Synthesis method of flurobixafen metabolite

Abstract

The invention discloses a synthesis method of a flurobixafen metabolite. The synthesis method comprises the following steps: carrying out condensation reaction on ethyl difluoroacetoacetate and triethyl orthoformate to prepare an intermediate A; carrying out cyclization reaction on the intermediate A and hydrazine hydrate to generate an intermediate B; carrying out N-benzylation reaction on the intermediate B and a methoxybenzyl derivative to obtain an intermediate C; performing hydrolysis and acidification reaction on the intermediate C to obtain an intermediate D; reacting the intermediate D with thionyl chloride or oxalyl chloride to obtain an intermediate E; reacting the intermediate E with 2-(3, 4-dichlorophenyl)-4-fluoroaniline to obtain an intermediate F; and carrying out N-benzyl removal reaction on the intermediate F to obtain the flurobixafen metabolite. The method has the advantages of cheap raw materials, mild reaction conditions, simplicity in operation, environmental friendliness, no need of special and expensive catalysts, high yield and the like, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a method for synthesizing chlorofluorobiphenylpyridine metabolites. Background Technology

[0002] Chlorothalonil is an important fungicide, belonging to the succinate dehydrogenase inhibitor class. It acts on complex II of the mitochondrial respiratory electron transport chain in pathogens, inhibiting mitochondrial function, hindering energy metabolism, and suppressing pathogen growth. After entering the organism, chlorrothalonil is converted into demethylated chlorrothalonil metabolites. The biotoxicity of chlorrothalonil can be detected by measuring the toxicity of these metabolites. There are two main synthetic routes for chlorrothalonil: Route 1 (see appendix) Figure 1 The reaction conditions are mild and the overall yield is high, with no major safety concerns. However, the specific palladium catalyst required for Suzuki coupling is expensive, the intermediate synthesis is complex, and the overall cost is high. Route 2 (see appendix) Figure 2 The reaction steps are few, and the overall yield is high. It also eliminates the need for separate synthesis of the intermediate 3-difluoromethyl-1-methylpyrazole-4-formyl chloride, as the latter two steps can be completed in one step. However, the final step requires high temperature and pressure and the introduction of carbon monoxide, posing safety risks and hindering industrial production. Testing biotoxicity by introducing chlorofluorobiphenylpyramide into organisms is complex and costly. Therefore, developing a method to synthesize a chlorofluorobiphenylpyramide metabolite for direct biotoxicity testing is crucial.

[0003] Chinese invention patent application CN107556199A discloses a method for preparing 3,4-dichloro-2-amino-5-fluorobiphenyl. Under nitrogen protection, 3,4-dichlorophenylboronic acid and an organic solvent are added to a reaction flask, followed by the sequential addition of 2-bromo-4-fluoroaniline and a base. The mixture is heated to 70°C, protected under nitrogen, and a copper catalyst is added. The mixture is then heated to reflux and the reaction proceeds for 4.0-6.0 hours. Post-treatment yields 3',4'-dichloro-2-amino-5-fluorobiphenyl. The preparation process requires the addition of a heavy metal catalyst, resulting in high preparation costs. Chinese invention patent application CN115160226A discloses a one-step condensation method for preparing bifenthiophanate-methyl. Using 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid as a raw material, it reacts with 3′,4′-dichloro-5-fluoro-2-benzidine hydrochloride in an organic solvent under the action of an alkali and a catalyst, resulting in a one-step condensation to generate bifenthiophanate-methyl. After post-processing, the product bifenthiophanate-methyl is obtained. However, the synthesis of the intermediates is complex. Summary of the Invention

[0004] To develop a synthetic method with fewer side reactions and higher yield, and to realize the industrialization of chlorofluorobiphenylpyridine metabolites, the first aspect of this invention provides a method for synthesizing chlorofluorobiphenylpyridine metabolites, comprising the following steps: S1: Intermediate A is prepared by the condensation reaction of ethyl difluoroacetoacetate and triethyl orthoformate; S2: Intermediate A and hydrated hydrazine undergo a cyclization reaction to generate intermediate B; S3: Intermediate B undergoes an N-benzylation reaction with a methoxybenzyl derivative to obtain intermediate C; S4: Intermediate C undergoes hydrolysis and acidification to obtain intermediate D; S5: Intermediate D reacts with thionyl chloride or oxalyl chloride to give intermediate E; S6: Intermediate E reacts with 2-(3,4-dichlorophenyl)-4-fluoroaniline to give intermediate F; S7: Intermediate F undergoes a de-N-benzylation reaction to yield the chlorofluorobifenpyroxenamine metabolite.

[0005] In one embodiment, S1 specifically involves: heating ethyl difluoroacetoacetate, adding dropwise a mixture of triethyl orthoformate and a dehydrating agent, continuing the condensation reaction at this temperature, performing a first vacuum distillation to remove the lighter component, and a second vacuum distillation to obtain intermediate A. The reaction route diagram is shown below. Figure 3 .

[0006] In one embodiment, the molar ratio of ethyl difluoroacetoacetate, triethyl orthoformate, and dehydrating agent is 1:(0.5-10):(0.5-10).

[0007] In one embodiment, the dehydrating agent includes at least one of acetic anhydride, trifluoroacetic anhydride, cyanuric chloride, methanesulfonyl chloride, or titanium tetrachloride.

[0008] In one embodiment, the dehydrating agent includes at least one of acetic anhydride and trifluoroacetic anhydride.

[0009] In one embodiment, the temperature of the single vacuum distillation is 50-200℃ and the pressure is -98kPa to -50kPa.

[0010] In one embodiment, the temperature of the single vacuum distillation is 85-105℃ and the pressure is -98kPa to -50kPa.

[0011] In one embodiment, the temperature of the secondary vacuum distillation is 15-35°C and the pressure is 50-300 Pa.

[0012] In one embodiment, the temperature of the secondary vacuum distillation is 15-35°C and the pressure is 50-150 Pa.

[0013] In one implementation method, S2 specifically involves: mixing hydrazine hydrate with solvent 1, adding dropwise a mixture of intermediate A and solvent, controlling the temperature to be <60°C, and maintaining the temperature for an addition-elimination reaction for 0.5-20 hours after the addition is complete; after the reaction is complete, separating the phases, washing the organic phase with water until neutral, distilling to remove the solvent, and then performing vacuum distillation to obtain intermediate B. See the reaction flowchart below. Figure 4 .

[0014] In one embodiment, the solvent is including, but is not limited to, at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, chloroform, carbon tetrachloride, DMF, DMSO, benzene, toluene, or xylene.

[0015] In one embodiment, the mass ratio of the hydrazine hydrate to solvent one is 1:(1-5); In one embodiment, the mass ratio of intermediate A to solvent A is 1:(0.5-9). In one embodiment, the molar ratio of intermediate A to hydrazine hydrate is 1:(0.5-9).

[0016] In one embodiment, the pressure of vacuum distillation in S2 is -98kPa to -50kPa, and the temperature is 50-250℃.

[0017] In one embodiment, the pressure of vacuum distillation in S2 is -89 kPa and the temperature is 70°C.

[0018] In one implementation method, S3 specifically involves: mixing intermediate B, solvent II, the methoxybenzyl derivative, and a base; heating the mixture to react; then filtering; washing the filter cake with organic solvent I; adding a water phase to the filtrate; washing the organic phase with water until neutral; distilling to remove the solvent; and then distilling under reduced pressure to obtain intermediate C. See the reaction flowchart below. Figure 5 .

[0019] In one embodiment, the solvent two includes, but is not limited to, at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, chloroform, carbon tetrachloride, DMF, DMSO, benzene, toluene, or xylene.

[0020] In one embodiment, the methoxybenzyl derivative includes at least one of methoxychlorobenzyl, methoxybromobenzyl, methoxyiodobenzyl, methoxyfluorobenzyl, or methoxyaminebenzyl.

[0021] In one embodiment, the alkali is an organic or inorganic alkali, wherein the inorganic alkali includes at least one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, or ammonia water. The organic alkali includes at least one of triethylamine, diethylamine, sodium methoxide, or sodium ethoxide.

[0022] In one embodiment, the molar ratio of intermediate B, methoxybenzyl derivative and base is 1:(0.5-5):(0.5-5).

[0023] In one embodiment, the mass ratio of intermediate B to solvent II is 1:(1-10).

[0024] In one embodiment, the reaction temperature of S3 is 0-100℃ and the reaction time is 0.5-10h.

[0025] In one embodiment, the reaction temperature of S3 is 50-55°C and the reaction time is 0.5-3h.

[0026] In one embodiment, the organic solvent of the rinsing filter cake includes, but is not limited to, at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, chloroform, carbon tetrachloride, DMF, DMSO, benzene, toluene, or xylene.

[0027] In one embodiment, the pressure of vacuum distillation in S3 is -99kPa to -50kPa, and the temperature is 50-150℃.

[0028] In one embodiment, the pressure of vacuum distillation in S3 is -99 kPa and the temperature is 100°C.

[0029] In one implementation method, S4 specifically involves: adding liquid alkali to intermediate C, heating to 0-120℃ for hydrolysis reaction for 0.5-8 hours, cooling to 60-80℃ after the reaction, adding organic solvent II to remove organic impurities, adding acid to the aqueous phase to adjust the pH to 1-12 for acidification reaction, filtering, rinsing the filter cake with water, drying, and purifying by column chromatography to obtain intermediate D. See the reaction route diagram below. Figure 6 .

[0030] As one implementation method, S4 specifically involves: adding liquid alkali to intermediate C, heating to 70-90℃ for hydrolysis reaction for 1-3 hours, cooling to 60-70℃ after the reaction, adding organic solvent II to remove organic impurities, adding acid to the aqueous phase to adjust the pH to 2-3 for acidification reaction, filtration, washing the filter cake with water, drying, and purifying by column chromatography to obtain intermediate D.

[0031] In one embodiment, the liquid alkali is an organic or inorganic alkali; the inorganic alkali includes at least one selected from potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide. The organic alkali includes at least one selected from triethylamine, diethylamine, sodium methoxide, sodium ethoxide, or ammonia water.

[0032] In one embodiment, the acid solution is an organic acid or an inorganic acid; the inorganic acid includes at least one selected from sulfuric acid, phosphoric acid, or hydrochloric acid. The organic acid includes at least one selected from chlorosulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, or acetic acid.

[0033] In one embodiment, the molar ratio of intermediate C to liquid alkali is 1:(1-8).

[0034] In one embodiment, the mass fraction of the liquid alkali is 5%-30%.

[0035] In one implementation method, S5 specifically involves: mixing intermediate D, solvent IV, and catalyst, heating, and then adding thionyl chloride or oxalyl chloride dropwise. After the addition is complete, the reaction proceeds, followed by solvent removal under normal pressure and cooling under nitrogen protection to obtain intermediate E. The reaction route diagram is shown below. Figure 7 .

[0036] In one embodiment, the solvent four includes, but is not limited to, at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, chloroform, carbon tetrachloride, DMF, DMSO, benzene, toluene, or xylene.

[0037] In one embodiment, the catalyst includes at least one of pyridine, dimethylformamide, dimethylacetamide, DCC, DMAP, ethylene oxide, or triethylamine.

[0038] In one embodiment, the molar ratio of intermediate D, catalyst and thionyl chloride (or oxalyl chloride) is 1:(0.001-1):(0.5-7).

[0039] In one embodiment, the amount of catalyst added is 1-5% of the mass of intermediate D.

[0040] In one embodiment, the mass ratio of intermediate D to solvent IV is 1:(1-10).

[0041] In one embodiment, the reaction temperature of S5 is 0-150℃ and the reaction time is 0.5-10h.

[0042] In one embodiment, the reaction temperature of S5 is 80-100℃, and the reaction time is 0.5-2h.

[0043] In one embodiment, the reaction temperature of S5 is 90°C and the reaction time is 1 hour.

[0044] In one embodiment, S6 specifically involves: dissolving solvent 5 and 2-(3,4-dichlorophenyl)-4-fluoroaniline under nitrogen protection, then adding intermediate E dropwise at room temperature, controlling the system temperature to ≤50℃. After the addition is complete, the temperature is raised to 0-150℃ to continue the amidation reaction for 0.5-10 hours. After the reaction is complete, the temperature is lowered to 0-150℃, and an alkaline solution is added to adjust the pH of the aqueous phase to 3-12, causing a precipitate to form. The precipitate is then cooled, filtered, dried, and purified by column chromatography to obtain intermediate F. The reaction route diagram is shown below. Figure 8 .

[0045] In one embodiment, S6 specifically involves: solvent V, acid-binding agent, and 2-(3,4-dichlorophenyl)-4-fluoroaniline being stirred and dissolved, then protected with nitrogen. Intermediate E is added dropwise at room temperature, with the system temperature controlled at ≤50℃. After the addition is complete, the temperature is raised to 120℃ to continue the amidation reaction for 10 hours. After the reaction is complete, the mixture is cooled, filtered, dried, and purified by column chromatography to obtain intermediate F.

[0046] In one embodiment, solvent five includes at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, chloroform, carbon tetrachloride, DMF, DMSO, benzene, toluene, or xylene.

[0047] In one embodiment, the molar ratio of intermediate E to 2-(3,4-dichlorophenyl)-4-fluoroaniline is 1:(0.9-5).

[0048] In one embodiment, the mass fraction of the alkaline solution is 0.1%-10%.

[0049] In one embodiment, the acid-binding agent includes at least one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, diethylamine, sodium methoxide, sodium ethoxide, or ammonia water.

[0050] In one embodiment, the molar ratio of the acid-binding agent to 2-(3,4-dichlorophenyl)-4-fluoroaniline is 1:(1-3). In one implementation method, S7 specifically involves: mixing intermediate F and acid, heating to 0-150°C, and performing acid hydrolysis for 0.5-10 hours. After the reaction is complete, solvent VI is added and the mixture is concentrated under reduced pressure. Then, the mixture is cooled to room temperature, and alkali solution is gradually added to adjust the pH to 1-12. A large amount of solid precipitates out. The solid is filtered, and the filter cake is the crude chlorofluorobifenpyraclostrobin metabolite. Purified chlorofluorobifenpyraclostrobin metabolite is obtained by DCM pulping and purification. See the reaction flowchart below. Figure 9 .

[0051] In one embodiment, S7 specifically involves: mixing intermediate F with acid, heating to 75-80°C, and performing acid hydrolysis for 1-5 hours. After the reaction is complete, solvent VI is added and the mixture is concentrated under reduced pressure. Then, the mixture is cooled to room temperature and alkali solution is gradually added to adjust the pH to 8-9. A large amount of solid precipitates out. The mixture is filtered, and the filter cake is crude chlorofluorobifenpyraclostrobin metabolite. Purified chlorofluorobifenpyraclostrobin metabolite is obtained by DCM pulping and purification.

[0052] As one embodiment, the acid includes, but is not limited to, at least one of sulfuric acid, phosphoric acid, hydrochloric acid, chlorosulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and acetic acid.

[0053] In one embodiment, the mass ratio of intermediate F to acid is 1:(1-5).

[0054] In one embodiment, the solvent six includes, but is not limited to, at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, chloroform, carbon tetrachloride, DMF, DMSO, benzene, toluene, or xylene.

[0055] In one embodiment, the alkali is an organic or inorganic alkali, wherein the inorganic alkali includes at least one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, or ammonia water. The organic alkali includes at least one of triethylamine, diethylamine, sodium methoxide, sodium ethoxide, or ammonia water.

[0056] Compared with the prior art, the present invention has the following beneficial effects; (1) In the method for synthesizing the chlorofluorobiphenylpyridine metabolite of the present invention, the molar ratio of ethyl difluoroacetoacetate, triethyl orthoformate and dehydrating agent is 1:(0.5-10):(0.5-10), which can effectively promote the condensation reaction of ethyl difluoroacetoacetate and triethyl orthoformate, reduce side reactions, improve the purity and yield of intermediate A, and trifluoroacetic anhydride can effectively remove the water generated in the reaction, further promoting the reaction in the positive direction.

[0057] (2) The method for synthesizing the chlorofluorobifenpyroxenamine metabolite of the present invention involves an addition-elimination cyclization reaction between hydrazine hydrate and intermediate A. By precisely controlling the ratio of reactants and the temperature, side reactions caused by high temperature can be avoided. Furthermore, controlling the temperature during the dropwise addition process can prevent the system from darkening in color, reduce the generation of impurities, and improve the purity of the product.

[0058] (3) In the method for synthesizing the chlorofluorobifenpyroxenamine metabolite of the present invention, the intermediate B undergoes an N-benzylation reaction with a methoxybenzyl derivative, which can promote the deprotonation of intermediate B and enhance its nucleophilicity, thereby improving the reaction efficiency and selectivity.

[0059] (4) In the method for synthesizing the chlorofluorobiphenylpyridine metabolite described in this invention, intermediate D undergoes an acylation reaction with thionyl chloride or oxalyl chloride. By optimizing the catalyst and reaction conditions, the reaction efficiency can be improved, while side reactions are reduced, avoiding the safety hazards of using carbon monoxide in the traditional route and improving production safety.

[0060] (5) The method for synthesizing chlorofluorobifenpyraclostrobin metabolites described in this invention, by selecting appropriate acid systems and reaction conditions, can effectively break N-benzyl bonds, while avoiding the destruction of other functional groups, preventing excessive acidolysis or side reactions, thereby improving the yield and purity of the target product.

[0061] (6) The method for synthesizing chlorofluorobiphenylpyridine metabolites described in this invention uses inexpensive raw materials, mild reaction conditions, simple operation, is environmentally friendly, does not require special expensive catalysts, has a high yield, and is suitable for industrial production. Attached Figure Description

[0062] Figure 1 This is a flowchart of the traditional route for the synthesis of chlorofluorobifenpyraclostrobin; Figure 2 This is a flowchart of the second route for the traditional synthesis of chlorofluorobifenpyraclostrobin; Figure 3 The reaction route diagram for the synthesis of intermediate A; Figure 4 This is a reaction route diagram for the synthesis of intermediate B; Figure 5 The reaction route diagram for the synthesis of intermediate C; Figure 6 The reaction route diagram for the synthesis of intermediate D; Figure 7 The reaction route diagram for the synthesis of intermediate E; Figure 8 The reaction route diagram for the synthesis of intermediate F; Figure 9 A reaction route diagram for the synthesis of chlorofluorobiphenylpyridine metabolites; Figure 10 The 1H NMR spectrum of the synthetic chlorofluorobifenpyroxenamine metabolite synthesized in Example 1; Figure 11 The image shows the carbon NMR spectrum of the synthetic chlorofluorobiphenylpyridine metabolite synthesized in Example 1. Detailed Implementation

[0063] Example 1 A method for synthesizing a chlorofluorobifenpyraclostrobin metabolite includes the following steps: S1: Intermediate A is prepared by the condensation reaction of ethyl difluoroacetoacetate and triethyl orthoformate; S2: Intermediate A and hydrated hydrazine undergo a cyclization reaction to generate intermediate B; S3: Intermediate B undergoes an N-benzylation reaction with a methoxybenzyl derivative to obtain intermediate C; S4: Intermediate C undergoes hydrolysis and acidification to obtain intermediate D; S5: Intermediate D reacts with thionyl chloride or oxalyl chloride to give intermediate E; S6: Intermediate E reacts with 2-(3,4-dichlorophenyl)-4-fluoroaniline to give intermediate F; S7: Intermediate F undergoes a de-N-benzylation reaction to yield the chlorofluorobifenpyroxenamine metabolite.

[0064] S1 specifically involves heating 3 kg of ethyl difluoroacetoacetate to 90-100°C, then adding dropwise a mixture of 5.5 kg of triethyl orthoformate and 6.2 kg of dehydrating agent, controlling the temperature at 90-100°C. Low-boiling-point products are distilled off while the addition is complete. After the addition is finished, the reaction is continued at this temperature for 2 hours. After the reaction is complete, the water pump is depressurized by -70 kPa to 100°C to remove light components. The temperature is then lowered to room temperature, and an oil pump is switched to 50-70 Pa to remove the fraction before the vapor temperature reaches 130°C. The condensation reaction is continued at 90-100°C to obtain intermediate A. The yield is 82%.

[0065] The dehydrating agent is acetic anhydride.

[0066] Specifically, S2 involves mixing 2.3 kg of hydrazine hydrate with 10 kg of solvent, then adding dropwise a mixture of 3.6 kg of intermediate A and 6 kg of solvent, controlling the temperature below 60°C to prevent the system from darkening in color due to excessive temperature. After the addition is complete, the mixture is kept at this temperature for an addition-elimination reaction for 3 hours. After the reaction, the phases are separated. The organic phase is washed with 5 kg × 3 kg of water until neutral, then distilled to remove the solvent. Vacuum distillation is then performed, and intermediate B is obtained after chromatography. The yield is 90%.

[0067] The solvent is 1,2-dichloroethane.

[0068] The pressure of vacuum distillation in S2 is -89 kPa and the temperature is 70 °C.

[0069] Specifically, S3 involves mixing 3.12 kg (14.76 mol, calculated at 90%) of intermediate B, 7 kg of solvent II, 2.85 kg (1.1 eq, 98%) of methoxybenzyl derivative, and 3.36 kg (1.5 eq) of alkali. The mixture is heated to 50-55 °C and reacted for 2 hours. The mixture is then filtered, and the filter cake is washed with 5 kg of organic solvent I. 10 kg of aqueous phase is added to the filtrate, and the organic phase is washed with 2 kg of water until neutral. The organic phase is then distilled to remove solvent, followed by vacuum distillation to obtain intermediate C. The yield is 85%.

[0070] The second solvent is DMF. The base is potassium carbonate. The first organic solvent is ethyl acetate.

[0071] The pressure of vacuum distillation in S3 is -99 kPa and the temperature is 100 °C.

[0072] S4 specifically involves adding 7.09 kg (1.5 eq) of 15% sodium hydroxide aqueous solution to 5.49 kg of intermediate C, heating to 80°C, and hydrolyzing for 2 hours. As the reaction proceeds, the solution gradually becomes clear. After the reaction is complete, the temperature is lowered to 65°C, and 2 L of organic solvent is added for secondary extraction to remove organic impurities. Acid is added to the aqueous phase to adjust the pH to 2-3 for acidification. The mixture is then filtered, and the filter cake is washed with 3 kg of water and dried at 100°C for 8 hours. The resulting product is purified by column chromatography to obtain intermediate D. The yield is 85-90%.

[0073] The organic solvent is toluene.

[0074] The acid solution is concentrated hydrochloric acid.

[0075] S5 specifically involves: connecting the reactor to a tail gas absorption device; mixing 4.4 kg of dried intermediate D, solvent IV, and catalyst and heating to 90°C; adding 1.1 eq of thionyl chloride dropwise; maintaining the temperature for 1 hour after the addition; and then sampling until intermediate D is less than 0.5 wt% (when sampling, 2 drops of the reaction solution are added to 1 mL of methanol and kept at 50°C for 10 min to quench the reaction before liquid chromatography analysis); after the reaction, desolventizing under normal pressure to 130°C; and cooling under nitrogen protection to obtain intermediate E with a yield of 98%.

[0076] The solvent four is 10 kg of toluene.

[0077] The catalyst is 120g of dimethylformamide.

[0078] Specifically, S6 consists of: 10 kg of solvent V, 1.1 eq of acid-binding agent, and 1.02 eq of 2-(3,4-dichlorophenyl)-4-fluoroaniline, stirred and dissolved under nitrogen protection. 4.51 kg of intermediate E is added dropwise at room temperature, controlling the system temperature to ≤50℃. After the addition is complete, the temperature is raised to 120℃ and the amidation reaction continues for 10 h. The mixture is then cooled and filtered. The resulting filter cake is dried at 100℃ for 8 h and purified by column chromatography to obtain intermediate F with a yield of 75-80%.

[0079] The solvent is toluene. The acid-binding agent is triethylamine.

[0080] Specifically, S7 involves gradually adding 4.5 kg of dried intermediate F under stirring with 10 kg of acid, heating to 75-80 °C, and acid hydrolysis for 4 hours. After the reaction, 10 L of solvent VI is added and concentrated under reduced pressure to 10 L. Then, the mixture is cooled to room temperature and 10 wt% sodium carbonate aqueous solution is gradually added to adjust the pH to 8-9. A solid precipitates out, is filtered, and the filter cake is the crude chlorofluorobifenpyraclostrobin metabolite. Purified chlorofluorobifenpyraclostrobin metabolite is obtained by DCM pulping. The yield is 80%, and the normalized HPLC purity is >97%.

[0081] The acid is trifluoroacetic acid; the solvent is toluene.

[0082] The 1H and 1C NMR spectra of the prepared chlorofluorobifenpyraclostrobin metabolite are shown below. (See spectrum) Figure 10 and Figure 11 .

[0083] 1 H NMR (400 MHz, dmso) δ 13.57 (s, 1H), 9.65 (s, 1H), 8.26 (s, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 8.8, 5.5 Hz, 1H), 7.37 (dd, J = 8.4, 2.1 Hz, 1H), 7.33-7.26 (m, 2H). 13 C NMR (101 MHz, dmso) δ 161.95, 161.45, 159.52, 138.99, 137.98 (d, J = 8.5 Hz), 131.47, 131.03, 130.97, 130.90, 130.86, 129.27, 117.07 (d, J = 23.3Hz), 115.84 (d, J = 22.1 Hz), 115.53, 112.62, 110.29, 107.96. Example 2 A method for synthesizing a chlorofluorobifenpyraclostrobin metabolite, the specific implementation method is the same as in Example 1, except that S1 is as follows: 3 kg of ethyl difluoroacetoacetate is heated to 70-80°C, and a mixture of 3.6 kg of triethyl orthoformate and 4.34 kg of dehydrating agent is added dropwise, controlling the temperature at 100-110°C. The low-boiling-point product is distilled off while the addition is complete. After the addition is complete, the reaction is continued at this temperature for 1 hour. After the reaction is complete, the water pump is depressurized by -70 kPa to 100°C to remove the light components. The temperature is then lowered to room temperature, and the oil pump is switched to 80-100 Pa to remove the fraction before the vapor temperature reaches 130°C. The mixture is then kept at 90-100°C for a condensation reaction to obtain intermediate A. The yield is 85%.

[0084] The dehydrating agent is trifluoroacetic anhydride.

[0085] Example 3 A method for synthesizing a chlorofluorobifenpyraclostrobin metabolite, the specific implementation method is the same as in Example 1, except that S1 is as follows: 3 kg of ethyl difluoroacetoacetate is heated to 75-85°C, and a mixture of 2.4 kg of triethyl orthoformate and 3.5 kg of dehydrating agent is added dropwise while controlling the temperature at 75-85°C. The low-boiling-point product is distilled off while the addition is complete. After the addition is complete, the reaction is continued at this temperature for 6 hours. After the reaction is complete, the water pump is depressurized by -100 kPa to 85°C to remove the light components. The temperature is then lowered to room temperature, and the oil pump is switched to 100-150 Pa to remove the fraction before the vapor temperature reaches 150°C. The mixture is then kept at 90-100°C for a condensation reaction to obtain intermediate A. The yield is 87%.

[0086] The dehydrating agent is trifluoroacetic anhydride.

[0087] Example 4 A method for synthesizing a chlorofluorobifenpyraclostrobin metabolite, the specific implementation method is the same as in Example 1, except that S1 is as follows: 3 kg of ethyl difluoroacetoacetate is heated to 110-120°C, and a mixture of 5.5 kg of triethyl orthoformate and 6.9 kg of dehydrating agent is added dropwise while controlling the temperature at 110-120°C. The low-boiling-point product is distilled off while the addition is complete. After the addition is complete, the reaction is continued at this temperature for 6 hours. After the reaction is complete, the water pump is depressurized by -100 kPa to 105°C to remove the light component. The temperature is then lowered to room temperature, and the oil pump is switched to 100-150 Pa to remove the fraction before the gas phase temperature reaches 130°C. The condensation reaction is continued at 90-100°C to obtain intermediate A. The yield is 89%.

[0088] The dehydrating agent is acetic anhydride.

Claims

1. A method for synthesizing a chlorofluorobifenpyroxenamine metabolite, characterized in that, Includes the following steps: S1: Intermediate A is prepared by the condensation reaction of ethyl difluoroacetoacetate and triethyl orthoformate; S2: Intermediate A and hydrated hydrazine undergo a cyclization reaction to generate intermediate B; S3: Intermediate B undergoes an N-benzylation reaction with a methoxybenzyl derivative to obtain intermediate C; S4: Intermediate C undergoes hydrolysis and acidification to obtain intermediate D; S5: Intermediate D reacts with thionyl chloride or oxalyl chloride to give intermediate E; S6: Intermediate E reacts with 2-(3,4-dichlorophenyl)-4-fluoroaniline to give intermediate F; S7: Intermediate F undergoes a de-N-benzylation reaction to yield the chlorofluorobifenpyroxenamine metabolite.

2. The method for synthesizing the chlorofluorobifenpyraclostrobin metabolite according to claim 1, characterized in that, S1 specifically involves heating ethyl difluoroacetoacetate, adding a mixture of triethyl orthoformate and a dehydrating agent dropwise, continuing the condensation reaction under heat, performing a first vacuum distillation to remove the light component, and a second vacuum distillation to obtain intermediate A.

3. The method for synthesizing the chlorofluorobifenpyroxenamine metabolite according to claim 2, characterized in that, The molar ratio of ethyl difluoroacetoacetate, triethyl orthoformate, and dehydrating agent is 1:(0.5-10):(0.5-10).

4. The method for synthesizing the chlorofluorobifenpyraclostrobin metabolite according to claim 2, characterized in that, The dehydrating agent includes at least one of acetic anhydride, trifluoroacetic anhydride, cyanuric chloride, methanesulfonyl chloride, or titanium tetrachloride.

5. The method for synthesizing the chlorofluorobifenpyraclostrobin metabolite according to claim 2, characterized in that, The temperature of the first vacuum distillation is 50-200℃, and the pressure is -98kPa to -50kPa.

6. The method for synthesizing the chlorofluorobifenpyraclostrobin metabolite according to claim 2, characterized in that, The temperature of the secondary vacuum distillation is 15-35℃, and the pressure is 50-300Pa.

7. The method for synthesizing the chlorofluorobifenpyraclostrobin metabolite according to claim 1, characterized in that, S2 specifically involves: mixing hydrazine hydrate with solvent 1, adding dropwise a mixture of intermediate A and solvent, controlling the temperature to be <60℃, and maintaining the temperature after the addition is completed to carry out an addition-elimination reaction; after the reaction is completed, the phases are separated, the organic phase is washed with water until neutral, then distilled to remove solvent, and then vacuum distilled to obtain intermediate B.

8. The method for synthesizing the chlorofluorobifenpyraclostrobin metabolite according to claim 1, characterized in that, S3 specifically involves mixing intermediate B, solvent di, methoxybenzyl derivative, and base, heating the mixture to react, then filtering it, washing the filter cake with an organic solvent, adding an aqueous phase to the filtrate, washing the organic phase with water until neutral, distilling to remove the solvent, and then distilling under reduced pressure to obtain intermediate C.

9. The method for synthesizing the chlorofluorobifenpyroxenamine metabolite according to claim 1, characterized in that, Specifically, S5 involves mixing intermediate D, solvent IV, and catalyst, heating the mixture, adding thionyl chloride or oxalyl chloride dropwise, reacting after the addition is complete, removing the solvent under normal pressure after the reaction is complete, and cooling under nitrogen protection to obtain intermediate E.

10. The method for synthesizing the chlorofluorobifenpyraclostrobin metabolite according to claim 1, characterized in that, Specifically, S6 consists of: solvent V, acid-binding agent and 2-(3,4-dichlorophenyl)-4-fluoroaniline, which are stirred and dissolved under nitrogen protection. Intermediate E is added dropwise at room temperature, and the system temperature is controlled to be ≤50℃. After the addition is completed, the temperature is raised to continue the amidation reaction. After the reaction is completed, the temperature is lowered, filtered and dried, and then purified by column chromatography to obtain intermediate F.

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