Preparation method of 1-[5-(2, 6-difluorophenyl)-4, 5-dihydroisoxazole-3-yl] ethanone compound or salt thereof

Abstract

The invention discloses a preparation method and application of a 1-[5-(2, 6-difluorophenyl)-4, 5-dihydroisoxazole-3-yl] ethanone compound or a salt thereof, and the method comprises the following steps: in the presence of an organic solvent, a catalyst acid and an oxidizing agent, cyclizing 2-oxopropionaldehyde-1-oxime and 2, 6-difluorostyrene in a formula (II) to obtain a 1-[5-(2, 6-difluorophenyl)-4, 5-dihydroisoxazole-3-yl] ethanone compound in a formula I; the compound is (2, 6-difluorophenyl)-4, 5-dihydroisoxazole-3-yl) ethanone. The preparation method disclosed by the invention is simple in production operation process, high in reaction yield, high in reaction selectivity, simple and convenient in post-treatment, free of column chromatography and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, and more particularly to a method for preparing a 1-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl]acetone compound or a salt thereof. Background Technology

[0002] Oxathiapiprolin, chemically known as 1-[4-[4-[(5RS)-5-(2,6-difluorophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazo-2-yl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetone, is the first piperidinylthiazolium isoxazoline fungicide developed by DuPont. This compound has a unique target site, a novel mechanism of action, and exhibits good rapid and sustained effects. It is also resistant to rain washout and demonstrates excellent efficacy at extremely low dosages, thus attracting increasing attention and application.

[0003] Currently reported synthetic routes for fluoxetine are lengthy, involving the key intermediate 1-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl]acetone, resulting in high costs, low yields, and poor purity. While US patents (US2010240619, CN102933577A) use 1,3-dichloroacetone and tert-butyl nitrite as raw materials to prepare chlorooxime, followed by cyclization with 2,6-difluorostyrene to prepare the intermediate, this method also suffers from low yields and operational difficulties.

[0004]

[0005] Chinese patent (CN105541830A) reports that 2-oxopropanal-1-oxime reacts with NCS to form chlorooxime, which is then cyclized to prepare the intermediate. This type of reaction belongs to 1,3-dipolar cyclization, and generally requires chlorination of 2-oxopropanal-1-oxime to obtain chlorooxime before cyclization can proceed. However, when the inventors repeated this method, they found the reaction still difficult, and subsequent column chromatography purification was required, making it unsuitable for industrial scale-up. The inventors speculate that this may be due to the poor stability of chlorooxime, its tendency to self-polymerize, resulting in numerous byproducts and necessitating column chromatography purification.

[0006]

[0007] The reaction route reported in World Patent (WO2011085170 A1) requires a low-temperature reaction of methyl magnesium bromide, which is a long route with high equipment requirements and is also unsuitable for industrial production.

[0008]

[0009] The disadvantages of the methods reported in the literature are: low yield, numerous side reactions, long or complex routes, and unsuitability for industrial production. Currently, there is no simple, high-yield method suitable for industrial production of 1-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl]acetone compound (I) or its salts. Summary of the Invention

[0010] Purpose of the invention

[0011] To overcome the above shortcomings, the present invention aims to provide a method for preparing the 1-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl]acetone compound or its salt as shown in formula (I). The preparation method of the present invention has a simple production process, high reaction yield, high reaction selectivity, and simple post-processing without the need for column chromatography, making it suitable for industrial production.

[0012] Solution

[0013] To achieve the objectives of this invention, the technical solution adopted is as follows:

[0014] In a first aspect, the present invention provides a method for preparing a 1-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl] ethyl ketone compound or a salt thereof, the method comprising the following steps: cyclizing 2-oxopropanal-1-oxime of formula (II) with 2,6-difluorostyrene to obtain 1-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl] ethyl ketone of formula I in the presence of an organic solvent, a catalyst acid and an oxidant.

[0015]

[0016] Furthermore, the oxidizing agent includes at least one of the following: a mixture of iodobenzene and hydrogen peroxide, or a high-valent iodine compound;

[0017] The iodobenzene mentioned refers to C6H5I.

[0018] And / or, the high-valent iodine compounds include trivalent and pentavalent iodine compounds, such as diacetobenzene, (dichloroiodo)benzene, 2-iodobenzoic acid, and Desmond reagent.

[0019] Furthermore, when the oxidant is a mixture of iodobenzene and hydrogen peroxide, the molar ratio of 2,6-difluorostyrene, iodobenzene, and hydrogen peroxide is 1:(0.01–0.5):(1–3), optionally 1:(0.05–0.5):(1–2), optionally 1:(0.08–0.5):(1–2), optionally 1:(0.095–0.5):(1–2), optionally 1:(0.095–0.2). :(1~1.5), optionally 1:(0.09~0.12):(1~1.5), optionally 1:(0.095~0.1):(1~1.5), optionally 1:(0.095~0.1):(1.01~1.5), optionally 1:(0.095~0.1):(1.01~1.2), optionally 1:(0.095~0.1):(1.01~1.1);

[0020] Optionally, the molar ratio of 2-oxopropanal-1-oxime to 2,6-difluorostyrene is (1-3):1, (1-1.5):1, (1.01-1.2):1, (1.01-1.2):1, or (1.01-1.2):1.

[0021] Further, 2-oxopropanal-1-oxime is added in solution to a solution containing iodobenzene, catalyst acid, and 2,6-difluorostyrene, and then hydrogen peroxide is added to carry out the reaction; optionally, 2-oxopropanal-1-oxime is added dropwise; optionally, hydrogen peroxide is added dropwise.

[0022] Furthermore, when the oxidant is a high-valent iodine compound, the molar ratio of 2,6-difluorostyrene to the high-valent iodine compound is 1:(0.9-3), optionally 1:(1-3), optionally 1:(1-1.64), optionally 1:(1-1.5), optionally 1:(1-1.3), optionally 1:(1-1.2), optionally 1:(1.01-1.3), optionally 1:(1.01-1.2);

[0023] Optionally, the molar ratio of 2-oxopropanal-1-oxime to 2,6-difluorostyrene is (1-3):1, (1-2):1, (1-1.5):1, (1-1.34):1, (1-1.2):1, or (1.05-1.2):1.

[0024] Further, 2-oxopropanal-1-oxime is added in solution form to a solution containing a high-valent iodine compound, a catalyst acid, and 2,6-difluorostyrene; optionally, 2-oxopropanal-1-oxime is added dropwise.

[0025] Furthermore, the reaction temperature is 0–50°C, and optionally 15–25°C;

[0026] And / or, the reaction time is 1 to 15 hours, optionally 4 to 10 hours, optionally 5 to 10 hours.

[0027] Furthermore, the organic solvent includes at least one selected from methanol, ethanol, isopropanol, n-butanol, and acetonitrile, and optionally methanol.

[0028] Furthermore, the catalyst acid includes at least one of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, optionally trifluoroacetic acid.

[0029] Furthermore, the amount of catalyst acid added is 0.005 to 0.1 equivalents of 2-oxopropanal-1-oxime, optionally 0.01 to 0.10 equivalents, optionally 0.01 to 0.02 equivalents.

[0030] Further, after the reaction is completed, post-processing is performed. Optionally, the post-processing steps include adding a solvent that can precipitate the target product, filtering, and drying to obtain the target product. Optionally, the precipitation solvent includes at least one of n-heptane, n-hexane, cyclohexane, and petroleum ether, and optionally n-heptane.

[0031] Optionally, the drying temperature is 20–40°C.

[0032] Secondly, the invention provides the application of the compound of formula I prepared by the above-described preparation method in the preparation of fluthiazopyrone.

[0033] One possible reaction route of the present invention is as follows:

[0034]

[0035] Beneficial effects

[0036] 1) The present invention saves process steps, eliminating the need for chlorination reaction of 2-oxopropanal-1-oxime. By using a mixture of iodobenzene and hydrogen peroxide or a high-iodine compound as an oxidant, the direct cyclization of 2-oxopropanal-1-oxime with difluorostyrene can be achieved, thereby obtaining the target product, thus achieving process savings.

[0037] 2) This invention is simple to operate, is a one-step reaction, does not require separation of intermediates, and the product precipitates directly from the system after the reaction is completed, with high purity, avoiding column chromatography separation;

[0038] 3) The present invention exhibits high reaction selectivity and high product yield;

[0039] 4) The process conditions of this invention are mild, the solvent can be recycled and reused, it is green and environmentally friendly, and suitable for industrial production;

[0040] 5) The process of the present invention is more economical and safer. When using high-iodine compounds for the reaction, the amount of high-iodine compounds used is small. When using iodobenzene for the reaction, the iodobenzene can be recycled. Attached Figure Description

[0041] 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.

[0042] Figure 1 This is a liquid chromatographic analysis spectrum of the reaction solution after the reaction in Example 1 of the present invention.

[0043] Figure 2 The above is the 1H NMR spectrum of the yellow solid (target product) of Example 1 of this invention. Detailed Implementation

[0044] 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.

[0045] 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.

[0046] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "containing," "including," or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0047] The reagents used in the following examples are commercially available; unless otherwise specified, the reaction process and results were detected by high performance liquid chromatography (HPLC), and the content was determined by the area normalization method.

[0048] This application provides a method for preparing 1-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl]acetone (Formula I) or a salt thereof, comprising the following steps:

[0049] In the presence of an organic solvent and a catalyst acid, 2-oxopropanal-1-oxime (Formula II), a mixture of iodobenzene and hydrogen peroxide or a high-iodine compound, and 2,6-difluorostyrene cyclize to yield 1-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl]acetone (Formula I), an intermediate of fluothiazolyl acetone. The reaction equation is as follows:

[0050]

[0051] This invention eliminates the need for chlorination of 2-oxopropanal-1-oxime. Instead, it uses a mixture of iodobenzene and hydrogen peroxide or a high iodide as an oxidant to achieve direct cyclization of 2-oxopropanal-1-oxime with difluorostyrene, thereby obtaining the target product. The reaction of this invention is a one-step reaction, requiring no separation of intermediates and simplifying the operation.

[0052] Example 1

[0053] 15g of methanol was added to a reaction vessel, followed by 6.9g of diacetic iodobenzene, 0.03g of trifluoroacetic acid, and 3.0g of 2,6-difluorostyrene under stirring. The temperature was controlled at 0–20°C. 10mL of a methanol solution containing 2.2g of 2-oxopropanal-1-oxime was slowly added dropwise. The reaction was maintained at 0–20°C for 5 hours until the reaction was complete. 25mL of n-heptane was added, and the solid was filtered to precipitate. The solid was dried at 30°C to obtain 4.3g of a yellow solid of formula (I) with a purity of 98% and a yield of 87%.

[0054] The reactants were analyzed by liquid chromatography, and the results are as follows: Figure 1 The results showed that, apart from the peaks of the target product and iodobenzene (abbreviation for diacetic iodobenzene), there were almost no impurity peaks (no peaks were observed in methanol solvent), indicating that the preparation method of the present invention produces few byproducts.

[0055] The NMR results of the yellow solid (target product) obtained in this embodiment are as follows: Figure 2 As shown, the results indicate that the present invention can prepare and obtain the target product.

[0056] Example 2

[0057] 300g of methanol was added to a reaction vessel, followed by the addition of 150g of diacetic iodobenzene, 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. The temperature was controlled at 0–20°C. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was slowly added dropwise. The reaction was maintained at 0–20°C for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered to precipitate. The solid was dried at 30°C to obtain 79.6g of a yellow solid of formula (I), with a purity of 97% and a yield of 80%. The inventors speculate that the poor stability of diacetic iodobenzene led to a decrease in yield after scale-up of the reaction.

[0058] Example 3

[0059] 300g of methanol was added to a reaction vessel, followed by 117g of (dichloroiodine)benzene (CAS No. 932-72-9), 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. The temperature was controlled at 0-20℃, and 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was slowly added dropwise. The reaction was maintained at 0-20℃ for 5 hours until the reaction was complete. 500mL of n-heptane was added, and the solid was filtered to precipitate. The solid was dried at 30℃ to obtain 87.5g of a yellow solid of formula (I), with a purity of 96% and a yield of 87%.

[0060] Example 4

[0061] 300g of methanol was added to a reaction vessel, followed by 120g of 2-iodobenzoic acid, 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. The temperature was controlled at 0–20°C. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was slowly added dropwise. The reaction was maintained at 0–20°C for 5 hours until the reaction was complete. 500mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30°C to obtain 88.6g of a yellow solid of formula (I), with a purity of 97% and a yield of 89%.

[0062] Example 5

[0063] 300 g of methanol was added to a reaction vessel, followed by 182 g of Des Martin reagent, 0.6 g of trifluoroacetic acid, and 60.0 g of 2,6-difluorostyrene under stirring. The temperature was controlled at 0–20 °C. 200 mL of a methanol solution containing 44 g of 2-oxopropanal-1-oxime was slowly added dropwise. The reaction was maintained at 0–20 °C for 5 hours until the reaction was complete. 500 mL of n-heptane was added, and the solid was filtered to precipitate. The solid was dried at 30 °C to obtain 87.7 g of a yellow solid of formula (I), with a purity of 98% and a yield of 89%.

[0064] Example 6

[0065] Add 300g of methanol to a reaction vessel, and add 200g of Des Martin reagent, 0.6g of trifluoroacetic acid and 60.0g of 2,6-difluorostyrene while stirring. Control the temperature at 0-20℃, and slowly add 200mL of methanol solution containing 44g of 2-oxopropanal-1-oxime. Keep the reaction at 0-20℃ for 5 hours until the reaction is complete. Add 500mL of n-heptane, filter to precipitate the solid, and dry at 30℃ to obtain 86.7g of yellow solid of formula (I) with a purity of 98% and a yield of 88%.

[0066] Example 7

[0067] 300 g of methanol was added to a reaction vessel, followed by 218 g of Des Martin reagent, 0.6 g of trifluoroacetic acid, and 60.0 g of 2,6-difluorostyrene under stirring. The temperature was controlled at 0–20 °C. 200 mL of a methanol solution containing 44 g of 2-oxopropanal-1-oxime was slowly added dropwise. The reaction was maintained at 0–20 °C for 5 hours until the reaction was complete. 500 mL of n-heptane was added, and the solid was filtered to precipitate. The solid was dried at 30 °C to obtain 85.7 g of a yellow solid of formula (I), with a purity of 98% and a yield of 87%.

[0068] Example 8

[0069] 300 g of methanol was added to a reaction vessel, followed by 182 g of Des Martin reagent, 0.6 g of trifluoroacetic acid, and 60.0 g of 2,6-difluorostyrene under stirring. The temperature was controlled at 0–20 °C. 200 mL of a methanol solution containing 50 g of 2-oxopropanal-1-oxime was slowly added dropwise. The reaction was maintained at 0–20 °C for 5 hours until the reaction was complete. 500 mL of n-heptane was added, and the solid was filtered to precipitate. The solid was dried at 30 °C to obtain 80.8 g of a yellow solid of formula (I), with a purity of 98% and a yield of 82%.

[0070] Example 9

[0071] 300 g of methanol was added to a reaction vessel, followed by 182 g of Des Martin reagent, 0.6 g of trifluoroacetic acid, and 60.0 g of 2,6-difluorostyrene under stirring. The temperature was controlled at 0–20 °C. 200 mL of a methanol solution containing 56 g of 2-oxopropanal-1-oxime was slowly added dropwise. The reaction was maintained at 0–20 °C for 5 hours until the reaction was complete. 500 mL of n-heptane was added, and the solid was filtered to precipitate. The solid was dried at 30 °C to obtain 78.9 g of a yellow solid of formula (I), with a purity of 98% and a yield of 80%.

[0072] Example 10

[0073] 300g of methanol was added to a reaction vessel, followed by the addition of 8.7g of iodobenzene, 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20°C, and 49g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20°C for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30°C to obtain 87.7g of a yellow solid of formula (I), with a purity of 98% and a yield of 89%.

[0074] Example 11

[0075] 300g of methanol was added to a reaction vessel, followed by the addition of 8.3g of iodobenzene, 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20℃, and 49g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20℃ for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30℃ to obtain 83.7g of a yellow solid of formula (I), with a purity of 98% and a yield of 85%.

[0076] Example 12

[0077] 300g of methanol was added to a reaction vessel, followed by the addition of 8.5g of iodobenzene, 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20℃, and 49g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20℃ for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30℃ to obtain 84.7g of a yellow solid of formula (I), with a purity of 98% and a yield of 86%.

[0078] Example 13

[0079] 300 g of methanol was added to a reaction vessel, followed by the addition of 4.4 g of iodobenzene, 0.6 g of trifluoroacetic acid, and 60.0 g of 2,6-difluorostyrene under stirring. 200 mL of a methanol solution containing 44 g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20 °C, and 49 g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20 °C for 5 hours until completion. 500 mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30 °C to obtain 81.8 g of a yellow solid of formula (I), with a purity of 97% and a yield of 82%.

[0080] Example 14

[0081] 300g of methanol was added to a reaction vessel, followed by the addition of 44g of iodobenzene, 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20℃, and 49g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20℃ for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30℃ to obtain 84.5g of a yellow solid of formula (I), with a purity of 98% and a yield of 86%.

[0082] Example 15

[0083] 300g of methanol was added to a reaction vessel, followed by the addition of 8.7g of iodobenzene, 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20℃, and 53g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20℃ for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30℃ to obtain 86.7g of a yellow solid of formula (I), with a purity of 98% and a yield of 88%.

[0084] Example 16

[0085] 300g of methanol was added to a reaction vessel, followed by the addition of 8.7g of iodobenzene, 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20°C, and 59g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20°C for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30°C to obtain 85.7g of a yellow solid of formula (I), with a purity of 98% and a yield of 87%.

[0086] Example 17

[0087] 300g of methanol was added to a reaction vessel, followed by the addition of 8.7g of iodobenzene, 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20℃, and 73g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20℃ for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered to precipitate. The solid was dried at 30℃ to obtain 86.9g of a yellow solid of formula (I), with a purity of 98% and a yield of 88%.

[0088] Example 18

[0089] 300g of methanol was added to a reaction vessel, followed by the addition of 8.7g of iodobenzene, 1.2g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20°C, and 49g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20°C for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30°C to obtain 87.6g of a yellow solid of formula (I), with a purity of 97% and a yield of 88%.

[0090] Example 19

[0091] 300g of methanol was added to a reaction vessel, followed by the addition of 8.7g of iodobenzene, 6.0g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20°C, and 49g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20°C for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30°C to obtain 87.7g of a yellow solid of formula (I), with a purity of 98% and a yield of 89%.

[0092] Example 20

[0093] 300g of methanol was added to a reaction vessel, followed by 8.7g of recovered iodobenzene, 0.6g of trifluoroacetic acid, and 60.0g of 2,6-difluorostyrene under stirring. 200mL of a methanol solution containing 44g of 2-oxopropanal-1-oxime was added dropwise. The temperature was controlled at 0–20℃, and 49g of 30% hydrogen peroxide was slowly added dropwise. The reaction was maintained at 0–20℃ for 5 hours until completion. 500mL of n-heptane was added, and the solid was filtered out. The solid was dried at 30℃ to obtain 85.7g of a yellow solid of formula (I), with a purity of 98% and a yield of 87%.

[0094] In this example 20, the iodobenzene used is recovered iodobenzene. The method for recovering iodobenzene is to use vacuum distillation to easily recover iodobenzene from the mother liquor (filtrate) after filtration.

[0095] The inventors also tried to use tert-butyl hydrogen peroxide to replace iodobenzene and hydrogen peroxide in Example 10, but the reaction could not proceed.

[0096] The inventors also tried to repeat Example 10 without adding iodobenzene, but the reaction still could not proceed.

[0097] This invention eliminates the need for chlorination of 2-oxopropanal-1-oxime. Instead, it utilizes a mixture of iodobenzene and hydrogen peroxide or a high-iodide as the oxidant to achieve direct cyclization of 2-oxopropanal-1-oxime with difluorostyrene, thereby obtaining the target product. The reaction is a one-step reaction, eliminating the need for intermediate separation and simplifying operation. Furthermore, the reaction exhibits high selectivity and high product yield. After the reaction, the product precipitates directly from the system with high purity, avoiding column chromatography separation. The process conditions are mild, suitable for industrial production. The solvent can be recycled, making it environmentally friendly. The process uses a small amount of high-iodine compound, enhancing safety. When iodobenzene is used as the catalytic catalyst, it can be recycled, making it more economical and safer.

[0098] 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 1-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl]acetone compound or a salt thereof, characterized in that, The method comprises the following steps: cyclizing 2-oxopropanal-1-oxime of formula (II) with 2,6-difluorostyrene to obtain 1-[5-(2,6-difluorophenyl)-4,5-dihydroisoxazol-3-yl] ethyl ketone of formula I in the presence of an organic solvent, a catalyst acid, and an oxidant.

2. The preparation method according to claim 1, characterized in that, Oxidizing agents include at least one of the following: a mixture of iodobenzene and hydrogen peroxide, or a high-valent iodine compound; And / or, the high-valent iodine compound includes at least one of diacetobenzene, (dichloroiodo)benzene, 2-iodobenzoic acid, and Desmond-Martin reagent.

3. The preparation method according to claim 1 or 2, characterized in that, When the oxidant is a mixture of iodobenzene and hydrogen peroxide, the molar ratio of 2,6-difluorostyrene, iodobenzene, and hydrogen peroxide is 1:(0.01~0.5):(1~3), optionally 1:(0.05~0.5):(1~2), optionally 1:(0.08~0.5):(1~2), optionally 1:(0.095~0.5):(1~2), optionally 1:(0.095~0.2):( 1~1.5), optionally 1:(0.09~0.12):(1~1.5), optionally 1:(0.095~0.1):(1~1.5), optionally 1:(0.095~0.1):(1.01~1.5), optionally 1:(0.095~0.1):(1.01~1.2), optionally 1:(0.095~0.1):(1.01~1.1); Optionally, the molar ratio of 2-oxopropanal-1-oxime to 2,6-difluorostyrene is (1-3):1, (1-1.5):1, (1.01-1.2):1, (1.01-1.2):1, or (1.01-1.2):

1. Optionally, 2-oxopropanal-1-oxime is added in solution form to a solution containing iodobenzene, catalyst acid, and 2,6-difluorostyrene, and then hydrogen peroxide is added to carry out the reaction; optionally, 2-oxopropanal-1-oxime is added dropwise; optionally, hydrogen peroxide is added dropwise.

4. The preparation method according to any one of claims 1 to 3, characterized in that, When the oxidant is a high-valent iodine compound, the molar ratio of 2,6-difluorostyrene to the high-valent iodine compound is 1:(0.9-3), optionally 1:(1-3), optionally 1:(1-1.64), optionally 1:(1-1.5), optionally 1:(1-1.3), optionally 1:(1-1.2), optionally 1:(1.01-1.3), optionally 1:(1.01-1.2); Optionally, the molar ratio of 2-oxopropanal-1-oxime to 2,6-difluorostyrene is (1-3):1, (1-2):1, (1-1.5):1, (1-1.34):1, (1-1.2):1, or (1.05-1.2):

1. Optionally, 2-oxopropanal-1-oxime is added in solution form to a solution containing a high-valent iodine compound, a catalyst acid, and 2,6-difluorostyrene; alternatively, 2-oxopropanal-1-oxime is added dropwise.

5. The preparation method according to any one of claims 1 to 4, characterized in that, The reaction temperature is 0–50℃, and optionally 15–25℃; And / or, the reaction time is 1 to 15 hours, optionally 4 to 10 hours, optionally 5 to 10 hours.

6. The preparation method according to any one of claims 1 to 5, characterized in that, The organic solvent includes at least one of methanol, ethanol, isopropanol, n-butanol, and acetonitrile, and optionally methanol.

7. The preparation method according to any one of claims 1 to 6, characterized in that, The catalyst acid includes at least one of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, optionally trifluoroacetic acid.

8. The preparation method according to claim 7, characterized in that, The amount of catalyst acid added is 0.005 to 0.1 equivalents of 2-oxopropanal-1-oxime, optionally 0.01 to 0.10 equivalents, optionally 0.01 to 0.02 equivalents.

9. The preparation method according to any one of claims 1 to 6, characterized in that, After the reaction is completed, post-processing is performed. Optionally, the post-processing steps include adding a solvent that can precipitate the target product, filtering, and drying to obtain the target product. Optionally, the precipitation solvent includes at least one of n-heptane, n-hexane, cyclohexane, and petroleum ether, and optionally n-heptane. Optionally, the drying temperature is 20–40°C.

10. The use of a compound of formula I prepared by any one of claims 1 to 9 in the preparation of fluthiazopyrone.

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