Preparation method of isoxazole herbicide

Abstract

The invention discloses a preparation method of an isoxazole herbicide (3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl) methyl) sulfonyl)-5, 5-dimethyl-4, 5-dihydroisoxazole), which comprises the following steps: in a dual-catalyst system of sodium tungstate and a phase transfer catalyst, reacting at the temperature of between 20 and 30 DEG C for 2 to 4 hours, thereby obtaining the isoxazole herbicide (3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl) methyl) sulfonyl)-5, 5-dimethyl-4, 5-dihydroisoxazole). Under the oxidation effect of hydrogen peroxide, the compound shown in the formula (II) is obtained into a compound shown in the formula I; the organic solvent immiscible with water is adopted, and under a double-catalyst system, the safety is enhanced, the explosion risk is reduced, the reaction efficiency is improved, the reaction time is shortened, and the content and the yield of the product are improved.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and in particular to a method for preparing an isoxazole herbicide (3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole). Background Art

[0002] 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole is a pre-emergence soil treatment herbicide developed by Kumihiko Chemical Co., Ltd. and Ibara Chemical Co., Ltd., Japan, suitable for most crop fields. Its mechanism of action is that after being absorbed by weed roots and shoots, it damages the seedling meristem and coleoptile. It is a potential inhibitor of VLCFA (very long-chain fatty acid) biosynthesis in plants, inhibiting early seedling growth. Its broad-spectrum, high-efficiency, and environmentally friendly properties have attracted widespread attention.

[0003] Currently, the preparation methods disclosed in the prior art for the preparation of the final target product ultimately require oxidation of the thioether intermediate to obtain 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole. The production process route is as follows:

[0004]

[0005] For example, CN117545741A uses sodium tungstate as a catalyst and hydrogen peroxide to directly oxidize sulfide into sulfone. However, the above method has a long reaction time (6-8 hours), resulting in a long production cycle and low product yield, which is not conducive to industrial production.

[0006] CN118255757A uses a microchannel reactor for the final oxidation step, also utilizing sodium tungstate as a catalyst and hydrogen peroxide as an oxidant. However, this method requires complex post-processing, including recrystallization, due to numerous side reactions. It also offers no advantages in terms of reaction time, and the resulting product yield is relatively low.

[0007] Although patent CN119241526B also uses a microchannel to synthesize 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole, it has problems with low content and yield, and also requires complex post-processing methods such as crystallization. In addition, it adds light source equipment and introduces photosensitizers, which has no advantage in production cost.

[0008] That is, the problems existing in the existing process are:

[0009] 1) Existing processes generally use intermittent reactions, which have problems such as excessive local concentration of hydrogen peroxide leading to excessive oxidation (generating sulfone oxide impurities), long reaction time (>8 hours), and low yield.

[0010] 2) Existing processes mostly use water-soluble solvents (such as methanol and acetonitrile) for oxidation reactions, which affects the yield of the product.

[0011] 3) Existing kettle-type reactions have low heat transfer efficiency and uneven mixing; and oxidation processes are all high-risk processes, which may pose safety risks when the reaction volume is relatively large.

[0012] 4) Although the use of microchannel reactors solves the problem of potential safety hazards to a certain extent, the problem of low yield still exists, which requires complex post-processing methods such as crystallization and recrystallization, which is not conducive to industrial production.

[0013] Therefore, a preparation method that is safer, more environmentally friendly, has higher yield and is simpler to post-process is still a technical problem that needs to be solved urgently by those skilled in the art. Summary of the Invention

[0014] Purpose of the Invention

[0015] To overcome the above-mentioned shortcomings, the object of the present invention is to provide a method for preparing 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole, which is safer, more environmentally friendly, has a higher yield, and is simple to post-process. The present invention adopts dual catalysts, which not only improves the oxidation reaction rate and conversion rate, but also reduces the process risk, and improves the product content and yield.

[0016] Solution

[0017] To achieve the purpose of the present invention, the technical solution adopted by the present invention is as follows:

[0018] In a first aspect, the present invention provides a method for preparing 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole represented by Formula I, the method comprising the following steps:

[0019] In a dual catalyst system of sodium tungstate and phase transfer catalyst, the compound of formula (II) is oxidized by hydrogen peroxide to obtain the compound of formula I;

[0020]

[0021] Furthermore, the phase transfer catalyst includes one or more of tetrabutylammonium bromide, 18-crown-6, benzyltriethylammonium chloride, and tetrabutylammonium chloride.

[0022] Furthermore, in the dual catalyst, the molar ratio of sodium tungstate to the phase transfer catalyst is 1:(0.2-5), optionally 1:(0.4-5), optionally 1:(0.6-5), optionally 1:(0.6-2), optionally 1:(0.8-2), optionally 1:(1-2), optionally 1:0.2, 1:0.4, 1:0.5, 1:0.6, 1:0.8, 1:1, 1:1.5 or 1:2, or a ratio range between any two thereof;

[0023] Furthermore, the molar ratio of the compound of formula II, the dual catalyst and hydrogen peroxide is 1:(0.001-0.05):(2-4), optionally 1:(0.003-0.02):(2.01-4), optionally 1:(0.005-0.015):(2.05-4), optionally 1:(0.006-0.015):(2.05-4), optionally 1:(0.008-0.015):(2.05-4), optionally 1:(0.006-0.015):(2.05-3), optionally 1:(0.008-0.015):(2.05-3), optionally 1:(0.008-0.015):(2.05-2.2).

[0024] Further, the molar ratio of the compound of formula II and the dual catalyst is 1:(0.001-0.05), optionally 1:(0.003-0.02), optionally 1:(0.005-0.015), optionally 1:(0.006-0.015), optionally 1:(0.008-0.015), optionally 1:0.006, 1:0.007, 1:0.008, 1:0.009, 1:0.01, 1:0.012 or 1:0.015, or a ratio range between any two thereof;

[0025] Furthermore, in the reaction system, the compound of formula II is dissolved in an organic solvent. Optionally, the organic solvent is an inert organic solvent that is immiscible with water; alternatively, the organic solvent includes a chlorine-containing organic solvent that is immiscible with water, and optionally includes any one or more of dichloromethane, 1,2-dichloroethane or chloroform;

[0026] Furthermore, the amount of the organic solvent is at least an amount sufficient to dissolve the compound of formula II. Optionally, the mass ratio of the compound of formula II to the organic solvent is 1:(2-9), optionally 1:(4-8), optionally 1:(5-6), optionally 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:9, or a range between any two values.

[0027] Furthermore, the method further comprises the following steps: after the reaction is completed, a reducing agent is added to quench excess hydrogen peroxide, wherein the reducing agent optionally comprises any one or more of sodium sulfite, sodium thiosulfate, sodium pyrosulfate, sodium hydroxide and sodium bisulfite, and optionally, the concentration of the reducing agent is 5-20%, optionally 10-20%, optionally 5%, 6%, 8%, 10%, 12%, 15%, 18%, 20%, or a range between any two values.

[0028] Further, the temperature of the oxidation reaction is 20-110°C, optionally 30-110°C, optionally 20-80°C, optionally 30-80°C, optionally 35-80°C, optionally 30-50°C, optionally 30-40°C; optionally 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 90°C, 95°C, 100°C, 110°C, 120°C, or any temperature range therebetween.

[0029] And / or, the reaction pressure is 0.1-2.0 MPa, optionally 0.1-1.0 MPa, optionally 0.12-1.0 MPa, optionally 0.3-1.0 MPa, optionally 0.1 MPa, 0.12 MPa, 0.15 MPa, 0.18 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa, 0.8 MPa, 1.0 MPa, 1.5 MPa, 2 MPa, or any pressure range therebetween.

[0030] And / or, the oxidation reaction time is 10s to 360min, optionally 10s, 20s, 30s, 40s, 50s, 60s, 70s, 90s, 120s, 10min, 20min, 30min, 40min, 50min, 60min, 80min, 100min, 120min, 150min, 200min, 250min, 300min, 360min, or any range therebetween.

[0031] Optionally, a kettle reaction is adopted, and the oxidation reaction time is 60min to 360min, optionally 120min to 360min, optionally 150min to 360min; optionally 60min, 80min, 100min, 120min, 150min, 200min, 250min, 300min, 360min, or any range therebetween.

[0032] Optionally, a tubular continuous reaction is adopted, and the oxidation reaction residence time is 10s to 100s, optionally 20s to 60s, optionally 30s to 60s, optionally 10s, 20s, 30s, 40s, 50s, 60s, or any range therebetween.

[0033] In a second aspect, a method for preparing 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole of Formula I is provided, the method comprising the following steps:

[0034] In a microchannel continuous reactor, in the presence of a dual catalyst system of sodium tungstate and a phase transfer catalyst, the compound of formula (II) is oxidized by hydrogen peroxide to obtain a compound of formula I;

[0035]

[0036] Furthermore, the microchannel continuous reactor includes a microchannel main reactor for performing a continuous oxidation reaction, and optionally further includes at least one of the following:

[0037] At least three raw material tanks for storing the compound of formula II, hydrogen peroxide and dual catalysts respectively;

[0038] a premixer for premixing the compound of formula II and the dual catalyst;

[0039] A liquid quenching kettle is used to quench excess hydrogen peroxide in the reaction solution; the reducing agent used for quenching includes any one or more of sodium sulfite, sodium thiosulfate, sodium pyrosulfate, sodium hydroxide and sodium bisulfite, and optionally, the concentration of the reducing agent is 5-20%, optionally 10-20%;

[0040] Optionally, it also includes pressure gauges and thermometers, flow meters, material transfer pumps and control systems, valves, safety valves, heat exchange control systems, high and low temperature integrated machines and various connected pipelines.

[0041] Furthermore, the compound of formula II is dissolved in an organic solvent. Optionally, the organic solvent is an inert organic solvent that is immiscible with water; optionally, the organic solvent includes a chlorine-containing organic solvent that is immiscible with water, optionally including any one or more of dichloromethane, 1,2-dichloroethane or chloroform; optionally, the amount of the organic solvent is at least an amount that dissolves the compound of formula II. Optionally, the mass ratio of the compound of formula II to the organic solvent is 1:(2 to 9), optionally 1:(4 to 8), and optionally 1:(5 to 6).

[0042] Optionally, sodium tungstate and a phase transfer catalyst are dissolved in water to form a dual catalyst aqueous solution;

[0043] Optionally, the organic solvent solution of the compound of formula II, the dual catalyst aqueous solution, and the hydrogen peroxide solution are introduced into the microchannel main reactor through independent inlets to perform a continuous oxidation reaction;

[0044] Optionally, the organic solvent solution of the compound of formula II and the dual catalyst aqueous solution are premixed and then introduced into the microchannel reactor through independent inlets with hydrogen peroxide for continuous oxidation reaction;

[0045] Optionally, the phase transfer catalyst includes one or more of tetrabutylammonium bromide, 18-crown-6, benzyltriethylammonium chloride, and tetrabutylammonium chloride;

[0046] And / or, in the dual catalyst, the molar ratio of sodium tungstate to the phase transfer catalyst is 1:(0.2-5), optionally 1:(0.4-5), optionally 1:(0.6-5), optionally 1:(0.6-2), optionally 1:(0.8-2), optionally 1:(1-2), optionally 1:0.2, 1:0.4, 1:0.5, 1:0.6, 1:0.8, 1:1, 1:1.5 or 1:2, or any ratio range between the two.

[0047] And / or, when introduced into the microchannel reactor, the molar ratio of the compound of formula II, the catalyst and the hydrogen peroxide is 1:(0.001-0.05):(2-4), optionally 1:(0.003-0.02):(2.01-4), optionally 1:(0.005-0.015):(2.05-4), optionally 1:(0.006-0.015):(2.05-4), optionally 1:(0.008-0.015):(2.05-4), optionally 1:(0.006-0.015):(2.05-3), optionally 1:(0.008-0.015):(2.05-3), optionally 1:(0.008-0.015):(2.05-2.2).

[0048] Furthermore, the molar ratio of the compound of formula II and the dual catalyst is 1:(0.001-0.05), optionally 1:(0.003-0.02), optionally 1:(0.005-0.015), optionally 1:(0.006-0.015), optionally 1:(0.008-0.015), optionally 1:0.006, 1:0.007, 1:0.008, 1:0.009, 1:0.01, 1:0.012, 1:0.015, 1:0.02, 1:0.03, 1:0.04 or 1:0.05, or any ratio range between the two.

[0049] Further, the temperature of the oxidation reaction is 30-110°C, optionally 35-110°C, optionally 30-80°C, optionally 45-80°C, optionally 55-60°C, optionally 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 90°C, 95°C, 100°C, 110°C, 120°C, or any temperature range therebetween.

[0050] And / or, the reaction pressure is 0.1-2.0 MPa, optionally 0.1-1.0 MPa, optionally 0.3-1.0 MPa, optionally 0.5-1.0 MPa, optionally 0.7-1.0 MPa, optionally 0.1 MPa, 0.12 MPa, 0.15 MPa, 0.18 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa, 0.8 MPa, 1.0 MPa, 1.5 MPa, 2 MPa, or any pressure range therebetween.

[0051] And / or, the oxidation reaction residence time is 10s to 100s, optionally 20s to 60s, optionally 30s to 60s, optionally 10s, 20s, 30s, 40s, 50s, 60s, or any range therebetween.

[0052] Optionally, a post-processing method is also included, which may include: liquid separation, water washing, and desolventizing treatment; no crystallization or precipitation step is required, and the post-processing method is simple.

[0053] As an embodiment, the microchannel reactor model is FX3000-G1, Corning (Shanghai) Management Co., Ltd.

[0054] Beneficial effects

[0055] (1) The present invention adopts a dual catalyst system, which greatly improves the reaction rate, significantly reduces the accumulation of hydrogen peroxide, reduces the risk of explosion, enhances safety, improves reaction efficiency, shortens the reaction cycle, and increases the content and yield of the product.

[0056] (2) The present invention adopts a chlorine-containing solvent that is immiscible with water. When a chlorine-containing reagent that is immiscible with water is used as a solvent, the product is dissolved in the organic phase. After water-oil phase separation, the solvent in the oil phase is desolvated to obtain the product. The product yield is significantly improved, and the solvent recovery rate is greater than 80%. The solvent recovered by desolvation has a low water content and can be directly applied. While ensuring a high yield, the solvent refining cost is reduced, which is suitable for industrial production and has good economic benefits and application value. The problem of the prior art using methanol, acetonitrile and other water-miscible solvents, resulting in a small amount of the product of formula I being dissolved in the mother liquor and the loss of the product of formula I is solved (the reason is: the product of formula I will mostly precipitate in the prior art reaction system. A solid product can be obtained by directly filtering the reaction liquid, but a small amount of the product of formula I is still dissolved in the filtrate (methanol or acetonitrile) and is directly filtered out, resulting in loss).

[0057] (3) The present invention uses a chlorine-containing solvent that is immiscible with water. During post-treatment, the aqueous phase and the organic phase are completely separated, and after the organic phase is washed with water multiple times, the tungsten impurities in the sulfonepyraclostrobin product are significantly reduced.

[0058] (4) The inventors surprisingly discovered that when the reaction system of the present invention uses dichloromethane as the solvent and tetrabutylammonium chloride as the phase transfer catalyst, the product contains very small amounts of sulfoxide impurities, and the optimal embodiment contains no sulfoxide impurities. A very high-purity product can be obtained by simple water washing and desolventizing, which solves the problem of the prior art requiring complex post-processing steps such as crystallization to obtain a high-purity product, greatly reducing energy consumption and post-processing costs.

[0059] (5) The system of the present invention exhibits superior yield and safety in a microchannel reactor. The present invention utilizes a water-immiscible solvent and the continuous flow reaction characteristics of a microchannel to address the problems of low yield and intense heat release during the oxidation reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] One or more embodiments are exemplarily illustrated by the accompanying figures, and these exemplary illustrations do not limit the embodiments. The word "exemplary" is used herein to mean "serving as an example, example, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior or preferred over other embodiments.

[0061] Figure 1 This is the LC-MS liquid phase spectrum of the product prepared in Example 1 of the present invention.

[0062] Figure 2 This is the MS spectrum of the product prepared in Example 1 of the present invention in LC-MS.

[0063] Figure 3 This is a liquid chromatogram of the white solid obtained in Example 1 of the present invention. 1.656 min is the peak position of the compound of formula I.

[0064] Figure 4 This is a liquid chromatogram of the white solid of Example 2 of the present invention. The sulfoxide peak is at 1.244 min, and the compound of Formula I peak is at 1.660 min.

[0065] Figure 5 This is a liquid chromatogram of the white solid of Example 3 of the present invention. The sulfoxide peak is at 1.261 min, and the compound of Formula I peak is at 1.670 min.

[0066] Figure 6 This is a liquid chromatogram of the white solid of Example 4 of the present invention. The sulfoxide peak is at 1.294 min, and the compound of Formula I peak is at 1.710 min.

[0067] Figure 7 This is a liquid chromatogram of the white solid obtained in Example 5 of the present invention. The sulfoxide peak is at 1.207 min, and the compound of Formula I peak is at 1.662 min.

[0068] Figure 8 This is a liquid chromatogram of the white solid of Example 6 of the present invention. The sulfoxide peak is at 1.255 min, and the compound of Formula I peak is at 1.664 min.

[0069] Figure 9 This is a liquid chromatogram of the white solid of Example 7 of the present invention. The sulfoxide peak is at 1.255 min, and the compound of Formula I peak is at 1.662 min.

[0070] Figure 10 This is the liquid chromatogram of the white solid of Comparative Example 1. The peak at 0.941 min is an unknown impurity, the peak at 1.264 min is the sulfoxide peak, and the peak at 1.678 min is the compound of Formula I.

[0071] Figure 11 This is a liquid chromatogram of the white solid of Example 8 of the present invention. The sulfoxide peak is at 1.209 min, and the compound of Formula I peak is at 1.665 min.

[0072] Figure 12 This is a liquid chromatogram of the white solid of Comparative Example 2 of the present invention. 1.250 min is the peak position of sulfoxide, and 1.658 min is the peak position of the compound of formula I.

[0073] Figure 13 This is a liquid chromatogram of the white solid of Comparative Example 3 of the present invention. 1.283 min is the peak position of sulfoxide, and 1.695 min is the peak position of the compound of formula I.

[0074] Figure 14 This is a liquid chromatogram of the white solid of Example 9 of the present invention. 0.937 min is an unidentified impurity, 1.259 min is the elution position of sulfoxide, and 1.668 min is the elution position of the compound of Formula I.

[0075] Figure 15 This is a liquid chromatogram of the white solid of Example 11 of the present invention. The sulfoxide peak is at 1.381 min, and the compound of Formula I peak is at 1.711 min.

[0076] Figure 16 This is a liquid chromatogram of the white solid of Comparative Example 4 of the present invention. 1.252 min is the sulfoxide peak position, 1.658 min is the compound of Formula I peak position, and 2.459 min is the raw material sulfide peak position.

[0077] Figure 17 1 is a flow chart of the synthesis of the compound of formula I in Example 12 of the present invention.

[0078] Figure 18 This is a liquid chromatogram of the white solid of Example 12 of the present invention. The sulfoxide peak is at 1.280 min, and the compound of Formula I peak is at 1.681 min.

[0079] Figure 19 This is a liquid chromatogram of the white solid of Example 13 of the present invention. The sulfoxide peak is at 1.294 min, and the compound of Formula I peak is at 1.710 min. DETAILED DESCRIPTION

[0080] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0081] In addition, in order to better illustrate the present invention, numerous specific details are provided in the following specific embodiments. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In some embodiments, raw materials, schemes, methods, means, etc. well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0082] Unless expressly stated otherwise, throughout the specification and claims, the term "comprise" or variations such as "include" or "comprising", etc., will be understood to include the stated elements or components but not to exclude other elements or other components.

[0083] The product contents in the following examples were confirmed by liquid chromatography or gas chromatography. If not otherwise specified, the reaction process was tracked by liquid chromatography (LC), and the yield was determined by external standard method.

[0084] The present invention uses sodium tungstate and a phase transfer catalyst as a dual catalyst system, performs an oxidation reaction on an organic solution of a compound of formula (II) and hydrogen peroxide, and after the reaction is completed, sequentially performs quenching, liquid separation, water washing, and solvent removal on the reaction solution to obtain 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole of formula (I).

[0085]

[0086] The phase transfer catalyst is a quaternary ammonium salt, which may optionally include any one or more of tetrabutylammonium bromide, 18-crown-6, benzyltriethylammonium chloride, and tetrabutylammonium chloride.

[0087] Impurities that may be produced by the reaction include sulfoxide impurities, as shown in Formula III.

[0088]

[0089] The method of the present invention can adopt a tank reaction or a pipeline continuous reaction. Some embodiments are as follows:

[0090] I. Tank reaction:

[0091] Example 1

[0092] To a 100 mL three-necked reaction flask, 20 mL of dichloromethane was added, followed by the addition of the compound of formula II (3.59 g, 0.01 mol, 1 eq). After stirring and dissolving, sodium tungstate dihydrate (0.016 g, 0.05 mmol, 0.005 eq) and tetrabutylammonium chloride (0.014 g, 0.05 mmol, 0.005 eq) were added in sequence. The system temperature was controlled at 35° C., and hydrogen peroxide (2.535 g, 27.5%, 0.0205 mol, 2.05 eq) was added dropwise to the system. After the addition was complete, stirring was continued at the same temperature for 3 h. The reaction was detected to be complete by liquid chromatography.

[0093] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL tubes to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), and then the organic phase was desolvated to obtain 3.84 g of the compound of Formula I as a white solid, with a yield of 98.1%.

[0094] To confirm that the product is the compound of formula I, the LC-MS spectrum of the white solid in this example is as follows Figure 1 and Figure 2 As shown, analysis confirmed that the product was the target compound represented by Formula I. (LC-MS / MS conditions: Instrument: LC-MS 6520B-QTOF, chromatographic column C18, mobile phase: acetonitrile and 0.05% phosphoric acid aqueous solution; flow rate: 0.4 ml / min; gradient elution: acetonitrile: phosphoric acid aqueous solution, volume ratio: 1:1, 0-20 min; acetonitrile: phosphoric acid aqueous solution, volume ratio: 9:1, 20-45 min).

[0095] The purity of the obtained white solid compound of formula I was determined using an Agilent 1260 liquid chromatograph. The detection conditions were: Agilent HPH-C18 stainless steel column, 100 mm x 3.6 mm, particle size 2.7 μm, mobile phase: acetonitrile: 0.05% phosphoric acid aqueous solution = 50:50, wavelength 210 nm, sample solvent: acetonitrile, sample concentration: 10 mg / ml, injection volume: 0.2 μL.

[0096] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 3 As shown. Figure 3 It can be seen that the product obtained in this example does not contain the sulfoxide impurity represented by Formula III, and the content of the target compound represented by Formula I is 100%.

[0097] Example 2

[0098] To a 100 mL three-necked reaction flask, 20 mL of dichloromethane was added, followed by the addition of the compound of formula II (3.59 g, 0.01 mol, 1 eq). After stirring and dissolving, sodium tungstate dihydrate (0.016 g, 0.05 mmol, 0.005 eq) and tetrabutylammonium bromide (0.016 g, 0.05 mmol, 0.005 eq) were added in sequence. The system temperature was controlled at 35° C., and hydrogen peroxide (2.535 g, 27.5%, 0.0205 mol, 2.05 eq) was added dropwise to the system. After the addition was complete, stirring was continued at the same temperature for 4 h. The reaction was detected to be complete by liquid chromatography.

[0099] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL tubes to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), followed by solvent removal, to yield 3.82 g of compound of Formula I as a white solid, in a 97.5% yield.

[0100] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 4 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 4 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 0.19%, and the purity of the target compound represented by Formula I is 99.81%.

[0101] Example 3

[0102] To a 100 mL three-necked reaction flask, 20 mL of dichloromethane was added, followed by the compound of formula II (3.59 g, 0.01 mol, 1 eq). After stirring and dissolving, sodium tungstate dihydrate (0.016 g, 0.05 mmol, 0.005 eq) and tetrabutylammonium chloride (0.003 g, 0.01 mmol, 0.001 eq) were added in sequence. The system temperature was controlled at 35 ° C. Hydrogen peroxide (2.535 g, 27.5%, 0.0205 mol, 2.05 eq) was added dropwise to the system. After the addition was complete, stirring was continued at the same temperature for 7 h. The reaction was detected to be complete by liquid chromatography.

[0103] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL tubes to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), and then the organic phase was desolvated to obtain 3.90 g of the compound of Formula I as a white solid, with a yield of 95.1%.

[0104] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 5 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 5 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 4.5%, and the purity of the target compound represented by Formula I is 95.5%.

[0105] Example 4

[0106] To a 100 mL three-necked reaction flask, 20 mL of dichloromethane was added, followed by the addition of the compound of formula II (3.59 g, 0.01 mol, 1 eq). After stirring and dissolving, sodium tungstate dihydrate (0.016 g, 0.05 mmol, 0.005 eq) and tetrabutylammonium chloride (0.009 g, 0.03 mmol, 0.003 eq) were added in sequence. The system temperature was controlled at 35° C., and hydrogen peroxide (2.535 g, 27.5%, 0.0205 mol, 2.05 eq) was added dropwise to the system. After the addition was complete, stirring was continued at the same temperature for 5 h. The reaction was detected to be complete by liquid chromatography.

[0107] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL tubes to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), and then the organic phase was desolventized to obtain 3.85 g of the compound of Formula I as a white solid, with a yield of 97.7%.

[0108] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 6 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 6 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 0.71%, and the purity of the target compound represented by Formula I is 99.29%.

[0109] Example 5

[0110] To a 100 mL three-necked reaction flask, 20 mL of dichloromethane was added, followed by the addition of the compound of formula II (3.59 g, 0.01 mol, 1 eq). After stirring and dissolving, sodium tungstate dihydrate (0.016 g, 0.05 mmol, 0.005 eq) and tetrabutylammonium chloride (0.028 g, 0.1 mmol, 0.01 eq) were added in sequence. The system temperature was controlled at 35° C., and hydrogen peroxide (2.535 g, 27.5%, 0.0205 mol, 2.05 eq) was added dropwise to the system. After the addition was complete, stirring was continued at the same temperature for 2 h. The reaction was detected to be complete by liquid chromatography.

[0111] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL tubes to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), and then the organic phase was desolvated to obtain 3.85 g of the compound of Formula I as a white solid, with a yield of 97.8%.

[0112] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 7 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 7 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 0.5%, and the purity of the target compound represented by Formula I is 99.5%.

[0113] Example 6

[0114] To a 100 mL three-necked reaction flask, 20 mL of dichloromethane was added, followed by the addition of the compound of formula II (3.59 g, 0.01 mol, 1 eq). After stirring and dissolving, sodium tungstate dihydrate (0.016 g, 0.05 mmol, 0.005 eq) and benzyltriethylammonium chloride (0.011 g, 0.05 mmol, 0.005 eq) were added in sequence. The system temperature was controlled at 35° C., and hydrogen peroxide (2.535 g, 27.5%, 0.0205 mol, 2.05 eq) was added dropwise to the system. After the addition was complete, stirring was continued at the same temperature for 5 h. The reaction was detected to be complete by liquid chromatography.

[0115] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL tubes to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), and then the organic phase was desolvated to obtain 3.83 g of the compound of Formula I as a white solid, with a yield of 96.8%.

[0116] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 8 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 8 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 1.08%, and the purity of the target compound represented by Formula I is 98.92%.

[0117] Example 7

[0118] To a 100 mL three-necked reaction flask, 20 mL of dichloromethane was added, followed by the addition of the compound of formula II (3.59 g, 0.01 mol, 1 eq). After stirring and dissolving, sodium tungstate dihydrate (0.016 g, 0.05 mmol, 0.005 eq) and 18-crown-6 (0.013 g, 0.05 mmol, 0.005 eq) were added in sequence. The system temperature was controlled at 35 ° C. Hydrogen peroxide (2.535 g, 27.5%, 0.0205 mol, 2.05 eq) was added dropwise to the system. After the addition was complete, stirring was continued at the same temperature for 8 h. The reaction was detected to be complete by liquid chromatography.

[0119] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL tubes to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), followed by solvent removal, to yield 3.88 g of compound of Formula I as a white solid, in a 95.2% yield.

[0120] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 9 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 9 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 3.89%, and the purity of the target compound represented by Formula I is 96.11%.

[0121] Comparative Example 1

[0122] To a 100mL three-necked reaction flask, 20mL of dichloromethane was added, followed by the addition of the compound of formula II (3.59g, 0.01mol, 1eq). After stirring and dissolving, sodium tungstate dihydrate (0.016g, 0.05mmol, 0.005eq) was added. The system temperature was controlled at 35°C, and hydrogen peroxide (2.535g, 27.5%, 0.0205mol, 2.05eq) was added dropwise. After the addition was complete, stirring was continued at the same temperature for 10h, and the reaction was detected by liquid chromatography to be complete.

[0123] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL tubes to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), and then the organic phase was desolvated to yield 3.87 g of compound of Formula I as a white solid, with a yield of 75.8%.

[0124] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 10 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 10 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 21.51%, and the purity of the target compound represented by Formula I is 76.60%.

[0125] The comparison results of Examples 1 to 6 and Comparative Example 1 are shown in Table 1.

[0126] Table 1. Reaction results corresponding to different phase transfer catalyst types and dosages

[0127]

[0128]

[0129] As shown in Table 1, the use of a dual catalyst of sodium tungstate and a phase transfer catalyst can not only accelerate the reaction process, but also effectively improve the production efficiency and yield. The content of sulfoxide impurities in the obtained product is extremely low, and a product of extremely high purity can be obtained by simple water washing and desolvation.

[0130] In Comparative Example 1, even when water-immiscible dichloromethane was used as the solvent and no phase transfer catalyst was added, the reaction rate was significantly reduced, requiring 10 hours of reaction for the raw materials to react completely. Not only was the yield low, but the product also contained 21.51% of the sulfoxide impurity represented by Formula III, requiring complex post-processing steps such as crystallization to further obtain a high-purity product.

[0131] In addition, the inventors surprisingly found that when tetrabutylammonium chloride was used as a phase transfer catalyst, not only was the yield high, but the product did not contain the sulfoxide impurity of formula III; while when tetrabutylammonium bromide, benzyltriethylammonium chloride, and 18-crown-6 were used as phase transfer catalysts, the product contained a small amount of the sulfoxide impurity of formula III, but the purity was still much higher than that of Comparative Example 1.

[0132] Example 8

[0133] To a 100 mL three-necked reaction flask, 20 mL of 1,2-dichloroethane was added, followed by the addition of the compound of formula II (3.59 g, 0.01 mol, 1 eq). After stirring and dissolving, sodium tungstate dihydrate (0.016 g, 0.05 mmol, 0.005 eq) and tetrabutylammonium chloride (0.014 g, 0.05 mmol, 0.005 eq) were added in sequence. The system temperature was controlled at 35 ° C. Hydrogen peroxide (2.535 g, 27.5%, 0.0205 mol, 2.05 eq) was added dropwise to the system. After the addition was completed, stirring was continued at the same temperature for 4 h. The reaction was detected to be complete by liquid chromatography.

[0134] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL x 10 mL to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), followed by solvent removal, to yield 3.83 g of compound of Formula I as a white solid, in a 97.1% yield.

[0135] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 11 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 11 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 0.8%, and the purity of the target compound represented by Formula I is 99.2%.

[0136] Comparative Example 2

[0137] To a 100mL three-necked reaction flask, 20mL of acetonitrile was added, followed by the addition of a compound of formula II (3.59g, 0.01mol, 1eq). After stirring and dissolving, sodium tungstate dihydrate (0.016g, 0.05mmol, 0.005eq) was added in sequence. The system temperature was controlled at 35°C, and hydrogen peroxide (2.535g, 27.5%, 0.0205mol, 2.05eq) was added dropwise. After reacting for 3h, liquid chromatography detected the reaction solution, and the intermediate sulfoxide was not completely reacted. After continuing to stir for 3h, the reaction was terminated. 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. The addition was stopped when the starch potassium iodide test paper did not turn blue. Water (10mL) was added to the system, stirred thoroughly, filtered, and dried over the filter cakes to obtain 3.90g of a white solid compound of formula I in a yield of 92.4%. The filtered mother liquor is desolventized and refined to remove water to reach the standard solvent recovery application.

[0138] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 12 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 12 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 7.39%, and the purity of the target compound represented by Formula I is 92.61%.

[0139] Comparative Example 3

[0140] Add 20mL of ethanol to a 100mL three-necked reaction flask, then add the compound of formula II (3.59g, 0.01mol, 1eq), stir and dissolve, then add sodium tungstate dihydrate (0.016g, 0.05mmol, 0.005eq), control the system temperature to 35°C, start to drip hydrogen peroxide (2.535g, 27.5%, 0.0205mol, 2.05eq) into the system, react for 3h, liquid chromatography detection reaction solution, there is intermediate sulfoxide unreacted, continue stirring for 3h, the reaction ends. Add 10% sodium sulfite solution to the system to quench the excess hydrogen peroxide, stop dripping when the starch potassium iodide test paper does not turn blue. Add water (10mL) to the system, stir thoroughly, filter, filter cake dry, and obtain 3.87g of the compound of formula I as a white solid, with a yield of 92.6%. After the mother liquor filtered out is desolventized, refined and dehydrated to meet the standard solvent recovery requirements.

[0141] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 13 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 13 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 6.31%, and the purity of the target compound represented by Formula I is 93.69%.

[0142] Table 2. Reaction results corresponding to different solvents

[0143]

[0144] The detection method of tungsten content in the samples in Table 2 is as follows: the samples were burned in a muffle furnace at 400°C, digested with hydrofluoric acid and nitric acid, and then detected by OES (atomic emission spectrometer).

[0145] As shown in Table 2, the following problems exist when using alcohols or acetonitrile as solvents: (1) The compound of formula I has a certain solubility in the mother liquor after filtration (Comparative Examples 2 and 3 contain 1.2% and 1.5% of the compound of formula I, respectively), resulting in a reduced yield and increased difficulty in treating the mother liquor and wastewater. (2) After desolventizing the mother liquor containing alcohols or acetonitrile, the recovered solvent contains a large amount of water and requires further treatment before it can be recycled, further increasing the recycling cost. (3) When using alcohols or acetonitrile as solvents, it has been found that the content of transition metal tungsten in the product is significantly higher than that of dichloromethane or 1,2-dichloroethane, which has a certain impact on subsequent preparation processing and the ecological environment.

[0146] The raw material cost of the present invention is lower, and a comparison is made between Example 1 and Comparative Example 2, as shown in the following table.

[0147]

[0148]

[0149] As can be seen from the above table, for every ton of compound of formula I produced, the raw material cost can be saved by RMB 8,800 compared with that of Comparative Example 2 by adopting the method of Example 1 of the present invention.

[0150] In addition, the solvent (e.g., dichloromethane) of the present invention is easier to recover and can be easily separated from the aqueous phase. It can be recovered by simply distilling off the solvent. In contrast, the acetonitrile or alcohol mother liquor of the comparative example needs to be purified to remove water (e.g., membrane separation or distillation) because it is miscible with water, which greatly increases the recovery cost and energy consumption. For example, the energy consumption for recovering one ton of dichloromethane is 144 yuan less than that for recovering one ton of acetonitrile mother liquor (containing water).

[0151] Example 9

[0152] To a 100 mL three-necked reaction flask, 20 mL of dichloromethane was added, followed by the addition of the compound of formula II (3.59 g, 0.01 mol, 1 eq). After stirring and dissolving, sodium tungstate dihydrate (0.016 g, 0.05 mmol, 0.005 eq) and tetrabutylammonium chloride (0.014 g, 0.05 mmol, 0.005 eq) were added in sequence. The system temperature was controlled at 35° C., and hydrogen peroxide (2.473 g, 27.5%, 0.020 mol, 2.00 eq) was added dropwise to the system. After the addition was complete, stirring was continued at the same temperature for 5 h, and the reaction was detected by liquid chromatography to be complete.

[0153] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL tubes to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), and then the organic phase was desolvated to obtain 3.75 g of the compound of Formula I as a white solid, with a yield of 87.1%.

[0154] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 14 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 14 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 7.92%, and the purity of the target compound represented by Formula I is 90.998%.

[0155] Example 10

[0156] To a 100 mL three-necked reaction flask, 20 mL of dichloromethane was added, followed by the addition of the compound of formula II (3.59 g, 0.01 mol, 1 eq). After stirring and dissolving, sodium tungstate dihydrate (0.016 g, 0.05 mmol, 0.005 eq) and tetrabutylammonium chloride (0.014 g, 0.05 mmol, 0.005 eq) were added in sequence. The system temperature was controlled at 35° C., and hydrogen peroxide (2.597 g, 27.5%, 0.021 mol, 2.10 eq) was added dropwise to the system. After the addition was complete, stirring was continued at the same temperature for 3 h, and the reaction was detected by liquid chromatography to be complete.

[0157] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 10 mL tubes to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), followed by solvent removal, to yield 3.84 g of compound of Formula I as a white solid, in a 98.1% yield.

[0158] The liquid chromatography of the white solid obtained in this example showed that the purity of the target compound represented by Formula I was 100%.

[0159] Table 3. Reaction results corresponding to different reaction times

[0160] Example Hydrogen peroxide dosage Reaction time (h) Yield (%) content(%) Example 1 2.05 3 98.1 100 Example 9 2.00 5 87.1 90.998 Example 10 2.10 3 98.1 100

[0161] As can be seen from the above table, a slightly excessive amount of hydrogen peroxide is helpful in producing the target product.

[0162] Example 11 Amplification reaction

[0163] To a 1000L reactor, 200L of dichloromethane was added, followed by the compound of formula II (35.9Kg, 100mol, 1eq). After stirring and dissolving, sodium tungstate dihydrate (160g, 0.5mol, 0.005eq) and tetrabutylammonium chloride (140g, 0.5mol, 0.005eq) were added in sequence. The system temperature was controlled at 35°C, and hydrogen peroxide (25.35kg, 27.5%, 205mol, 2.05eq) was added dropwise to the system. After the addition was complete, stirring was continued at the same temperature for 3h, and the reaction was detected by liquid chromatography to confirm completion.

[0164] After the reaction, 10% sodium sulfite solution was added dropwise to quench the excess hydrogen peroxide. Addition was stopped when the starch potassium iodide test paper stopped turning blue. After thorough stirring, the mixture was allowed to stand for separation. The organic phase was washed with water (3 times 100 L to remove water-soluble impurities such as sodium tungstate and the phase transfer catalyst), followed by solvent removal, to yield 38.45 kg of the compound of Formula I as a white solid, with a yield of 98.0%.

[0165] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 15 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 15 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 0.23%, and the purity of the target compound represented by Formula I is 99.77%.

[0166] Comparative Example 4

[0167] To a 100mL three-necked reaction flask, 20mL of dichloromethane was added, followed by the addition of the compound of formula II (3.59g, 0.01mol, 1eq). After stirring and dissolving, tetrabutylammonium chloride (0.014g, 0.05mmol, 0.005eq) was added. The system temperature was controlled at 35°C, and hydrogen peroxide (2.535g, 27.5%, 0.0205mol, 2.05eq) was added dropwise. After the addition was completed, stirring was continued at this temperature for 10h. The liquid chromatogram of the white solid obtained in this comparative example was as shown below. Figure 16 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 16 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 4.44%, the raw material remains 70.74%, and the content of the compound of Formula I is only 24.83%.

[0168] According to the reaction results, in Comparative Example 4, only a single phase transfer catalyst was added, a large amount of raw materials remained, and both the raw material conversion rate and the product yield were low.

[0169] II. Microchannel Reaction

[0170] Example 12

[0171] The flow chart for synthesizing the compound of formula I is as follows Figure 17 shown; specifically:

[0172] 1) Material Preparation: At room temperature, the thioether compound of formula (II) (359.3 g, 1 mol, 1 eq) was dissolved in 1.5 L of dichloromethane and temporarily stored in storage tank 1; hydrogen peroxide (253.5 g, 27.5%, 2.05 mol, 2.05 eq) was placed in storage tank 2, and sodium tungstate dihydrate (1.65 g, 0.005 mol, 0.005 eq) and tetrabutylammonium chloride (1.39 g, 0.005 mol, 0.005 eq) were dissolved in water (200 mL) and placed in storage tank 3 as a dual catalyst solution.

[0173] 2) The microchannel reactor was preheated to about 30 ° C, and then the dichloromethane solution of the compound of formula (II) in storage tank 1 and the catalyst system solution in storage tank 3 were respectively injected into the first microchannel pre-reactor at a molar ratio of 1:0.005 (molar ratio of the compound of formula (II) to the dual catalyst solution) using a metering pump to mix. Then, the hydrogen peroxide solution in storage tank 2 was injected into the main reactor of the microchannel reactor at a molar ratio of 1:2.05 (molar ratio of the compound of formula (II) to hydrogen peroxide) using a metering pump to mix with the previous materials. The main channel was controlled at 55 ° C, the pressure was 0.7 MPa, and the reaction residence time was 30 s. The outlet channel was then cooled for 70 s, and the material flowing out of the channel outlet was sampled and tested. The raw material conversion was complete and the material was collected into a 5L reaction bottle.

[0174] 3) Add 10% sodium sulfite solution to the 5 L reaction flask where the collected material was collected to quench the reaction and stir for 10 min.

[0175] 4) The reaction mixture was allowed to stand for separation, and the collected organic phase was washed with water, dried, and desolventized to obtain 388.2 g of a white solid compound of formula I with a yield of 99.08% and a content of 99.87%.

[0176] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 18 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 18 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 0.13%, and the content of the target compound represented by Formula I is 99.87%.

[0177] Example 13

[0178] The compound of Formula I was synthesized according to the method of Example 12, except that the materials in the three storage tanks were simultaneously introduced into the mixing zone of the reactor using metering pumps at a molar ratio of 1:0.005:2.05 (molar ratio of the compound of Formula (II), the dual catalyst solution, and hydrogen peroxide). Under the same reaction conditions, 385.4 g of the corresponding compound of Formula I was obtained with a yield of 97.8% and a content of 99.29%.

[0179] The liquid chromatogram of the white solid obtained in this embodiment is as follows Figure 19 As shown (the analysis and detection method is the same as the detection method described in Example 1). Figure 19 It can be seen that the content of the sulfoxide impurity represented by Formula III in the product obtained in this example is 0.71%, and the content of the target compound represented by Formula I is 99.29%.

[0180] Compared with Example 12, the content and yield of the product in Example 13 are relatively low. The inventors believe that the premature introduction of hydrogen peroxide leads to premature decomposition of hydrogen peroxide, which reduces the concentration of the oxidant and directly affects its oxidizing ability, resulting in a small amount of intermediate sulfoxide remaining, resulting in low product content and yield.

[0181] Example 14

[0182] The compound of formula I was synthesized by referring to the method of Example 12, except that the dichloromethane solvent was replaced with 1,2-dichloroethane. Under the same reaction conditions, 387.9 g of the corresponding compound of formula I was obtained with a yield of 98.2% and a content of 99.1%.

[0183] Example 15

[0184] The compound of formula I was synthesized by referring to the method of Example 12, except that the phase transfer catalyst was replaced with tetrabutylammonium bromide (1.612 g, 0.005 mol, 0.005 eq). Under the same reaction conditions, 386.6 g of compound of formula I was obtained with a yield of 97.2% and a content of 98.4%.

[0185] Examples 16-21

[0186] The compound of formula I was synthesized by referring to the method of Example 12, except that different phase transfer catalysts and concentrations of the phase transfer catalysts (adjusted according to the dosage) were used. The results are shown in Table 4.

[0187] Table 4. Reaction results of different phase transfer catalyst types and dosages

[0188] Example Phase transfer catalyst Dosage (mol) Yield (%) content(%) Example 12 Tetrabutylammonium chloride 0.005 99.08 99.87 Example 15 Tetrabutylammonium bromide 0.005 97.2 98.4 Example 16 Tetrabutylammonium chloride 0.004 98.0 98.9 Example 17 Tetrabutylammonium chloride 0.01 98.4 99.4 Example 18 Tetrabutylammonium bromide 0.01 97.9 98.9 Example 19 Benzyltriethylammonium chloride 0.005 97.8 98.7 Example 20 18-Crown-6 0.005 96.2 97.1 Example 21 — — 94.5 90.2

[0189] Example 22

[0190] The compound of formula I was synthesized by referring to the method of Example 12, except that the temperature of the mixed reaction zone was increased to 80° C. Under the same reaction conditions, 390.2 g of compound of formula I was obtained with a yield of 97.9% and a content of 98.2%.

[0191] Compared with Example 12, the content of the compound of formula I in Example 22 has a decreasing trend. After research, the inventors believe that increasing the temperature of the mixed oxidation reaction will cause the generation of impurities at high temperatures.

[0192] Examples 23-27

[0193] The compound of formula I was synthesized by referring to the method of Example 12, except that different temperatures were used. The reaction results are shown in Table 5.

[0194] Table 5. Reaction results at different temperatures

[0195] Example Reaction temperature (℃) Yield (%) content(%) Example 12 55 99.08 99.87 Example 22 80 97.9 98.2 Example 23 45 97.4 98.0 Example 24 60 98.4 99.3 Example 25 70 97.8 98.6 Example 26 100 97.0 98.0 Example 27 110 96.8 97.5

[0196] Example 28

[0197] The compound of formula I was synthesized by referring to the method of Example 12, except that the residence time in the oxidation reaction zone was extended to 40 s. Under the same reaction conditions, 387.8 g of compound of formula I was obtained with a yield of 98.4% and a content of 99.3%.

[0198] Compared with Example 12, extending the oxidation reaction residence time has little effect on the content and yield of the product.

[0199] Example 29

[0200] The compound of formula I was synthesized by referring to the method of Example 12, except that the residence time in the oxidation reaction zone was shortened to 20 s. Under the same reaction conditions, 386.9 g of compound of formula I was obtained with a yield of 97.1% and a content of 98.2%.

[0201] Compared with Example 12, Example 29 shortens the residence time of the oxidation reaction, and the intermediate sulfoxide is not completely converted, resulting in low product content and yield.

[0202] Examples 30-31

[0203] The compound of formula I was synthesized by referring to the method of Example 12, except that different residence times were used. The reaction results are shown in Table 6.

[0204] Table 6. Reaction results at different residence times

[0205] Example Residence time (s) Yield (%) content(%) Example 12 30 99.08 99.87 Example 28 40 98.4 99.3 Example 29 20 97.1 98.2 Example 30 35 98.4 99.4 Example 31 60 98.5 99.1

[0206] Examples 32-34

[0207] With reference to the synthesis method of Example 12, the reaction pressure of the microchannel reaction was studied. The reaction results are shown in Table 7.

[0208] Table 7. Reaction results under different pressures

[0209]

[0210]

[0211] Examples 35-40

[0212] The compound of formula I was synthesized according to the method of Example 12, except that the organic solvent used was recycled dichloromethane. Under the same reaction conditions, 388.0 g of compound of formula I was obtained with a yield of 98.4% and a content of 99.2%. The dichloromethane was recovered by atmospheric distillation in this example.

[0213] Compared with Example 12, Example 35 uses recycled solvent, which does not affect the content and yield of the product.

[0214] The recovered dichloromethane was used as the solvent and multiple application tests were carried out. It was verified that the recovered dichloromethane had no significant effect on the reaction results and yield. The reaction results are shown in Table 8.

[0215] The solvent application is to collect the solvents recovered each time in Examples 12 and 15 to 34 and apply them together, collect the solvents recovered in the first application again and use them for the second application, and so on.

[0216] Table 8. Dichloromethane reaction results

[0217] Example Number of applications Yield (%) content(%) Recovered dichloromethane content (%) Water content (%) Example 12 0 99.08 99.87 98.3 1.0 Example 36 1 98.4 99.2 98.1 1.2 Example 37 2 98.0 99.0 98.0 1.2 Example 38 3 98.2 98.9 98.2 1.1 Example 39 4 98.1 99.0 98.0 1.1 Example 40 5 98.3 99.1 98.0 1.0

[0218] In summary, the present invention adopts a chlorinated solvent and a dual catalyst system that is immiscible with water, which enhances safety, can accelerate the reaction, avoids the accumulation of large amounts of hydrogen peroxide, reduces the risk of explosion, and shortens the reaction time; the chlorinated reagent reduces the content of the compound of formula I in the mother liquor compared to the organic solvent miscible with water, and the product yield is significantly improved, and the solvent recovery rate is greater than 80%. The solvent recovered by desolventizing has a low water content and can be directly applied, reducing the solvent refining cost, being suitable for industrial production, and having good economic benefits and application value. The system of the present invention shows better yield and safety in a microchannel reactor.

[0219] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for preparing 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole of formula I, characterized in that: The method comprises the following steps: In a dual catalyst system of sodium tungstate and phase transfer catalyst, the compound of formula (II) is oxidized by hydrogen peroxide to obtain the compound of formula I; 2. The preparation method according to claim 1, characterized in that The phase transfer catalyst includes one or more of tetrabutylammonium bromide, 18-crown-6, benzyltriethylammonium chloride and tetrabutylammonium chloride.

3. The preparation method according to claim 1 or 2, characterized in that In the dual catalyst, the molar ratio of sodium tungstate to the phase transfer catalyst is 1:(0.2-5), optionally 1:(0.4-5), optionally 1:(0.6-5), optionally 1:(0.6-2), optionally 1:(0.8-2), optionally 1:(1-2), optionally 1:0.2, 1:0.6, 1:1 or 1:2; And / or, the molar ratio of the compound of formula II, the dual catalyst, and hydrogen peroxide is 1:(0.001-0.05):(2-4), optionally 1:(0.003-0.02):(2.01-4), optionally 1:(0.005-0.015):(2.05-4), optionally 1:(0.006-0.015):(2.05-4), optionally 1:(0.008-0.015):(2.05-4), optionally 1:(0.006-0.015):(2.05-3), optionally 1:(0.008-0.015):(2.05-3), optionally 1:(0.008-0.015):(2.05-2.2); And / or, the molar ratio of the compound of formula II and the dual catalyst is 1:(0.001-0.05), optionally 1:(0.003-0.02), optionally 1:(0.005-0.015), optionally 1:(0.006-0.015), optionally 1:(0.008-0.015), optionally 1:0.006, 1:0.007, 1:0.008, 1:0.009, 1:0.01, 1:0.012, 1:0.015, 1:0.02, 1:0.03, 1:0.04 or 1:0.

05.

4. The preparation method according to any one of claims 1 to 3, characterized in that In the reaction system, the compound of formula II is dissolved in an organic solvent. Optionally, the organic solvent is an inert organic solvent that is immiscible with water; alternatively, the organic solvent includes a chlorine-containing organic solvent that is immiscible with water, and optionally includes any one or more of dichloromethane, 1,2-dichloroethane or chloroform; Optionally, the amount of the organic solvent is at least enough to dissolve the compound of formula II. Optionally, the mass ratio of the compound of formula II to the organic solvent is 1:(2-9), optionally 1:(4-8), optionally 1:(5-6).

5. The preparation method according to any one of claims 1 to 4, characterized in that The method further comprises the following steps: adding a reducing agent to quench excess hydrogen peroxide after the reaction is completed, wherein the reducing agent comprises any one or more of sodium sulfite, sodium thiosulfate, sodium pyrosulfate, sodium hydroxide and sodium bisulfite, and wherein the concentration of the reducing agent is 5-20%, and optionally 10-20%; And / or, it also includes a post-processing method, which optionally includes: liquid separation, water washing, and desolventizing treatment.

6. The preparation method according to any one of claims 1 to 5, characterized in that The temperature of the oxidation reaction is 20-110° C., optionally 30-110° C., optionally 20-80° C., optionally 30-80° C., optionally 35-80° C., optionally 30-60° C., optionally 30-50° C., optionally 30-40° C.; and / or, the reaction pressure is 0.1 to 2.0 MPa, optionally 0.1 to 1.0 MPa, optionally 0.12 to 1.0 MPa, optionally 0.3 to 1.0 MPa; and / or, the oxidation reaction time is 10s to 360min, Optionally, a kettle reaction is adopted, and the oxidation reaction time is 60 min to 360 min, optionally 120 min to 360 min, optionally 150 min to 360 min; Optionally, a tubular continuous reaction is adopted, and the oxidation reaction residence time is 10s to 100s, optionally 20s to 60s, optionally 30s to 60s.

7. A method for preparing 3-(((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)sulfonyl)-5,5-dimethyl-4,5-dihydroisoxazole of Formula I, characterized in that: The method comprises the following steps: In a microchannel continuous reactor, in the presence of a dual catalyst system of sodium tungstate and a phase transfer catalyst, the compound of formula (II) is oxidized by hydrogen peroxide to obtain a compound of formula I; 8. The preparation method according to claim 7, characterized in that The microchannel continuous reactor includes a microchannel main reactor for performing a continuous oxidation reaction, and optionally further includes at least one of the following: At least three raw material tanks for storing the compound of formula II, hydrogen peroxide and dual catalysts respectively; a premixer for premixing the compound of formula II and the dual catalyst; A liquid quenching kettle is used to quench excess hydrogen peroxide in the reaction solution; the reducing agent used for quenching includes any one or more of sodium sulfite, sodium thiosulfate, sodium pyrosulfate, sodium hydroxide and sodium bisulfite, and optionally, the concentration of the reducing agent is 5-20%, optionally 10-20%; Optionally, it also includes pressure gauges and thermometers, flow meters, material transfer pumps and control systems, valves, safety valves, heat exchange control systems, high and low temperature integrated machines and various connected pipelines; And / or, it also includes a post-processing method, which optionally includes: liquid separation, water washing, and desolventizing treatment.

9. The preparation method according to claim 7 or 8, characterized in that The compound of formula II is dissolved in an organic solvent, optionally, the organic solvent is an inert organic solvent that is immiscible with water; optionally, the organic solvent includes a chlorine-containing organic solvent that is immiscible with water, optionally including any one or more of dichloromethane, 1,2-dichloroethane or chloroform; optionally, the amount of the organic solvent is at least an amount that dissolves the compound of formula II, optionally, the mass ratio of the compound of formula II to the organic solvent is 1:(2-9), optionally 1:(4-8), optionally 1:(5-6); Optionally, sodium tungstate and a phase transfer catalyst are dissolved in water to form a dual catalyst aqueous solution; Optionally, the organic solvent solution of the compound of formula II, the dual catalyst aqueous solution, and the hydrogen peroxide solution are introduced into the microchannel main reactor through independent inlets to perform a continuous oxidation reaction; Optionally, the organic solvent solution of the compound of formula II and the dual catalyst aqueous solution are premixed and then introduced into the microchannel reactor through independent inlets with hydrogen peroxide for continuous oxidation reaction; Optionally, the phase transfer catalyst includes one or more of tetrabutylammonium bromide, 18-crown-6, benzyltriethylammonium chloride, and tetrabutylammonium chloride; And / or, in the dual catalyst, the molar ratio of sodium tungstate to the phase transfer catalyst is 1:(0.2-5), optionally 1:(0.4-5), optionally 1:(0.6-5), optionally 1:(0.6-2), optionally 1:(0.8-2), optionally 1:(1-2), optionally 1:0.2, 1:0.6, 1:1 or 1:2; And / or, when passing into the microchannel reactor, the molar ratio of the compound of formula II, the dual catalyst, and hydrogen peroxide is 1: (0.001-0.05): (2-4), optionally 1: (0.003-0.02): (2.01-4), optionally 1: (0.005-0.015): (2.05-4), optionally 1: (0.006-0.0 15): (2.05-4), optionally 1: (0.008-0.015): (2.05-4), optionally 1: (0.006-0.015): (2.05-3), optionally 1: (0.008-0.015): (2.05-3), optionally 1: (0.008-0.015): (2.05-2.2); And / or, the molar ratio of the compound of formula II and the dual catalyst is 1:(0.001-0.05), optionally 1:(0.003-0.02), optionally 1:(0.005-0.015), optionally 1:(0.006-0.015), optionally 1:(0.008-0.015), optionally 1:0.006, 1:0.007, 1:0.008, 1:0.009, 1:0.01, 1:0.012, 1:0.015, 1:0.02, 1:0.03, 1:0.04 or 1:0.

05.

10. The preparation method according to any one of claims 7 to 9, characterized in that: The temperature of the oxidation reaction is 30-110° C., optionally 35-110° C., optionally 30-80° C., optionally 45-80° C., optionally 55-60° C.; and / or, the reaction pressure is 0.1 to 2.0 MPa, optionally 0.1 to 1.0 MPa, optionally 0.3 to 1.0 MPa, optionally 0.5 to 1.0 MPa, optionally 0.7 to 1.0 MPa; And / or, the oxidation reaction residence time is 10s to 100s, optionally 20s to 60s, optionally 30s to 60s.

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