A method for preparing pyroxasulfone

Abstract

The application provides a novel preparation method of metrafenone. The preparation method provided by the application has the advantages of high reaction yield, high product purity, mild reaction condition, short reaction time, short reaction route, easy availability of raw materials, low cost, good safety, no need of using chlorinating reagents, less generation of three wastes, good environmental friendliness, and suitability for green large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a preparation method of topramezone. BACKGROUND

[0002] Pyroxasulfone (CAS No. 447399-55-5) is an isoxazole herbicide developed by Nippon Shokubai Co., Ltd., Japan, and its chemical structure is as follows:

[0003]

[0004] Pyroxasulfone

[0005] Pyroxasulfone is a broad-spectrum herbicide, and its mechanism of action is similar to that of acetochlor and related herbicides. After application, it is absorbed by the young roots and young shoots of weeds, inhibits the early growth of seedlings, destroys the meristem and hypocotyl, and is a potential inhibitor in the biosynthesis of VLCFA (very long chain fatty acid) in plants. However, its application crop species is wide, and its biological activity is much higher than that of acetochlor and isopropyl amine. In terms of unit area dosage, pyroxasulfone is 8-10 times lower than acetochlor and other chloroacetamide herbicide varieties, and its water solubility is low (3.1 mg / L at 20℃), which means that it has little possibility of polluting surface water and groundwater through rainfall and leaching, and can reduce the damage to the ecology.

[0006] The weed spectrum of pyroxasulfone is similar to that of acetochlor, isopropyl amine and other chloroacetamide herbicides, but its control effect on almost all weeds such as Setaria viridis, Ambrosia artemisiifolia, Euphorbia heterophylla, Digitaria sanguinalis and others is better than that of isopropyl amine, and the stable control effect lasts for 85 days after spraying; under drought conditions, its control effect on green dog tail grass, sunflower and amaranth is better than that of S-isopropyl amine; the effective period of low-dose control of various weeds is longer. The low unit area dosage, good weed control effect and long weed control period are the outstanding features of pyroxasulfone, which may partially replace acetochlor and isopropyl amine in the future.

[0007] The preparation method of pyroxasulfone disclosed in the prior art has a long reaction route, a complex operation process, and needs to perform a chlorination step; or the preparation method needs to use expensive cyclic secondary amine reagents, which not only increases the production cost, but also generates cyclic ammonium chloride salt by reacting with hydrochloric acid in the system, which is not conducive to the reaction. In addition, the existing method also has problems such as low yield of pyroxasulfone, low conversion rate of raw materials, large amount of by-products, difficult post-treatment, easy to cause environmental pollution and the like. SUMMARY

[0008] To solve the above technical problems, the present application provides a preparation method of metalochlor, wherein the preparation method comprises the following steps:

[0009] Step S5: the compound of formula (6) is reacted with sodium hypochlorite to obtain metalochlor of formula (1);

[0010]

[0011] According to an embodiment of the present application, the molar ratio of the compound of formula (6) to sodium hypochlorite in step S5 is 1:(1-8), preferably 1:(1.5-5), for example 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0012] According to an embodiment of the present application, step S5 is carried out in the presence of an organic solvent. For example, the organic solvent is selected from one, two or more of methanol, ethanol, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, toluene, dichloroethane, dichloromethane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), sulfolane, acetonitrile.

[0013] According to an embodiment of the present application, the weight ratio of the amount of substance of the compound of formula (6) to the organic solvent is selected from 1 mol:(100-1000)g, for example 1 mol:(200-800)g, such as 1 mol:300g, 1 mol:400g, 1 mol:500g, 1 mol:600g, 1 mol:700g.

[0014] According to an embodiment of the present application, the reaction temperature of step S5 is 40℃-120℃, preferably 60℃-100℃, for example 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃ or 100℃.

[0015] According to an embodiment of the present application, the reaction time of step S5 is 0.5h-10h, for example 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h.

[0016] According to an embodiment of the present application, after the reaction of step S5 is completed, the organic solvent is removed, and extraction separation is carried out using water and an organic extraction solvent (such as ethyl acetate or dichloromethane); preferably, after extraction, the organic phase is desolventized, toluene is added, and recrystallization purification is carried out.

[0017] According to an embodiment of the present application, when extracting, the weight ratio of the amount of substance of the compound of formula (6) to water is selected from 1 mol:(50-800)g, for example 1 mol:(100-500)g, such as 1 mol:200g, 1 mol:300g, 1 mol:400g.

[0018] According to an embodiment of the present application, the weight ratio of water and organic extraction solvent during extraction is selected from 1:(0.2-5), for example 1:(0.5-2), such as 1:0.5, 1:1, 1:1.5.

[0019] According to an embodiment of the present application, the weight ratio of the amount of substance of the compound of formula (6) and the toluene during recrystallization purification is selected from 1 mol:(100-1000) g, for example 1 mol:(200-800) g, such as 1 mol:300 g, 1 mol:400 g, 1 mol:500 g, 1 mol:600 g, 1 mol:700 g.

[0020] According to an embodiment of the present application, the preparation method of step S5 comprises: sequentially adding the compound of formula (6) and an organic solvent into a reactor, and after warming, adding sodium hypochlorite to react, to obtain the sulfentrazone represented by formula (1).

[0021] According to an embodiment of the present application, the preparation method of the compound of formula (6) comprises the following steps:

[0022] Step S4: synthesizing the compound of formula (6) from the compound of formula (5) in the presence of an oxidant and a catalyst;

[0023]

[0024] According to an embodiment of the present application, the molar ratio of the compound of formula (5) to the oxidant in step S4 is 1:(1-10), preferably 1:(2-8), for example 1:3, 1:4, 1:5, 1:6, 1:7, 1:8.

[0025] According to an embodiment of the present application, the oxidant in step S4 is selected from one, two or more of hydrogen peroxide, oxygen, meta-chloro peroxide benzoic acid, sodium percarbonate.

[0026] According to an embodiment of the present application, when the oxidant in step S4 is hydrogen peroxide, the hydrogen peroxide is an aqueous hydrogen peroxide solution, and the concentration is for example 10wt%-50wt%, such as 20wt%, 30wt%, 40wt%.

[0027] According to an embodiment of the present application, the molar ratio of the compound of formula (5) to the catalyst in step S4 is 1:(0.01-5), preferably 1:(0.1-2.0), for example 1:0.2, 1:0.5, 1:1, 1:1.5, 1:2.

[0028] According to an embodiment of the present application, in step S4, the catalyst is a mixed acid, for example, a mixed acid of sulfuric acid and acetic acid; the molar ratio of sulfuric acid and acetic acid can be 1:(2-10), for example, 1:(5-8), such as 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5.

[0029] According to an embodiment of the present application, step S4 is carried out in the presence of an organic solvent. For example, the organic solvent is selected from one, two or more of ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, toluene, dichloroethane, dichloromethane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), sulfolane, acetonitrile; for example, toluene.

[0030] According to an embodiment of the present application, the reaction temperature of step S4 is -10℃-150℃, preferably 30℃-70℃, for example, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃ or 70℃.

[0031] According to an embodiment of the present application, the reaction time of step S4 is 0.2h-5h, for example, 0.5h, 1h, 2h, 3h, 4h, 5h.

[0032] According to an embodiment of the present application, after the reaction of step S4 is completed, the solvent is removed or no post-treatment is performed and it is directly used in the subsequent reaction.

[0033] According to an embodiment of the present application, the preparation method of step S4 comprises: sequentially adding the compound of formula (5), acetic acid, sulfuric acid, an organic solvent into a reactor, after warming, adding an aqueous hydrogen peroxide solution to react, to obtain the compound of formula (6).

[0034] According to an embodiment of the present application, the preparation method of the above-mentioned compound of formula (5) comprises the following steps:

[0035] Step S3: the compound of formula (4) is reacted with freon in the presence of a base to obtain the compound of formula (5);

[0036]

[0037] According to an embodiment of the present application, in step S3, the molar ratio of the compound of formula (5), freon and the base is 1:(1-5):(1-5), preferably 1:(1.1-2.0):(1.1-2.0), for example, 1:2:2. Wherein each of the "1.1-2.0" at least records 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0.

[0038] According to an embodiment of the present application, in step S3, the base is selected from one, two or more of an organic base and an inorganic base, for example, one, two or more of sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, and the like, for example, sodium hydroxide.

[0039] According to an embodiment of the present application, in step S3, the base can be an aqueous solution of the base, for example, at a concentration of 10wt%-50wt%, such as 20wt%, 30wt%, 40wt%.

[0040] According to an embodiment of the present application, step S3 is carried out in the presence of water and / or an organic solvent. For example, the organic solvent is selected from one, two or more of ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, toluene, dichloroethane, dichloromethane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), sulfolane, acetonitrile; for example, water, acetonitrile; the volume ratio of water to the organic solvent can be (1-5):10, such as 2:10, 3:10, 4:10.

[0041] According to an embodiment of the present application, the reaction temperature of step S3 is -10℃-50℃, preferably 0℃-30℃, for example, 10℃, 15℃, 20℃, 25℃ or 30℃.

[0042] According to an embodiment of the present application, the reaction time of step S3 is 0.5h-8h, for example, 1h, 2h, 3h, 4h, 5h, 6h.

[0043] According to an embodiment of the present application, the preparation method of step S3 is specifically as follows: the compound of formula (4), an organic solvent, and a base are sequentially added to a reactor, and then Freon is introduced at low temperature (10-20℃) to react, to obtain the compound of formula (5).

[0044] According to an embodiment of the present application, the preparation method of the compound of formula (4) comprises the following steps:

[0045] Step S2: reacting the compound of formula (3) with methylhydrazine to obtain the compound of formula (4);

[0046]

[0047] wherein R is selected from C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl; preferably, R is selected from C1-C6 alkyl; more preferably, R is methyl.

[0048] According to an embodiment of the present application, step S2 is carried out in the presence of water and / or an organic solvent. For example, the organic solvent is selected from one, two or more of methanol, ethanol, acetonitrile and the like. For example, the volume ratio of water to the organic solvent is (1-9):(9-1), for example (2-8):(8-2), (3-7):(7-3), (4-6):(6-4) or 1:1.

[0049] According to an embodiment of the present application, the molar ratio of the compound of formula (3) to the organic solvent in step S2 is selected from 1 mol:(100-1000) mL, for example 1 mol:(200-800) mL, such as 1 mol:300 mL, 1 mol:400 mL, 1 mol:500 mL, 1 mol:600 mL, 1 mol:700 mL.

[0050] According to an embodiment of the present application, the molar ratio of the compound of formula (3) to methylhydrazine in step S2 is (0.5-5):(0.5-5), preferably (1.0-3.0):(1.0-3.0), for example 1:2, 1:1 and the like. Wherein each of the "1.0-3.0" at least records 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0.

[0051] According to an embodiment of the present application, the reaction temperature of step S2 is 10-100°C, preferably 30-70°C, for example 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C or 70°C.

[0052] According to an embodiment of the present application, the reaction time of step S2 is 0.5-5h, for example 1h, 2h, 3h, 4h, 5h.

[0053] According to an embodiment of the present application, after the reaction of step S2 is completed, the preparation method is extracted with ethyl acetate, desolventized to obtain the compound of formula (4).

[0054] According to an embodiment of the present application, after the reaction of step S2 is completed, it can be directly used for subsequent reactions without post-treatment.

[0055] According to an embodiment of the present application, the preparation method of step S2 comprises: sequentially adding an organic solvent and methylhydrazine to a reactor containing the compound of formula (3), warming and reacting to obtain the compound of formula (4).

[0056] According to an embodiment of the present application, the preparation method of the compound of formula (3) comprises the following steps:

[0057] Step S1: reacting a compound of formula (2) with trifluoroacetaldehyde in the presence of a base to obtain a compound of formula (3);

[0058]

[0059] wherein R is selected from C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl; preferably, R is selected from C1-C6 alkyl; more preferably, R is methyl.

[0060] According to an embodiment of the present application, in step S1, the molar ratio of the compound of formula (2), trifluoroacetaldehyde and the base is 1:(1-5):(1-5), preferably 1:(1.1-2.0):(1.1-2.0), for example 1:1.1:1.1. Wherein each of said "1.1-2.0" at least recites 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0.

[0061] According to an embodiment of the present application, in step S1, the base is selected from one, two or more of an organic base and an inorganic base, for example, is selected from one, two or more of sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, triethylamine and the like, for example, is sodium hydroxide.

[0062] According to an embodiment of the present application, in step S1, the base can be an aqueous solution of the base, for example, has a concentration of 10wt%-50wt%, such as 20wt%, 30wt%, 40wt%.

[0063] According to an embodiment of the present application, step S1 is carried out in the presence of an organic solvent. For example, the organic solvent is selected from one, two or more of methanol, ethanol, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, toluene, dichloroethane, dichloromethane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), sulfolane, acetonitrile; for example, ethanol.

[0064] According to an embodiment of the present application, in step S1, the amount of substance of the compound of formula (2) to the volume of the organic solvent is selected from 1 mol:(100-1000) mL, for example, 1 mol:(200-800) mL, such as 1 mol:300 mL, 1 mol:400 mL, 1 mol:500 mL, 1 mol:600 mL, 1 mol:700 mL.

[0065] According to an embodiment of the present application, the reaction temperature of step S1 is -10℃-150℃, preferably 30℃-70℃, for example, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃ or 70℃.

[0066] According to an embodiment of the present application, the reaction time of step S1 is 0.5h-8h, for example, 1h, 2h, 3h, 4h, 5h, 6h.

[0067] According to an embodiment of the present application, the preparation method of step S1 is specifically as follows: sequentially adding the compound of formula (2), an organic solvent, and a base into a reactor, and then adding trifluoroacetaldehyde after warming to obtain the compound of formula (3).

[0068] According to an embodiment of the present application, in the preparation method of step S1, after the reaction is completed, cooling and crystallization, vacuum filtration, and drying are performed to obtain the compound of formula (3).

[0069] The present application also provides an intermediate compound as shown below:

[0070]

[0071] wherein R is selected from C1-C8 alkyl, C3-C8 cycloalkyl, and C3-C8 halocycloalkyl; preferably, R is selected from C1-C6 alkyl; more preferably, R is methyl.

[0072] The present application also provides an application of the intermediate compound in the preparation of metrafenone.

[0073] Advantages

[0074] The present application provides a novel preparation method of metrafenone. The preparation method provided by the present application has high reaction yield, high product purity, mild reaction conditions, short reaction time, and short reaction route. Moreover, the preparation method provided by the present application has the advantages of easy availability of raw materials, low cost, good safety, no need to use chlorinating reagents, less waste, and environmental friendliness, and is suitable for green large-scale production. DETAILED DESCRIPTION

[0075] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustrative and explanatory of the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application.

[0076] In the following examples, the raw materials used are commercially available from Beijing Coupling Technology Co., Ltd. without special instructions.

[0077] In the following examples, the content (purity) of the reactants and products is measured by high performance liquid chromatography (Agilent HPLC 1260).

[0078] Example 1: Synthesis of compound 5

[0079] Into a 500 mL four-necked flask, add 1 mol of compound 2, then add 500 mL of anhydrous ethanol, 1.1 mol of 30 wt% sodium hydroxide, stir, heat to about 50°C, then dropwise add 1.1 mol of trifluoroacetaldehyde aqueous solution, keep at 50°C for 5 h, cool and crystallize, reduce pressure and filter, and dry to obtain yellow solid compound 3.

[0080] Into the reactor, add the compound 3 obtained above, 500 mL of methanol, and 1.2 mol of methylhydrazine, heat to 65-70°C, and react for 2 h. The reaction is considered complete when the area of compound 3 is less than 0.1% as detected by liquid chromatography. Compound 4 is obtained and used directly in the next step without treatment. M / Z is 311.09.

[0081] To the reaction solution of the previous step, continue to add 30 mL of water, 100 mL of acetonitrile, and 2 mol of 30 wt% sodium hydroxide aqueous solution. Start to pass 2.0 mol of freon (1-chloro-2-fluoromethane) at 10-20°C, and react for 3 h at 20°C. The reaction is considered complete when the area of compound 4 is less than 0.1% as detected by liquid chromatography. After extraction with ethyl acetate, compound 5 is obtained by desolventizing, with a yield of 85% and a purity of 95%. M / Z is 361.09.

[0082] The reaction scheme is as follows, where R is methyl:

[0083]

[0084] Example 2: Synthesis of compound 6

[0085] Into a 500 mL four-necked flask, add 1 mol of compound 2, then add 500 mL of anhydrous ethanol, 1.1 mol of 30 wt% sodium hydroxide, stir, heat to about 50°C, then dropwise add 1.1 mol of trifluoroacetaldehyde aqueous solution, keep at 50°C for 5 h, cool and crystallize, reduce pressure and filter, and dry to obtain yellow solid compound 3.

[0086] The reaction scheme is as follows:

[0087]

[0088] Example 3: Synthesis of compound 1

[0089] In a 2000 mL four-necked flask, compound 6 (1 mol) was added, 500 g of methanol was added, heated to 65-70℃, then 3 mol of sodium hypochlorite was added dropwise, the reaction was carried out for 1 h, liquid phase HPLC detection showed that the area of compound 6 was less than 0.1%, the reaction was completed, the methanol mother liquor of compound 1 was obtained, after recovering the solvent by reduced pressure distillation, 500 g of water and 500 g of ethyl acetate were added, the extraction was separated into layers, the organic phase was removed from the solvent, then 300 g of toluene was added, and the target compound 1, metrafenone, was obtained by recrystallization, with a content of 99% and a yield of 98% (calculated based on compound 6).

[0090] The reaction route is as follows:

[0091]

[0092] The white solid product synthesized by the above route was subjected to nuclear magnetic detection, and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ: 6.83 (t, J = 71.9 Hz, 1H), 4.60 (s, 2H), 3.88 (s, 3H), 3.11 (s, 2H), 1.52 (s, 6H). It can be seen that the white solid prepared in this embodiment is metrafenone.

[0093] The above describes the preferred embodiments of the present application in detail. However, the protection scope of the present application is not limited thereto. Within the technical concept of the present application, those skilled in the art can make various modifications to the technical solutions of the present application, including combining various technical features in any other suitable manner, and these simple modifications and combinations should also be covered within the protection scope of the claims of the present application.

Claims

1. A method for preparing metrafenone, wherein the method comprises the following steps: Step S1: reacting a compound of formula (2) with trifluoroacetaldehyde in the presence of a base to obtain a compound of formula (3) ; ； Step S2: reacting the compound of formula (3) with methylhydrazine to obtain a compound of formula (4) ; ； Step S3: reacting the compound of formula (4) with freon in the presence of a base to obtain a compound of formula (5) ; ； Step S4: synthesizing a compound of formula (6) from the compound of formula (5) in the presence of an oxidant and a catalyst; ； Step S5: reacting the compound of formula (6) with sodium hypochlorite to obtain the metrafenone of formula (1) ; ； wherein R is selected from C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl; In step S1, the molar ratio of the compound of formula (2), trifluoroacetaldehyde and the base is 1: (1-5) : (1-5) ; In step S1, the base is selected from one, two or more of sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide and triethylamine; In step S2, the volume ratio of the amount of substance of the compound of formula (3) to the organic solvent is selected from 1 mol: (100-1000) mL; In step S2, the molar ratio of the compound of formula (3) to methylhydrazine is (0.5-5) : (0.5-5) ; In step S3, the molar ratio of the compound of formula (5), freon and the base is 1: (1-5) : (1-5) ; In step S3, the base is selected from one, two or more of sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide and triethylamine; In step S4, the molar ratio of the compound of formula (5) to the oxidant is 1: (1-10) ; In step S4, the oxidant is selected from one, two or more of hydrogen peroxide, oxygen, meta-chloroperoxybenzoic acid and sodium percarbonate; In step S4, the molar ratio of the compound of formula (5) to the catalyst is 1: (0.01-5) ; In step S4, the catalyst is a mixed acid of sulfuric acid and acetic acid; the molar ratio of sulfuric acid to acetic acid is 1: (2-10) ; In step S5, the molar ratio of the compound of formula (6) to sodium hypochlorite is 1: (1-8).

2. The production method according to claim 1, characterized by, Step S5 is carried out in the presence of an organic solvent; the organic solvent is selected from one, two or more of methanol, ethanol, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, toluene, dichloroethane, dichloromethane, N, N-dimethylformamide, N, N-dimethylacetamide, sulfolane and acetonitrile; The reaction temperature of step S5 is 40-120℃; The reaction time of step S5 is 0.5-10h; After the reaction of step S5 is completed, the organic solvent is removed, and water and an organic extraction solvent are used for extraction and separation; after extraction, the organic phase is desolventized, toluene is added, and recrystallization purification is carried out; In the recrystallization purification, the weight ratio of the amount of substance of the compound of formula (6) to toluene is selected from 1 mol: (100-1000) g.

3. The preparation method according to claim 1, characterized in that, The preparation method of step S5 comprises: sequentially adding the compound of formula (6) and an organic solvent to a reactor, heating, then adding sodium hypochlorite to react to obtain the metrafenone of formula (1).

4. The method of claim 1, wherein, The molar ratio of the compound of formula (5) to the oxidant in step S4 is 1:(2-8); In step S4, when the oxidant is hydrogen peroxide, the hydrogen peroxide is an aqueous hydrogen peroxide solution with a concentration of 10wt%-50wt%; The molar ratio of the compound of formula (5) to the catalyst in step S4 is 1:(0.1-2.0); The molar ratio of sulfuric acid to acetic acid in step S4 is 1:(5-8); Step S4 is carried out in the presence of an organic solvent selected from one, two or more of ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, toluene, dichloroethane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, sulfolane, acetonitrile; The reaction temperature of step S4 is-10°C-150°C; The reaction time of step S4 is 0.2h-5h.

5. The preparation method according to claim 1, characterized in that, The preparation method of step S4 comprises: sequentially adding the compound of formula (5), acetic acid, sulfuric acid, an organic solvent into a reactor, and then adding an aqueous hydrogen peroxide solution after warming to obtain the compound of formula (6).

6. The method of claim 1, wherein, In step S3, the molar ratio of the compound of formula (5), freon and base is 1:(1.1-2.0):(1.1-2.0); Step S3 is carried out in the presence of water and / or an organic solvent; the organic solvent is selected from one, two or more of ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, toluene, dichloroethane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, sulfolane, acetonitrile; The reaction temperature of step S3 is-10°C-50°C; The reaction time of step S3 is 0.5h-8h.

7. The preparation method according to claim 1, characterized in that, The preparation method of step S3 is specifically: sequentially adding the compound of formula (4), an organic solvent and a base into a reactor, and then introducing freon at 10-20°C to react to obtain the compound of formula (5).

8. The method of claim 1, wherein, Step S2 is carried out in the presence of water and / or an organic solvent; the organic solvent is selected from one, two or more of methanol, ethanol, acetonitrile; In step S2, the amount-of-substance ratio of the compound of formula (3) to the organic solvent is selected from 1mol:(200-800)mL; In step S2, the molar ratio of the compound of formula (3) to methylhydrazine is(1.0-3.0):(1.0-3.0); The reaction temperature of step S2 is 10-100°C; The reaction time of step S2 is 0.5h-5h.

9. The method of claim 1, wherein, The preparation method of step S2 comprises: sequentially adding an organic solvent and methylhydrazine into a reactor containing the compound of formula (3), and then reacting after warming to obtain the compound of formula (4).

10. The method of claim 1, wherein, In step S1, the molar ratio of the compound of formula (2), trifluoroacetaldehyde and base is 1:(1.1-2.0):(1.1-2.0); Step S1 is carried out in the presence of an organic solvent; the organic solvent is selected from one, two or more of methanol, ethanol, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, toluene, dichloroethane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, sulfolane, acetonitrile; The reaction temperature of step S1 is-10°C-150°C; The reaction time of step S1 is 0.5 h-8 h.

11. The method of claim 1, wherein, The preparation method of step S1 is specifically as follows: the compound of formula (2), an organic solvent and a base are sequentially added into a reactor, and after warming, trifluoroacetaldehyde is added for reaction to obtain the compound of formula (3).

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