Preparation method of isoxaflutole

Abstract

The invention provides a preparation method of isoxaflutole, and belongs to the technical field of medicine synthesis. According to the method, 2-nitro-4-trifluoromethyl benzoic acid is taken as a raw material, an important intermediate 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl) propane-1, 3-diketone is generated through esterification, methylthio and condensation reaction, and then the target product isoxaflutole is generated through nucleophilic substitution, ring closing reaction and oxidation reaction. The preparation parameters of the methylthio and condensation reaction and the ring closing reaction are precisely limited, so that the whole-course yield of the isoxaflutole is 67.24% (based on 2-nitro-4-trifluoromethyl benzoic acid).

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of isoxaflutole. Background Art

[0002] Isoxaflutole is an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), which has advantages such as excellent crop selectivity, broad-spectrum control of weeds, low dosage of active ingredients, low toxicity and environmental safety. It is mainly used in dry crop fields such as corn and sugarcane. The global market of isoxaflutole technical has shown a steady growth trend. Many scholars (CN105712944A, CN 107417587A, CN 111454228A) have studied the synthesis of isoxaflutole before, but there is less research on the impurities generated in the synthesis route. The impurities in the route may affect the purity of the final product isoxaflutole, make the reaction system complex, not only consume more raw materials in the subsequent reaction, but also reduce the reaction yield. Summary of the Invention

[0003] The purpose of the present invention is to provide a preparation method of isoxaflutole, which can significantly improve the yield of isoxaflutole and consume less raw materials.

[0004] In order to achieve the above invention purpose, the present invention provides the following technical solutions:

[0005] The present invention provides a preparation method of isoxaflutole, comprising the following steps:

[0006] Mix compound 1, methanol and concentrated sulfuric acid, and carry out an esterification reaction to obtain compound 2;

[0007] Mix the compound 2, a first organic solvent and an aqueous solution of sodium methyl mercaptide, carry out a methylthio reaction, and separate the crude product of compound 3 to obtain compound 3 and impurity 1; the concentration of compound 2 in the first organic solvent is 0.3 - 0.4 mol / L; the molar ratio of sodium methyl mercaptide to compound 2 in the aqueous solution of sodium methyl mercaptide is 1 - 1.4:1; the temperature of the methylthio reaction is 0 - 20 °C; the molar percentage content of impurity 1 in the crude product of compound 3 is 1 - 6%;

[0008] Mix the compound 3, cyclopropyl methyl ketone, a second organic solvent and a base, carry out a condensation reaction to obtain compound 4; the concentration of compound 3 in the condensation reaction raw material mixture is 0.04 - 0.4 mol / L; the molar ratio of the base to compound 3 is 1 - 1.5:1; the temperature of the condensation reaction is -10 - 80 °C;

[0009] Mix the compound 4, DMF-DMA and a third organic solvent, carry out a nucleophilic substitution reaction to obtain compound 5;

[0010] Mix the compound 5, hydroxylamine hydrochloride, concentrated sulfuric acid and a fourth organic solvent, and carry out a ring-closing reaction. Separate the crude product of the obtained compound 6 to obtain compound 6 and impurity 2; the molar ratio of the hydroxylamine hydrochloride to the compound 5 is 1 to 1.6:1; the temperature of the ring-closing reaction is 25 to 65 °C, and the reaction time is 0.5 to 2 h; the molar percentage content of the impurity 2 in the crude product of the compound 6 is 1 to 8%;

[0011] Mix the compound 6, sodium tungstate dihydrate, glacial acetic acid, concentrated sulfuric acid and hydrogen peroxide, and carry out an oxidation reaction to obtain isoxaflutole;

[0012] The compound 1 is The compound 2 is

[0013] The compound 3 is The compound 4 is

[0014] The compound 5 is The compound 6 is

[0015] The impurity 1 is The impurity 2 is

[0016] Preferably, the mass ratio of the compound 1 to the concentrated sulfuric acid is 1:1 to 1.5; the temperature of the esterification reaction is 60 to 75 °C, and the time is 24 h.

[0017] Preferably, the first organic solvent includes dichloromethane, acetone, toluene or DMF; the time of the methylthio reaction is 0.5 to 2 h.

[0018] Preferably, the molar ratio of the cyclopropyl methyl ketone to the compound 3 is 1 to 1.5:1; the base includes sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the second organic solvent includes DMF, toluene or THF.

[0019] Preferably, the molar ratio of the DMF-DMA to the compound 4 is 1 to 1.6:1; the temperature of the nucleophilic substitution reaction is 25 to 100 °C, and the reaction time is 1 to 5 h;

[0020] Preferably, the third organic solvent includes toluene, methanol, DMF or dichloroethane.

[0021] Preferably, the fourth organic solvent includes methanol, ethanol or isopropanol.

[0022] Preferably, the mass ratio of the compound 6, sodium tungstate dihydrate, glacial acetic acid and concentrated sulfuric acid is 1: 0.01-0.08: 3-8: 0.02-0.1; the molar ratio of the compound 6 to hydrogen peroxide is 1: 4-8;

[0023] Preferably, the temperature of the oxidation reaction is 20-60 °C, and the total time is 10-25 h; the mass concentration of the hydrogen peroxide is 3-16%.

[0024] The present invention provides a preparation method of isoxaflutole. Using 2-nitro-4-trifluoromethylbenzoic acid as a raw material, through esterification, methylthio and condensation reactions to generate an important intermediate 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione (compound 4), and then through nucleophilic substitution, ring-closing reaction, oxidation reaction to generate the target product isoxaflutole. Impurity 1 was found during the methylthio and condensation reactions, and impurity 2 was found during the ring-closing reaction. By precisely defining the preparation parameters of the methylthio and condensation reactions and the ring-closing reaction, the overall yield of isoxaflutole is 67.24% (calculated based on 2-nitro-4-trifluoromethylbenzoic acid), and the purity of the prepared isoxaflutole is 97.53%. Description of the Drawings

[0025] Figure 1 1H NMR spectrum of methyl 2-nitro-4-trifluoromethylbenzoate in Example 1 1 1H NMR spectrum;

[0026] Figure 2 1H NMR spectrum of methyl 2-methylthio-4-trifluoromethylbenzoate in Example 1 1 1H NMR spectrum;

[0027] Figure 3 LC-MS spectrum of methyl 2-methylthio-4-trifluoromethylbenzoate in Example 1

[0028] Figure 4 1H NMR spectrum of 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione in Example 1 1 1H NMR spectrum;

[0029] Figure 5 LC-MS spectrum of 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione in Example 1

[0030] Figure 6 1H NMR spectrum of 1-[2-(methylthio-4-trifluoromethyl)phenyl]-3-cyclopropyl-2-(dimethylamino)methylene)-1,3-dione in Example 1 1 1H NMR spectrum;

[0031] Figure 7 LC-MS spectrum of 1-[2-(methylthio-4-trifluoromethyl)phenyl]-3-cyclopropyl-2-(dimethylamino)methylene)-1,3-dione in Example 1;

[0032] Figure 8 For 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl]isoxazole in Example 1 1 HNMR spectrum;

[0033] Figure 9 LC-MS spectrum of 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl]isoxazole in Example 1;

[0034] Figure 10 For the 1 H NMR spectrum of clomazone in Example 1;

[0035] Figure 11 LC-MS spectrum of clomazone in Example 1;

[0036] Figure 12 For impurity 1 1 H NMR spectrum;

[0037] Figure 13 LC-MS spectrum of impurity 1;

[0038] Figure 14 For impurity 2 1 H NMR spectrum;

[0039] Figure 15 LC-MS spectrum of impurity 2. Detailed implementation mode

[0040] In the present invention, unless otherwise specified, the raw materials or reagents required for preparation are all commercially available products well-known to those skilled in the art.

[0041] The present invention provides a method for preparing clomazone, comprising the following steps:

[0042] Mix compound 1, methanol, and concentrated sulfuric acid, and carry out an esterification reaction to obtain compound 2;

[0043] Mix the compound 2, a first organic solvent, and an aqueous solution of sodium methyl mercaptide, and carry out a methylthio reaction. Separate the crude product of the obtained compound 3 to obtain compound 3 and impurity 1; the concentration of compound 2 in the first organic solvent is 0.3 - 0.4 mol / L; the molar ratio of sodium methyl mercaptide to compound 2 in the aqueous solution of sodium methyl mercaptide is 1 - 1.4:1; the temperature of the methylthio reaction is 0 - 20°C; the molar percentage content of impurity 1 in the crude product of compound 3 is 1 - 6%;

[0044] Mix the compound 3, cyclopropyl methyl ketone, a second organic solvent and a base, and carry out a condensation reaction to obtain compound 4; the concentration of the compound 3 in the raw material mixture for the condensation reaction is 0.04 - 0.4 mol / L; the molar ratio of the base to the compound 3 is 1 - 1.5:1; the temperature of the condensation reaction is -10 - 80 °C;

[0045] Mix the compound 4, DMF - DMA and a third organic solvent, and carry out a nucleophilic substitution reaction to obtain compound 5;

[0046] Mix the compound 5, hydroxylamine hydrochloride, concentrated sulfuric acid and a fourth organic solvent, and carry out a ring - closing reaction. Separate the crude product of the obtained compound 6 to obtain compound 6 and impurity 2; the molar ratio of the hydroxylamine hydrochloride to the compound 5 is 1 - 1.6:1; the temperature of the ring - closing reaction is 25 - 65 °C, and the reaction time is 0.5 - 2 h; the molar percentage content of the impurity 2 in the crude product of the compound 6 is 1 - 8%;

[0047] Mix the compound 6, sodium tungstate dihydrate, glacial acetic acid, concentrated sulfuric acid and hydrogen peroxide, and carry out an oxidation reaction to obtain isoxaflutole;

[0048] The compound 1 is The compound 2 is

[0049] The compound 3 is The compound 4 is

[0050] The compound 5 is The compound 6 is

[0051] The impurity 1 is The impurity 2 is

[0052] The synthesis reaction formula of the present invention is

[0053]

[0054] In the present invention, the compound 1, methanol and concentrated sulfuric acid are mixed to carry out an esterification reaction to obtain compound 2.

[0055] Preferably in the present invention, the compound 1, methanol and concentrated sulfuric acid are added to a reaction flask, heated, sampled and tracked by TLC until the raw material spots disappear, the methanol is evaporated, separated by water and ethyl acetate, the aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with a saturated aqueous sodium bicarbonate solution until neutral, washed with saturated brine, dried with anhydrous sodium sulfate for 5 h, filtered and concentrated to dryness to obtain a light yellow liquid compound 2.

[0056] In the present invention, the mass ratio of the compound 1 to concentrated sulfuric acid is preferably 1:1 to 1.5, more preferably 1:1.25; the temperature of the esterification reaction is preferably 60 to 75 °C, more preferably 75 °C, and the time is preferably 24 h; the mass concentration of the concentrated sulfuric acid is preferably 98%. The present invention has no special limitation on the dosage of the methanol, and it can be adjusted according to the demand to ensure the smooth progress of the reaction.

[0057] In the present invention, the compound 2, the first organic solvent and an aqueous solution of sodium methyl mercaptide are mixed to carry out a methylthio reaction, and the crude product of the obtained compound 3 is separated to obtain the compound 3 and the impurity 1.

[0058] The present invention clarifies that the impurity 1 is 2-methylthio-4-trifluoromethylbenzoic acid, and its formation reason is that the compound 3 undergoes a hydrolysis reaction under alkaline conditions. The structural formula of the impurity 1 is:

[0059]

[0060] Structural data of the impurity 1: 1 H NMR(500MHz,DMSO,δ:ppm)13.73(s,1H),8.08(d,J=8.3Hz,1H),7.59(d,J=19.1Hz,1H),7.56(s,1H),2.51(s,3H).(See Figure 12 )MS:[M+1] + =234.98.(See Figure 13 ).

[0061] In the present invention, the concentration of the compound 2 in the first organic solvent is 0.3 to 0.4 mol / L, more preferably 0.3 mol / L; the present invention limits the concentration of the compound 2 to 0.3 to 0.4 mol / L, which can reduce hydrolysis while maintaining a high yield of the compound 3.

[0062] In the present invention, the molar ratio of sodium methyl mercaptide to the compound 2 in the aqueous solution of sodium methyl mercaptide is 1 to 1.4:1, more preferably 1 to 1.1:1. The present invention limits the dosage of the above sodium methyl mercaptide to avoid incomplete reaction due to too little amount, and at the same time avoid increasing the dosage of sodium methyl mercaptide, which will lead to an increase in the alkalinity of the reaction solution. The side reaction of hydrolysis of the compound 3 will cause a large increase in the impurity 1 and a decrease in the yield.

[0063] In the present invention, the temperature of the methylthio reaction is 0 to 20 °C, more preferably 20 °C, and the time is preferably 0.5 to 2 h, more preferably 2 h; after 20 °C, continuing to increase the temperature will cause the ester hydrolysis to shift in the forward reaction direction, and the ester hydrolysis rate will increase, resulting in an increase in the impurity 1 and a decrease in the product yield.

[0064] Through the above-mentioned methylthio reaction conditions, the present invention can control the molar percentage content of impurity 1 in the crude product of compound 3 within the range of 1-6%, which can meet the high yield of the yield of compound 3 above 93%.

[0065] In the present invention, the first organic solvent preferably includes dichloromethane, acetone, toluene or DMF, more preferably DMF; the concentration of the sodium methyl mercaptide aqueous solution is preferably 20%.

[0066] The present invention preferably adds compound 2 and the first organic solvent into a reaction flask, drops the sodium methyl mercaptide aqueous solution, samples and tracks by TLC until the raw material spot disappears, adjusts the pH to 3-4 with hydrochloric acid, dilutes with water, a pale yellow solid precipitates, filters by suction, dries to obtain the crude product of compound 3, slurries with petroleum ether, and filters by suction to separate the white solid impurity 1.

[0067] The present invention mixes the compound 3, cyclopropyl methyl ketone, the second organic solvent and a base to carry out a condensation reaction to obtain compound 4.

[0068] Under the action of the base, compound 3 is prone to hydrolysis reaction, and at the same time, impurity 1 is generated.

[0069] In the present invention, the concentration of compound 3 in the condensation reaction raw material mixture is 0.04-0.4 mol / L, more preferably 0.31-0.35 mol / L; the present invention limits this concentration so that the main reaction rate is fast, the ester is quickly consumed, and the hydrolysis side reaction is reduced, thereby reducing the generation of impurity 1.

[0070] In the present invention, the molar ratio of the base to compound 3 is 1-1.5:1, more preferably 1-1.35:1; the temperature of the condensation reaction is -10-80 °C, more preferably 65 °C.

[0071] In the present invention, the molar ratio of cyclopropyl methyl ketone to compound 3 is preferably 1-1.5:1, more preferably 1:1; the base preferably includes sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, more preferably potassium tert-butoxide; the base is preferably used in the form of a base solution; wherein potassium tert-butoxide is preferably used in the form of a 1 mol / L THF solution of potassium tert-butoxide; the second organic solvent preferably includes DMF, toluene or THF, more preferably DMF.

[0072] The present invention preferably adds compound 3, cyclopropyl methyl ketone, the second organic solvent and the base solution into a reaction flask, samples at intervals starting from 30 min of the reaction, monitors the reaction process by TLC, terminates the reaction until the raw material spot completely disappears, adjusts the pH to 3-4 with hydrochloric acid, dilutes with water, a pale yellow solid precipitates, filters by suction, dries to obtain compound 4.

[0073] The present invention mixes the compound 4, DMF-DMA (N,N-dimethylformamide dimethyl acetal), and a third organic solvent to carry out a nucleophilic substitution reaction to obtain compound 5.

[0074] In the present invention, the molar ratio of DMF-DMA to compound 4 is preferably 1 to 1.6:1, more preferably 1.2 to 1.4:1; the temperature of the nucleophilic substitution reaction is preferably 25 to 100 °C, more preferably 75 °C, and the reaction time is preferably 1 to 5 h, more preferably 4 h; the present invention limits the above reaction temperature to achieve a higher yield, avoiding continuously increasing the temperature in exchange for a meager increase in yield, which will significantly increase the energy consumption.

[0075] In the present invention, the third organic solvent preferably includes toluene, methanol, DMF, or dichloroethane, more preferably toluene. The present invention has no special limitation on the dosage of the third organic solvent, and it can be adjusted according to actual needs to ensure the smooth progress of the reaction.

[0076] The present invention preferably adds compound 4, DMF-DMA, and the third organic solvent into a reaction flask, samples TLC for tracking until the raw material spots disappear, and directly dries it by rotary evaporation to obtain compound 5.

[0077] The present invention mixes the compound 5, hydroxylamine hydrochloride, concentrated sulfuric acid, and a fourth organic solvent to carry out a ring-closing reaction, separates the crude product of the obtained compound 6, and obtains compound 6 and impurity 2.

[0078] The present invention clarifies the isomer (impurity 2) of compound 6 in the ring-closing reaction, with the chemical name of 5-(cyclopropylcarbonyl)-4-[2-methylthio-4-(trifluoromethyl)phenyl]isoxazole, and the structural data of impurity 2: 1 H NMR (400 MHz, CDCl3) δ: 8.81 - 8.66 (m, 1H), 7.58 (s, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.53 (s, 1H), 2.63 - 2.38 (m, 3H), 2.01 - 1.82 (m, 1H), 1.24 - 1.15 (m, 2H), 0.92 - 0.86 (m, 2H). (See Figure 14 ); HPLC-MS: [M - 1] - = 326.11. (See Figure 15 ).

[0079] The structural formula of impurity 2 is

[0080]

[0081] During the ring - closing reaction, the nitrogen atom of hydroxylamine acts as a nucleophile, undergoes nucleophilic addition to the carbon - carbon double bond, and then elimination to form a monoxime. The oxygen atom in the monoxime overcomes steric hindrance and undergoes nucleophilic addition to the carbonyl group connected to the benzene ring. After eliminating a molecule of water, impurity 2 is formed.

[0082] In the present invention, the molar ratio of hydroxylamine hydrochloride to compound 5 is 1 - 1.6:1, more preferably 1.4:1. Hydroxylamine hydrochloride is prone to decomposition by itself. In the present invention, a slightly excessive amount of hydroxylamine hydrochloride is defined to avoid side reactions between hydroxylamine hydrochloride and other components in the reaction system, resulting in a decrease in the yield of compound 6.

[0083] In the present invention, the temperature of the ring - closing reaction is 25 - 65 °C, more preferably 45 - 55 °C, and the reaction time is 0.5 - 2 h, more preferably 1.5 h. The above temperature is defined in the present invention to avoid that too high a temperature will inhibit the ring - closing reaction. Moreover, since the formation of impurity 2 requires overcoming a large steric hindrance and the rate is slow, as the reaction time prolongs, the accumulation of side reactions leads to a gradual increase in the yield of impurity 2. Therefore, the reaction time is controlled within 0.5 - 2 h. By the above conditions of the ring - closing reaction in the present invention, the molar percentage content of impurity 2 in the crude product of compound 6 is controlled within the range of 1 - 8%, which can meet the requirement of a high yield of more than 90% for the yield of compound 3.

[0084] In the present invention, the molar ratio of concentrated sulfuric acid to compound 5 is preferably 1 - 1.5:1, more preferably 1.18:1.

[0085] In the present invention, the fourth organic solvent preferably includes methanol, ethanol or isopropanol, more preferably methanol. There is no special limitation on the dosage of the fourth organic solvent in the present invention, and it can be adjusted according to actual needs to ensure the smooth progress of the reaction. The fourth organic solvent used in the present invention has strong polarity, can well dissolve many polar reactants and reagents, provides a homogeneous reaction environment for the reaction, is conducive to the full contact and effective collision between reactant molecules, and thus improves the yield of the reaction.

[0086] In the present invention, compound 5, hydroxylamine hydrochloride, the fourth organic solvent and concentrated sulfuric acid are preferably added to a reaction flask. Samples are taken for TLC tracking until the raw material spots disappear. The solvent is evaporated to dryness, water and ethyl acetate are added for separation. The aqueous phase is extracted with ethyl acetate. After combining the organic phases, they are washed with saturated sodium bicarbonate aqueous solution until neutral, and then washed with saturated brine, dried with anhydrous sodium sulfate for 5 h, concentrated to dryness to obtain the crude product of compound 6. Impurity 2 is obtained by thin - layer chromatography (the developing agent condition is petroleum ether:ethyl acetate = 5:1 (volume ratio)); when the molar percentage content of impurity 2 in the crude product of compound 6 ≤ 8%, there is no need to separate the impurity, and the crude product of compound 6 is recrystallized with petroleum ether to obtain compound 6.

[0087] In the present invention, the compound 6, sodium tungstate dihydrate, glacial acetic acid, concentrated sulfuric acid and hydrogen peroxide are mixed for an oxidation reaction to obtain isoxaflutole.

[0088] In the present invention, the mass ratio of the compound 6, sodium tungstate dihydrate, glacial acetic acid and concentrated sulfuric acid is preferably 1:0.01 - 0.08:3 - 8:0.02 - 0.1, more preferably 1:0.05:6.3:0.07. The molar ratio of the compound 6 to hydrogen peroxide is preferably 1:4 - 8, more preferably 1:5.1.

[0089] In the present invention, the temperature of the oxidation reaction is preferably 20 - 60 °C, more preferably 40 - 60 °C, and the total time is 10 - 25 h, more preferably 14 h; the mass concentration of the hydrogen peroxide is preferably 3 - 16%, more preferably 8%, and a higher yield can be achieved. In the present invention, it is preferred to first oxidize the methylthio group to sulfoxide with hydrogen peroxide having a mass concentration of 3.87%, and then oxidize the sulfoxide to sulfone with hydrogen peroxide having a mass concentration of 4 - 16%.

[0090] In the present invention, it is preferred to add the compound 6 to the reaction flask, dropwise add hydrogen peroxide, add sodium tungstate dihydrate and glacial acetic acid, dropwise add concentrated sulfuric acid. After reacting for 1 h, heat to the temperature of the oxidation reaction, continue to dropwise add hydrogen peroxide. After the reaction is completed by high performance liquid chromatography detection, quench the excess hydrogen peroxide with sodium bisulfite solution, cool down, precipitate a solid, filter, wash the filter cake with water by pulping, and dry to obtain isoxaflutole.

[0091] The specific embodiments of the present invention will be described in detail below, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the protection scope of the present invention. The experimental methods in the embodiments of the present invention are all conventional methods unless otherwise specified.

[0092] The following experimental methods and detection methods are all conventional methods unless otherwise specified; the following reagents and raw materials are all commercially available unless otherwise specified.

[0093] Experimental Example 1

[0094] Explore the influence of the concentration of compound 2 (the concentration of compound 2 in DMF solvent when the aqueous solution of sodium methyl mercaptide is not added) on the synthesis yield of compound 3.

[0095] At 20 °C, 1 g (0.004 mol) of Compound 2 and DMF (the amounts of DMF were 5 mL, 10 mL, 13 mL, and 20 mL respectively) were added to a 50 mL three-necked reaction flask. 1.54 g (0.0044 mol) of a 20% aqueous sodium methyl mercaptide solution was added dropwise. During the addition, the temperature was controlled at 20 °C, and the mixture was stirred for 1 h. The reaction was monitored by TLC sampling until the starting material spot disappeared. The pH was adjusted to 3 with 10 mL of 1N hydrochloric acid, and then diluted with 50 mL of water. A pale yellow solid precipitated out. The solid was filtered by suction and dried to obtain the crude product of Compound 3. The crude product was slurried with petroleum ether, and then filtered by suction to separate the white solid impurity 1 and Compound 3.

[0096] The yields of Compound 3 and impurity 1 were calculated by measuring the contents of Compound 2 and impurity 1 in the reaction solution by the external standard method of HPLC.

[0097] Liquid phase conditions: Chromatographic column: Agilent C18 reverse chromatographic column (4.6 mm × 250 mm, 5 μm); Mobile phase: Acetonitrile: water (adjusted to pH = 3.5 with phosphoric acid) = 8:2 (V:V); Flow rate: 1.0 mL / min; Column temperature: 25 °C; Detection wavelength: 205 nm; Injection volume: 20 μL.

[0098] Table 1 Effect of the concentration of Compound 2 on the nucleophilic substitution reaction

[0099]

[0100] As can be seen from Table 1, as the concentration of the reactant decreased, the yield of Compound 3 gradually increased. In this reaction, the concentration of Compound 2 was decreased by increasing the amount of the solvent. During the dropwise addition, since the dropwise addition rate of the aqueous sodium methyl mercaptide solution remained unchanged, the concentration of sodium methyl mercaptide in the local area remained at a relatively high level at the moment of dropwise addition, but its total concentration decreased due to solvent dilution. As a strong base, the concentration of sodium hydroxide generated by the hydrolysis of sodium methyl mercaptide decreased accordingly, weakening the driving force for the hydrolysis of the ester group, thereby reducing the formation of impurity 1 and improving the selectivity of the main and side reactions. When the reaction concentration decreased to 0.3 mol / L, further decreasing the concentration of Compound 2 led to a decrease in the yield. It was speculated that decreasing the reactant concentration reduced the number of reactant molecules per unit volume, decreased the intermolecular collision frequency, and also decreased the probability of effective collisions, resulting in a slower reaction rate. In the same reaction time, the amount of Compound 3 formed decreased and the yield decreased. Therefore, 0.3 - 0.4 mol / L was selected as the optimal concentration for the reaction.

[0101] Explore the effect of the amount of sodium methyl mercaptide on the synthesis yield of Compound 3.

[0102] 1 g (0.004 mol) of Compound 2 and 10 mL of DMF were added to a 50 mL three-necked reaction flask at 20 °C. Aqueous sodium methanethiolate solution (1.40 g, 1.47 g, 1.54 g, 1.68 g, 1.96 g) of 20% was added dropwise respectively. During the addition, the temperature was controlled at 20 °C and stirred for 1 h. Sampling was carried out for TLC tracking until the raw material spots disappeared. 10 mL of 1N hydrochloric acid was used to adjust the acidity to pH = 3, and then diluted with 50 mL of water. Pale yellow solid precipitated out. It was filtered by suction and dried to obtain the crude product of Compound 3. It was slurried with petroleum ether and separated by suction filtration to obtain white solid Impurity 1 and Compound 3.

[0103] Table 2 Influence of the amount of sodium methanethiolate on the nucleophilic substitution reaction

[0104]

[0105] As can be seen from Table 2, sodium methanethiolate needs to be in excess for Compound 2 to react completely. Sodium methanethiolate will hydrolyze into methanethiol in water. The boiling point of methanethiol is extremely low, only 6 °C, and it is volatile. Therefore, sodium methanethiolate needs to be in excess. When the amount of sodium methanethiolate is 4.4 mmol, the yield is relatively high. Continuing to increase the amount of sodium methanethiolate will lead to an increase in the alkalinity in the reaction solution, and the side reaction of hydrolysis of Compound 3 will increase, resulting in a decrease in the yield. Experiments show that the highest yield can be obtained when 4.4 mmol of sodium methanethiolate is used. However, from the perspective of comprehensive economic cost trade-off, using 4.2 - 4.4 mmol of sodium methanethiolate can not only save raw materials, but also still achieve a relatively high yield level.

[0106] Experimental Example 2

[0107] Experiment on influencing factors of Impurity 2:

[0108] Using methanol as the solvent at 45 °C, explore the influence of reaction time on the synthesis of Compound 6:

[0109] At 45 °C, 0.5 g of Compound 5 (0.0014 mol), 0.14 g of hydroxylamine hydrochloride (0.002 mol), 100 mL of methanol and 0.167 g of concentrated sulfuric acid (0.0017 mol) were added to a 50 mL three-necked reaction flask. After reacting for a fixed time (see Table 3), sampling was carried out for TLC tracking until the raw material spots disappeared. The methanol was evaporated to dryness, 10 mL of water and 10 mL of ethyl acetate were added for separation. The aqueous phase was extracted with 5 × 3 mL of ethyl acetate. After combining the organic phases, it was washed with saturated sodium bicarbonate aqueous solution until neutral, and washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate for 5 h, concentrated to dryness to obtain the crude product of Compound 6. By thin layer method (developing agent condition: petroleum ether:ethyl acetate = 5:1 (volume ratio)), Impurity 2 and Compound 6 were obtained.

[0110] The yields of Compound 6 and Impurity 2 were calculated by determining the contents of Compound 6 and Impurity 2 in the reaction solution by HPLC external standard method.

[0111] Chromatographic column: Agilent C18 reverse-phase chromatographic column (4.6 mm × 250 mm, 5 μm); mobile phase: acetonitrile: water (adjusted to pH = 3.5 with phosphoric acid) = 7:3 (V:V); flow rate: 1.0 mL / min; column temperature: 25 °C; detection wavelength: 205 nm; injection volume: 20 μL.

[0112] Table 3 Effect of reaction time on the synthesis of compound 6

[0113]

[0114] From the data analysis of Table 3, it can be seen that compound 5 has high activity and is easily subjected to nucleophilic attack by the nitrogen atom in hydroxylamine hydrochloride, enabling the reaction to proceed rapidly. In addition, concentrated sulfuric acid is used as a catalyst in this reaction, which also accelerates the reaction rate. In the initial stage (0.5 h), the main reaction proceeds rapidly. As time extends, the reaction gradually approaches equilibrium, and the growth rate of the yield slows down, indicating that the consumption of raw materials tends to be complete. Since the formation of impurity 2 requires overcoming a large steric hindrance, the rate is slow. As time extends, the accumulation of side reactions leads to a gradual increase in the yield of impurity 2. It may decompose or convert into other products in the later stage of the reaction, and the yield of impurity 2 slightly decreases after 2 h. Considering factors such as production cost and energy consumption, it is considered the most suitable choice to determine the reaction time as 1.5 h, which can not only ensure a high product yield but also achieve a good balance between economy and operational convenience.

[0115] The mass fraction of concentrated sulfuric acid used in the following examples is 98%.

[0116] Example 1

[0117] 1.1) Preparation of methyl 2-nitro-4-(trifluoromethyl)benzoate

[0118] At room temperature, 20 g (0.085 mol) of compound 1, 200 mL of methanol, and 25 g of concentrated sulfuric acid were added to a 500 mL three-necked flask, heated to 75 °C and refluxed for 24 h. Sampling was carried out for TLC tracking until the raw material spots disappeared. Methanol was evaporated off, 200 mL of water and 200 mL of ethyl acetate were added for separation. The aqueous phase was extracted with 3 × 30 mL of ethyl acetate. After combining the organic phases, they were washed to neutral with saturated sodium bicarbonate aqueous solution (30 mL × 3) and washed with saturated brine (150 mL × 3). Dried over anhydrous sodium sulfate for 5 h, filtered and concentrated to dryness to obtain a light yellow liquid compound 2 with a yield of 94.24%. 1 HNMR (500 MHz, CDCl3, δ: ppm) 8.21 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H). (See Figure 1 )

[0119] 1.2) Preparation of methyl 2-(methylthio)-4-(trifluoromethyl)benzoate

[0120] At 20 °C, 18.20 g (0.073 mol) of Compound 2 and 240 mL of DMF were added to a 500 mL three-necked reaction flask. An aqueous solution of sodium methyl mercaptide (20%, 28.14 g, 0.080 mol) was added dropwise. During the addition, the temperature was controlled at 20 °C, and the mixture was stirred for 2 h. Sampling was carried out for TLC tracking until the raw material spots disappeared. The pH was adjusted to 3 with 200 mL of 1N hydrochloric acid, and then diluted with 1 L of water. A pale yellow solid precipitated out. It was filtered by suction and dried to obtain Compound 3 with a yield of 96.35%. 1 1H NMR (500 MHz, CDCl3, δ: ppm) 8.09 (d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 3.95 (s, 3H), 2.50 (s, 3H). (See Figure 2 ); HPLC-MS: [M - 1] - = 251.07. (See Figure 3 )

[0121] 1.3) Preparation of 1-cyclopropyl-3-(2-(methylthio)-4-(trifluoromethyl)phenyl)propane-1,3-dione

[0122] At 65 °C, 10 g of Compound 3 (0.040 mol), 3.36 g of cyclopropyl methyl ketone (0.040 mol), 75 mL of DMF, and 54 mL of a THF solution of potassium tert-butoxide (1 mol / L, 0.054 mol) were added to a 100 mL three-necked flask. Sampling was carried out at intervals starting from 30 min of the reaction, and the reaction progress was monitored by TLC. The reaction was terminated when the raw material spots completely disappeared. The pH was adjusted to 3 with 150 mL of 1N hydrochloric acid, and then diluted with 200 mL of water. A pale yellow solid precipitated out. It was filtered by suction and dried to obtain Compound 4 with a yield of 82.61%. 1 1H NMR (500 MHz, CDCl3, δ: ppm) 15.98 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.10 (s, 1H), 2.50 (s, 3H), 1.73 - 1.70 (m, 1H), 1.27 - 1.18 (m, 2H), 1.04 - 1.00 (m, 2H). (See Figure 4 ); HPLC-MS: [M - 1] - = 300.85. (See Figure 5 )

[0123] 1.4) Preparation of 1-[2-(methylthio-4-trifluoromethyl)phenyl]-3-cyclopropyl-2-(dimethylamino)methylene)-1,3-dione

[0124] At 75 °C, 7.6 g of compound 4 (0.025 mol), 4.2 g of DMF-DMA (0.035 mol) and 80 mL of toluene were added to a 250 mL three-necked reaction flask. After reacting for 4 h, a sample was taken and tracked by TLC until the raw material spots disappeared. It was directly evaporated to dryness to obtain compound 5 with a yield of 97.13%. 1 HNMR(500MHz,CDCl3,δ:ppm)7.53(s,1H),7.51(s,1H),7.45(d,J=1.6Hz,1H),7.36(dd,J=8.0,1.7Hz,1H),3.24(s,3H),2.76(s,3H),2.47(s,3H),1.79(s,1H),0.95 - 0.85(m,2H),0.59 - 0.53(m,2H).(See Figure 6 ); HPLC-MS: [M - 1] - =358.12.(See Figure 7 )

[0125] 1.5) Preparation of 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl]isoxazole

[0126] At 45 °C, 4.00 g of compound 5 (0.011 mol), 1.09 g of hydroxylamine hydrochloride (0.015 mol), 60 mL of methanol and 1.32 g of concentrated sulfuric acid (0.013 mol) were added to a 150 mL three-necked reaction flask. After reacting for 1.5 h, a sample was taken and tracked by TLC until the raw material spots disappeared. The methanol was evaporated to dryness, 50 mL of water and 50 mL of ethyl acetate were added for separation. The aqueous phase was extracted with 20×3 mL of ethyl acetate. After combining the organic phases, it was washed with saturated sodium bicarbonate aqueous solution until neutral, and then washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate for 5 h, concentrated to dryness to obtain the crude product of compound 6, and recrystallized with petroleum ether to obtain compound 6 with a reaction yield of 92.70%. 1 H NMR(500MHz,CDCl3,δ:ppm)8.18(s,1H),7.59(s,1H),7.53(d,J=7.9Hz,1H),7.49(dd,J=8.1,1.6Hz,1H),2.73 - 2.68(m,1H),2.51(s,3H),1.38 - 1.35(m,2H),1.27 - 1.23(m,2H).(See Figure 8 );HPLC-MS: [M + 1] + =328.02.(See Figure 9 )

[0127] 1.6) Preparation of isoxaflutole

[0128] At 20 °C, 5.00 g (15.27 mmol) of compound 6 was added to a 100 mL three-necked reaction flask, and 13.89 g (16.80 mmol) of hydrogen peroxide with a mass concentration of 3.87%, 0.25 g (0.76 mmol) of sodium tungstate dihydrate, 31.47 g of glacial acetic acid, and 0.35 g of concentrated sulfuric acid were added dropwise. After reacting for 1 h, the temperature was raised to 60 °C, and 12.98 g of hydrogen peroxide with a mass concentration of 16% was added dropwise continuously. After 13 h, after the reaction was completed by high performance liquid chromatography detection, the excess hydrogen peroxide was quenched with a sodium bisulfite solution, the temperature was lowered, a solid was precipitated, and after stirring for 1 h, it was filtered, the filter cake was washed with water by pulping, dried, and white solid isoxaflutole was obtained with a yield of 99.57%. 1 H NMR (500 MHz, CDCl3, δ: ppm) 8.44 - 8.40 (m, 1H), 8.14 (s, 1H), 8.03 - 7.97 (m, 1H), 7.62 (d, J = 7.9 Hz, 1H), 3.33 (s, 3H), 2.54 (tt, J = 8.3, 4.9 Hz, 1H), 1.40 - 1.36 (m, 2H), 1.26 - 1.23 (m, 2H). (See Figure 10 ); HPLC-MS: [M + 1] + = 358.14. (See Figure 11 )

[0129] Example 2

[0130] 2.1) Preparation of methyl 2-nitro-4-(trifluoromethyl)benzoate

[0131] At room temperature, 20 g (0.085 mol) of compound 1, 150 mL of methanol, and 25 g of concentrated sulfuric acid were added to a 500 mL three-necked flask, heated to 75 °C and refluxed for 24 h. Sampling was carried out for TLC tracking until the raw material spot disappeared. Methanol was evaporated, 200 mL of water and 200 mL of ethyl acetate were added for separation. The aqueous phase was extracted with 3 × 30 mL of ethyl acetate. After combining the organic phases, it was washed to neutral with saturated sodium bicarbonate aqueous solution (30 mL × 3), and washed with saturated brine (150 mL × 3), dried over anhydrous sodium sulfate for 5 h, filtered and concentrated to dryness to obtain a light yellow liquid compound 2 with a yield of 90.48%.

[0132] 2.2) Preparation of methyl 2-(methylthio)-4-(trifluoromethyl)benzoate

[0133] At 0 °C, 18.20 g (0.073 mol) of Compound 2 and 240 mL of DMF were added to a 500 mL three-necked reaction flask. 28.14 g (0.080 mol) of a 20% aqueous solution of sodium methyl mercaptide was added dropwise. During the addition, the temperature was controlled at 20 °C and stirred for 2 h. The reaction was monitored by TLC sampling until the starting material spot disappeared. The pH was adjusted to 3 with 200 mL of 1N hydrochloric acid, diluted with 1 L of water, and a pale yellow solid precipitated. It was filtered by suction and dried to obtain Compound 3 with a yield of 88.32%.

[0134] 2.3) Preparation of 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione

[0135] At 65 °C, 10 g of Compound 3 (0.040 mol), 3.36 g of cyclopropyl methyl ketone (0.040 mol), 75 mL of toluene, and 54 mL of potassium tert-butoxide (1 mol / L, 0.054 mol) were added to a 100 mL three-necked flask. Samples were taken at intervals starting from 30 min of the reaction, and the reaction progress was monitored by TLC until the starting material spot completely disappeared to terminate the reaction. The pH was adjusted to 3 with 150 mL of 1N hydrochloric acid, diluted with 200 mL of water, and a pale yellow solid precipitated. It was filtered by suction and dried to obtain Compound 4 with a yield of 79.00%

[0136] 2.4) Preparation of 1-[2-(methylthio-4-trifluoromethyl)phenyl]-3-cyclopropyl-2-(dimethylamino)methylene)-1,3-dione

[0137] At 75 °C, 7.6 g of Compound 4 (0.025 mol), 3.6 g of DMF-DMA (0.03 mol), and 80 mL of toluene were added to a 250 mL three-necked reaction flask. After reacting for 4 h, the reaction was monitored by TLC sampling until the starting material spot disappeared, and then directly evaporated to dryness to obtain Compound 5 with a yield of 90.67%.

[0138] 2.5) Preparation of 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl]isoxazole

[0139] At 55 °C, 4.00 g of Compound 5 (0.011 mol), 1.09 g of hydroxylamine hydrochloride (0.015 mol), 60 mL of methanol, and 1.32 g of concentrated sulfuric acid (0.013 mol) were added to a 150 mL three-necked reaction flask. After reacting for 1.5 h, the reaction was monitored by TLC sampling until the starting material spot disappeared. The methanol was evaporated to dryness, 50 mL of water and 50 mL of ethyl acetate were added for separation. The aqueous phase was extracted with 20 × 3 mL of ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate aqueous solution until neutral, and then washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate for 5 h, concentrated to dryness to obtain the crude product of Compound 6, and recrystallized with petroleum ether. The reaction yield was 89.91%.

[0140] 2.6) Preparation of Isoxaflutole

[0141] At 20 °C, 5.00 g (15.27 mmol) of Compound 6 was added to a 100 mL three-necked reaction flask, and 13.89 g (16.80 mmol) of hydrogen peroxide with a mass concentration of 3.87%, 0.25 g (0.76 mmol) of sodium tungstate dihydrate, 31.47 g of glacial acetic acid, and 0.35 g of concentrated sulfuric acid were added dropwise. After reacting for 1 h, the temperature was raised to 60 °C, and 25.97 g (61.11 mmol) of hydrogen peroxide with a mass concentration of 8% was continued to be added dropwise. After 13 h, after the reaction was detected by high-performance liquid chromatography to be complete, the excess hydrogen peroxide was quenched with a sodium bisulfite solution. The temperature was lowered, and a solid was precipitated. After stirring for 1 h, filtration was carried out, and the filter cake was washed with water slurry and dried to obtain white solid isoxaflutole with a yield of 93.33%.

[0142] Example 3

[0143] 3.1) Preparation of Methyl 2-Nitro-4-(trifluoromethyl)benzoate

[0144] At room temperature, 20 g (0.085 mol) of Compound 1, 200 mL of methanol, and 25 g of concentrated sulfuric acid were added to a 500 mL three-necked flask, and the mixture was heated to 60 °C and reacted for 24 h. Methanol was evaporated, 200 mL of water and 200 mL of ethyl acetate were added for separation. The aqueous phase was extracted with 3 × 30 mL of ethyl acetate. After combining the organic phases, the mixture was washed with saturated sodium bicarbonate aqueous solution (30 mL × 3) until neutral, and washed with saturated brine (150 mL × 3). It was dried over anhydrous sodium sulfate for 5 h, filtered and concentrated to dryness to obtain a light yellow liquid Compound 2 with a yield of 86.35%.

[0145] 3.2) Preparation of Methyl 2-(methylthio)-4-(trifluoromethyl)benzoate

[0146] At 20 °C, 18.20 g (0.073 mol) of Compound 2 and 240 mL of DMF were added to a 500 mL three-necked reaction flask, and 25.67 g (0.073 mol) of 20% aqueous sodium methyl mercaptide solution was added dropwise. During the dropping process, the temperature was controlled at 20 °C and stirred for 2 h. Sampling was carried out for TLC tracking until the raw material spot disappeared. The pH was adjusted to 3 with 200 mL of 1N hydrochloric acid, diluted with 1 L of water, and a light yellow solid was precipitated. Filtration was carried out by suction and dried to obtain Compound 3 with a yield of 93.47%.

[0147] 3.3) Preparation of 1-Cyclopropyl-3-(2-(methylthio)-4-(trifluoromethyl)phenyl)propane-1,3-dione

[0148] At 65 °C, 10 g of compound 3 (0.040 mol), 3.36 g of cyclopropyl methyl ketone (0.040 mol), 75 mL of DMF, and 40 mL of potassium tert-butoxide (1 mol / L, 0.04 mol) were added to a 100 mL three-necked flask. Samples were taken at intervals starting from 30 min of the reaction, and the reaction progress was monitored by TLC. The reaction was terminated when the raw material spots completely disappeared. The pH was adjusted to 3 with 150 mL of 1N hydrochloric acid, diluted with 200 mL of water, and a pale yellow solid precipitated. It was filtered by suction and dried to obtain compound 4 with a yield of 76.21%.

[0149] 3.4) Preparation of 1-[2-(methylthio-4-trifluoromethyl)phenyl]-3-cyclopropyl-2-(dimethylamino)methylene)-1,3-dione

[0150] At 75 °C, 7.6 g of compound 4 (0.025 mol), 4.2 g of DMF-DMA (0.035 mol), and 80 mL of DMF were added to a 250 mL three-necked reaction flask. After reacting for 4 h, samples were taken and tracked by TLC until the raw material spots disappeared. It was directly evaporated to dryness to obtain compound 5 with a yield of 83.93%.

[0151] 3.5) Preparation of 5-cyclopropyl-4-[2-methylthio-4-(trifluoromethyl)benzoyl]isoxazole

[0152] At 45 °C, 4.00 g of compound 5 (0.011 mol), 1.09 g of hydroxylamine hydrochloride (0.015 mol), 60 mL of ethanol, and 1.32 g of concentrated sulfuric acid (0.013 mol) were added to a 150 mL three-necked reaction flask. After reacting for 1.5 h, samples were taken and tracked by TLC until the raw material spots disappeared. The methanol was evaporated to dryness, 50 mL of water and 50 mL of ethyl acetate were added for separation. The aqueous phase was extracted with 20×3 mL of ethyl acetate. After combining the organic phases, it was washed with saturated sodium bicarbonate aqueous solution until neutral, and washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate for 5 h, concentrated to dryness, and the crude product of compound 6 was obtained. It was recrystallized with petroleum ether, and the reaction yield was 84.79%.

[0153] 3.6) Preparation of clomazone

[0154] At 20 °C, 5.00 g (15.27 mmol) of compound 6 was added to a 100 mL three-necked reaction flask, and 13.89 g (16.80 mmol) of hydrogen peroxide with a mass concentration of 3.87%, 0.25 g (0.76 mmol) of sodium tungstate dihydrate, 31.47 g of glacial acetic acid, and 0.35 g of concentrated sulfuric acid were added dropwise. After reacting for 1 h, the temperature was heated to 40 °C, and 12.98 g of hydrogen peroxide with a mass concentration of 16% was added dropwise continuously. After 13 h, after the reaction was detected by high performance liquid chromatography to be completed, the excess hydrogen peroxide was quenched with a sodium bisulfite solution. The temperature was lowered, and a solid was precipitated. After stirring for 1 h, filtration was carried out, and the filter cake was washed with water by pulping and then dried to obtain the white solid isoxaflutole with a yield of 94.31%.

[0155] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A preparation method of clomazone, characterized in that, It includes the following steps: Mix compound 1, methanol, and concentrated sulfuric acid, and carry out an esterification reaction to obtain compound 2; Mix the compound 2, a first organic solvent, and an aqueous solution of sodium methyl mercaptide, carry out a methylthio reaction, and separate the obtained crude product of compound 3 to obtain compound 3 and impurity 1; the concentration of compound 2 in the first organic solvent is 0.3 - 0.4 mol / L; the molar ratio of sodium methyl mercaptide to compound 2 in the aqueous solution of sodium methyl mercaptide is 1 - 1.4:1; the temperature of the methylthio reaction is 0 - 20 °C; the molar percentage content of impurity 1 in the crude product of compound 3 is 1 - 6%; Mix the compound 3, cyclopropyl methyl ketone, a second organic solvent, and a base, carry out a condensation reaction to obtain compound 4; the concentration of compound 3 in the raw material mixture for the condensation reaction is 0.04 - 0.4 mol / L; the molar ratio of the base to compound 3 is 1 - 1.5:1; the temperature of the condensation reaction is -10 - 80 °C; Mix the compound 4, DMF - DMA, and a third organic solvent, carry out a nucleophilic substitution reaction to obtain compound 5; Mix the compound 5, hydroxylamine hydrochloride, concentrated sulfuric acid, and a fourth organic solvent, carry out a ring - closing reaction, and separate the obtained crude product of compound 6 to obtain compound 6 and impurity 2; the molar ratio of hydroxylamine hydrochloride to compound 5 is 1 - 1.6:1; the temperature of the ring - closing reaction is 25 - 65 °C, and the reaction time is 0.5 - 2 h; the molar percentage content of impurity 2 in the crude product of compound 6 is 1 - 8%; Mix the compound 6, sodium tungstate dihydrate, glacial acetic acid, concentrated sulfuric acid, and hydrogen peroxide, carry out an oxidation reaction to obtain isoxaflutole; The compound 1 is The compound 2 is The compound 3 is The compound 4 is The compound 5 is The compound 6 is The impurity 1 is The impurity 2 is 2. The preparation method according to claim 1, characterized in that, The mass ratio of compound 1 to concentrated sulfuric acid is 1:1 - 1.5; the temperature of the esterification reaction is 60 - 75 °C, and the time is 24 h.

3. The preparation method according to claim 1, wherein The first organic solvent includes dichloromethane, acetone, toluene, or DMF; the time of the methylthio reaction is 0.5 - 2 h.

4. The preparation method according to claim 1, characterized in that, The molar ratio of cyclopropyl methyl ketone to compound 3 is 1 - 1.5:1; the base includes sodium methoxide, sodium ethoxide, sodium tert - butoxide, or potassium tert - butoxide; the second organic solvent includes DMF, toluene, or THF.

5. The preparation method according to claim 1, characterized in that, The molar ratio of DMF - DMA to compound 4 is 1 - 1.6:1; the temperature of the nucleophilic substitution reaction is 25 - 100 °C, and the reaction time is 1 - 5 h.

6. The preparation method according to claim 1, characterized in that, The third organic solvent includes toluene, methanol, DMF, or dichloroethane.

7. The preparation method according to claim 1, wherein The fourth organic solvent includes methanol, ethanol, or isopropanol.

8. The preparation method according to claim 1, wherein The mass ratio of compound 6, sodium tungstate dihydrate, glacial acetic acid, and concentrated sulfuric acid is 1:0.01 - 0.08:3 - 8:0.02 - 0.1; the molar ratio of compound 6 to hydrogen peroxide is 1:4 - 8.

9. The preparation method according to claim 1 or 8, characterized in that, The temperature of the oxidation reaction is 20 - 60 °C, the total time is 10 - 25 h; the mass concentration of hydrogen peroxide is 3 - 16%.

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