Preparation method and application of pydiflumetofen intermediate

Abstract

The invention discloses a preparation method and application of a pydiflumetofen intermediate, and the method comprises the following step: in the presence of cuprous oxide or cuprous salt and acid, synthesizing 2, 4, 6-trichlorobenzene diazonium fluoroborate and isopropenyl acetate into the pydiflumetofen intermediate of formula I, according to the invention, 2, 4, 6-trichloroaniline which is cheap and easy to obtain is used as a raw material to improve a Meerwein arylation reaction method, and finally industrial cheap and mass production of the intermediate I is realized.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, and in particular to a method for preparing a fluopyram intermediate and its application. Background Technology

[0002] Fluopyram is a novel pyrazole amide fungicide developed by Syngenta, targeting succinate dehydrogenase. Its development code is SYN545974. It obtained its ISO pesticide generic name in 2015, received its first global registration in Argentina in November 2016, and was launched on the market in 2017. It was approved for registration in the United States and Canada in 2018, and the technical grade and formulation were officially registered in my country in 2019. As an SDHI fungicide, fluopyram inhibits pathogen growth by interfering with respiratory chain complex II, preventing energy synthesis. It boasts numerous advantages, such as: a wide range of applicable crops, suitable for grains, corn, soybeans, rapeseed, vegetables, fruit trees, and specialty crops; and highly effective control of various diseases. According to Syngenta, among all chemical products, fluopyram has the highest activity against leaf spot and powdery mildew, and is highly effective against diseases caused by Botrytis cinerea and Sclerotinia sclerotiorum. It also provides breakthrough control of Fusarium diseases such as Fusarium head blight, and is highly effective against Sclerotinia sclerotinia, brown spot, Fusarium head blight, and bakanae disease, among many others. This indicates that fluopyram is a broad-spectrum fungicide. Its structural formula is as follows:

[0003]

[0004] The structural formula of Pydiflumetofen

[0005] Currently, there are few reports on the synthetic process of fluopyram. Most routes involve reacting l-(2,4,6-trichlorophenyl)-prop-2-one (Ⅰ) with an aqueous solution of methoxyhydroxylamine hydrochloride to obtain a mixture of E / Z isomers of the oxime (Ⅱ), followed by reduction to obtain an intermediate (Ⅲ), which is then condensed with pyrazolyl chloride (Ⅳ) to obtain fluopyram. The synthetic route is as follows:

[0006]

[0007] Among them, l-(2,4,6-trichlorophenyl)-prop-2-one is a key intermediate of fluopyram, and its preparation method is as follows:

[0008] In 2009, Syngenta patent CN102239137B reported a method of condensing 2,4,6-trichlorobenzaldehyde with nitrobenzene, followed by reducing hydrolysis with iron powder in hydrochloric acid to obtain l-(2,4,6-trichlorophenyl)-prop-2-one (Ⅰ). The drawback is that the starting material 2,4,6-trichlorobenzaldehyde is not readily available and is expensive, resulting in high production costs. The synthetic route is as follows:

[0009]

[0010] The patent also reports another synthetic method: using 2,4,6-trichlorobenzoic acid as a starting material, 2,4,6-trichlorobenzyl chloride is generated through reduction and chlorination, further converted to 2,4,6-trichlorophenylacetonitrile, and then added to a CH3-MgBr Grignard reagent to obtain l-(2,4,6-trichloro-phenyl)-propyl-2-one. However, 2,4,6-trichlorobenzoic acid is very expensive, and the reaction steps are too numerous, making it unsuitable for large-scale production. The synthetic route is as follows:

[0011]

[0012] In 2013, Syngenta patent CN104144914A reported the preparation of l-(2,4,6-trichlorophenyl)-prop-2-one by adding isopropyl acetate and tert-amyl nitrite to an acetonitrile solution of 2,4,6-trichloroaniline at room temperature using acetonitrile as a solvent. The purity was only 34.8%, and the yield was 48%, making this method difficult to meet the requirements for industrial production. The synthetic route is as follows:

[0013]

[0014] In 2023, Taihe Chemical Co., Ltd.'s patent CN 115703701 B reported a microchannel reaction, which improved Syngenta's method and achieved a yield of over 90%. It also used organic nitrite, a strong carcinogen.

[0015] In 2018, Liu Anchang et al. reported in CN108610290A a method for preparing 4-chlorophenylacetone from p-chloroaniline using potassium carbonate, isopropyl acetate, and ethyl nitrite, followed by chlorination catalyzed by ferric chloride to yield l-(2,4,6-trichlorophenyl)-prop-2-one. The yield of l-(4-chlorophenyl)-prop-2-one was 80.2%. The reaction used a prohibited solvent and the relatively expensive N-chlorosuccinimide (NCS), making this route costly. The synthetic route is as follows:

[0016]

[0017] In 2021, Chen Yuexia et al. reported in CN113004131A a method for preparing 2,4,6-trichlorobenzyl bromide from 2,4,6-trichlorotoluene via N-bromosuccinimide (NBS), followed by a coupling reaction with acetylenyl magnesium halide in the presence of anhydrous nickel dichloride to yield 2,4,6-trichlorophenylpropyne, and then an addition reaction with water in the presence of an acid catalyst to obtain l-(2,4,6-trichlorophenyl)-prop-2-one. The drawbacks are that 2,4,6-trichlorotoluene is expensive and difficult to prepare, the reaction process is lengthy, generates a lot of waste, and is costly.

[0018] The synthesis route is as follows:

[0019]

[0020] The preparation methods of the aforementioned intermediate I can be divided into two categories according to existing technologies: 1) One category involves raw materials that are not easy to obtain and have high production costs, but there are processes that can be scaled up, such as the typical route using 2,4,6-trichlorobenzaldehyde as a raw material; 2) The other category uses relatively cheap and readily available 2,4,6-trichloroaniline as a raw material to prepare intermediate I via the Meerwein arylation reaction, but the purity and yield are poor, making it difficult to scale up production, or it uses strong carcinogens such as organic nitrites and requires the use of organic solvents such as toluene and acetonitrile, increasing the reaction cost and solvent post-processing cost.

[0021] Given the existing methods for synthesizing l-(2,4,6-trichlorophenyl)-prop-2-one (a key intermediate of fluopyram), which suffer from low yields and use of environmentally unfriendly organic nitrites, hindering industrial production, there is an urgent need to find new methods for preparing l-(2,4,6-trichlorophenyl)-prop-2-one. Summary of the Invention

[0022] Purpose of the invention

[0023] To overcome the above shortcomings, the purpose of this invention is to provide a method for preparing fluoxetine intermediate that is readily available, inexpensive, and easy to scale up, as well as its application. This invention improves the Meerwein arylation reaction method using readily available and inexpensive 2,4,6-trichloroaniline as a raw material, and finally achieves industrially inexpensive and large-scale production of intermediate I.

[0024] Solution

[0025] To achieve the objectives of this invention, the technical solution adopted is as follows:

[0026] In a first aspect, the present invention provides a method for preparing a fluopyram intermediate, the method comprising the following steps:

[0027] In the presence of cuprous oxide or its salt and an acid, 2,4,6-trichlorobenzyl diazofluoroborate and isopropenyl acetate are used to synthesize fluopyram intermediate of formula I.

[0028]

[0029] In the cuprous salt CuX, X represents Cl, Br, or I.

[0030] Furthermore, acids include one or more of the following: organic acids, inorganic acids, resins containing acidic groups, Lewis acids, halogens, and phenols with electron-withdrawing substituents.

[0031] Optionally, the inorganic acid includes one or more of hydrochloric acid, sulfuric acid, and phosphoric acid;

[0032] Optionally, the organic acid is a C1-C6 aliphatic organic acid, aromatic carboxylic acid, or sulfonic acid, and is optionally selected from one or more of formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, malonic acid, succinic acid, tartaric acid, citric acid monohydrate, maleic acid, fumaric acid, and mandelic acid; the aromatic carboxylic acid is optionally selected from one or more of benzoic acid, 4-methylbenzoic acid containing an electron-donating group, nitrobenzoic acid containing an electron-withdrawing group, and halobenzoic acid; the sulfonic acid is optionally selected from one or more of p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethylsulfonic acid, camphorsulfonic acid, and chlorosulfonic acid.

[0033] Optionally, the resin containing acidic groups is selected from resins containing sulfonic acid groups or carboxylic acid groups;

[0034] Optionally, the Lewis acid is selected from one or more of boron trichloride, boron trifluoride, ferric chloride, ferrous chloride, aluminum trichloride, and zinc chloride;

[0035] Optionally, the halogen element is selected from one or more of chlorine, bromine, and elemental iodine;

[0036] Optionally, the electron-withdrawing substituent phenol is selected from electron-withdrawing substituent phenols, optionally from halogenated phenols or nitro-substituted phenols, optionally from one or more of o-fluorophenol, o-chlorophenol, o-nitrophenol, and p-nitrophenol;

[0037] Among the acids mentioned above, inorganic acids, sulfonic acids, and citric acid monohydrate are preferred, with hydrochloric acid being the preferred acid catalyst.

[0038] Optionally, the acid is selected from one or more of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid monohydrate, and o-nitrophenol.

[0039] Further, the molar ratio of 2,4,6-trichlorobenzyl diazofluoroborate to cuprous oxide is 1:0.075 to 1, optionally 1:0.075 to 0.5, optionally 1:0.075 to 0.3, optionally 1:0.1 to 0.3, optionally 1:0.15 to 0.5;

[0040] Further, the molar ratio of 2,4,6-trichlorobenzenediazofluoroborate to acid is 1:0.05 to 0.3, optionally 1:0.1 to 0.3, optionally 1:0.15 to 0.3, optionally 1:0.18 to 0.3, optionally 1:0.2 to 0.3.

[0041] Furthermore, the molar ratio of 2,4,6-trichlorobenzenediazofluoroborate to isopropyl acetate is 1:5 to 20.

[0042] Furthermore, it also includes buffering substances, optionally using sodium acetate, disodium hydrogen phosphate-sodium phosphate buffer system, sodium carboxylate, or carbonate buffer system;

[0043] Further, the molar ratio of 2,4,6-trichlorobenzenediazofluoroborate to the buffer substance is 1:0 to 5, optionally 1:0.5 to 5, optionally 1:1.5 to 5, optionally 1:1.5 to 2.5, optionally 1:1.5 to 2.

[0044] Furthermore, the reaction temperature is -5 to 20°C, optionally -5 to 10°C, or optionally -5 to 5°C;

[0045] And / or, no additional solvent is required when 2,4,6-trichlorobenzenediazofluoroborate reacts with isopropyl acetate.

[0046] Furthermore, 2,4,6-trichlorobenzyl diazofluoroborate was prepared according to the method reported in the literature Aryl Pyrazoles from Photocatalytic Cycloadditions of Arenediazonium, Organic Letters, 2020, 22(18), 7219-7224.

[0047] Furthermore, the post-treatment of 2,4,6-trichlorobenzenediazofluoroborate and isopropyl acetate after reaction includes: removal of insoluble matter, washing, extraction, removal of solvent, and drying to obtain the target product;

[0048] Optionally, washing may be performed using saturated salt water;

[0049] Optionally, ethyl acetate may be used as the extractant;

[0050] Optionally, the extractant can be removed by vacuum distillation.

[0051] In a second aspect, the application of 2,4,6-trichlorobenzenediazofluoroborate in the preparation of 1-(2,4,6-trichlorophenyl)-prop-2-one of formula I is provided.

[0052]

[0053] Thirdly, the application of 2,4,6-trichlorobenzyl diazofluoroborate in the preparation of fluopyram is provided.

[0054] Beneficial effects

[0055] This invention improves the Meerwein arylation reaction method using inexpensive and readily available 2,4,6-trichloroaniline as a raw material, ultimately achieving the goal of industrially producing intermediate I inexpensively and in large quantities, with a reaction yield exceeding 90%. This invention does not require the use of highly carcinogenic organic nitrosamines, making it environmentally and worker-friendly. Attached Figure Description

[0056] One or more embodiments are illustrated by way of example with reference to the accompanying drawings, and these illustrative examples are not intended to limit the embodiments. The term "illustrative" as used herein means "serving as an example, embodiment, or illustration." Any embodiment illustrated herein as "illustrative" is not necessarily to be construed as superior to or better than other embodiments.

[0057] Figure 1 This is the NMR H spectrum of the analytical sample in Example 2 of the present invention.

[0058] Figure 2 This is the NMR C spectrum of the analytical sample in Example 2 of the present invention. Detailed Implementation

[0059] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, 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.

[0060] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In some embodiments, materials, methods, means, etc., well-known to those skilled in the art, are not described in detail in order to highlight the spirit of the present invention.

[0061] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0062] The product content in the following examples was confirmed by liquid chromatography or gas chromatography. Unless otherwise specified, LCMS was used to monitor the reaction process, and the yield was calculated by HPLC area normalization method instead of external standard method. This yield should differ slightly from the actual yield (the difference is very small). The molecular weight was determined by LCMS or GCMS.

[0063] LCMS: Liquid chromatography mass spectrometry, liquid quality.

[0064] GCMS: Gas chromatography mass spectrometry, temperament.

[0065] HPLC: High Performance Liquid Chromatography.

[0066] NMR: Nuclear magnetic resonance spectrometry.

[0067] This invention uses 2,4,6-trichloroaniline hydrochloride as raw material to prepare fluoroborate via diazotization reaction, and then reacts it with isopropyl acetate under the catalysis of cuprous oxide-acid (containing Lewis acid) to prepare intermediate I with high purity and high yield.

[0068]

[0069] Example of preparation of 2,4,6-trichlorobenzenediazofluoroborate:

[0070] In a 100 mL four-necked flask, fluoroboric acid solution (23.60 g, 40%, 107.5 mmol) and 2,4,6-trichloroaniline hydrochloride (5.00 g, 84.7%, 21.5 mmol) were stirred until homogeneous. The mixture was cooled to -15 °C in an ice-salt bath, and 4.46 g (22.6 mmol) of sodium nitrite was added in a single batch until the solution was submerged. After this step, the reaction was continued in an ice bath for 0.5 hours, and the reaction was monitored by TLC. A large amount of white solid precipitated. After stirring in an ice-water bath for 1 hour to allow the solid to separate, the mixture was filtered. The filter cake was washed with petroleum ether and dried to obtain a white solid, 2,4,6-trichlorobenzenediazofluoroborate. The mother liquor of 2,4,6-trichlorobenzenediazofluoroborate and fluoroboric acid solution was then replenished with fluoroboric acid solution (9.46 g, 40%, 43.1 mmol), 2,4,6-trichloroaniline hydrochloride (5.00 g, 84.7%, 21.5 mmol), and sodium nitrite (4.46 g, 22.6 mmol). The above steps were repeated to obtain a total of 12.59 g of white solid 2,4,6-trichlorobenzenediazofluoroborate, with a yield of 99.2%.

[0071] While reviewing relevant literature on the Meerwein arylation reaction, the inventors noted that the literature "Study on the Synthesis of 1-Aryl-2-Propane" (Organic Chemistry, 2007, 27(10), 1244-1249) describes an improved method for the Meerwein arylation reaction. It mentions that the steric hindrance of the diazonium substituent at the ortho position on the aromatic ring is a significant factor affecting the Meerwein arylation reaction. For example, when synthesizing the corresponding ketones using the diazonium salts of 2-chloroaniline, 2-methylaniline, 2,6-difluoroaniline, and 2,3-dichloroaniline, the number of byproducts increases, and the yield decreases significantly, with corresponding yields of 75%, 70%, 50%, and 60%, respectively. Furthermore, it was noted that the yield was lowest when there were two halogen atoms at the ortho position of the amino group (e.g., X = F).

[0072] The inventors repeated the method described in the literature using 2,4,6-trichlorobenzenediazofluoroborate, and obtained the target product at 20°C for 24 hours with a purity of 16.2% and a yield of 15.8% (see Example 1). Through continuous research, reflection, and experimentation, the inventors finally discovered that lowering the temperature to 0°C and adding a catalytic amount of hydrochloric acid significantly accelerated the reaction rate. After only one hour of reaction, the purity of the target product l-(2,4,6-trichlorophenyl)-prop-2-one reached 94.8%, and the yield reached 91.6% (see Example 2), a very surprising result.

[0073] Example 1

[0074] In a 50 mL single-necked flask, isopropyl acetate (5 mL), cuprous oxide (24.3 mg, 0.17 mmol), and sodium acetate (344.5 mg, 4.2 mmol) were added. After stirring for 1 minute, 2,4,6-trichlorobenzenediazofluoroborate (507 mg, 1.7 mmol) was slowly added. The mixture was reacted at 20 °C for 24 hours and then filtered. The filtrate was washed with saturated brine, extracted with ethyl acetate, and the organic phases were combined. The solvent was removed under reduced pressure, and the product was dried to give a black oily product (0.41 g, purity 16.2%, yield 16.5%).

[0075] In this embodiment, the yield and purity were both very low without acid catalysis.

[0076] Example 2

[0077] Under ice-salt bath conditions, isopropyl acetate (5 mL), cuprous oxide (36.4 mg, 0.25 mmol), and sodium acetate (347.3 mg, 4.2 mmol) were added to a 50 mL single-necked flask. After stirring for 1 minute, 2,4,6-trichlorobenzenediazofluoroborate (507 mg, 1.7 mmol) was slowly added, followed by dropwise addition of hydrochloric acid (101.9 mg, 12.0%, 0.34 mmol), resulting in the release of a large amount of gas. After reacting at 0 °C for 2 hours, the mixture was filtered. LC-MS showed that the reaction proceeds were completely reacted, with the product accounting for 94.0% and three main impurities accounting for 4.2%. Insoluble matter was filtered off, and the filtrate was washed with saturated brine, extracted with ethyl acetate, and the organic phases were combined. The solvent (ethyl acetate) was removed under reduced pressure, and the mixture was dried to obtain light brown needle-like crystals (0.39 g, purity 94.8%, yield 91.6%). The crude product was purified by simple column chromatography to obtain the analytical sample. The sample was analyzed by H-spectrum and C-spectrum analysis, and the results are as follows: Figure 1 , Figure 2 .

[0078] LC-MS: M+1 = 237, isotope peak M+3 = 239

[0079] 1 H NMR (CDCl3, 500MHz), δ (ppm): 7.354 (s, 2H), 4.058 (s, 2H), 2.267 (s, 3H)

[0080] 13 C NMR (CDCl3, 126MHz), δ (ppm): 202.520,136.378,133.750,130.593,128.079,45.449,29.644

[0081] Example 2 illustrates that the addition of acid catalysis has a significant effect, shortening the reaction time and resulting in higher yield and purity.

[0082] The inventors also investigated the effects of using a common diazonium salt, or without adding cuprous oxide, or without adding sodium acetate on the reaction, see Examples 3-5.

[0083] Example 3 (Common Diazonium Salt)

[0084] In a 50 mL single-necked flask, add water (1.5 mL), hydrochloric acid solution (577.4 mg, 36.0%, 5.7 mmol), and 2,4,6-trichloroaniline hydrochloride (786 mg, 83.0%, 2.8 mmol). Cool to 0 °C in an ice-salt bath, and slowly add sodium nitrite solution (1.08 g, 20.0%, 3.1 mmol). React in an ice bath for 0.5 hours, then store at low temperature for later use. In another 50 mL single-necked flask under ice-salt bath conditions, add isopropyl acetate (8 mL), cuprous oxide (61.8 mg, 0.43 mmol), and sodium acetate (590.6 mg, 7.2 mmol). After stirring for 1 minute, slowly add the reaction solution from the first step, resulting in the generation of a large amount of gas. After reacting at 0℃ for 1 hour, the insoluble matter was filtered off. The filtrate was washed with saturated brine, extracted with ethyl acetate, and the organic phases were combined. The solvent was removed under reduced pressure, and the product was dried to obtain 0.59 g of a brownish-black oily substance with a purity of 30.6% and a yield of 27.1%.

[0085] Example 3 illustrates that the Meerwein arylation reaction is less effective when diazonium salts are not converted to fluoroborate.

[0086] Example 4 (without cuprous oxide)

[0087] Under ice-salt bath conditions, isopropyl acetate (5 mL) and sodium acetate (347.3 mg, 4.2 mmol) were added to a 50 mL single-necked flask. After stirring for 1 minute, 2,4,6-trichlorobenzyl diazofluoroborate (507 mg, 1.7 mmol) was slowly added, followed by dropwise addition of hydrochloric acid (101.9 mg, 12.0%, 0.34 mmol). After reacting at 0 °C for 1 hour, the mixture was filtered, the filtrate was washed with saturated brine, extracted with ethyl acetate, the organic phases were combined, the solvent was removed under reduced pressure, and the product was dried to give a black oily crude product of 1-(2,4,6-trichlorophenyl)-prop-2-one (0.40 g, purity 1.8%, yield 1.8%).

[0088] Example 4 demonstrates that the yield is extremely low without the catalysis of copper salt, indicating that copper salt is indispensable for the catalysis of the Meerwein reaction.

[0089] Example 5 (without sodium acetate)

[0090] Under ice-salt bath conditions at 0°C, isopropyl acetate (5 mL) and cuprous oxide (36.4 mg, 0.25 mmol) were added to a 50 mL single-necked flask. After stirring for 1 minute, 2,4,6-trichlorobenzenediazofluoroborate (507 mg, 1.7 mmol) was slowly added, followed by dropwise addition of hydrochloric acid (101.9 mg, 12.0%, 0.34 mmol), resulting in the release of a large amount of gas. The reaction was maintained at 0°C for 3 hours. LC-MS monitoring showed that 21.8% of the starting material remained, and the product accounted for 72.4%. The three main byproducts were 1,2,3,5-tetrachlorobenzene, 1,3,5-trichlorobenzene, and 1,3,5-trichloro-2-fluorobenzene, accounting for a total of 5.2%. Insoluble matter was filtered off, and the filtrate was washed with saturated brine, extracted with ethyl acetate, and the organic phases were combined. The solvent was removed under reduced pressure, and the product was dried to obtain 0.39 g of a black oil with a purity of 74.2% and a yield of 71.7%.

[0091] Example 5 shows that, without the addition of sodium acetate, there is still a large amount of unconverted raw material after a reaction time of 3 hours. Extending the reaction time does not significantly change the unconverted product. The conversion rate and selectivity are lower than when sodium acetate is added, but the reaction effect exceeds expectations.

[0092] Therefore, the results of Examples 2, 3, and 4 demonstrate that whether the diazonium salt is in the form of a fluoroborate and whether cuprous oxide is added as a catalyst have a significant impact on the reaction. The results of Example 5 show that the sodium acetate buffer system has a significant impact on the reaction. Thus, the three key materials affecting the reaction of this invention are diazonium fluoroborate, cuprous oxide, and acid.

[0093] The inventors also investigated the effects of different copper salts, acids and their amounts, the amount of sodium acetate, and the reaction temperature on the reaction. Some examples are as follows:

[0094] Examples 6-10 were used to investigate the catalytic effects of different metal salts on the reaction.

[0095] Example 6

[0096] Under ice-salt bath conditions at 0°C, isopropyl acetate (5 mL), cuprous oxide (73.0 mg, 0.51 mmol), and sodium acetate (347.3 mg, 4.2 mmol) were added to a 50 mL single-necked flask. After stirring for 1 minute, 2,4,6-trichlorobenzenediazofluoroborate (507 mg, 1.7 mmol) was slowly added, followed by dropwise addition of hydrochloric acid (101.9 mg, 12.0%, 0.34 mmol), resulting in the release of a large amount of gas. After reacting at 0°C for 1 hour, the mixture was filtered, the filtrate was washed with saturated brine, extracted with ethyl acetate, the organic phases were combined, the solvent was removed under reduced pressure, and the mixture was dried to obtain orange-yellow needle-like crystals (0.40 g, purity 94.4%, yield 93.5%).

[0097] Example 7

[0098] Under ice-salt bath conditions at 0°C, isopropyl acetate (5 mL), cuprous chloride (74.3 mg, 0.75 mmol), and sodium acetate (347.3 mg, 4.2 mmol) were added to a 50 mL single-necked flask. After stirring for 1 minute, 2,4,6-trichlorobenzenediazofluoroborate (507 mg, 1.7 mmol) was slowly added, followed by dropwise addition of hydrochloric acid (101.9 mg, 12.0%, 0.34 mmol), resulting in the release of a large amount of gas. After reacting at 0°C for 1 hour, the insoluble matter was filtered off. The filtrate was washed with saturated brine, extracted with ethyl acetate, and the organic phases were combined. The solvent was removed under reduced pressure, and the product was dried to give a black, oily crude product (0.42 g, purity 70.8%, yield 73.6%).

[0099] Example 8

[0100] Copper chloride (100.8 mg, 0.75 mmol) was added in place of cuprous chloride in Example 7. A black oily product (0.41 g, purity 1.6%, yield 1.6%) was obtained.

[0101] Example 9

[0102] Anhydrous copper sulfate (119.7 mg, 0.75 mmol) was added in place of cuprous chloride in Example 7. A black oily product (0.40 g) with a purity of 1.7% and a yield of 1.7% was obtained.

[0103] Example 10

[0104] Ferric chloride (124.9 mg, 0.75 mmol) was added in place of cuprous chloride in Example 7. A black oily substance (0.40 g) with a purity of 9.7% and a yield of 9.7% was obtained.

[0105] The comparison results of Examples 2, 6-10 are shown in Table 1.

[0106] Table 1. Effects of different metal salt catalysts on the reaction.

[0107] Example catalyst purity(%) Yield (%) Example 7 Cuprous chloride 70.8 73.6 Example 8 Copper chloride 1.6 1.6 Example 9 Copper sulfate 1.7 1.7 Example 10 Ferric chloride 9.7 9.7

[0108] Note: In Table 1, diazonium salt refers to 2,4,6-trichlorobenzenediazofluoroborate. Furthermore, the amounts of the different catalysts mentioned above are the relatively optimal amounts obtained through experiments.

[0109] As shown in Table 1, except for the +1 valence copper salt, the other salts have poor catalytic effects. Cuprous chloride has a better effect, but the purity is poor. The main impurities detected by GCMS are 1,2,3,5-tetrachlorobenzene, 1,3,5-trichlorobenzene and 1,3,5-trichloro-2-fluorobenzene. Among them, cuprous oxide has the best catalytic effect, with high product purity and high yield.

[0110] The effect of different amounts of cuprous oxide on the reaction was investigated in Examples 2, 4, 6, and 11-15.

[0111] Example 11

[0112] Under ice-salt bath conditions at 0°C, isopropyl acetate (5 mL), cuprous oxide (12.2 mg, 0.085 mmol), and sodium acetate (209 mg, 2.55 mmol) were added to a 50 mL single-necked flask. After stirring for 1 minute, 2,4,6-trichlorobenzenediazofluoroborate (507 mg, 1.7 mmol) was slowly added, followed by dropwise addition of hydrochloric acid (101.9 mg, 12.0%, 0.34 mmol), resulting in the release of a large amount of gas. After reacting at 0°C for 1 hour, the mixture was filtered. The filtrate was washed with saturated brine, extracted with ethyl acetate, and the organic phases were combined. The solvent was removed under reduced pressure, and the product was dried to obtain a black oily substance (0.41 g, purity 6.8%, yield 6.9%).

[0113] Example 12

[0114] Referring to Example 11, only cuprous oxide (18.2 mg, 0.13 mmol) was added. Pale green needle-like crystals (0.38 g) were obtained with a purity of 92.9% and a yield of 88.4%.

[0115] Example 13

[0116] Referring to Example 11, only cuprous oxide (24.4 mg, 0.17 mmol) was added. Pale yellow needle-like crystals (0.39 g) were obtained with a purity of 92.7% and a yield of 89.5%.

[0117] Example 14

[0118] Referring to Example 11, only cuprous oxide (30.6 mg, 0.21 mmol) was added. Pale yellow needle-like crystals (0.39 g) were obtained with a purity of 93.3% and a yield of 90.1%.

[0119] Example 15

[0120] Referring to Example 11, only cuprous oxide (54.5 mg, 0.38 mmol) was added. Light brown flaky crystals (0.40 g) were obtained with a purity of 93.1% and a yield of 92.2%.

[0121] The effects of the amount of catalyst cuprous oxide on the reaction yield are compared in Table 2.

[0122] Table 2. Effect of the amount of cuprous oxide catalyst on reaction yield and purity.

[0123] Example Diazonium salt: Sodium acetate: Hydrochloric acid (molar ratio) Cuprous oxide (eq) purity(%) Yield (%) Example 4 1:2.5:0.2 0 1.8 1.8 Example 11 1:1.5:0.2 0.05 6.8 6.9 Example 12 1:1.5:0.2 0.075 92.9 88.4 Example 13 1:1.5:0.2 0.1 92.7 89.5 Example 14 1:1.5:0.2 0.125 93.3 90.1 Example 2 1:2.5:0.2 0.15 94.8 91.6 Example 15 1:2.5:0.2 0.22 93.1 92.2 Example 6 1:2.5:0.2 0.30 94.4 93.5

[0124] Note: In Table 2, diazonium salt refers to 2,4,6-trichlorobenzenediazofluoroborate; cuprous oxide (eq) refers to the molar equivalent of cuprous oxide relative to diazonium salt. For example, in Example 11, the molar ratio of diazonium salt to cuprous oxide is 1:0.05, and the molar equivalent of cuprous oxide is 0.05eq. The molar equivalent (eq) of other materials is also relative to the molar equivalent of diazonium salt.

[0125] Table 2 shows that the reaction yield varies significantly depending on the amount of cuprous oxide added. When the amount added is less than 0.05 eq, cuprous oxide has no obvious catalytic effect; when the amount added is not less than 0.075 eq, the catalytic effect of cuprous oxide is greatly improved, but the increase in yield slows down with the continuous increase of cuprous oxide amount. Therefore, the preferred amount of cuprous oxide added is 0.075–0.30 eq. As the amount added exceeds 0.30 eq, the yield and purity will gradually increase. Therefore, from the perspective of catalytic efficiency and reaction safety, the amount of cuprous oxide added can be controlled between 0.1 and 0.3 eq.

[0126] The catalytic effects of different acids on the reaction were investigated in Examples 6, 16-23.

[0127] Example 16

[0128] Under ice-salt bath conditions, isopropyl acetate (5 mL), cuprous oxide (54.5 mg, 0.38 mmol), and sodium acetate (347.3 mg, 4.2 mmol) were added to a 50 mL single-necked flask. After stirring for 1 minute, 2,4,6-trichlorobenzenediazofluoroborate (507 mg, 1.7 mmol) was slowly added, followed by dropwise addition of dilute sulfuric acid (328.8 mg, 10.0%, 0.34 mmol), resulting in the release of a large amount of gas. After reacting at 0 °C for 1 hour, the insoluble matter was removed by filtration. The filtrate was washed with saturated brine, extracted with ethyl acetate, and the organic phases were combined. The solvent was removed under reduced pressure, and the product was dried to obtain pale yellow needle-like crystals (0.40 g, purity 91.7%, yield 90.8%).

[0129] Example 17

[0130] Referring to Example 16, except that p-toluenesulfonic acid monohydrate (64.7 mg, 0.34 mmol) was used instead of sulfuric acid. Pale yellow needle-like crystals (0.39 g) were obtained with a purity of 95.8% and a yield of 92.5%.

[0131] Example 18

[0132] Referring to Example 16, except that methanesulfonic acid (32.7 mg, 0.34 mmol) was used instead of sulfuric acid. Pale yellow needle-like crystals (0.39 g, purity 94.3%, yield 91.1%) were obtained.

[0133] Example 19

[0134] Referring to Example 16, except that acetic acid (20.4 mg, 0.34 mmol) was used instead of sulfuric acid. Light brown needle-like crystals (0.40 g) were obtained with a purity of 91.1% and a yield of 90.3%.

[0135] Example 20

[0136] Referring to Example 16, except that maleic acid (39.5 mg, 0.34 mmol) was used instead of sulfuric acid. Light brown needle-like crystals (0.39 g) were obtained with a purity of 89.7% and a yield of 86.6%.

[0137] Example 21

[0138] Referring to Example 16, except that citric acid monohydrate (71.4 mg, 0.34 mmol) was used instead of sulfuric acid. Pale yellow needle-like crystals (0.39 g) were obtained with a purity of 95.5% and a yield of 92.2%.

[0139] Example 22

[0140] Referring to Example 16, except that ferric chloride (55.2 mg, 0.34 mmol) was used instead of sulfuric acid. Light brown needle-like crystals (0.38 g) were obtained with a purity of 90.5% and a yield of 85.2%.

[0141] Example 23

[0142] Referring to Example 16, except that elemental iodine (86.3 mg, 0.34 mmol) was used instead of sulfuric acid. Brown needle-like crystals (0.39 g) were obtained with a purity of 86.5% and a yield of 83.6%.

[0143] Example 24

[0144] Referring to Example 16, except that a strong acidic ion exchange resin (100 mg) was used instead of sulfuric acid. Brown needle-like crystals (0.39 g) were obtained with a purity of 87.4% and a yield of 84.4%.

[0145] Example 25

[0146] Referring to Example 16, except that o-nitrophenol (47.3 mg, 0.34 mmol) was used instead of sulfuric acid. Pale yellow needle-like crystals (0.40 g) were obtained with a purity of 91.7% and a yield of 90.8%.

[0147] The effects of different acid catalysts on reaction yield and purity are compared in Table 3.

[0148] Table 3: Effects of different acid catalysts on reaction yield and purity

[0149] Example Types of acids purity(%) Yield (%) Example 15 hydrochloric acid 93.1 92.2 Example 16 dilute sulfuric acid 91.7 90.8 Example 17 p-Toluenesulfonic acid 95.8 92.5 Example 18 mesylate 94.3 91.1 Example 19 Acetic acid 91.1 90.3 Example 20 Maleic acid 89.7 86.6 Example 21 Citric acid monohydrate 95.5 92.2 Example 22 Ferric chloride 90.5 85.2 Example 23 iodine 86.5 83.6 Example 24 Strong acid ion exchange resin 87.4 84.4 Example 25 o-nitrophenol 91.7 90.8

[0150] Note: In Table 3, diazonium salts refer to 2,4,6-trichlorobenzenediazofluoroborate.

[0151] As shown in Table 3, among acids in the broad sense, inorganic acids and sulfonic acids, as well as citric acid monohydrate among organic acids, have better catalytic effects. For example, hydrochloric acid, dilute sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid monohydrate, and o-nitrophenol all have good effects, with hydrochloric acid, p-toluenesulfonic acid, and citric acid monohydrate having the best catalytic effects.

[0152] The effect of the amount of sodium acetate added on the reaction was investigated in Examples 2, 5, 26-31.

[0153] Example 26

[0154] Following the method and steps of Example 2, except that the amount of sodium acetate added was adjusted to (69.7 mg, 0.85 mmol). The reaction was maintained at 0°C for 3 hours. LCMS monitoring showed that 17.2% of the raw material remained, with three main impurities accounting for 5.7%, and the product accounting for 74.4%. Extending the reaction time resulted in almost no further conversion of the raw material. Post-processing yielded a brown solid (0.38 g) with a purity of 74.8% and a yield of 70.4%.

[0155] Example 27

[0156] Following the method and steps of Example 2, except that the amount of sodium acetate added was adjusted to (106 mg, 1.3 mmol). The reaction was maintained at 0°C for 3 hours. LCMS monitoring showed that 17.8% of the raw material remained, with three main impurities accounting for 5.6%, and the product accounting for 76.0%. Extending the reaction time resulted in almost no further conversion of the raw material. Post-processing yielded a brown solid (0.38 g) with a purity of 76.0% and a yield of 71.5%.

[0157] Example 28

[0158] Following the method and steps of Example 2, except that the amount of sodium acetate added was adjusted to (139.4 mg, 1.7 mmol). The reaction was maintained at 0°C for 2 hours. LCMS monitoring showed that 11.9% of the raw material remained, with three main impurities accounting for 5.9%, and the product accounting for 81.8%. Extending the reaction time resulted in almost no further conversion of the raw material. Post-processing yielded a light brown solid (0.39 g) with a purity of 82.0% and a yield of 79.2%.

[0159] Example 29

[0160] Following the method and steps of Example 2, except that the amount of sodium acetate added was adjusted to (174.3 mg, 2.1 mmol). The reaction was maintained at 0°C for 2 hours. LCMS monitoring showed that 12.6% of the raw material remained, with three main impurities accounting for 4.1%, and the product accounting for 82.8%. Extending the reaction time resulted in almost no further conversion of the raw material. Post-processing yielded a light brown solid (0.39 g) with a purity of 83.3% and a yield of 80.5%.

[0161] Example 30

[0162] Following the method and steps of Example 2, except that the amount of sodium acetate added was adjusted to (209.1 mg, 2.55 mmol). The reaction was maintained at 0°C for 2 hours. LCMS monitoring showed complete conversion of the raw materials, with three main impurities accounting for 4.1% and the product accounting for 94.5%. After post-processing, 0.40 g of pale yellow needle-like crystals were obtained with a purity of 95.2% and a yield of 94.3%.

[0163] Example 31

[0164] Following the method and steps of Example 2, except that the amount of sodium acetate added was adjusted to (278.8 mg, 3.4 mmol). The reaction was maintained at 0°C for 2 hours. LCMS monitoring showed complete conversion of the raw materials, with three main impurities accounting for 4.0% and the product accounting for 94.2%. After post-processing, 0.40 g of pale yellow needle-like crystals with a purity of 95.0% and a yield of 94.1% were obtained.

[0165] The effects of different amounts of sodium acetate added on the reaction are compared in Table 4.

[0166] Table 4. Effect of sodium acetate addition on the reaction

[0167]

[0168] Note: In Table 4, diazonium salt refers to 2,4,6-trichlorobenzenediazofluoroborate; the molar ratio of diazonium salt:cuprous oxide:hydrochloric acid is 1:0.15:0.2, and the contents of the products in the table refer to the contents controlled and normalized in LCMS.

[0169] As shown in Table 4, the amount of sodium acetate added has no significant effect on the generation of impurities and little effect on the selectivity of the reaction, but has a significant effect on the conversion rate and reaction rate. When the amount added is less than 1.25 eq, it has a significant effect on the conversion rate, and even if the conversion rate of the remaining raw materials is extended, it is difficult to further improve the conversion rate. When it is not less than 1.5 eq, the amount of sodium acetate added has almost no effect on the reaction, and the selectivity and yield tend to be consistent. However, if the amount of sodium acetate added is too large (e.g., in Example 2), the yield will not increase. Therefore, the optimal amount of sodium acetate added is 1.5 to 2.5 eq, and optionally 1.5 to 2.0 eq.

[0170] The effects of the amount of hydrochloric acid added on the reaction were considered through Examples 32-34.

[0171] Example 32

[0172] Following the method and steps of Example 30, except that the amount of hydrochloric acid added was adjusted to (25.5 mg, 12.0%, 0.085 mmol). After reacting for 4 hours, a black oily substance (0.38 g) with a purity of 67.6% and a yield of 63.6% was obtained.

[0173] Example 33

[0174] Following the method and steps of Example 30, except that the amount of hydrochloric acid added was adjusted to (51 mg, 12.0%, 0.17 mmol). After reacting for 3 hours and post-processing, 0.39 g of pale hydrazone needle-like crystals with a purity of 88.9% and a yield of 85.9% were obtained.

[0175] Example 34

[0176] Following the method and steps of Example 30, except that the amount of hydrochloric acid added was adjusted to (155 mg, 12.0%, 0.51 mmol). After reacting for 2 hours, post-treatment yielded 0.40 g of pale yellow needle-like crystals with a purity of 91.5% and a yield of 90.7%.

[0177] The comparison results of the effects of different amounts of hydrochloric acid added on the reaction are shown in Table 5.

[0178] Table 5: Effect of different amounts of hydrochloric acid added on the reaction

[0179] Example Hydrochloric acid (eq) purity(%) Yield (%) Example 32 0.05 67.6 63.6 Example 33 0.1 88.9 85.9 Example 30 0.2 95.2 94.3 Example 34 0.3 91.5 90.7

[0180] Note: In Table 5, diazonium salts refer to 2,4,6-trichlorobenzenediazofluoroborate.

[0181] As shown in Table 5, the amount of acid added has a significant impact on the reaction. When it is below 0.05 eq, the reaction rate decreases, and the yield and purity decrease significantly. When it is above 0.3 eq, the reaction rate increases with the increase of acid amount, but the purity and yield of the product tend to decrease.

[0182] The effect of reaction temperature on the reaction was investigated through Examples 35-38.

[0183] Example 35

[0184] Following the method and steps of Example 30, except that the reaction temperature was adjusted to -5°C, 0.40 g of pale yellow needle-like crystals were obtained after post-processing, with a purity of 94.8% and a yield of 93.9%.

[0185] Example 36

[0186] Following the method and steps of Example 30, except that the reaction temperature was adjusted to 5°C, 0.40 g of pale yellow needle-like crystals were obtained after post-processing, with a purity of 95.0% and a yield of 94.1%.

[0187] Example 37

[0188] Following the method and steps of Example 30, except that the reaction temperature was adjusted to 10°C, 0.39 g of pale yellow needle-like crystals were obtained after post-processing, with a purity of 90.8% and a yield of 87.7%.

[0189] Example 38

[0190] Following the method and steps of Example 30, except that the reaction temperature was adjusted to 20°C, 0.38 g of pale yellow needle-like crystals were obtained after post-processing, with a purity of 90.8% and a yield of 87.7%.

[0191] Example 39

[0192] Following the method and steps of Example 30, except that the reaction temperature was adjusted to 30°C, 0.38 g of pale yellow needle-like crystals were obtained after post-processing, with a purity of 90.8% and a yield of 87.7%.

[0193] The results of comparing the effects of different reaction temperatures on the reaction are shown in Table 6.

[0194] Table 6: Effect of different reaction temperatures on the reaction

[0195] Example Temperature (°C) purity(%) Yield (%) 35 -5 94.8 93.9 30 0 95.2 94.3 36 5 95.0 94.1 37 10 90.8 87.7 38 20 90.5 86.4 39 30 75.6 72.2

[0196] As shown in Table 6, temperature has a significant effect on the reaction. When the temperature reaches 10℃, the yield decreases. As the temperature increases, the yield and purity decrease significantly. When the temperature is between -5℃ and 5℃, the yield and purity are not significantly different.

[0197] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a fluopyram intermediate, characterized in that, The method includes the following steps: In the presence of cuprous oxide or its salt and an acid, 2,4,6-trichlorobenzyl diazofluoroborate and isopropenyl acetate are used to synthesize fluopyram intermediate of formula I. In the cuprous salt CuX, X represents Cl, Br, or I.

2. The preparation method according to claim 1, characterized in that, Acids include one or more of the following: organic acids, inorganic acids, resins containing acidic groups, Lewis acids, halogens, and phenols with electron-withdrawing substituents. Optionally, the inorganic acid includes one or more of hydrochloric acid, sulfuric acid, and phosphoric acid; Optionally, the organic acid is a C1-C6 aliphatic organic acid, aromatic carboxylic acid, or sulfonic acid, and is optionally selected from one or more of formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, malonic acid, succinic acid, tartaric acid, citric acid monohydrate, maleic acid, fumaric acid, and mandelic acid; the aromatic carboxylic acid is optionally selected from one or more of benzoic acid, 4-methylbenzoic acid containing an electron-donating group, nitrobenzoic acid containing an electron-withdrawing group, and halobenzoic acid; the sulfonic acid is optionally selected from one or more of p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethylsulfonic acid, camphorsulfonic acid, and chlorosulfonic acid. Optionally, the resin containing acidic groups is selected from strongly acidic ion exchange resins, and optionally from resins containing sulfonic acid groups or carboxylic acid groups; Optionally, the Lewis acid is selected from one or more of boron trichloride, boron trifluoride, ferric chloride, ferrous chloride, aluminum trichloride, and zinc chloride; Optionally, the halogen element is selected from one or more of chlorine, bromine, and elemental iodine; Optionally, the electron-withdrawing substituent phenol is selected from phenols with electron-withdrawing substituents, and is optionally selected from halogenated phenols or nitro-substituted phenols, and is optionally selected from one or more of o-fluorophenol, o-chlorophenol, o-nitrophenol, and p-nitrophenol; Optionally, the acid is selected from one or more of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid monohydrate, and o-nitrophenol.

3. The preparation method according to claim 1, characterized in that, The molar ratio of 2,4,6-trichlorobenzyl diazofluoroborate to cuprous oxide is 1:0.075 to 1, optionally 1:0.075 to 0.5, optionally 1:0.075 to 0.3, optionally 1:0.1 to 0.3, optionally 1:0.15 to 0.3; And / or, the molar ratio of 2,4,6-trichlorobenzyl diazofluoroborate to acid is 1:0.05 to 0.3, optionally 1:0.1 to 0.3, optionally 1:0.15 to 0.3, optionally 1:0.18 to 0.3, optionally 1:0.2 to 0.

3.

4. The preparation method according to claim 1, characterized in that, The molar ratio of 2,4,6-trichlorobenzenediazofluoroborate to isopropyl acetate is 1:5 to 20.

5. The preparation method according to claim 1, characterized in that, It also includes buffering substances, which may optionally be sodium acetate, disodium hydrogen phosphate-sodium phosphate buffer system, sodium carboxylate, or carbonate buffer system; Optionally, the molar ratio of 2,4,6-trichlorobenzenediazofluoroborate to the buffer substance is 1:0 to 5, optionally 1:0.5 to 5, optionally 1:1.5 to 5, optionally 1:1.5 to 2.5, optionally 1:1.5 to 2.

6. The preparation method according to any one of claims 1 to 5, characterized in that, The reaction temperature is -5 to 20℃, optionally -5 to 10℃, optionally -5 to 5℃; And / or, no additional solvent is required when 2,4,6-trichlorobenzenediazofluoroborate reacts with isopropyl acetate.

7. The preparation method according to any one of claims 1 to 6, characterized in that, 2,4,6-Trichlorobenzyl diazofluoroborate was prepared according to the method reported in the literature Aryl Pyrazoles from Photocatalytic Cycloadditions of Arenediazonium, Organic Letters, 2020, 22(18), 7219-7224.

8. The preparation method according to any one of claims 1 to 7, characterized in that, The post-treatment of 2,4,6-trichlorobenzenediazofluoroborate and isopropyl acetate after reaction includes: removal of insoluble matter, washing, extraction, removal of solvent, and drying to obtain the target product; Optionally, washing may be performed using saturated salt water; Optionally, extraction is performed using ethyl acetate; Optionally, solvent removal can be achieved by vacuum distillation. 9.2,4,6-Trichlorobenzyl diazofluoroborate in the preparation of l-(2,4,6-trichlorophenyl)-prop-2-one of formula I; Application of 10,2,4,6-trichlorobenzyl diazofluoroborate in the preparation of fluopyram.

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