A method for synthesizing pyraclostrobin

Abstract

The application belongs to the field of organic synthesis and particularly relates to a synthesis method of pyraclostrobin, comprising the following steps: under an inert gas environment, bromination reaction of compound 1 and bromide reagent NBS occurs in the presence of FeBr2 and phase transfer catalyst 1 to generate compound 2; etherification reaction of compound 2 and compound 3 occurs in the presence of alkali and phase transfer catalyst 2 to generate pyraclostrobin. The application realizes fine control of the concentration of bromine free radicals through coordination activation of FeBr2 to NBS and regulation of the reaction balance by the phase transfer catalyst, and the reaction condition is mild, the yield and purity are high, the post-treatment is simple, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing pyraclostrobin. Background Technology

[0002] Pyraclostrobin, with the following structural formula: Pyraclostrobin is a broad-spectrum fungicide of the methoxyacrylate class, developed by BASF in Germany in 1993, possessing a pyrazole structure. This fungicide exerts its bactericidal effect by inhibiting electron transport in the cytochrome bc1 complex in the mitochondrial respiratory chain, thus blocking the energy metabolism of pathogens. Pyraclostrobin exhibits excellent control activity against a variety of plant pathogens, including Ascomycetes, Basidiomycetes, Deuteromycetes, and Oomycetes. It also possesses the unique function of inducing systemic acquired resistance in plants, significantly improving crop tolerance to adverse environments. It is widely used in dozens of crops such as soybeans, wheat, corn, grapes, citrus, and potatoes, and is one of the most important pesticides in the agrochemical industry.

[0003] The industrial preparation routes for pyraclostrobin are mainly divided into two categories: the pre-condensation method and the post-condensation method. The pre-condensation method uses o-nitrotoluene and p-chlorophenylhydrazine as starting materials, proceeding through eight steps including cyclization, oxidation, bromination, etherification, reduction, esterification, and methylation to obtain the target product. The post-condensation method first reduces o-nitrotoluene, then N-carboxylates and O-methylates it to construct an N-methoxy-N-(2-methylphenyl)carbamate structural unit, followed by benzylic bromination, and finally etherification with 1-(4-chlorophenyl)-3-hydroxypyrazole to obtain pyraclostrobin. Compared to the pre-condensation method, the post-condensation method involves a substrate molecule containing an N-methoxycarbamate functional group in the bromination step. This functional group is more sensitive to strong acids, strong bases, and high temperatures; therefore, the selectivity and mildness of the bromination reaction become key bottlenecks determining the efficiency and product quality of the entire route.

[0004] In the post-condensation route of pyraclostrobin, the benzylic bromination reaction is essentially a free radical substitution reaction of the aromatic ring side chain methyl group, that is, converting methyl N-methoxy-N-(2-methylphenyl)carbamate into the corresponding methyl N-methoxy-N-(2-bromomethylphenyl)carbamate. This step is commonly carried out industrially using the Wohl-Ziegler bromination reaction, with N-bromosuccinimide (NBS) as the brominating agent and azobisisobutyronitrile (AIBN) or benzoyl peroxide (BPO) as the free radical initiator, under reflux in solvents such as carbon tetrachloride, dichloroethane, or chlorobenzene. CN106808472A discloses a six-step method for the synthesis of pyraclostrobin, in which the bromination step uses an NBS / AIBN system and reacts at room temperature in dichloromethane. Although the patent lowers the reaction temperature to room temperature, the decomposition efficiency of AIBN in dichloromethane is low, resulting in a significantly prolonged reaction time (typically requiring 8–12 hours). Furthermore, the single-pass conversion rate is insufficient, necessitating multiple additions of AIBN and NBS to achieve an acceptable conversion rate. While this "low-temperature, long-time" strategy reduces thermal degradation, it significantly decreases equipment turnover, and the repeated additions of initiator increase operational complexity and safety risks. The patent does not disclose specific yield and purity data for the bromination intermediate, but based on the overall yield of the subsequent etherification step, the actual yield of the bromination step is estimated to be no more than 85%, and the product purity is unlikely to meet the requirements of high-end active pharmaceutical ingredients. CN103396364A discloses a method for synthesizing alkyl N-alkoxy-N-2-[1-(4-halophenyl)-pyrazolyloxymethyl]phenylcarbamate, in which the bromination step uses an NBS / AIBN system and reacts in carbon tetrachloride. This patent claims a yield of up to 78%, but this yield level is significantly low for industrial production. More importantly, the patent uses AIBN at a concentration of over 10 mol%, resulting in high initiator costs.

[0005] In summary, the existing technologies have the following problems: (1) using AIBN or BPO as thermally decomposable initiators results in high reaction temperatures (77–80℃) or long reaction times (6–12h), leading to high energy consumption and low efficiency; (2) low yield and purity, making it difficult to meet the quality requirements of high-end pesticide technical materials; and (3) poor control of side reactions such as polybromination and aromatic ring bromination, resulting in cumbersome post-processing of the products. Therefore, there is an urgent need in this field to develop a novel benzylic bromination technology that can achieve high-yield and highly selective bromination reactions under mild conditions, while reducing catalyst costs, simplifying post-processing, and meeting the safety and environmental protection requirements of industrial production. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing pyraclostrobin preparation processes, such as high reaction temperature, long reaction time, poor selectivity, high initiator cost, and difficult waste liquid treatment, in the benign bromination step. This invention provides a novel method for selective benign bromination of NBS using a FeBr2 / phase transfer catalyst synergistically, thereby preparing the key intermediate N-methoxy-N-(2-bromomethylphenyl)carbamate in a mild, efficient, and low-cost manner. High-purity pyraclostrobin can then be obtained through etherification. To achieve the above objective, this invention provides the following technical solution: A method for synthesizing pyraclostrobin includes the following steps: Step 1: In an inert gas environment, compound 1 and the brominating reagent NBS undergo a bromination reaction in the presence of FeBr2 and phase transfer catalyst 1 to generate compound 2; Step 2: Compounds 2 and 3 undergo an etherification reaction in the presence of a base and phase transfer catalyst 2 to generate pyraclostrobin; The reaction formula is: .

[0007] Preferably, in step 1, the inert gas is nitrogen or argon; the reaction solvent is selected from one or more of dichloromethane, THF, ethyl acetate, chloroform and toluene.

[0008] Preferably, the phase transfer catalyst 1 is selected from one or more of tetrabutylphosphine bromide, tetraethylphosphine bromide, tetrapropylphosphine bromide, tetraoctylphosphine bromide, tetraphenylphosphine bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetraethylammonium bromide, tetrapropylammonium bromide, tetraoctylammonium bromide, and tetraphenylammonium bromide.

[0009] Preferably, the molar ratio of compound 1 to the brominated reagent NBS is 1:(1.0~1.5); the molar ratio of compound 1 to FeBr2 is 1:(0.01~0.1); and the molar ratio of compound 1 to phase transfer catalyst 1 is 1:(0.05~0.15).

[0010] Preferably, in step 1, the reaction temperature is 30~60℃ and the reaction time is 0.5~2h; after the reaction is completed, the reaction solution is cooled to room temperature, washed with saturated brine, and the organic phase is collected by separation. The organic phase is dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product; the crude product is recrystallized with a mixed solvent of dichloromethane / n-hexane to obtain compound 2.

[0011] Preferably, in step 2, the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.

[0012] Preferably, in step 2, the phase transfer catalyst 2 is selected from one or more of tetrabutylphosphine bromide, tetraethylphosphine bromide, tetrapropylphosphine bromide, tetraoctylphosphine bromide, tetraphenylphosphine bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetraethylammonium bromide, tetrapropylammonium bromide, tetraoctylammonium bromide, and tetraphenylammonium bromide.

[0013] Preferably, in step 2, the molar ratio of compound 2 to compound 3 is 1:(1.0~1.5); the molar ratio of compound 2 to phase transfer catalyst 2 is 1:(0.05~0.15); and the molar ratio of compound 2 to base is 1:(1~3).

[0014] Preferably, in step 2, the reaction solvent is a mixture of an organic solvent and water, wherein the organic solvent is selected from one or more of dichloromethane, THF, ethyl acetate, chloroform and acetonitrile; the reaction temperature is 60~80℃ and the reaction time is 1~5h.

[0015] Preferably, in step 2, after the reaction is completed, the reaction solution is cooled to room temperature, the pH of the solution is adjusted to 7.0~8.0 with dilute hydrochloric acid, the organic phase is collected by separation, the organic phase is dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain crude product; the crude product is recrystallized with ethyl acetate / n-hexane mixed solvent to obtain pyraclostrobin.

[0016] Compared with the prior art, the present invention has the following significant beneficial technical effects: (1) The reaction conditions are mild and the energy consumption is significantly reduced. This invention uses the FeBr2 catalytic system to replace the traditional AIBN thermal initiation system, which reduces the reaction temperature from above 77°C to 40-50°C and shortens the reaction time from more than 2 hours to 30-60 minutes. The utilization rate of equipment investment is significantly improved, making it suitable for industrial production.

[0017] (2) The yield is greatly improved and the product quality is excellent. This invention achieves precise control of the concentration of bromine radicals through the coordination activation of NBS by FeBr2 and the regulation of reaction equilibrium by the phase transfer catalyst. This effectively suppresses side reactions such as aromatic ring bromination and polybromination, and the bromination efficiency of NBS is fully released. The yield of monobrominated products is as high as 96% or more, the HPLC purity is as high as 98.3%, and the post-processing operation is simple. Detailed Implementation

[0018] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] The endpoints and any values ​​of the ranges described in this invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein. The raw materials and reagents used in the following examples are commercially available.

[0020] Example 1

[0021] A method for synthesizing pyraclostrobin includes the following steps: Step 1: Under nitrogen atmosphere, compound 1 (1.0 mol), brominator NBS (1.1 mol), anhydrous FeBr2 (0.01 mol), tetrabutylphosphine bromide (0.05 mol), and THF (300 mL) were added to a reactor, and the mixture was heated to 50 °C and stirred for 45 min. After the reaction was completed, the reaction solution was cooled to room temperature and washed with saturated brine (200 mL x 3). The organic phase was collected by separation, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from dichloromethane / n-hexane mixed solvent (volume ratio 1:4) to obtain compound 2 with a yield of 96.5% and an HPLC purity of 99.3%. Step 2: Compound 2 (1.0 mol), Compound 3 (1.2 mol), tetrabutylammonium bromide (0.05 mol), sodium hydroxide (1.5 mol), acetonitrile (250 mL), and water (150 mL) were added to the reactor, and the mixture was heated to 70°C and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the pH of the solution was adjusted to 7.5 with 1M dilute hydrochloric acid. The organic phase was collected by separation, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from the crude product using a mixed solvent of ethyl acetate / n-hexane (volume ratio 1:3) to obtain pyraclostrobin as a white solid with a yield of 94.8% and an HPLC purity of 99.1%. By comparison, the HPLC retention time of the product in this example was consistent with that of the pyraclostrobin standard.

[0022] Example 2

[0023] A method for synthesizing pyraclostrobin includes the following steps: Step 1: Under nitrogen atmosphere, compound 1 (1.0 mol), brominator NBS (1.2 mol), anhydrous FeBr2 (0.02 mol), tetraoctylphosphine bromide (0.05 mol), and dichloromethane (300 mL) were added to a reactor, and the mixture was heated to 45 °C and refluxed with stirring for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature and washed with saturated brine (200 mL x 3). The organic phase was collected by separation, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from a dichloromethane / n-hexane mixed solvent (volume ratio 1:4) to obtain compound 2 with a yield of 95.2% and an HPLC purity of 99.1%. Step 2: Compound 2 (1.0 mol), Compound 3 (1.1 mol), tetrabutylammonium bromide (0.05 mol), sodium carbonate (2.0 mol), acetonitrile (250 mL), and water (150 mL) were added to the reactor, and the mixture was heated to 75°C and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the pH of the solution was adjusted to 7.0 with 1M dilute hydrochloric acid. The organic phase was collected by separation, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from the crude product using a mixed solvent of ethyl acetate / n-hexane (volume ratio 1:3) to obtain pyraclostrobin as a white solid with a yield of 95.1% and an HPLC purity of 99.2%. By comparison, the HPLC retention time of the product in this example was consistent with that of the pyraclostrobin standard.

[0024] Example 3

[0025] A method for synthesizing pyraclostrobin includes the following steps: Step 1: Under nitrogen atmosphere, compound 1 (1.0 mol), brominated reagent NBS (1.15 mol), anhydrous FeBr2 (0.01 mol), tetraphenylphosphine bromide (0.05 mol), and chloroform (300 mL) were added to a reactor, and the mixture was heated to 50 °C and stirred for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature and washed with saturated brine (200 mL x 3). The organic phase was collected by separation, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from dichloromethane / n-hexane mixed solvent (volume ratio 1:4) to obtain compound 2 with a yield of 93.6% and an HPLC purity of 99.0%. The operation steps and parameters for step 2 are the same as in Example 1.

[0026] Example 4

[0027] A method for synthesizing pyraclostrobin includes the following steps: Step 1: Under nitrogen atmosphere, compound 1 (1.0 mol), brominator NBS (1.1 mol), anhydrous FeBr2 (0.01 mol), tetrabutylammonium bromide (0.05 mol), and THF (300 mL) were added to a reactor, and the mixture was heated to 50 °C and stirred for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature and washed with saturated brine (200 mL x 3). The organic phase was collected by separation, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from dichloromethane / n-hexane mixed solvent (volume ratio 1:4) to obtain compound 2 with a yield of 89.7% and an HPLC purity of 99.0%. The operation steps and parameters for step 2 are the same as in Example 1.

[0028] Comparative Example 1

[0029] Based on step 1 of Example 1, tetrabutylphosphine bromide was omitted, and other operating steps and conditions were the same as in Example 1. The yield of compound 2 was 76.5%, and the HPLC purity was 98.9%.

[0030] Comparative Example 2 Based on step 1 of Example 1, anhydrous FeBr2 was replaced with FeCl2, and other operating steps and conditions were the same as in Example 1. The yield of compound 2 was 50.2%, and the HPLC purity was 98.4%.

[0031] The above embodiments are merely illustrative examples and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations. Therefore, any obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for synthesizing pyraclostrobin, comprising the following steps: Step 1: In an inert gas environment, compound 1 and the brominating reagent NBS undergo a bromination reaction in the presence of FeBr2 and phase transfer catalyst 1 to generate compound 2; Step 2: Compounds 2 and 3 undergo an etherification reaction in the presence of a base and phase transfer catalyst 2 to generate pyraclostrobin; The reaction formula is: 。 2. The synthesis method according to claim 1, characterized in that, In step 1, the inert gas is nitrogen or argon; the reaction solvent is selected from one or more of dichloromethane, THF, ethyl acetate, chloroform and toluene.

3. The synthesis method according to claim 1, characterized in that, In step 1, the phase transfer catalyst 1 is selected from one or more of tetrabutylphosphine bromide, tetraethylphosphine bromide, tetrapropylphosphine bromide, tetraoctylphosphine bromide, tetraphenylphosphine bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetraethylammonium bromide, tetrapropylammonium bromide, tetraoctylammonium bromide, and tetraphenylammonium bromide.

4. The synthesis method according to claim 1, characterized in that, In step 1, the molar ratio of compound 1 to the brominated reagent NBS is 1:(1.0~1.5); the molar ratio of compound 1 to FeBr2 is 1:(0.01~0.1); and the molar ratio of compound 1 to phase transfer catalyst 1 is 1:(0.05~0.15).

5. The synthesis method according to claim 1, characterized in that, In step 1, the reaction temperature is 30~60℃ and the reaction time is 0.5~2h. After the reaction is completed, the reaction solution is cooled to room temperature, washed with saturated brine, and the organic phase is collected by separation. The organic phase is dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product is recrystallized with a mixed solvent of dichloromethane / n-hexane to obtain compound 2.

6. The synthesis method according to claim 1, characterized in that, In step 2, the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.

7. The synthesis method according to claim 1, characterized in that, In step 2, the phase transfer catalyst 2 is selected from one or more of tetrabutylphosphine bromide, tetraethylphosphine bromide, tetrapropylphosphine bromide, tetraoctylphosphine bromide, tetraphenylphosphine bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetraethylammonium bromide, tetrapropylammonium bromide, tetraoctylammonium bromide, and tetraphenylammonium bromide.

8. The synthesis method according to claim 1, characterized in that, In step 2, the molar ratio of compound 2 to compound 3 is 1:(1.0~1.5); the molar ratio of compound 2 to phase transfer catalyst 2 is 1:(0.05~0.15). The molar ratio of compound 2 to the base is 1:(1~3).

9. The synthesis method according to claim 1, characterized in that, In step 2, the reaction solvent is a mixture of an organic solvent and water, wherein the organic solvent is selected from one or more of dichloromethane, THF, ethyl acetate, chloroform and acetonitrile; the reaction temperature is 60~80℃ and the reaction time is 1~5h.

10. The synthesis method according to claim 1, characterized in that, In step 2, after the reaction is completed, the reaction solution is cooled to room temperature, the pH of the solution is adjusted to 7.0~8.0 with dilute hydrochloric acid, the organic phase is collected by separation, the organic phase is dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product; the crude product is recrystallized with ethyl acetate / n-hexane mixed solvent to obtain pyraclostrobin.

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