Preparation method of 3-(4, 5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl) benzoic acid

Abstract

The present invention relates to the technical field of herbicides, and discloses a 3-(4, 5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl) benzoic acid preparation method, which comprises: 1) carrying out an acetylation reaction on a compound represented by a formula I and an acetylation reagent in the presence of a first solvent and a Lewis acid to obtain a compound represented by a formula VIII; 2) in the presence of a second solvent and transition metal acetate, carrying out first oxidation reaction on the compound as shown in the formula VIII and a first oxidant to obtain a reaction product containing a compound as shown in a formula X; and 3) in the presence of tungstate, the reaction product containing the compound as shown in the formula X and a second oxidizing agent are subjected to a second oxidation reaction, a compound with a structure as shown in a formula IV is obtained, the first oxidizing agent is oxygen, and the second oxidizing agent is hydrogen peroxide. The method disclosed by the invention is high in reaction safety, simple to operate, less in three wastes, low in raw material cost and high in selectivity and conversion rate. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of herbicides, and in particular to a method for preparing 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid. Background Art

[0002] TOPRAMEZONE, a pyrazolone herbicide developed by BASF of Germany, is a parahydroxyphenylpyruvate dioxygenase (HPPD) inhibitor. It is primarily used to control weeds in corn fields, including common and certain broadleaf weeds. It achieves a 100% control rate against hemp, sedge, cocklebur, and foxtail grass, and has no phytotoxicity to corn.

[0003] The existing method for preparing fenpyrazone is to use the compound of the structure shown in formula I as the raw material, bromination and hydrogen peroxide oxidation to obtain the compound of the structure shown in formula III, which is then divided into a carbon insertion method and a rearrangement method.

[0004] For the carbon insertion method, the compound of the structure shown in Formula III reacts with carbon monoxide and 1-methyl-5-hydroxypyrazole in one step to obtain fenpyraclostrobin, which has a high yield and less three wastes, but requires the use of precious metal catalysts, which are expensive and difficult to recycle.

[0005] In the rearrangement method, the compound represented by Formula III is first coupled with carbon dioxide to produce the compound represented by Formula IV, which is then chlorinated to produce the compound represented by Formula V. This is then esterified with 1-methyl-5-hydroxypyrazole and then subjected to a transposition reaction to obtain fenpyrazone. While the chlorination, esterification, and transposition steps require simple equipment, resulting in low raw material costs and high yields, the coupling step requires the use of organometallic compounds such as alkyl lithium and Grignard reagents, which carries high reaction risks and low yields.

[0006]

[0007] In addition, the bromination step of the compound of formula I is costly and highly polluting. Therefore, a new method for preparing the compound of formula IV from the compound of formula I is urgently needed to meet the needs of industrial production. Summary of the Invention

[0008] The present invention provides a novel method for preparing 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid (a compound represented by Formula IV). The method uses the compound represented by Formula I as a starting material and obtains the target product through a one-step acetylation and two-step oxidation reaction. This method avoids the use of precious metal catalysts, bromination reagents, and organometallic compounds, and features high reaction safety, simple operation, minimal waste, low raw material costs, and high selectivity and conversion rates. Furthermore, the reduced amount of hydrogen peroxide used reduces the water content of the solvent, thereby reducing energy consumption for solvent recovery.

[0009] To find a method for preparing a compound of formula IV from a compound of formula I, the inventors tried various reaction routes, such as the following:

[0010]

[0011] For route 1, hydrogen peroxide oxidation can yield the compound of formula VI, but the acylation reaction does not yield the compound of formula VII.

[0012] In route 2, a compound of formula VII can be obtained, but it is difficult to be oxidized to a compound of formula IV by oxygen, and the conversion rate and selectivity are poor.

[0013] When using Route 3, the inventors of the present invention unexpectedly discovered that using oxygen to oxidize the compound of the structure represented by Formula VIII not only oxidizes the acetyl group to a carboxyl group, but also oxidizes the methylthio group to a sulfoxide (i.e., the compound of Formula X), with high conversion rate and selectivity. Furthermore, the amount of hydrogen peroxide used in the subsequent steps can be halved, and the water content of the solvent is also reduced, thereby reducing the energy consumption for solvent recovery.

[0014] Therefore, the present invention provides a method for preparing 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid, wherein the method comprises the following steps:

[0015] 1) in the presence of a first solvent, acetylation reaction is carried out with an acetylating agent under the catalysis of a Lewis acid to obtain a compound represented by formula VIII;

[0016] 2) in the presence of a second solvent, subjecting the compound represented by the structure of Formula VIII to a first oxidation reaction with a first oxidant under the catalysis of a transition metal acetate to obtain a reaction product comprising a compound represented by the structure of Formula X;

[0017] 3) Under the catalysis of tungstate, the reaction product containing the compound of the structure represented by formula X is subjected to a second oxidation reaction with a second oxidant to obtain a compound of the structure represented by formula IV.

[0018]

[0019] Wherein, the first oxidant is oxygen, and the second oxidant is hydrogen peroxide.

[0020] Preferably, the first solvent is a haloalkane, more preferably dichloromethane and / or 1,2-dichloroethane, more preferably dichloromethane.

[0021] Preferably, the amount of the first solvent used is 5-15 times by weight, more preferably 8-10 times by weight, of the compound having the structure represented by Formula I.

[0022] Preferably, the Lewis acid is one or more of aluminum chloride, ferric chloride and zinc chloride, more preferably aluminum chloride.

[0023] Preferably, the amount of the Lewis acid used is 1-5 moles, more preferably 1.05-1.15 moles, relative to 1 mole of the compound of the structure represented by Formula I.

[0024] Preferably, the acetylating agent is acetyl chloride.

[0025] Preferably, the amount of the acetylating agent used is 1-5 moles, more preferably 1.05-1.15 moles, relative to 1 mole of the compound of the structure represented by Formula I.

[0026] Preferably, the conditions for the acetylation reaction include: a reaction temperature of 20-80° C., preferably 30-40° C., and a reaction time of 2-10 h, preferably 2-5 h.

[0027] Preferably, the second solvent is one or more of formic acid, acetic acid, tert-butanol and ethanol, more preferably acetic acid.

[0028] Preferably, the amount of the second solvent used is 3-10 times by weight, more preferably 5-9 times by weight, of the compound of the structure represented by Formula VIII.

[0029] Preferably, the transition metal acetate is one or more of manganese acetate, cobalt acetate, nickel acetate and copper acetate, more preferably manganese acetate;

[0030] Preferably, the amount of the transition metal acetate used is 0.001-1 mole, more preferably 0.05-0.15 mole, relative to 1 mole of the compound represented by formula VIII.

[0031] Preferably, the first oxidation reaction is also carried out in the presence of a co-catalyst, which is a bromide salt, more preferably sodium bromide.

[0032] Preferably, the amount of the co-catalyst used is 0.001-1 mole, more preferably 0.005-0.01 mole, relative to 1 mole of the compound represented by formula VIII.

[0033] Preferably, the volume fraction of oxygen is 21-100%, more preferably pure oxygen;

[0034] Preferably, the conditions of the first oxidation reaction include: reaction temperature of 90-150° C., preferably 110-130° C., reaction pressure of 1-20 bar, preferably 4-6 bar, and reaction time of 1-5 h, preferably 1.5-2.5 h.

[0035] Preferably, the tungstate is sodium tungstate and / or potassium tungstate.

[0036] Preferably, the amount of the tungstate used is 0.001-1 mole, more preferably 0.02-0.05 mole, relative to 1 mole of the compound of formula X.

[0037] Preferably, the amount of the second oxidant used is 1-5 moles, more preferably 1.1-1.3 moles, relative to 1 mole of the compound represented by formula X.

[0038] Preferably, the conditions of the second oxidation reaction include: reaction temperature of 10-80°C, preferably 60-70°C, and reaction time of 2-10h, preferably 2-5h.

[0039] Preferably, the reaction product of the second oxidation reaction is subjected to crystallization by cooling, filtration, and drying to obtain a compound having a structure shown in Formula IV.

[0040] Through the above technical solution, the present invention provides a novel method for preparing 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid (a compound represented by Formula IV). This method uses the compound represented by Formula I as a raw material and obtains the target product through a one-step acetylation and two-step oxidation reaction. This method avoids the use of precious metal catalysts, bromination reagents, and organometallic compounds, and offers high reaction safety, simple operation, minimal waste, low raw material costs, and high selectivity and conversion rates. Furthermore, the reduced amount of hydrogen peroxide used reduces the water content of the solvent, thereby reducing energy consumption for solvent recovery. DETAILED DESCRIPTION

[0041] The endpoints of the ranges and any values ​​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 endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0042] According to the present invention, a method for preparing 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid is provided, wherein the method comprises the following steps:

[0043] 1) in the presence of a first solvent, acetylation reaction is carried out with an acetylating agent under the catalysis of a Lewis acid to obtain a compound represented by formula VIII;

[0044] 2) in the presence of a second solvent, subjecting the compound represented by the structure of Formula VIII to a first oxidation reaction with a first oxidant under the catalysis of a transition metal acetate to obtain a reaction product comprising a compound represented by the structure of Formula X;

[0045] 3) Under the catalysis of tungstate, the reaction product containing the compound of the structure represented by formula X is subjected to a second oxidation reaction with a second oxidant to obtain a compound of the structure represented by formula IV.

[0046]

[0047] Wherein, the first oxidant is oxygen, and the second oxidant is hydrogen peroxide.

[0048] The present invention is described below in steps.

[0049] Acetylation reaction

[0050] According to the present invention, in step 1), in the presence of a first solvent, the compound of formula I is subjected to an acetylation reaction with an acetylating agent under the catalysis of a Lewis acid to obtain a compound of formula VIII.

[0051] According to the present invention, preferably, the first solvent is a haloalkane; more preferably, the first solvent is dichloromethane and / or 1,2-dichloroethane; particularly preferably, the first solvent is dichloromethane.

[0052] The amount of the first solvent can be selected based on the weight of the compound of Formula I, as long as it can effectively dissolve the compound of Formula I. For example, the amount of the first solvent is 5-15 times the weight of the compound of Formula I; preferably, the amount of the first solvent is 8-10 times the weight of the compound of Formula I, for example, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, etc., and ranges consisting of any two of the above values.

[0053] According to the present invention, preferably, the Lewis acid is one or more of aluminum chloride, ferric chloride and zinc chloride.

[0054] As described later, when the Lewis acid is aluminum chloride, the conversion rate and selectivity of the acetylation reaction are significantly improved. Therefore, in the present invention, the Lewis acid is particularly preferably aluminum chloride.

[0055] According to the present invention, the amount of the Lewis acid can be selected according to the compound of the structure shown in Formula I. Preferably, the amount of the Lewis acid is 1-5 moles relative to 1 mole of the compound of the structure shown in Formula I; more preferably, the amount of the Lewis acid is 1.05-1.15 moles relative to 1 mole of the compound of the structure shown in Formula I.

[0056] Preferably, the acetylating agent is acetyl chloride.

[0057] According to the present invention, the amount of the acetylating agent can be selected according to the compound of the structure shown in Formula I. Preferably, the amount of the acetylating agent is 1-5 moles relative to 1 mole of the compound of the structure shown in Formula I; More preferably, the amount of the acetylating agent is 1.05-1.15 moles relative to 1 mole of the compound of the structure shown in Formula I, for example, 1.02 moles, 1.05 moles, 1.08 moles, 1.1 moles, 1.15 moles, 1.2 moles, 1.3 moles, 1.35 moles, 1.4 moles, 1.5 moles. mol, 3.4 mol, 3.5 mol, 3.6 mol, 3.7 mol, 3.8 mol, 3.9 mol, 4.0 mol, 4.3 mol, 4.5 mol, 5.0 mol, etc., and the range formed by any two of the above values.

[0058] According to the present invention, preferably, the acetylation reaction conditions include: a reaction temperature of 20-80°C and a reaction time of 2-10 hours; more preferably, the acetylation reaction conditions include: a reaction temperature of 30-40°C and a reaction time of 2-5 hours. Here, the acetylation reaction time includes the dropwise addition time and the holding time when dropwise addition is performed.

[0059] In a preferred embodiment of the present invention, the acetylation reaction time includes the dropping time and the insulation time. The dropping time is the time for dropping acetyl chloride and the dichloromethane solution of the compound represented by formula I, respectively. The dropping time is generally 0.5-2h, and the insulation time is generally 0.5-3h.

[0060] According to the present invention, after the acylation reaction is completed, the conventional refining method in the art can be used for purification. Preferably, after the acylation reaction is completed, water (for example, the molar equivalent of water is 25-35 eq. relative to the compound represented by the structure of Formula I) is added for extraction, and the solvent is removed from the organic phase to obtain the compound represented by the structure of Formula VIII, which can be directly used in the next reaction.

[0061] First oxidation reaction

[0062] In step 2) of the present invention, in the presence of a second solvent, the compound represented by formula VIII is subjected to a first oxidation reaction with a first oxidant under the catalysis of a transition metal acetate to obtain a reaction product containing a compound represented by formula X.

[0063] According to the present invention, the second solvent can be various solvents commonly used in oxidation reactions in the art. Preferably, the second solvent is one or more of formic acid, acetic acid, tert-butanol and ethanol; more preferably, the second solvent is acetic acid.

[0064] The amount of the second solvent can be selected according to the weight of the compound of the structure represented by Formula VIII. For example, the amount of the second solvent is 3-10 times the weight of the compound of the structure represented by Formula VIII. Preferably, the amount of the second solvent is 5-9 times the weight of the compound of the structure represented by Formula VIII, for example, it can be 3 times the weight, 4 times the weight, 5 times the weight, 6 times the weight, 7 times the weight, 8 times the weight, 9 times the weight, 10 times the weight, etc., and the range formed by any two of the above values.

[0065] According to the present invention, preferably, the transition metal acetate is one or more of manganese acetate, cobalt acetate, nickel acetate and copper acetate; more preferably, the transition metal acetate is manganese acetate.

[0066] According to the present invention, the amount of the transition metal acetate can be selected according to the amount of the compound of the structure represented by formula VIII. Preferably, the amount of the transition metal acetate is 0.001-1 mole relative to 1 mole of the compound of the structure represented by formula VIII; more preferably, the amount of the transition metal acetate is 0.05-0.15 mole relative to 1 mole of the compound of the structure represented by formula VIII, for example, it can be 0.001 mole, 0.005 mole, 0.01 mole, 0.03 mole, 0.05 mole, 0.07 mole, 0.08 mole, 0.1 mole, 0.13 mole, 0.15 mole, 0.15 mole, 0.2 mole, 0.3 mole, 0.4 mole, 0.5 mole, 0.6 mole, 0.7 mole, 0.8 mole, 0.9 mole, 1 mole, etc., and the range formed by any two of the above values.

[0067] In a preferred embodiment of the present invention, the first oxidation reaction is further carried out in the presence of a co-catalyst, and the co-catalyst is a bromide salt, for example, a salt having bromide ions such as sodium bromide.

[0068] When a co-catalyst is used, the amount of the co-catalyst can be selected based on the amount of the compound of formula VIII. Preferably, the amount of the co-catalyst is 0.001-1 mole per 1 mole of the compound of formula VIII; more preferably, the amount of the co-catalyst is 0.005-0.01 mole per 1 mole of the compound of formula VIII. By using a co-catalyst, the reaction time can be significantly reduced when the catalyst is the same.

[0069] Specific examples of the amount of the co-catalyst used relative to 1 mole of the compound represented by formula VIII include: 0.001 mole, 0.005 mole, 0.006 mole, 0.007 mole, 0.008 mole, 0.009 mole, 0.01 mole, 0.03 mole, 0.05 mole, 0.07 mole, 0.08 mole, 0.1 mole, 0.13 mole, 0.15 mole, 0.15 mole, 0.2 mole, 0.3 mole, 0.4 mole, 0.5 mole, 0.6 mole, 0.7 mole, 0.8 mole, 0.9 mole, 1 mole, etc., and the range formed by any two of the above values.

[0070] In the present invention, the volume fraction of oxygen may be 21-100%, preferably pure oxygen.

[0071] According to the present invention, preferably, the conditions of the first oxidation reaction include: reaction temperature of 90-150°C, reaction pressure of 1-20 bar, and reaction time of 1-5h; more preferably, the conditions of the first oxidation reaction include: reaction temperature of 110-130°C, reaction pressure of 4-6 bar, and reaction time of 1.5-2.5h.

[0072] Examples of the reaction temperature include 90° C., 100° C., 110° C., 120° C., 130° C., 140° C., and 150° C., and ranges consisting of any two of the above values.

[0073] Examples of the reaction time include 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 1.5 h, and the like, and ranges consisting of any two of the above values.

[0074] Examples of the reaction pressure include 2 bar, 3 bar, 4 bar, 5 bar, 6 bar, 7 bar, 8 bar, 10 bar, 12 bar, 15 bar, 20 bar, and the like, and a range formed by any two of the above values.

[0075] According to the present invention, after the second oxidation reaction is completed, the solvent can be removed before the next reaction, or the second oxidation reaction product can be directly used for the next reaction.

[0076] Second oxidation reaction

[0077] In step 3) of the present invention, the reaction product containing the compound having the structure represented by formula X is subjected to a second oxidation reaction with a second oxidant under the catalysis of tungstate to obtain a compound having the structure represented by formula IV.

[0078] According to the present invention, preferably, the tungstate is sodium tungstate and / or potassium tungstate.

[0079] According to the present invention, the amount of the tungstate can be selected according to the compound of the structure shown in Formula X. Preferably, the amount of the tungstate is 0.001-1 mol relative to 1 mol of the compound of the structure shown in Formula X; more preferably, the amount of the tungstate is 0.02-0.05 mol relative to 1 mol of the compound of the structure shown in Formula X, for example, 0.001 mol, 0.005 mol, 0.006 mol, 0.007 mol, 0.008 mol, 0.009 mol, 0.01 mol, 0.02 mol, 0.03 mol, 0.05 mol, 0.07 mol, 0.08 mol, 0.1 mol, 0.13 mol, 0.15 mol, 0.15 mol, 0.2 mol, 0.3 mol, 0.4 mol, 0.5 mol, 0.6 mol, 0.7 mol, 0.8 mol, 0.9 mol, 1 mol, etc., and the range consisting of any two of the above values.

[0080] According to the present invention, the amount of the second oxidant can be selected according to the compound of the structure shown in formula X. Preferably, the amount of the second oxidant is 1-5 moles relative to 1 mole of the compound of the structure shown in formula X; more preferably, the amount of the second oxidant is 1.1-1.3 moles relative to 1 mole of the compound of the structure shown in formula X, for example, 1.02 moles, 1.05 moles, 1.08 moles, 1.1 moles, 1.15 moles, 1.2 moles, 1.3 moles, 1.35 moles, 1.4 moles, 1.5 moles. , 1.6 mole, 1.7 mole, 1.8 mole, 1.9 mole, 2.0 mole, 2.1 mole, 2.2 mole, 2.3 mole, 2.4 mole, 2.5 mole, 2.6 mole, 2.7 mole, 2.8 mole, 2.9 mole, 3.0 mole, 3.1 mole, 3.2 mole, 3.3 mole, 3.4 mole, 3.5 mole, 3.6 mole, 3.7 mole, 3.8 mole, 3.9 mole, 4.0 mole, 4.3 mole, 4.5 mole, 5.0 mole, etc., and the range formed by any two of the above values.

[0081] According to the present invention, preferably, the conditions for the second oxidation reaction include: a reaction temperature of 10-80°C and a reaction time of 2-10 hours; more preferably, the conditions for the second oxidation reaction include: a reaction temperature of 60-70°C and a reaction time of 2-5 hours. Here, the second oxidation reaction time, when dropwise addition is present, includes the dropwise addition time and the holding time.

[0082] According to the present invention, after the second oxidation reaction is completed, the conventional refining method in the field can be used for purification. Preferably, after the second oxidation reaction is completed, the reaction product of the second oxidation reaction is subjected to cooling crystallization (the temperature of cooling crystallization can be, for example, -10 to 20°C, preferably 0-5°C), filtered, and dried to obtain a compound with a structure shown in Formula IV.

[0083] The present invention provides a method for preparing 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid (a compound of Formula IV). This method uses the compound of Formula I as a raw material and obtains the target product through a one-step acetylation and two-step oxidation reaction. This method avoids the use of precious metal catalysts, bromination reagents, and organometallic compounds, and offers high reaction safety, simple operation, minimal waste, low raw material costs, and high selectivity and conversion rates. Furthermore, the reduced amount of hydrogen peroxide used reduces the water content of the solvent, thereby reducing energy consumption for solvent recovery.

[0084] Moreover, in step 1), the next reaction can be carried out by simple extraction and concentration, the reaction product of step 2) can be directly used in step 3), and step 3) can simply obtain the target product in high yield and high purity by cooling crystallization. The operation is very simple and suitable for industrialization.

[0085] The present invention will be described in detail below through examples, but the present invention is not limited to the following embodiments.

[0086] Example 1

[0087] 1) Into a 2 L four-necked flask equipped with a thermometer, a reflux condenser, and a mechanical stirrer, 59.3 g (0.440 mol) of 99% (w / w) aluminum chloride and 377.5 g (4.400 mol) of dichloromethane (99 wt%) were added dropwise at 25-30° C. over 0.5 h, and the mixture was kept warm for 0.5 h. Then, 83.8 g (0.400 mol) of the compound represented by the structure of formula I (99 wt%) and 377.5 g (4.400 mol) of dichloromethane (99 wt%) were added dropwise at 30-35°C over 0.5 h. After the addition was completed, the mixture was kept warm for 0.5 h. Then, the temperature was controlled at 25-30°C, and 216.2 g (12.000 mol) of water was added dropwise over 2 h. The mixture was allowed to stand for stratification and the aqueous phase was discarded to obtain 849.0 g of a dichloromethane solution of the compound represented by formula VIII with a content of 11.18% (W / W) and a reaction yield of 95.2% (based on the compound of formula I).

[0088] 2) Into a 2 L four-necked flask equipped with a thermometer, a reflux condenser, and a mechanical stirrer was placed 849.0 g (0.381 mol) of a 11.18% (w / w) dichloromethane solution of the compound of formula VIII. The solution was distilled to dryness, and 716.0 g (11.805 mol) of acetic acid (99 wt%) was added to dissolve the solution. The solution was then transferred to a 1 L autoclave, and 6.7 g (0.038 mol) of manganese acetate (99 wt%) was added. The autoclave was then purged with oxygen three times. The temperature was raised to 120° C. and the pressure was increased to 5 bar. The reaction was maintained at this temperature for 2 h, then cooled to room temperature and vented to obtain 846.1 g of an acetic acid solution of the compound of formula X with a content of 11.02% (w / w). The reaction yield was 91.6% (based on the compound of formula VIII).

[0089] 3) Into a 2 L four-necked flask equipped with a thermometer, a reflux condenser, and a mechanical stirrer were added 846.1 g (0.349 mol) of an 11.02% (w / w) solution of the compound of formula X in acetic acid and 4.1 g (0.014 mol) of sodium tungstate (99 wt%). 43.5 g (0.384 mol) of 30% hydrogen peroxide were added dropwise at 65-70°C over 0.5 h. The mixture was incubated for 0.5 h to obtain 885.5 g of a 10.96% (w / w) solution of the compound of formula IV in acetic acid. The reaction yield was 98.2% (based on the compound of formula X). The mixture was slowly cooled to 0°C over 3 h, filtered and dried to obtain 93.9 g of 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid (compound of formula IV) as a solid with a content of 98.21% (W / W) and an isolated yield of 81.4% (based on the compound of formula I).

[0090] Example 2

[0091] 1) In a 2 L four-necked flask equipped with a thermometer, reflux condenser and mechanical stirring, add 74.1 g (0.550 mol) of 99% (w / w) aluminum chloride and 499.7 g (5.000 mol) of 99% 1,2-dichloroethane. Add 43.6 g (0.550 mol) of 99% acetyl chloride dropwise at 25-30°C over 0.5 h. Incubate for 0.5 h after addition. Then, 104.7 g (0.500 mol) of 99% of the compound of formula I and 499.7 g (5.000 mol) of 99% 1,2-dichloroethane solution were added dropwise at 30-35°C over 0.5 h. After the addition was completed, the mixture was kept warm for 0.5 h. Then, the temperature was controlled at 25-30°C, and 270.3 g (15.000 mol) of water was added dropwise over 2 h. The mixture was allowed to stand for stratification, and the aqueous phase was discarded to obtain 1116.5 g of a 1,2-dichloroethane solution of the compound of formula VIII with a content of 10.59% (W / W) and a reaction yield of 94.8% (based on the compound of formula I).

[0092] 2) Into a 2 L four-necked flask equipped with a thermometer, a reflux condenser, and a mechanical stirrer, was placed 1116.5 g (0.474 mol) of a 10.59% (w / w) solution of the compound of formula VIII in 1,2-dichloroethane. The solution was distilled to dryness, and 891.3 g (14.694 mol) of 99% acetic acid was added for dissolution. The solution was then transferred to a 2 L autoclave, and 16.6 g (0.095 mol) of 99% manganese acetate was added. The reaction was replaced with oxygen three times, and the temperature was raised to 120° C. and oxygen was introduced to 5 bar. The reaction was maintained at this temperature for 1.5 h, then cooled to room temperature and vented to obtain 1062.5 g of a 10.95% (w / w) solution of the compound of formula X in acetic acid. The reaction yield was 91.8% (based on the compound of formula VIII).

[0093] 3) Into a 2 L four-necked flask equipped with a thermometer, a reflux condenser, and a mechanical stirrer were added 1062.5 g (0.435 mol) of a 10.95% (w / w) solution of the compound of formula X in acetic acid and 5.2 g (0.017 mol) of 99% sodium tungstate. 54.3 g (0.479 mol) of 30% hydrogen peroxide were added dropwise at 65-70°C over 0.5 h. The mixture was incubated for 0.5 h to obtain 1112.6 g of a 10.86% (w / w) solution of the compound of formula IV in acetic acid. The reaction yield was 98.0% (based on the compound of formula X). The mixture was slowly cooled to 0°C over 3 h, filtered and dried to obtain 116.9 g of 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid (compound of formula IV) as a solid with a content of 98.16% (W / W) and an isolated yield of 81.0% (based on the compound of formula I).

[0094] Example 3

[0095] 1) In a 2 L four-necked flask equipped with a thermometer, reflux condenser and mechanical stirring, 66.7 g (0.495 mol) of 99% (w / w) aluminum chloride and 424.7 g (4.495 mol) of 99% dichloromethane were added dropwise at 25-30°C over 0.5 h. The mixture was then incubated for 0.5 h. Then, 94.2 g (0.450 mol) of 99% of the compound of formula I and 424.7 g (4.495 mol) of 99% dichloromethane solution were added dropwise at 30-35°C over 0.5 h. After the addition was completed, the mixture was kept warm for 0.5 h. Then, the temperature was controlled at 25-30°C, and 243.3 g (13.500 mol) of water was added dropwise over 2 h. The mixture was allowed to stand for stratification, and the aqueous phase was discarded to obtain 955.1 g of a dichloromethane solution of the compound of formula VIII with a content of 11.17% (W / W) and a reaction yield of 95.1% (based on the compound of formula I).

[0096] 2) Into a 2 L four-necked flask equipped with a thermometer, a reflux condenser, and a mechanical stirrer was placed 955.1 g (0.428 mol) of a 11.17% (w / w) dichloromethane solution of the compound of formula VIII. The solution was distilled to dryness, and 804.7 g (13.266 mol) of 99% acetic acid was added for dissolution. The solution was then transferred to a 2 L autoclave, and 7.5 g (0.043 mol) of 99% manganese acetate and 0.2 g (0.002 mol) of 99% sodium bromide were added. The solution was replaced with oxygen three times, the temperature was raised to 120° C., and oxygen was introduced to 5 bar. The reaction was maintained at this temperature for 1.5 h, then cooled to room temperature and vented to obtain 951.2 g of an acetic acid solution of the compound of formula X with a content of 11.00% (w / w). The reaction yield was 91.5% (based on the compound of formula VIII).

[0097] 3) Into a 2 L four-necked flask equipped with a thermometer, a reflux condenser, and a mechanical stirrer were added 951.2 g (0.392 mol) of an 11.00% (w / w) solution of the compound of formula X in acetic acid and 5.2 g (0.016 mol) of 99% potassium tungstate. 48.8 g (0.431 mol) of 30% hydrogen peroxide were added dropwise at 65-70°C over 0.5 h. The mixture was incubated for 0.5 h to obtain 996.8 g of a 10.93% (w / w) solution of the compound of formula IV in acetic acid. The reaction yield was 98.2% (based on the compound of formula X). The mixture was slowly cooled to 0°C over 3 h, filtered and dried to obtain 105.4 g of 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid (compound of formula IV) as a solid with a content of 98.19% (W / W) and an isolated yield of 81.2% (based on the compound of formula I).

[0098] Example 4

[0099] This example is used to illustrate the acetylation reaction.

[0100] The method of step 1) of Example 1 was followed, except that the conditions and results of step 1) were as shown in Table 1.

[0101] Table 1

[0102] Lewis acid Lewis acid dosage solvent Solvent amount Acetyl chloride dosage Reaction temperature Conversion rate Selectivity zinc chloride 1.1eq. dichloromethane 9w / w 1.1eq. 30～35℃ 15.3％ 48.2％ Ferric chloride 1.1eq. dichloromethane 9w / w 1.1eq. 30～35℃ 27.1％ 54.3％ Aluminum chloride 1.1eq. dichloromethane 9w / w 1.1eq. 30～35℃ 100.0％ 95.2％ Aluminum chloride 1.1eq. 1.2-Dichloroethane 9w / w 1.1eq. 30～35℃ 100.0％ 94.8％

[0103] As shown in Table 1, when the Lewis acid is aluminum chloride, the conversion rate and selectivity of the acetylation reaction are significantly improved.

[0104] Example 5

[0105] This example is used to illustrate the first oxidation reaction.

[0106] Step 1): proceed according to step 1) of Example 1.

[0107] Step 2): proceed as in step 2) of Example 1, except that the conditions and results of step 2) are as shown in Table 1.

[0108] Table 2

[0109] serial number catalyst Catalyst dosage Sodium bromide solvent Solvent amount oxidants pressure temperature time Conversion rate Selectivity 1 Copper acetate 0.1eq. none Acetic acid 7w / w pure oxygen 5bar 120℃ 2.0h 19.3％ 41.5％ 2 Nickel acetate 0.1eq. none Acetic acid 7w / w pure oxygen 5bar 120℃ 2.0h 32.5％ 43.3％ 3 Cobalt acetate 0.1eq. none Acetic acid 7w / w pure oxygen 5bar 120℃ 2.0h 100.0％ 7.2％ 4 Manganese acetate 0.1eq. none Acetic acid 7w / w pure oxygen 5bar 120℃ 2.0h 100.0％ 91.6％ 5 Manganese acetate 0.2eq. none Acetic acid 7w / w pure oxygen 5bar 120℃ 1.5h 100.0％ 91.8％ 6 Manganese acetate 0.1eq. 0.005eq. Acetic acid 7w / w pure oxygen 5bar 120℃ 1.5h 100.0％ 91.5％ 7 Manganese acetate 0.1eq. none Acetic acid 7w / w Air 5bar 120℃ 2.0h 36.2％ 92.2％ 8 Manganese acetate 0.1eq. none Acetic acid 7w / w pure oxygen 2bar 120℃ 2.0h 55.7％ 92.5％ 9 Manganese acetate 0.1eq. none Acetic acid 7w / w pure oxygen 5bar 100℃ 2.0h 44.3％ 92.4％ 10 Manganese acetate 0.1eq. none Formic acid 7w / w pure oxygen 5bar 120℃ 2.0h 98.8％ 90.8％ 11 Manganese acetate 0.1eq. none tert-Butanol 7w / w pure oxygen 5bar 120℃ 2.0h 97.5％ 89.8％ 12 Manganese acetate 0.1eq. none ethanol 7w / w pure oxygen 5bar 120℃ 2.0h 96.7％ 89.4％

[0110] In Table 2, by comparing 1 to 4, it can be seen that when the catalyst is manganese acetate, the conversion rate and selectivity can be significantly improved.

[0111] By comparing 4 and 6, it can be seen that by adding bromide salt, the reaction time can be significantly shortened when the amount of catalyst is the same.

[0112] By comparing 4 and 7, it can be seen that the use of pure oxygen can further improve the conversion rate compared to the use of air.

[0113] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. A method for preparing 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid, characterized in that: The method The following steps are included: 1) in the presence of a first solvent, acetylation reaction is carried out with an acetylating agent under the catalysis of a Lewis acid to obtain a compound represented by formula VIII; 2) in the presence of a second solvent, subjecting the compound represented by the structure of Formula VIII to a first oxidation reaction with a first oxidant under the catalysis of a transition metal acetate to obtain a reaction product comprising a compound represented by the structure of Formula X; 3) Under the catalysis of tungstate, the reaction product containing the compound of the structure represented by formula X is subjected to a second oxidation reaction with a second oxidant to obtain a compound of the structure represented by formula IV. Wherein, the first oxidant is oxygen, and the second oxidant is hydrogen peroxide.

2. The method according to claim 1, wherein The first solvent is a haloalkane, preferably dichloromethane and / or 1,2-dichloroethane, more preferably dichloromethane; Preferably, the amount of the first solvent is 5-15 times by weight, preferably 8-10 times by weight, of the compound of the structure represented by Formula I; Preferably, the Lewis acid is one or more of aluminum chloride, ferric chloride and zinc chloride, preferably aluminum chloride; Preferably, the amount of the Lewis acid used is 1-5 moles, preferably 1.05-1.15 moles, relative to 1 mole of the compound of the structure represented by formula I; Preferably, the acetylating agent is acetyl chloride; Preferably, the amount of the acetylating agent used is 1-5 moles, preferably 1.05-1.15 moles, relative to 1 mole of the compound of the structure represented by Formula I.

3. The method according to claim 1, wherein The conditions for the acetylation reaction include: a reaction temperature of 20-80° C., preferably 30-40° C., and a reaction time of 2-10 h, preferably 2-5 h.

4. The method according to any one of claims 1 to 3, wherein: The second solvent is one or more of formic acid, acetic acid, tert-butanol and ethanol, preferably acetic acid; Preferably, the amount of the second solvent used is 3-10 times by weight, preferably 5-9 times by weight, of the compound having the structure represented by Formula VIII.

5. The method according to any one of claims 1 to 3, wherein: The transition metal acetate is one or more of manganese acetate, cobalt acetate, nickel acetate and copper acetate, preferably manganese acetate; Preferably, the amount of the transition metal acetate used is 0.001-1 mole, preferably 0.05-0.15 mole, relative to 1 mole of the compound represented by formula VIII.

6. The method according to claim 5, wherein: The first oxidation reaction is also carried out in the presence of a co-catalyst, which is a bromide salt, preferably sodium bromide; Preferably, the amount of the co-catalyst used is 0.001-1 mole, preferably 0.005-0.01 mole, relative to 1 mole of the compound represented by formula VIII.

7. The method according to any one of claims 1 to 3, wherein: The volume fraction of oxygen is 21-100%, preferably pure oxygen; Preferably, the conditions of the first oxidation reaction include: reaction temperature of 90-150° C., preferably 110-130° C., reaction pressure of 1-20 bar, preferably 4-6 bar, and reaction time of 1-5 h, preferably 1.5-2.5 h.

8. The method according to any one of claims 1 to 3, wherein: The tungstate is sodium tungstate and / or potassium tungstate; Preferably, the amount of the tungstate used is 0.001-1 mole, preferably 0.02-0.05 mole, relative to 1 mole of the compound of formula X.

9. The method according to any one of claims 1 to 3, wherein: The amount of the second oxidizing agent used is 1-5 moles, preferably 1.1-1.3 moles, relative to 1 mole of the compound represented by formula X.

10. The method according to any one of claims 1 to 3, wherein: The conditions of the second oxidation reaction include: reaction temperature of 10-80°C, preferably 60-70°C, reaction time of 2-10h, preferably 2-5h; Preferably, the reaction product of the second oxidation reaction is subjected to crystallization by cooling, filtration, and drying to obtain a compound having a structure shown in Formula IV.

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