1,2-dichloromethane, and dimethylformamide.

3. A method for producing methiozolin, characterized in that in paragraph 1, the alkali metal base is any one selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, and potassium bicarbonate.

4. A method for producing methiozolin, characterized in that in the step (2) of paragraph 1, the single solvent is isopropanol or ethanol, and the mixed solvent is water / isopropanol or isopropanol / n-heptane.

5. A method for producing methiozolin, characterized in that in the first paragraph, the organic solvent is ethyl acetate, the alkali metal base is sodium bicarbonate, the reaction temperature of the step (1) is 20 to 50°C, and the organic layer concentrate in the step (2) is crystallized using isopropanol or a mixed solvent of isopropanol / n-heptane.

6. A method for producing methiozolin, characterized in that in claim 1, the compound of formula 2 is produced by a method including a step of reacting a compound of formula 9 below and a compound of formula 10 below in the presence of a single organic solvent, a base, and a metal catalyst. [Chemical formula 9] [Chemical Formula 10] 7. A method for producing methiozolin, characterized in that in paragraph 6, the organic solvent is any one selected from toluene, 1,2-dichloromethane, 1,2-dichloroethane, acetonitrile, acetone, methyl ethyl ketone, and tetrahydrofuran.

8. A method for producing methiozolin, characterized in that in paragraph 6, the metal catalyst is any one selected from tetrabutylammonium sulfate, tetrabutylammonium iodide, and tetrabutylphosphonium bromide.

9. A method for producing methiozolin, characterized in that in paragraph 6, the base is any one selected from potassium carbonate, sodium hydride, triethylamine, sodium carbonate, sodium bicarbonate, and sodium hydroxide.

10. A method for producing methiozolin, characterized in that in claim 1, the compound of formula 2 is produced by a method including a step of reacting a compound of formula 9 below with 1.2 to 1.5 equivalents of a compound of formula 10 below at 0 to 90°C in the presence of sodium hydroxide as a base and tetrabutylphosphonium bromide as a metal catalyst, without using an organic solvent as a reaction solution. [Chemical formula 9] [Chemical Formula 10] 11. A method for producing a 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene compound, comprising the step of reacting a compound of the following chemical formula 9 with a compound of the following chemical formula 10 in the presence of a single organic solvent, a base and a metal catalyst. [Chemical formula 9] [Chemical Formula 10] 12. A manufacturing method according to claim 11, characterized in that the organic solvent is any one selected from toluene, 1,2-dichloromethane, 1,2-dichloroethane, acetonitrile, acetone, methyl ethyl ketone, and tetrahydrofuran.

13. A manufacturing method according to claim 11, characterized in that the metal catalyst is any one selected from tetrabutylammonium sulfate, tetrabutylammonium iodide, and tetrabutylphosphonium bromide.

14. A manufacturing method according to claim 11, characterized in that the base is any one selected from potassium carbonate, sodium hydride, triethylamine, sodium carbonate, sodium bicarbonate, and sodium hydroxide.

15. Use as an intermediate of a 1,3-difluoro-(((2-methylallyl)oxy)methyl)benzene compound represented by the following chemical formula 2 in the production of [5-(2,6-difluorobenzyloxy)methyl-4,5-dihydro-5-methyl-3-(3-methylthiophen-2-yl)-isoxazole] represented by the chemical formula 1. [Chemical Formula 1] [Chemical formula 2]

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