Process for the preparation of isoxaflutole

Abstract

The application relates to the field of organic synthesis and discloses a preparation method of isoxaflotole. The preparation method comprises the following steps: sequentially performing a methylthiolation reaction, an addition reaction, a hydrolysis reaction, an enol etherization reaction, a cyclization reaction and an oxidation reaction on 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene to obtain isoxaflotole. The preparation method disclosed by the application has a single solvent, avoids cross contamination caused by switching of multiple solvents, has multiple solvent recovery equipment, has high energy consumption and the like, and greatly simplifies process operation.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing isoxazolidin. Background Technology

[0002] Isoxaflutole is a p-hydroxyphenyl pyruvate dioxygenase (HPPD) inhibitor developed by Rhône-Plunkett. It possesses broad-spectrum herbicidal activity, can be absorbed through plant roots or leaves, and can be applied pre- and post-emergence. It is primarily used in dryland fields such as cornfields, sugarcane fields, and sugar beets to control various annual broadleaf and grass weeds.

[0003] The synthetic process for isoxazolidin developed by Rhône-Plunkett involves oxidation followed by enol etherification and cyclization (EP0496630B1), and its synthetic route is as follows:

[0004]

[0005] However, the sulfone group is an easily leaving group, which will generate desulfone impurities in the subsequent enol etherification and cyclization steps. Therefore, US6392099B1 reported the following synthetic route of first enol etherification, cyclization, and then oxidation:

[0006]

[0007] In this process, the compound shown in formula (Ⅲ) undergoes an enol etherification reaction with triethyl orthoformate and acetic anhydride, and then undergoes a cyclization reaction with the inorganic acid salt of hydroxylamine in the presence of an acid-binding agent. The oxidation step uses m-chloroperoxybenzoic acid as the oxidant.

[0008] However, this synthetic route has the following problems: m-chloroperoxybenzoic acid is expensive and the byproducts are difficult to handle; the acid-binding agent generates a large amount of waste salt, which is environmentally unfriendly; for the enol etherification step, acetic anhydride is expensive and generates acetylation byproduct impurities.

[0009]

[0010] CN110128308B reports a method for using carboxylic acids as solvents and Lewis acid catalysis to etherify triethyl orthoformate as an enol, avoiding the use of acetic anhydride. However, this method requires switching the solvent to a carboxylic acid (the paper emphasizes the necessity of using carboxylic acids as solvents), making the operation cumbersome, posing solvent cross-contamination problems, and requiring additional solvent recovery equipment and energy consumption. Furthermore, carboxylic acid solvents are inherently highly corrosive to equipment.

[0011] For the synthesis of the compound shown in formula (Ⅲ), Rhône-Plextor reported two methods, one of which is through a ketone ester condensation reaction (EP0994840B1):

[0012]

[0013] The problem with this method is that the condensation reaction of the two raw materials needs to be carried out under strongly alkaline conditions. However, under these conditions, the methyl ester raw material undergoes a hydrolysis side reaction, which greatly reduces the yield. In addition, the methyl ester raw material needs to be prepared by first chlorinating and then esterifying the corresponding carboxylic acid, which is costly.

[0014] Another method is to perform an addition reaction of cyclopropyl methyl ketone to the cyano group in the compound shown in formula (I) under strongly alkaline conditions to obtain the compound shown in formula (II), and then hydrolyze it under acidic conditions (EP0705243B1):

[0015]

[0016] The problem with this method is similar to that above: the addition reaction of the two raw materials needs to be carried out under strongly alkaline conditions, but under strongly alkaline conditions, the cyano group in the compound shown in formula (Ⅰ) will undergo a hydrolysis side reaction.

[0017] For the synthesis of the compound shown in (Ⅰ), Rhône-Plextor reported a process (EP0994852B1) involving the reaction of 3-nitro-4-cyanotrifluoromethylbenzene or 3-chloro-4-cyanotrifluoromethylbenzene with a metal salt of methanethiol as the starting material. Regarding solvent selection, although it is mentioned that aromatic hydrocarbons and haloalkanes, which are immiscible with water, can also be reacted using phase transfer catalysts, the text emphasizes that highly polar solvents such as ketones, ethers, amides, and sulfones are preferred, even though these solvents are typically difficult to recover.

[0018]

[0019] In summary, existing synthesis processes at each step all have some problems, and a new synthesis process is urgently needed to meet the needs of industrial production. Summary of the Invention

[0020] The purpose of this invention is to overcome the above-mentioned problems existing in the prior art and provide a method for preparing isoxazoline, which simplifies the process operation, inhibits the generation of some impurities, and has high reaction selectivity and conversion rate.

[0021] To achieve the above objectives, the present invention provides a method for preparing isoxazoline, the method comprising the following steps:

[0022] (1) Methyl sulfidation reaction: In the presence of a first phase transfer catalyst, an organic solvent and water, 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene are subjected to a methyl sulfidation reaction with a methanethiol salt, and then allowed to stand for separation to obtain an organic phase containing the compound shown in Formula I.

[0023] (2) Addition reaction: In the presence of alkoxide, the compound of formula I in the organic phase obtained in step (1) is subjected to an addition reaction with cyclopropyl methyl ketone, and a light component is extracted. After the reaction is completed, acid is added to the reaction product for acidification treatment, and then the mixture is allowed to stand and separate into layers to obtain an organic phase containing the compound of formula II.

[0024] (3) Hydrolysis reaction: In the presence of a second phase transfer catalyst and acid, the compound shown in formula II in the organic phase obtained in step (2) is hydrolyzed, and then allowed to stand and separate into layers to obtain an organic phase containing the compound shown in formula III.

[0025] (4) Enol etherification reaction: In the presence of Lewis acid, the compound shown in formula III in the organic phase obtained in step (3) is subjected to enol etherification reaction with triethyl orthoformate, and the light component is extracted to obtain an organic phase containing the compound shown in formula IV.

[0026] (5) Cycling reaction: In the presence of a third phase transfer catalyst, hydroxylamine salt and water, the compound shown in formula IV in the organic phase obtained in step (4) undergoes a cyclization reaction, and then is allowed to stand and separate into layers to obtain an organic phase containing the compound shown in formula V.

[0027] (6) Oxidation reaction: In the presence of an oxidation catalyst and a fourth phase transfer catalyst, the compound shown in formula V in the organic phase obtained in step (5) is oxidized by hydrogen peroxide, and then allowed to stand for layering to obtain an organic phase containing isoxazolidin.

[0028] The organic solvent is toluene and / or chlorobenzene;

[0029]

[0030] Preferably, in step (1), the first phase transfer catalyst is one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride and benzyltriethylammonium chloride, preferably tetrabutylammonium bromide; more preferably, relative to 1 mole of 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene, the amount of the first transfer catalyst is 0.001 to 0.1 moles, preferably 0.005 to 0.02 moles.

[0031] Preferably, in step (1), the methanethiol salt is one or more of sodium salt, potassium salt, and lithium salt, preferably sodium salt; more preferably, the amount of methanethiol salt used relative to 1 mole of 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene is 1 to 5 moles, preferably 1.15 to 1.25 moles.

[0032] Preferably, in step (1), when 3-nitro-4-cyanotrifluoromethylbenzene is used as the starting material, the temperature of the methyl sulfidation reaction is 0-50°C, preferably 20-30°C; when 3-chloro-4-cyanotrifluoromethylbenzene is used as the starting material, the temperature of the methyl sulfidation reaction is 50-100°C, preferably 70-80°C.

[0033] Preferably, in step (2), the alkoxide is one or more alkali metal salts selected from isopropanol, isobutanol, sec-butanol and tert-butanol, preferably sodium tert-butoxide; more preferably, the amount of the alkoxide used relative to 1 mole of the compound shown in Formula I is 1 to 5 moles, preferably 1.4 to 1.6 moles.

[0034] Preferably, in step (2), the amount of cyclopropyl methyl ketone used is 1 to 5 moles relative to 1 mole of the compound shown in Formula I, more preferably 1.2 to 1.4 moles.

[0035] Preferably, in step (2), the conditions for the addition reaction include: a temperature of 40 to 110°C, preferably 55 to 65°C, and a pressure of -0.095 MPa to atmospheric pressure, preferably -0.095 MPa to -0.05 MPa.

[0036] Preferably, in step (2), the acid used in the acidification treatment is one or more of hydrochloric acid, sulfuric acid and phosphoric acid, preferably sulfuric acid; more preferably, the final pH value of the acidification treatment is 1 to 6, preferably 4 to 6.

[0037] Preferably, in step (2), the addition reaction method includes: adding cyclopropyl methyl ketone dropwise while extracting the light component under negative pressure.

[0038] Preferably, in step (3), the second phase transfer catalyst is one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride and benzyltriethylammonium chloride, preferably tetrabutylammonium bromide; preferably, the amount of the second phase transfer catalyst is 0.001 to 0.5 moles relative to 1 mole of the compound shown in Formula II, preferably 0.01 to 0.05 moles.

[0039] Preferably, in step (3), the acid used in the hydrolysis reaction is one or more of hydrochloric acid, sulfuric acid, and phosphoric acid, preferably sulfuric acid; more preferably, the amount of acid used relative to 1 mole of the compound shown in Formula II is 1 to 5 moles, preferably 1.6 to 1.8 moles; more preferably, the concentration of the acid used in the hydrolysis reaction is 30 to 90% by weight, preferably 55 to 65% by weight.

[0040] Preferably, in step (3), the temperature of the hydrolysis reaction is 60-105℃, more preferably 90-95℃ or 100-105℃.

[0041] Preferably, in step (4), the Lewis acid is one or more of zinc chloride, aluminum chloride, tin chloride, ferric chloride, copper chloride, antimony chloride, nickel sulfate and sodium trifluoromethanesulfonate, preferably zinc chloride; more preferably, the amount of the Lewis acid is 0.01 to 1 mole relative to 1 mole of the compound shown in Formula III, preferably 0.05 to 0.2 moles.

[0042] Preferably, in step (4), the amount of triethyl orthoformate used is 1 to 5 moles relative to 1 mole of the compound shown in Formula III, and more preferably 1.5 to 2.5 moles.

[0043] Preferably, in step (4), the conditions for the enol etherification reaction include: a temperature of 50 to 100°C, preferably 50 to 60°C, and a pressure of -0.095 MPa to atmospheric pressure, preferably -0.095 to -0.085 MPa.

[0044] Preferably, in step (4), the enol etherification reaction system does not contain carboxylic acid.

[0045] Preferably, in step (5), the hydroxylamine salt is hydroxylamine sulfate and / or hydroxylamine hydrochloride, more preferably hydroxylamine sulfate; more preferably, the amount of the hydroxylamine salt is 0.5 to 2 moles relative to 1 mole of the compound shown in Formula IV, preferably 0.5 to 0.6 moles.

[0046] Preferably, in step (5), the third phase transfer catalyst is one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride and benzyltriethylammonium chloride, preferably tetrabutylammonium bromide; more preferably, the amount of the third phase transfer catalyst is 0.001 to 1 mole relative to 1 mole of the compound shown in Formula IV, preferably 0.01 to 0.1 moles.

[0047] Preferably, in step (5), the cyclization reaction temperature is 30–80°C, more preferably 40–50°C.

[0048] Preferably, in step (6), the oxidation catalyst is sodium tungstate; preferably, the amount of the oxidation catalyst is 0.001 to 0.1 moles relative to 1 mole of the compound shown in Formula V, and more preferably 0.001 to 0.01 moles.

[0049] Preferably, in step (6), the fourth phase transfer catalyst is one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride, preferably tetrabutylammonium bromide; more preferably, the amount of the fourth phase transfer catalyst relative to 1 mole of the compound shown in Formula V is 0.001 to 0.5 moles, preferably 0.01 to 0.05 moles.

[0050] Preferably, in step (6), the amount of hydrogen peroxide used is 2.5 to 5.0 moles relative to 1 mole of the compound shown in formula V, and more preferably 3.0 to 3.5 moles.

[0051] Preferably, in step (6), the temperature of the oxidation reaction is 10 to 100°C, and more preferably 35 to 75°C.

[0052] Preferably, the method further includes: (7) post-processing of the product: the organic phase containing isoxazolidin obtained in step (6) is subjected to solvent removal, crystallization, filtration and drying to obtain isoxazolidin solid.

[0053] The synthetic route of the present invention, through the above technical solution, has the following beneficial effects:

[0054] (1) The reaction solvent is singular, which avoids the problems of cross-contamination caused by switching between multiple solvents, multiple solvent recovery equipment, and high energy consumption, and greatly simplifies the process operation.

[0055] (2) Through the new process conditions, the generation of certain impurities is effectively controlled, the reaction selectivity and conversion rate are high, the amount of waste is small, and it is suitable for industrial production.

[0056] (3) The total yield can reach more than 75%, and the product content is greater than 98% (w / w). Detailed Implementation

[0057] The endpoints and any values ​​of the ranges disclosed herein 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.

[0058] This invention provides a method for preparing isoxazoline, the method comprising the following steps:

[0059] (1) Methyl sulfidation reaction: In the presence of a first phase transfer catalyst, an organic solvent and water, 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene are subjected to a methyl sulfidation reaction with a methanethiol salt, and then allowed to stand for separation to obtain an organic phase containing the compound shown in Formula I.

[0060] (2) Addition reaction: In the presence of alkoxide, the compound of formula I in the organic phase obtained in step (1) is subjected to an addition reaction with cyclopropyl methyl ketone, and a light component is extracted. After the reaction is completed, acid is added to the reaction product for acidification treatment, and then the mixture is allowed to stand and separate into layers to obtain an organic phase containing the compound of formula II.

[0061] (3) Hydrolysis reaction: In the presence of a second phase transfer catalyst and acid, the compound shown in formula II in the organic phase obtained in step (2) is hydrolyzed, and then allowed to stand and separate into layers to obtain an organic phase containing the compound shown in formula III.

[0062] (4) Enol etherification reaction: In the presence of Lewis acid, the compound shown in formula III in the organic phase obtained in step (3) is subjected to enol etherification reaction with triethyl orthoformate, and the light component is extracted to obtain an organic phase containing the compound shown in formula IV.

[0063] (5) Cycling reaction: In the presence of a third phase transfer catalyst, hydroxylamine salt and water, the compound shown in formula IV in the organic phase obtained in step (4) undergoes a cyclization reaction, and then is allowed to stand and separate into layers to obtain an organic phase containing the compound shown in formula V.

[0064] (6) Oxidation reaction: In the presence of an oxidation catalyst and a fourth phase transfer catalyst, the compound shown in formula V in the organic phase obtained in step (5) is oxidized by hydrogen peroxide, and then allowed to stand for layering to obtain an organic phase containing isoxazolidin.

[0065] The organic solvent is toluene and / or chlorobenzene;

[0066]

[0067] In this invention, by using toluene or chlorobenzene as the organic solvent, the problems of cross-contamination caused by switching between multiple solvents, multiple solvent recovery devices, and high energy consumption can be avoided, greatly simplifying the process operation.

[0068] According to the present invention, in step (1), the first phase transfer catalyst can be one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride, preferably tetrabutylammonium bromide. The amount of the first transfer catalyst relative to 1 mole of 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene is preferably 0.001 to 0.1 moles, more preferably 0.005 to 0.02 moles.

[0069] According to the present invention, in step (1), the methanethiol salt can be one or more of sodium salt, potassium salt, and lithium salt, preferably sodium salt. The amount of the methanethiol salt is preferably 1 to 5 moles, more preferably 1.15 to 1.25 moles, relative to 1 mole of 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene.

[0070] According to the present invention, in step (1), the methyl sulfidation reaction can be carried out by adding an aqueous solution of methanethiol salt dropwise to an organic solvent solution of 3-nitro-4-cyanotrifluoromethylbenzene or 3-chloro-4-cyanotrifluoromethylbenzene in the presence of a first phase transfer catalyst. Preferably, when 3-nitro-4-cyanotrifluoromethylbenzene is used as the starting material, the temperature of the methyl sulfidation reaction is 0-50°C, preferably 20-30°C; when 3-chloro-4-cyanotrifluoromethylbenzene is used as the starting material, the temperature of the methyl sulfidation reaction is 50-100°C, preferably 70-80°C.

[0071] According to the present invention, in step (2), the alkoxide may be one or more alkali metal salts selected from isopropanol, isobutanol, sec-butanol, and tert-butanol, preferably sodium tert-butoxide. The amount of the alkoxide used relative to 1 mole of the compound represented by Formula I is preferably 1 to 5 moles, more preferably 1.4 to 1.6 moles.

[0072] According to the present invention, in step (2), the amount of cyclopropyl methyl ketone used is preferably 1 to 5 moles, more preferably 1.2 to 1.4 moles, relative to 1 mole of the compound shown in Formula I.

[0073] According to the present invention, in step (2), the conditions for the addition reaction include: a temperature of 40–110°C, preferably 55–65°C, and a pressure of -0.095 MPa to atmospheric pressure, preferably -0.095 MPa to -0.05 MPa. When the organic solvent used is toluene, the pressure is preferably -0.090 to -0.085 MPa; when the organic solvent used is chlorobenzene, the pressure is preferably -0.095 to -0.090 MPa.

[0074] According to a preferred embodiment of the present invention, in step (2), the method of the addition reaction includes: adding cyclopropyl methyl ketone dropwise while extracting the light component under negative pressure.

[0075] Regarding the issue of hydrolysis impurities generated in step (2), EP0705243B1 proposed using an inert gas to apply a slight positive pressure. However, experiments have shown that this approach is ineffective and cannot effectively suppress the side reactions. Through in-depth research, the inventors of this invention discovered that the water in the reaction system does not originate from the external environment but is generated by the dimerization of cyclopropyl methyl ketone under strongly alkaline conditions. This leads to the hydrolysis of the cyano group in the compound shown in Formula I, and the resulting byproduct amide further condenses with the compound shown in Formula II. This generates impurities while releasing two molecules of water, which then continue to react with other compounds shown in Formula I. This chain-like side reaction produces a large number of impurities and significantly reduces the yield.

[0076]

[0077] Through in-depth research, the inventors of this invention discovered that using toluene or chlorobenzene as a solvent and employing a continuous negative pressure extraction method for adding cyclopropyl methyl ketone can effectively control the generation of hydrolysis byproducts and further improve the selectivity of the reaction.

[0078] According to the present invention, in step (2), the acid used in the acidification treatment is one or more of hydrochloric acid, sulfuric acid, and phosphoric acid, preferably sulfuric acid. The concentration of the acid can be, for example, 10-90% by weight, preferably 50-70% by weight. Preferably, the final pH value of the acidification treatment is 1-6, more preferably 4-6.

[0079] According to the present invention, in step (3), the second phase transfer catalyst can be one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride, preferably tetrabutylammonium bromide. The amount of the second phase transfer catalyst relative to 1 mole of the compound shown in Formula II is preferably 0.001 to 0.5 moles, more preferably 0.01 to 0.05 moles.

[0080] According to the present invention, in step (3), the acid used in the hydrolysis reaction can be one or more of hydrochloric acid, sulfuric acid, and phosphoric acid, preferably sulfuric acid. The concentration of the acid can be, for example, 30 to 90% by weight, preferably 55 to 65% by weight. The amount of acid used relative to 1 mole of the compound shown in Formula II is preferably 1 to 5 moles, more preferably 1.6 to 1.8 moles.

[0081] According to the present invention, in step (3), the temperature of the hydrolysis reaction is preferably 60-105°C, more preferably 90-95°C or 100-105°C. Wherein, when toluene is used as the organic solvent, the temperature of the hydrolysis reaction is preferably 90-95°C, and when chlorobenzene is used as the organic solvent, the temperature of the hydrolysis reaction is preferably 100-105°C.

[0082] According to the present invention, in step (4), the Lewis acid can be one or more of zinc chloride, aluminum chloride, tin chloride, ferric chloride, copper chloride, antimony chloride, nickel sulfate, and sodium trifluoromethanesulfonate, preferably zinc chloride. The amount of the Lewis acid used relative to 1 mole of the compound represented by Formula III is preferably 0.01 to 1 mole, more preferably 0.05 to 0.2 moles.

[0083] According to the present invention, in step (4), the amount of triethyl orthoformate used is preferably 1 to 5 moles, more preferably 1.5 to 2.5 moles, relative to 1 mole of the compound shown in Formula III.

[0084] According to the present invention, in step (4), the conditions for the enol etherification reaction include: a temperature of 50 to 100°C, preferably 50 to 60°C, and a pressure of -0.095 MPa to atmospheric pressure, preferably -0.095 to -0.085 MPa.

[0085] In response to the numerous problems with the use of carboxylic acids as solvents in the process reported in CN110128308B, the inventors of this invention unexpectedly discovered that good reaction results can also be obtained by using toluene and / or chlorobenzene as solvents without adding any carboxylic acid components (such as acetic acid). Furthermore, the method of this invention can directly use the toluene or chlorobenzene solution of the compound shown in Formula III obtained in the previous step, avoiding the solvent switching and equipment corrosion problems caused by using acetic acid, and also eliminating the need for equipment to recover acetic acid. Considering all factors, the method of this invention is more economical and more suitable for actual production. Therefore, in some preferred embodiments of this invention, the enol etherification reaction system in step (4) does not contain carboxylic acids.

[0086] According to the present invention, in step (5), the hydroxylamine salt may be, for example, hydroxylamine sulfate and / or hydroxylamine hydrochloride, preferably hydroxylamine sulfate. The amount of the hydroxylamine salt used relative to 1 mole of the compound represented by Formula IV is 0.5 to 2 moles, more preferably 0.5 to 0.6 moles.

[0087] According to the present invention, in step (5), the third phase transfer catalyst can be one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride, preferably tetrabutylammonium bromide. The amount of the third phase transfer catalyst relative to 1 mole of the compound shown in Formula IV is preferably 0.001 to 1 mole, more preferably 0.01 to 0.1 moles.

[0088] According to the present invention, in step (5), the temperature of the cyclization reaction can be 30 to 80°C, preferably 40 to 50°C.

[0089] Through in-depth research and experiments, the inventors of this invention have found that, compared with CN104788272B which uses polar solvents such as ethanol for the reaction, the reaction rate is relatively slow when toluene or chlorobenzene is used as a solvent in step (5) of the synthesis of the compound shown in formula V. However, the addition of a phase transfer catalyst can still achieve a good reaction effect.

[0090] According to the present invention, in step (6), the oxidation catalyst may be, for example, sodium tungstate. The amount of the oxidation catalyst is preferably 0.001 to 0.1 mol relative to 1 mol of the compound represented by Formula V, more preferably 0.001 to 0.01 mol.

[0091] According to the present invention, in step (6), the fourth phase transfer catalyst can be one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride, preferably tetrabutylammonium bromide. The amount of the fourth phase transfer catalyst relative to 1 mole of the compound shown in Formula V is preferably 0.001 to 0.5 moles, more preferably 0.01 to 0.05 moles.

[0092] According to the present invention, in step (6), the amount of hydrogen peroxide used is 2.5 to 5.0 moles, preferably 3.0 to 3.5 moles, relative to 1 mole of the compound represented by formula V. The concentration of the hydrogen peroxide solution used can be 10 to 50% by weight, preferably 25 to 35% by weight.

[0093] According to the present invention, in step (6), the temperature of the oxidation reaction can be 10 to 100°C, preferably 35 to 75°C.

[0094] Through in-depth research and experimentation, the inventors of this invention have discovered that, compared to CN104262278A which uses acetic acid as a solvent, in step (6) of isoxazoline, using toluene or chlorobenzene as a solvent and adding a phase transfer catalyst and an oxidation catalyst can also achieve good reaction results.

[0095] In steps (1) to (6) of the present invention, toluene or chlorobenzene can be used as the reaction solvent. That is, the solvent for the organic phase obtained in steps (1) to (6) of the present invention is toluene or chlorobenzene. Therefore, unlike the existing process which requires frequent solvent switching, the method of the present invention uses a single reaction solvent, avoiding cross-contamination caused by switching multiple solvents, multiple solvent recovery devices, and high energy consumption, and greatly simplifying the process operation.

[0096] According to the present invention, the method may further include: (7) post-processing of the product: the organic phase containing isoxazolidin obtained in step (6) is subjected to solvent removal, crystallization, filtration and drying to obtain isoxazolidin solid.

[0097] According to a particularly preferred embodiment of the present invention, as shown in the following synthetic route, the method for preparing isoxazoline of the present invention includes the following steps:

[0098] (1) Methyl sulfidation reaction: In the presence of a first phase transfer catalyst, an organic solvent solution of 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene is subjected to a methyl sulfidation reaction with an aqueous solution of methanethiol salt, and then allowed to stand for separation to obtain an organic phase containing the compound shown in Formula I.

[0099] (2) Addition reaction: In the presence of alkoxide, cyclopropyl ketone is added dropwise to the organic phase obtained in step (1) to make the compound shown in Formula I undergo an addition reaction with cyclopropyl ketone, and the light component is extracted under negative pressure. After the reaction is completed, acid is added to the reaction product for acidification treatment, and then the mixture is allowed to stand and separate into layers to obtain an organic phase containing the compound shown in Formula II.

[0100] (3) Hydrolysis reaction: In the presence of a second phase transfer catalyst and acid, the compound shown in formula II in the organic phase obtained in step (2) is hydrolyzed, and then allowed to stand and separate into layers to obtain an organic phase containing the compound shown in formula III.

[0101] (4) Enol etherification reaction: In the presence of Lewis acid, the compound shown in formula III in the organic phase obtained in step (3) is subjected to enol etherification reaction with triethyl orthoformate, and the light component is extracted under negative pressure to obtain an organic phase containing the compound shown in formula IV.

[0102] (5) Cycling reaction: In the presence of a third phase transfer catalyst, hydroxylamine salt and water, the compound shown in formula IV in the organic phase obtained in step (4) undergoes a cyclization reaction, and then is allowed to stand and separate into layers to obtain an organic phase containing the compound shown in formula V.

[0103] (6) Oxidation reaction: In the presence of an oxidation catalyst and a fourth phase transfer catalyst, the compound shown in formula V in the organic phase obtained in step (5) is oxidized by hydrogen peroxide, and then allowed to stand for layering to obtain an organic phase containing isoxazolidin.

[0104] The organic solvent is toluene or chlorobenzene;

[0105]

[0106] The present invention will be described in detail below through embodiments. In the present invention, unless otherwise specified, "%" refers to "weight %".

[0107] Example 1

[0108] Step 1 (methyl sulfidation reaction, using 3-nitro-4-cyanotrifluoromethylbenzene as the starting material and toluene as the solvent)

[0109] 0.400 mol of 3-nitro-4-cyanotrifluoromethylbenzene, 0.002 mol of tetrabutylammonium bromide, and 446.7 g of toluene were added to a 1 L four-necked flask equipped with a thermometer, reflux condenser, and mechanical stirrer. Sodium methanethiol aqueous solution (20%, 0.420 mol) was added dropwise over 1 hour at 25–30 °C. After the addition was complete, the reaction was continued at this temperature for another hour until the reaction was complete. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with 80.0 g of water and then refluxed for azeotropic dehydration to obtain 517.0 g of a toluene solution of the compound shown in Formula I (content 16.64% (w / w), yield 99% (based on 3-nitro-4-cyanotrifluoromethylbenzene)).

[0110] Step 2 (addition reaction, toluene as solvent)

[0111] In a 1L four-necked flask equipped with a thermometer, a distillation condenser, and a mechanical stirrer, 517.0g of a toluene solution of the compound shown in Formula I obtained in step 1 and 0.594mol of sodium tert-butoxide were added. The light fraction was slowly and continuously collected under a vacuum of -0.085 MPa and at 55–60°C. Simultaneously, a mixture of 0.515mol of cyclopropyl methyl ketone and 442.3g of toluene was added dropwise, controlling the addition rate to be the same as the collection rate. The addition was completed in approximately 3 hours, and the reaction continued at this temperature for another hour until completion. Under nitrogen protection, the atmosphere was broken to restore atmospheric pressure and the temperature was lowered to 20–25°C. 214.1g of water and 0.317mol of 60% sulfuric acid were added dropwise sequentially. After the addition was complete, the pH of the system was approximately 5. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with 100.0g of water to obtain a toluene solution of the compound shown in Formula II (content 20.53% (w / w), yield 96% (based on the compound shown in Formula I)).

[0112] Step 3 (hydrolysis reaction, toluene as solvent)

[0113] In a 1L four-necked flask equipped with a thermometer, reflux condenser, and mechanical stirrer, 557.9g of a toluene solution of the compound shown in Formula II obtained in step 2, 0.008mol of tetrabutylammonium bromide, and sulfuric acid (60%, 0.646mol) were added. The mixture was refluxed at 90–95°C for 3 hours until the reaction was complete. After standing and separating the layers, the organic phase was washed twice with 200.0g of water and then refluxed for azeotropic dehydration to obtain 523.8g of a toluene solution of the compound shown in Formula III (content 21.72% (w / w), yield 99% (based on the compound shown in Formula II)).

[0114] Step 4 (enol etherification reaction, toluene as solvent)

[0115] 523.8 g of a toluene solution of the compound shown in Formula III obtained in step 3, 0.038 mol of zinc chloride, and 0.753 mol of triethyl orthoformate were added to a 1 L four-necked flask equipped with a thermometer, a distillation condenser, and a mechanical stirrer. The light component was slowly and continuously collected under a vacuum of -0.095 MPa and at 50–55 °C. After 3 h, the reaction was completed, and 420.3 g of toluene was added to obtain 606.5 g of a toluene solution of the compound shown in Formula IV (content 20.91% (w / w), yield 94% (based on the compound shown in Formula III)).

[0116] Step 5 (cyclization reaction, toluene as solvent)

[0117] In a 1L four-necked flask equipped with a thermometer, reflux condenser, and mechanical stirrer, 606.5g of a toluene solution of the compound shown in Formula IV obtained in step 4, 0.195mol of hydroxylamine sulfate, 0.018mol of tetrabutylammonium bromide, and 3.538mol of water were added. The mixture was reacted at 40–45°C for 3 hours until the reaction was complete. After standing and separating the layers, 578.8g of a toluene solution of the compound shown in Formula V was obtained (content 18.81% (w / w), yield 94% (based on the compound shown in Formula IV)).

[0118] Step 6 (Oxidation reaction, toluene as solvent)

[0119] In a 1L four-necked flask equipped with a thermometer, reflux condenser, and mechanical stirrer, 578.8g of a toluene solution of the compound shown in Formula V obtained in step 5, 0.002mol of sodium tungstate, and 0.007mol of tetrabutylammonium bromide were added dropwise over 1 hour at 35–40°C, while gradually raising the temperature to 70–75°C. After the addition was complete, the reaction was continued at 70–75°C for another hour until the reaction was complete. The mixture was allowed to stand and separate into layers to obtain 534.9g of a toluene solution of isoxazoline (content 21.22% (w / w), yield 95% (based on the compound shown in Formula V)).

[0120] After solvent removal, crystallization, filtration and drying, 114.4 g of isoxazoline solid was obtained (content 98.20% (w / w), total yield 78.2% (based on 3-nitro-4-cyanotrifluoromethylbenzene)).

[0121] Example 2

[0122] Isoxazolidin was prepared according to the method of Example 1, except that in step 1, 3-chloro-4-cyanotrifluoromethylbenzene was used instead of 3-nitro-4-cyanotrifluoromethylbenzene as the starting material. Specifically, the method of step 1 is as follows:

[0123] Step 1 (methyl sulfidation reaction, using 3-chloro-4-cyanotrifluoromethylbenzene as the starting material and toluene as the solvent)

[0124] 0.400 mol of 3-chloro-4-cyanotrifluoromethylbenzene, 0.002 mol of tetrabutylammonium bromide, and 446.7 g of toluene were added to a 1 L four-necked flask equipped with a thermometer, reflux condenser, and mechanical stirrer. Sodium methanethiol aqueous solution (20%, 0.420 mol) was added dropwise over 1 hour at 75–80 °C. After the addition was complete, the reaction was continued at this temperature for another hour until the reaction was complete. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with 80.0 g of water and then refluxed for azeotropic dehydration to obtain a toluene solution of 512.7 g of the compound shown in Formula I (content 16.78% (w / w), yield 99% (based on 3-chloro-4-cyanotrifluoromethylbenzene)).

[0125] Finally, 113.9 g of isoxazoline solid was obtained (content 98.19% (w / w), total yield 77.8% (based on 3-nitro-4-cyanotrifluoromethylbenzene)).

[0126] A comparison of Example 2 and Example 1 shows that when using 3-chloro-4-cyanotrifluoromethylbenzene as the starting material, the methyl sulfidation reaction needs to be carried out at a higher temperature.

[0127] Example 3

[0128] Isoxazolidin was prepared according to the method in Example 1, except that chlorobenzene was used instead of toluene as a solvent in steps 1 to 6, and the reflux reaction temperature in step 3 was 100 to 105°C.

[0129] Step 1 yielded 677.7 g of a chlorobenzene solution of the compound shown in Formula I (content 12.69% (w / w), yield 99% (based on 3-nitro-4-cyanotrifluoromethylbenzene)); Step 2 yielded 713.9 g of a chlorobenzene solution of the compound shown in Formula II (content 16.05% (w / w), yield 96% (based on the compound shown in Formula I)); Step 3 yielded 673.7 g of a chlorobenzene solution of the compound shown in Formula III (content 16.89% (w / w), yield 99% (based on the compound shown in Formula II)).

[0130] Finally, 114.6 g of isoxazoline solid was obtained (content 98.03% (w / w), total yield 78.2% (based on 3-nitro-4-cyanotrifluoromethylbenzene)).

[0131] A comparison of Example 3 and Example 1 shows that when chlorobenzene is used instead of toluene as a solvent, the hydrolysis reaction can be carried out at a higher temperature, thereby shortening the reaction time.

[0132] Example 4

[0133] The compound of formula I was prepared according to step 1 of Example 1, except that the solvent and phase transfer catalyst listed in Table 1 were used, and the conversion and selectivity of the reaction are shown in Table 1.

[0134] Table 1

[0135] acetone - 100.00 97.70 Methyl tert-butyl ether - 100.00 87.51 Toluene - 33.60 - Methyl tert-butyl ether Benzyltrimethylammonium chloride 99.10 94.96 Methyl tert-butyl ether Tetrabutylammonium bromide 99.87 99.07 Toluene Benzyltrimethylammonium chloride 100.00 94.02 Toluene Tetrabutylammonium bromide 100.00 99.73 chlorobenzene Tetrabutylammonium bromide 100.00 99.46

[0136] The results in Table 1 show that without a phase transfer catalyst, toluene as a solvent fails to yield the product, and some of the raw materials decompose. Adding a phase transfer catalyst improves the product yield. In particular, the reaction is more efficient with tetrabutylammonium bromide as the phase transfer catalyst than with acetone. Replacing toluene with chlorobenzene yields similar results.

[0137] Example 5

[0138] The compound of formula II was prepared according to step 2 of Example 1, except that the operation methods and conditions in Table 2 below were used, and the conversion and selectivity of the reaction are shown in Table 2.

[0139] Table 2

[0140]

[0141] As shown in Table 2, under normal pressure and at 60°C, the addition of cyclopropyl ketone generates a significant amount of hydrolytic impurities, and a large amount of raw material remains, making complete reaction difficult. At normal pressure extraction, due to the higher temperature of the reaction system, a large amount of hydrolytic impurities are also generated. Under negative pressure extraction, only a small amount of hydrolytic impurities are generated, and the raw material is almost completely converted. Therefore, using toluene as a solvent and employing a continuous negative pressure extraction method for adding cyclopropyl ketone can effectively control the generation of hydrolysis byproducts.

[0142] In addition, when chlorobenzene is used instead of toluene, the reaction effect is similar, but because chlorobenzene has a higher boiling point, the reaction needs to be carried out under a higher vacuum.

[0143] Example 6

[0144] The compound of formula III was prepared according to step 3 of Example 1, except that the solvent, phase transfer catalyst and reaction conditions in Table 3 were used, and the conversion rates of the reaction are shown in Table 3.

[0145] Table 3

[0146]

[0147] *In the table, equivalents represent the molar amount relative to the compound shown in Formula II.

[0148] As shown in Table 3, the reaction was extremely slow even at reflux temperature of 95°C when toluene was used as the solvent and no phase transfer catalyst was added. The reaction rate increased significantly after the addition of the phase transfer catalyst. In particular, when tetrabutylammonium bromide was used as the phase transfer catalyst at a dosage of 0.02 equivalents, the reaction rate at 95°C exceeded that of methyl tert-butyl ether. When chlorobenzene was used instead of toluene, the reaction rate was even faster due to the higher reflux temperature.

[0149] In summary, when using toluene or chlorobenzene as solvents, the reaction rate is slower than that of polar solvents such as methyl tert-butyl ether, but good results can still be achieved by adding a phase transfer catalyst and appropriately increasing the reaction temperature.

[0150] Example 7

[0151] The compound of formula IV was prepared according to step 4 of Example 1, specifically as shown in Table 4. 0.1 equivalents of a Lewis acid catalyst and 2 equivalents of triethyl orthoformate were added to a solution of the compound of formula III in acetic acid, toluene, or chlorobenzene. The reaction was carried out at 50°C, and the light component was continuously collected under a vacuum of -0.095 MPa. Here, equivalents represent the molar amount relative to the compound of formula III. The conversion and selectivity of the reaction are shown in Table 4.

[0152] Table 4

[0153]

[0154] As can be seen from the results in Table 4, although the selectivity and rate of the reaction are slightly inferior to those of the acetic acid system, this method can directly use the toluene or chlorobenzene solution of the compound of Formula III obtained in the previous step, avoiding the solvent switching and equipment corrosion problems caused by using acetic acid, and also eliminating the need for equipment to recover acetic acid. Considering all factors, the method of this invention is more economical and more suitable for actual production.

[0155] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing isoxazoline, characterized in that, The preparation method includes the following steps: (1) Methyl sulfidation reaction: In the presence of a first phase transfer catalyst, an organic solvent and water, 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene are subjected to methyl sulfidation reaction with a methanethiol salt, and then allowed to stand for separation to obtain an organic phase containing the compound shown in Formula I; (2) Addition reaction: In the presence of alkoxide, the compound of formula I in the organic phase obtained in step (1) is added to cyclopropyl methyl ketone and the light component is extracted. After the reaction is completed, acid is added to the reaction product for acidification treatment, and then the mixture is allowed to stand and separate into layers to obtain an organic phase containing the compound of formula II. (3) Hydrolysis reaction: In the presence of a second phase transfer catalyst and acid, the compound shown in formula II in the organic phase obtained in step (2) is hydrolyzed, and then allowed to stand and separate into layers to obtain an organic phase containing the compound shown in formula III. (4) Enol etherification reaction: In the presence of Lewis acid, the compound of formula III in the organic phase obtained in step (3) is subjected to enol etherification reaction with triethyl orthoformate, and the light component is extracted to obtain an organic phase containing the compound of formula IV. (5) Cycling reaction: In the presence of a third phase transfer catalyst, hydroxylamine salt and water, the compound shown in formula IV in the organic phase obtained in step (4) undergoes a cyclization reaction, and then is allowed to stand and separate into layers to obtain an organic phase containing the compound shown in formula V. (6) Oxidation reaction: In the presence of an oxidation catalyst and a fourth phase transfer catalyst, the compound shown in formula V in the organic phase obtained in step (5) is oxidized by hydrogen peroxide, and then allowed to stand for layering to obtain an organic phase containing isoxazolidin. Wherein, the organic solvent is toluene and / or chlorobenzene; in step (2), the method of the addition reaction includes: adding cyclopropyl methyl ketone dropwise while extracting the light component under negative pressure; the acid used in the acidification treatment is one or more of hydrochloric acid, sulfuric acid and phosphoric acid; in step (4), the Lewis acid is one or more of zinc chloride, aluminum chloride, tin chloride, ferric chloride, copper chloride and nickel sulfate; the conditions for the enol etherification reaction include: temperature 50~100℃, pressure -0.095MPa to atmospheric pressure; In step (1), the first phase transfer catalyst is one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride; In step (3), the second phase transfer catalyst is one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride; The third phase transfer catalyst is one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride; The fourth phase transfer catalyst is one or more of tetrabutylammonium bromide, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride; 。 2. The preparation method according to claim 1, wherein, The amount of the first transfer catalyst is 0.001 to 0.1 mol relative to 1 mol of 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene.

3. The preparation method according to claim 1, wherein, In step (1), the first phase transfer catalyst is tetrabutylammonium bromide; and / or, relative to 1 mole of 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene, the amount of the first transfer catalyst is 0.005~0.02 moles.

4. The preparation method according to claim 1, wherein, The methanethiol salt is one or more of sodium, potassium, and lithium salts; and / or, relative to 1 mole of 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene, the amount of the methanethiol salt is 1 to 5 moles.

5. The preparation method according to claim 4, wherein, The methanethiol salt is a sodium salt; and / or, relative to 1 mole of 3-nitro-4-cyanotrifluoromethylbenzene and / or 3-chloro-4-cyanotrifluoromethylbenzene, the amount of the methanethiol salt is 1.15 to 1.25 moles.

6. The preparation method according to claim 1, wherein, When 3-nitro-4-cyanotrifluoromethylbenzene is used as the starting material, the temperature of the methyl sulfidation reaction is 0~50℃; when 3-chloro-4-cyanotrifluoromethylbenzene is used as the starting material, the temperature of the methyl sulfidation reaction is 50~100℃.

7. The preparation method according to claim 6, wherein, When 3-nitro-4-cyanotrifluoromethylbenzene is used as the starting material, the temperature of the methyl sulfidation reaction is 20~30℃; when 3-chloro-4-cyanotrifluoromethylbenzene is used as the starting material, the temperature of the methyl sulfidation reaction is 70~80℃.

8. The preparation method according to claim 1, wherein, In step (2), the alkoxide is one or more alkali metal salts selected from isopropanol, isobutanol, sec-butanol and tert-butanol; and / or, the amount of the alkoxide used is 1 to 5 moles relative to 1 mole of the compound shown in Formula I.

9. The preparation method according to claim 8, wherein, In step (2), the alkoxide is sodium tert-butoxide; and / or, the amount of the alkoxide is 1.4 to 1.6 moles relative to 1 mole of the compound shown in Formula I.

10. The preparation method according to claim 1, wherein, The amount of cyclopropyl methyl ketone used is 1 to 5 moles relative to 1 mole of the compound shown in Formula I; And / or, the conditions for addition reactions include: a temperature of 40~110℃ and a pressure of -0.095MPa to atmospheric pressure.

11. The preparation method according to claim 10, wherein, The amount of cyclopropyl methyl ketone used is 1.2 to 1.4 mol relative to 1 mol of the compound shown in Formula I; And / or, the conditions for the addition reaction include: a temperature of 55~65℃ and a pressure of -0.095MPa to -0.05MPa.

12. The preparation method according to claim 1, wherein, The final pH value of the acidification treatment is 1~6.

13. The preparation method according to claim 1, wherein, The acid used in the acidification treatment is sulfuric acid; and / or, the final pH value of the acidification treatment is 4 to 6.

14. The preparation method according to claim 1, wherein, The amount of the second phase transfer catalyst is 0.001 to 0.5 mol relative to 1 mol of the compound shown in Formula II.

15. The preparation method according to claim 1, wherein, In step (3), the second phase transfer catalyst is tetrabutylammonium bromide; and / or, relative to 1 mole of the compound shown in Formula II, the amount of the second phase transfer catalyst is 0.01 to 0.05 moles.

16. The preparation method according to claim 1, wherein, The acid used in the hydrolysis reaction is one or more of hydrochloric acid, sulfuric acid, and phosphoric acid; and / or, the amount of acid used is 1 to 5 moles relative to 1 mole of the compound shown in Formula II; and / or, the concentration of the acid used in the hydrolysis reaction is 30 to 90% by weight. And / or, the hydrolysis reaction temperature is 60~105℃.

17. The preparation method according to claim 16, wherein, The acid used in the hydrolysis reaction is sulfuric acid; and / or, the amount of acid used is 1.6 to 1.8 moles relative to 1 mole of the compound shown in Formula II; and / or, the concentration of the acid used in the hydrolysis reaction is 55 to 65% by weight. And / or, the hydrolysis reaction temperature is 90~95℃ or 100~105℃.

18. The preparation method according to claim 1, wherein, The amount of the Lewis acid is 0.01 to 1 mole relative to 1 mole of the compound represented by Formula III; And / or, relative to 1 mole of the compound shown in Formula III, the amount of triethyl orthoformate is 1 to 5 moles.

19. The preparation method according to claim 1, wherein, In step (4), the Lewis acid is zinc chloride; and / or, relative to 1 mole of the compound represented by formula III, the amount of the Lewis acid is 0.05 to 0.2 moles; And / or, relative to 1 mole of the compound shown in Formula III, the amount of triethyl orthoformate is 1.5 to 2.5 moles; And / or, the conditions for enol etherification reaction include: a temperature of 50~60℃ and a pressure of -0.095 to -0.085 MPa.

20. The preparation method according to claim 1, wherein, In step (5), the hydroxylamine salt is hydroxylamine sulfate and / or hydroxylamine hydrochloride; and / or, relative to 1 mole of the compound shown in Formula IV, the amount of the hydroxylamine salt is 0.5 to 2 moles.

21. The preparation method according to claim 20, wherein, In step (5), the hydroxylamine salt is hydroxylamine sulfate; and / or, the amount of the hydroxylamine salt is 0.5 to 0.6 moles relative to 1 mole of the compound shown in Formula IV.

22. The preparation method according to claim 1, wherein, The amount of the third phase transfer catalyst is 0.001 to 1 mole relative to 1 mole of the compound shown in Formula IV; And / or, the cyclization reaction temperature is 30~80℃.

23. The preparation method according to claim 1, wherein, The third phase transfer catalyst is tetrabutylammonium bromide; and / or, relative to 1 mole of the compound shown in Formula IV, the amount of the third phase transfer catalyst is 0.01 to 0.1 moles; And / or, the cyclization reaction temperature is 40~50℃.

24. The preparation method according to claim 1, wherein, In step (6), the oxidation catalyst is sodium tungstate; and / or, the amount of the oxidation catalyst is 0.001 to 0.1 moles relative to 1 mole of the compound shown in Formula V.

25. The preparation method according to claim 24, wherein, The amount of the oxidation catalyst is 0.001 to 0.01 moles relative to 1 mole of the compound shown in Formula V.

26. The preparation method according to claim 1, wherein, The amount of the fourth phase transfer catalyst is 0.001 to 0.5 mol relative to 1 mol of the compound shown in Formula V; And / or, relative to 1 mole of the compound shown in Formula V, the amount of hydrogen peroxide is 2.5 to 5.0 moles; And / or, the oxidation reaction temperature is 10~100℃.

27. The preparation method according to claim 1, wherein, The fourth phase transfer catalyst is tetrabutylammonium bromide; and / or, relative to 1 mole of the compound shown in Formula V, the amount of the fourth phase transfer catalyst is 0.01 to 0.05 moles; And / or, relative to 1 mole of the compound shown in Formula V, the amount of hydrogen peroxide is 3.0 to 3.5 moles; And / or, the oxidation reaction temperature is 35~75℃.

28. The preparation method according to any one of claims 1-27, wherein, The method also includes: (7) post-processing of the product: the organic phase containing isoxazolidin obtained in step (6) is desolventized, crystallized, filtered and dried to obtain isoxazolidin solid.

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