Preparation method of fluxapyroxad

Abstract

The invention discloses a preparation method of fluxapyroxad, and belongs to the field of fluxapyroxad preparation.The preparation method comprises the following steps that S1, under the protection of nitrogen, o-dichlorobenzene and magnesium metal react in an organic solvent under the co-initiation action of elemental iodine and bromoethane, and o-chlorophenyl magnesium chloride is obtained; s2, under the protection of nitrogen, adding 3, 4, 5-trifluorobromobenzene and a catalyst into an organic solvent, heating, dropwise adding the o-chlorphenyl magnesium chloride prepared in the step S1 at a constant temperature, stirring at a constant temperature after dropwise adding, and rectifying and purifying to obtain 2 '-chloro-3, 4, 5-trifluorobiphenyl; s3, in an alkali system, under the catalytic action of copper salt, 2 '-chloro-3, 4, 5-trifluorobiphenyl prepared in the step S2 and 1-methyl-3-difluoromethyl-1H-pyrazole-4-amide react in an organic solvent, and fluxapyroxad is obtained.The method avoids using expensive palladium metal, is low in cost, few in three wastes and environmentally friendly.

Description

Technical Field

[0001] The invention relates to the field of fungicide preparation, and more specifically, to a method for preparing fluopyraclostrobin. Background Art

[0002] Flupyraclostrobin is a succinate dehydrogenase inhibitor (SDHI) fungicide, which is widely used in crops such as cereals, soybeans, cotton, and fruit trees. Its classic compound products are launched in many countries around the world, new products are constantly being developed, and application crops are constantly expanding, with good market development prospects.

[0003] The preparation method of aromatic carboxamide announced in the U.S. Patent No. US8350046B2 announced on January 8, 2013 and the production method of N-substituted (3-dihalomethyl-1-methylpyrazol-4-yl) carboxamide announced in the U.S. Patent No. US12601966 announced on April 10, 2012 both reveal that the synthesis of fluopyrabamide is mainly prepared by condensation reaction of the key intermediate 3′, 4′, 5′-trifluorobiphenyl-2-amine with 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride, 4-bromo-3-difluoromethyl-1-methyl-1H-pyrazole or 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester.

[0004] The US patent number US13201562 announced on July 23, 2013, announced a method for producing 2-aminobiphenyl (2-aminobiphenyl is one of the intermediates of fluopyraclostrobin), the patent document uses 3,4,5-trifluorobromobenzene as raw material, and prepares 2-aminobiphenyl after Grignard reaction, complexation reaction and Negishi cross-coupling reaction, and the yield of 2-aminobiphenyl is 65%. This method not only has a low yield and a complex reaction system, but also requires a relatively expensive palladium catalyst, and the production cost is too high; in addition, the reaction will also produce a large amount of zinc salt wastewater, which is not suitable for industrial large-scale production.

[0005] In order to solve the above problems, a Chinese patent with publication number CN1 13402464A published on September 17, 2021 discloses a method for synthesizing fluopyram based on the Suzuki reaction, which uses 3-difluoromethyl-1-methyl-1-piperazole-4-carboxylic acid as a raw material and obtains fluopyram through condensation reaction and Suzuki reaction. Although this method shortens the reaction process, the raw materials and catalysts required for the reaction are relatively expensive, which makes the production cost high and is not conducive to industrial large-scale production.

[0006] Therefore, it is necessary to provide a method for synthesizing fluopyrabendazim, which has the characteristics of short process route, low cost, less three wastes and being environmentally friendly. Summary of the invention

[0007] In view of the problems existing in the prior art, the object of the present invention is to provide a method for preparing fluopyraclostrobin, which has the characteristics of high yield, short process route, low cost, less three wastes and is environmentally friendly.

[0008] To solve the above problems, the present invention adopts the following technical solutions.

[0009] A method for preparing fluopyraclostrobin comprises the following preparation process:

[0010] S1: Under nitrogen protection, under the joint initiation of iodine and ethyl bromide, o-dichlorobenzene and metallic magnesium react in an organic solvent to obtain o-chlorophenyl magnesium chloride;

[0011] S2: Under nitrogen protection, 3,4,5-trifluorobromobenzene and a catalyst are added to an organic solvent, heated, and then the o-chlorophenylmagnesium chloride prepared in step S1 is added dropwise while the temperature is maintained. After the addition is completed, the mixture is stirred and distilled to obtain 2'-chloro-3,4,5-trifluorobiphenyl;

[0012] S3: In an alkaline system and under the catalysis of copper salt, the 2'-chloro-3,4,5-trifluorobiphenyl prepared in step S2 and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxamide are reacted in an organic solvent to obtain trifloxystrobin;

[0013] The preparation process is as follows:

[0014]

[0015] Furthermore, in step S1, the molar ratio of o-dichlorobenzene to metallic magnesium is 1:1.05-1.3.

[0016] Furthermore, in step S1, the molar ratio of o-dichlorobenzene to metallic magnesium is preferably 1:1.1.

[0017] Furthermore, the catalyst in step S2 is a nickel-based catalyst containing a phosphorus ligand or a palladium-based catalyst containing a phosphorus ligand, and the catalyst is Ni(dppp)Cl2, Ni(dppe)Cl2, Ni(dppb)Cl2, Ni(PR3)2Cl2 or Pd(P(C6H5)3)2Cl2.

[0018] Furthermore, the catalyst in the step S2 is preferably Ni(dppe)Cl2.

[0019] Furthermore, in step S2, the molar ratio of the catalyst to 3,4,5-trifluorobromobenzene is 0.005 to 0.1:1.

[0020] Furthermore, in the step S2, the molar ratio of the catalyst to 3,4,5-trifluorobromobenzene is preferably 0.01:1.

[0021] Furthermore, in the step S3, the alkali system is provided by a metal salt, and the metal salt is one or a mixture of two or more of sodium carbonate, potassium carbonate, sodium methoxide and sodium ethoxide.

[0022] Furthermore, in the step S3, the metal salt is preferably potassium carbonate.

[0023] Furthermore, the copper salt in step S3 is one or a mixture of two or more of cuprous iodide, cuprous bromide, cuprous bromide and cuprous chloride; preferably cuprous bromide.

[0024] Furthermore, in step S3, the molar ratio of copper salt to 2'-chloro-3,4,5-trifluorobiphenyl is 0.05-0.2:1.

[0025] Furthermore, in step S3, the molar ratio of the copper salt to 2'-chloro-3,4,5-trifluorobiphenyl is preferably 0.1:1.

[0026] Furthermore, in step S1, the organic solvent is an aprotic nucleophilic solvent, and the aprotic nucleophilic solvent is one or a mixture of two or more selected from tetrahydrofuran, methyltetrahydrofuran, tert-butyl methyl ether and diethyl ether; in step S2, the organic solvent is one or a mixture of two or more selected from tetrahydrofuran, methyltetrahydrofuran, tert-butyl methyl ether and diethyl ether; in step S3, the organic solvent is one or a mixture of two or more selected from DMF, DMAC, NMP and cyclohexanol.

[0027] Furthermore, the reaction temperature of step S1 is 40-70°C, and the stirring time is 0.5-1h; in step S2, the temperature is heated to 20-50°C, and the dropwise addition time is 2-3h; in step S3, the temperature is raised to 110-150°C, and the stirring time is 8-12h.

[0028] The specific contents are as follows:

[0029] A method for preparing fluopyraclostrobin, the specific preparation steps are as follows:

[0030] S1: Under nitrogen protection, o-dichlorobenzene and metallic magnesium react in an organic solvent by co-initiating reaction with ethyl bromide and elemental iodine to prepare o-chlorophenyl magnesium chloride;

[0031] S2: o-Chlorophenylmagnesium chloride and 3,4,5-trifluorobromobenzene undergo a coupling reaction under the action of a catalyst, followed by distillation and purification to prepare 2'-chloro-3,4,5-trifluorobiphenyl;

[0032] S3: adding 2'-chloro-3,4,5-trifluorobiphenyl and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxamide into an organic solvent, and then performing a substitution reaction catalyzed by copper salt in an alkaline system to obtain trifloxystrobin.

[0033] Furthermore, the organic solvent described in step S1 is a non-protonic nucleophilic solvent, specifically one or a mixed solution of two or more of tetrahydrofuran, methyltetrahydrofuran, tert-butyl methyl ether and diethyl ether.

[0034] Furthermore, the organic solvent in step S1 is preferably tetrahydrofuran.

[0035] Furthermore, in step S1, the molar ratio of o-dichlorobenzene to metallic magnesium is 1:1.05N1.3.

[0036] Furthermore, in step S1, the molar ratio of o-dichlorobenzene to metallic magnesium is preferably 1:1.1.

[0037] Furthermore, the catalyst in step S2 is a nickel-based catalyst containing a phosphorus ligand or a palladium-based catalyst containing a phosphorus ligand, specifically Ni(dppp)Cl2, Ni(dppe)Cl2, Ni(dppb)Cl2, Ni(PR3)2Cl2 or Pd(P(C6H5)3)2Cl2.

[0038] Furthermore, in step S2, the catalyst is preferably Ni(dppe)Cl2.

[0039] Furthermore, in step S2, the molar ratio of the catalyst to 3,4,5-trifluorobromobenzene is 0.005N0.1:1.

[0040] Furthermore, in step S2, the molar ratio of the catalyst to 3,4,5-trifluorobromobenzene is preferably 0.01:1.

[0041] Furthermore, the reaction temperature of step S2 is 20-50°C.

[0042] Furthermore, the reaction temperature in step S2 is preferably 20-25°C.

[0043] Furthermore, in step S3, the organic solvent is one or a mixture of two or more of DMF, DMAC, NMP and cyclohexanol.

[0044] Furthermore, in step S3, the organic solvent is preferably DMAC.

[0045] Furthermore, in step S3, the alkaline system is provided by a metal salt, and the metal salt is specifically one or a mixture of two or more of sodium carbonate, potassium carbonate, sodium methoxide and sodium ethoxide, and the metal salt is preferably sodium carbonate.

[0046] Furthermore, in step S3, the copper salt is one or a mixture of two or more of cuprous iodide, cuprous bromide, cupric bromide and cuprous chloride, and the copper salt is preferably cuprous bromide.

[0047] Furthermore, the molar ratio of the copper salt to 2'-chloro-3,4,5-trifluorobiphenyl is 0.05-0.2:1.

[0048] Furthermore, the molar ratio of the copper salt to 2'-chloro-3,4,5-trifluorobiphenyl is 0.1:1.

[0049] Compared with the prior art, the advantages of the present invention are:

[0050] 1. This scheme uses o-dichlorobenzene and magnesium as substrates, and prepares fluopyrabamide through three steps of Grignard reaction, coupling reaction and substitution reaction. The preparation method has a simple process flow, and the raw materials are easily available. In addition, the method uses a relatively inexpensive and easily available catalyst to replace the expensive palladium catalyst, thereby reducing the production cost. In addition, the method also has the advantages of simple operation, high yield, less three wastes, and environmental friendliness, making the method suitable for large-scale industrial production.

[0051] Second, the content of flupyraclostrobin prepared by the method provided in this scheme can reach more than 98%, which helps to reduce the risk of phytotoxicity caused by excessive impurity content. In addition, the preparation method is carried out under the protection of nitrogen, which effectively avoids the occurrence of oxidation or other side reactions, thereby reducing the generation of three wastes. DETAILED DESCRIPTION

[0052] Embodiment 1:

[0053] Step 1: Add 26.4g magnesium, 50.0g tetrahydrofuran and 2.0g o-dichlorobenzene to the reaction vessel, and replace nitrogen three times under vacuum to form a tetrahydrofuran solution of magnesium. Add 2 iodine particles and 1ml bromoethane to the tetrahydrofuran solution of magnesium under nitrogen protection, heat to 50N60℃ and stir for 0.5-1h, wait for the brown color in the reaction vessel to fade to grayish white, and the temperature rises significantly to indicate successful initiation. Then control the temperature at 50-55℃, add a mixed solution of 145.0g o-dichlorobenzene and 930.0g tetrahydrofuran, and the addition time is 4-5h. After the addition is complete, keep warm and stir at 50-55℃ for 1-2h, and GC detects that the raw material o-dichlorobenzene is ≤0.5% to be qualified for conversion. Then cool to room temperature to obtain o-chlorophenyl magnesium chloride with a GC purity of more than 98%.

[0054] Step 2: Add 140.0g of 3,4,5-trifluorobromobenzene and 3.5g of Ni(dppe)Cl2 to 140.0g of tetrahydrofuran, replace with vacuum nitrogen three times, then under nitrogen protection, control the temperature to 20-25°C, dropwise add the o-chlorophenylmagnesium chloride prepared in step 1, and the dropwise addition time is 2-3h; after the dropwise addition is completed, continue to keep warm and stir at 20-25°C for 2-4h until the conversion rate of the raw material 3,4,5-trifluorobromobenzene reaches more than 95% by GC detection. Then cool to room temperature, dropwise add 300.0g of hydrochloric acid with a mass concentration of 15%, and stir for 30 minutes after the dropwise addition is completed. Then distill under reduced pressure to remove tetrahydrofuran and collect the substrate. Add 500.0g of dichloromethane to the substrate, and then remove the magnesium salt by extraction and stratification. Distill the stratified organic phase to remove the residual dichloromethane. The substrate after removal of dichloromethane was subjected to vacuum distillation to obtain 148 g of 2'-chloro-3,4,5-trifluorobiphenyl with a GC purity of 99% and a yield of 91.9% (based on 3,4,5-trifluorobromobenzene).

[0055] Step 3: At room temperature, add 148.0g of 2'-chloro-3,4,5-trifluorobiphenyl prepared in step 2, 107.0g of 1-methyl-3-difluoromethyl-1H-pyrazole-4-amide, 101.0g of potassium carbonate and 8.7g of cuprous bromide to 300.0g of DMAC organic solvent, then heat to 110-120°C, and stir for 8-10h. After HPLC detection to the conversion rate of raw material 2'-chloro-3,4,5-trifluorobiphenyl reaches 98%, cool to room temperature, filter to remove potassium salt and collect filtrate. The filtrate is subjected to reduced pressure distillation to recover DMAC until the substrate is slurry, then add 300g of water, stir for 1h, filter and dry to obtain 221g of fluopyram. The content of fluopyram is 98.0%, and the yield is 95.1% (based on 2'-chloro-3,4,5-trifluorobiphenyl).

[0056] Embodiment 2:

[0057] Step 1: Add 26.4g magnesium, 50.0g methyltetrahydrofuran and 2.0g o-dichlorobenzene into the reaction vessel, and replace nitrogen three times under vacuum to form a methyltetrahydrofuran solution of magnesium. Add 2 iodine particles and 1ml ethyl bromide to the methyltetrahydrofuran solution of magnesium under nitrogen protection, heat to 50N60℃ and stir for 0.5-1h, wait for the brown color in the reaction container to fade to grayish white, and the temperature rises significantly to indicate successful initiation. Then control the temperature at 50-55℃, add a mixed solution of 145.0g o-dichlorobenzene and 930.0g methyltetrahydrofuran, and the addition time is 4-5h. After the addition is complete, keep warm and stir at 50-55℃ for 1-2h, and GC detects that the raw material o-dichlorobenzene is ≤0.5% to be qualified for conversion. Then cool to room temperature to obtain o-chlorophenyl magnesium chloride with a GC purity of more than 98%.

[0058] Step 2: Add 140.0g 3,4,5-trifluorobromobenzene and 3.0g Ni(dppp)Cl2 to 140.0g methyltetrahydrofuran, replace with vacuum nitrogen three times, then under nitrogen protection, control the temperature to 20-25°C, dropwise add the o-chlorophenylmagnesium chloride prepared in step 1, and the dropwise addition time is 2-3h; after the dropwise addition is completed, continue to keep warm and stir at 20-25°C for 2-4h until the conversion rate of the raw material 3,4,5-trifluorobromobenzene reaches more than 95% by GC detection. Then cool to room temperature, dropwise add 300g hydrochloric acid with a mass concentration of 15%, and stir for 30 minutes after the dropwise addition is completed. Then separate the layers, and extract the aqueous phase once with 200.0g methyltetrahydrofuran. Combine the organic phases and distill under reduced pressure to remove the methyltetrahydrofuran. The substrate after removal of methyltetrahydrofuran was subjected to vacuum distillation to obtain 143.0 g of 2'-chloro-3,4,5-trifluorobiphenyl with a GC purity of 99.2% and a yield of 88.8% (based on 3,4,5-trifluorobromobenzene).

[0059] Step 3: At room temperature, add 143.0g of 2'-chloro-3,4,5-trifluorobiphenyl prepared in step 2, 104.0g of 1-methyl-3-difluoromethyl-1H-pyrazole-4-amide, 97.6g of potassium carbonate and 8.5g of cuprous bromide to 300.0g of DMF organic solvent, then heat to 110-120°C, and stir for 8-10h. After HPLC detection, the conversion rate of the raw material 2'-chloro-3,4,5-trifluorobiphenyl reaches 98%, cool to room temperature, filter to remove potassium salt and collect the filtrate. The filtrate is subjected to reduced pressure distillation to recover DMF until the substrate is in a slurry state, then add 300.0g of water, stir for 1h, filter and dry to obtain 217.0g of flupyraclostrobin. The content of flupyraclostrobin is 98.1%, and the yield is 96.6% (based on 2'-chloro-3,4,5-trifluorobiphenyl).

[0060] Embodiment 3:

[0061] Step 1: Add 26.4g magnesium, 50.0g tetrahydrofuran and 2.0g o-dichlorobenzene to the reaction vessel, and replace nitrogen three times under vacuum to form a tetrahydrofuran solution of magnesium. Add 2 iodine particles and 1ml bromoethane to the tetrahydrofuran solution of magnesium under nitrogen protection, heat to 50N60℃ and stir for 0.5-1h, wait for the brown color in the reaction vessel to fade to grayish white, and the temperature rises significantly to indicate successful initiation. Then control the temperature at 50-55℃, add a mixed solution of 145.0g o-dichlorobenzene and 930.0g tetrahydrofuran, and the addition time is 4-5h. After the addition is complete, keep warm and stir at 50-55℃ for 1-2h, and GC detects that the raw material o-dichlorobenzene is ≤0.5% to be qualified for conversion. Then cool to room temperature to obtain o-chlorophenyl magnesium chloride with a GC purity of more than 98%.

[0062] Step 2: Add 140.0g of 3,4,5-trifluorobromobenzene and 3.5g of Ni(dppp)Cl2 to 140.0g of tetrahydrofuran, replace with vacuum nitrogen three times, then under nitrogen protection, control the temperature to 20N25°C, dropwise add the o-chlorophenylmagnesium chloride prepared in step 1, and the dropwise addition time is 2-3h; after the dropwise addition is completed, continue to stir at 20-25°C for 2-4h until the conversion rate of the raw material 3,4,5-trifluorobromobenzene reaches more than 95% by GC detection. Then cool to room temperature, dropwise add 300.0g of hydrochloric acid with a mass concentration of 15%, and stir for 30 minutes after the dropwise addition is completed. Then distill under reduced pressure to remove tetrahydrofuran and collect the substrate. Add 500.0g of dichloromethane to the substrate, and then remove the magnesium salt by extraction and stratification. Distill the stratified organic phase to remove the residual dichloromethane. The substrate after removal of dichloromethane was subjected to vacuum distillation to obtain 150.0 g of 2'-chloro-3,4,5-trifluorobiphenyl with a GC purity of 99.4% and a yield of 93.1% (based on 3,4,5-trifluorobromobenzene).

[0063] Step 3: At room temperature, add 150.0g of 2'-chloro-3,4,5-trifluorobiphenyl prepared in step 2, 108.5g of 1-methyl-3-difluoromethyl-1H-pyrazole-4-amide, 103.0g of potassium carbonate and 9.5g of cuprous chloride to 300.0g of DMF organic solvent, then heat to 110-120°C, and stir for 8-10h. After HPLC detection to the conversion rate of raw material 2'-chloro-3,4,5-trifluorobiphenyl reaches 98%, cool to room temperature, filter to remove potassium salt and collect filtrate. The filtrate is subjected to reduced pressure distillation to recover DMF until the substrate is in a slurry state, then add 300.0g of water, stir for 1h, filter and dry to obtain 215.0g of flupyraclostrobin. The content of flupyraclostrobin is 98.3%, and the yield is 91.3% (based on 2'-chloro-3,4,5-trifluorobiphenyl).

Claims

1. A method for preparing fluopyraclostrobin, characterized in that: The preparation method includes the following: S1: Under nitrogen protection, under the joint initiation of iodine and ethyl bromide, o-dichlorobenzene and metallic magnesium react in an organic solvent to obtain o-chlorophenyl magnesium chloride; S2: Under nitrogen protection, 3,4,5-trifluorobromobenzene and a catalyst are added to an organic solvent, and then heated and the o-chlorophenylmagnesium chloride prepared in step S1 is added dropwise while the temperature is maintained. After the addition is completed, the mixture is stirred and distilled to obtain 2'-chloro-3,4,5-trifluorobiphenyl; S3: In an alkaline system and under the catalysis of copper salt, the 2'-chloro-3,4,5-trifluorobiphenyl prepared in step S2 and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxamide are reacted in an organic solvent to obtain trifloxystrobin.

2. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: In step S1, the molar ratio of o-dichlorobenzene to metallic magnesium is 1:1.05N1.

3.

3. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: The catalyst in step S2 is a nickel-based catalyst containing a phosphorus ligand or a palladium-based catalyst containing a phosphorus ligand, and the catalyst is Ni(dppp)Cl2, Ni(dppe)Cl2, Ni(dppb)Cl2, Ni(PR3)2Cl2 or Pd(P(C6H5)3)2Cl2.

4. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: In the step S2, the molar ratio of 3,4,5-trifluorobromobenzene to o-chlorophenylmagnesium chloride is 1:1 to 1.

45.

5. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: In the step S2, the molar ratio of the catalyst to 3,4,5-trifluorobromobenzene is 0.005 to 0.1:

1.

6. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: In the step S3, the alkali system is provided by a metal salt, and the metal salt is one or a mixture of two or more of sodium carbonate, potassium carbonate, sodium methoxide and sodium ethoxide.

7. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: The copper salt in step S3 is one or a mixture of two or more of cuprous iodide, cuprous bromide, cupric bromide and cuprous chloride.

8. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: In the step S3, the molar ratio of the copper salt to 2'-chloro-3,4,5-trifluorobiphenyl is 0.05-0.2:

1.

9. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: In step S1, the organic solvent is an aprotic nucleophilic solvent, and the aprotic nucleophilic solvent is one or a mixture of two or more of tetrahydrofuran, methyltetrahydrofuran, tert-butyl methyl ether and diethyl ether; In the step S2, the organic solvent is one or a mixture of two or more of tetrahydrofuran, methyltetrahydrofuran, tert-butyl methyl ether and diethyl ether; The organic solvent in step S3 is one or a mixture of two or more of DMF, DMAC, NMP and cyclohexanol.

10. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: The reaction temperature of step S1 is 40-70°C; in step S2, the temperature is heated to 20-50°C and the dropwise addition time is 2-3h; the reaction temperature of step S3 is 110-150°C.

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