Continuous synthesis method of pyroxasulfone

Abstract

The invention provides a continuous synthesis method of pyroxasulfone. According to the process, an alkaline system, especially a phosphate system, is adopted to replace traditional strong acid reaction media such as sulfuric acid and trifluoroacetic acid, corrosion of strong acid to equipment is thoroughly avoided, the equipment investment cost is greatly reduced, and the use amount of hydrogen peroxide or the concentration of hydrogen peroxide or additional addition of a transition metal catalyst does not need to be increased; the pyroxasulfone product with high yield and high purity can be obtained, the reaction time is greatly shortened, and the reaction efficiency is remarkably improved; in addition, the concentration of hydrogen peroxide is controlled at a lower level in the whole continuous reaction and oxidation reaction process, the reaction risk is reduced, the reaction time is short, few impurities are generated, the post-treatment method is simple and convenient, the operability is high, and the industrial practical value is very good.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a continuous synthesis method for sulfonylpyrazine. Background Technology

[0002] Pyroxasulfone is an isoxazole herbicide developed by Japan's Combinatorial Chemicals Co., Ltd. Its chemical name is 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-isooxazole, and its molecular formula is C2. 12 H 14 F5N3O4S, with a molecular weight of 391.32 and CAS Registry Number 447399-55-5, is a herbicide that has attracted widespread attention due to its broad-spectrum herbicidal activity, high activity, low dosage, and good safety profile. Sulfonazole can be used as a pre-emergence soil treatment agent in most crop fields. Because it belongs to the class of ultra-long-chain fatty acid elongation enzyme (VLCFAE) inhibitors, it exerts its efficacy by inhibiting VLCFAE. It inhibits the conversion of stearic acid to arachidic acid, arachidic acid to behenic acid, behenic acid to tetracosanoic acid, tetracosanoic acid to ceric acid, ceric acid to linalic acid, and ultimately inhibits the synthesis of myristic acid. Its structure is as follows:

[0003] ,

[0004] Currently, the final step of the sulfonylpyrazole reaction generally uses hydrogen peroxide as an oxidant for oxidation, as shown in the following reaction:

[0005]

[0006] Oxidation reactions are highly susceptible to serious accidents such as runaway reactions, fires, and explosions due to the inherent dangers of strong oxidants, their strong exothermic properties, the flammability and explosiveness of raw materials / products, and the precise requirements of process control. Therefore, it is listed as one of the 18 key hazardous chemical processes under national supervision. Existing technologies disclose two reaction systems using hydrogen peroxide as an oxidant: one is an acid system catalyzed by strong acids such as trifluoroacetic acid and sulfuric acid. Acid systems easily corrode pipelines and equipment, resulting in high equipment costs. Furthermore, the mixing of concentrated sulfuric acid and trifluoroacetic acid with hydrogen peroxide generates significant heat, and the decomposition rate of hydrogen peroxide under acidic conditions is 8-10 times that under alkaline conditions. Improper temperature control can easily lead to material spillage or even explosions, making continuous reactions particularly unfavorable. The other is an alkaline system catalyzed by carbonates. This system has low yields, produces many byproducts, and requires maturation / reaction times of over ten hours, often requiring the addition of transition metal catalysts such as sodium tungstate to increase the reaction rate. However, without transition metal catalysts, the alkaline system is difficult to implement for continuous reactions within microchannel equipment due to the limited reaction rate. Due to the inherent characteristics of the oxidation reaction in the synthesis of sulfonylpyrazine, hydrogen peroxide concentration decreases with the consumption of the reaction and the decomposition of substances unstable under heat, leading to incomplete oxidation and resulting in an excess of sulfoxide, an impurity that negatively impacts efficacy. Patents CN117924265A, CN113831333A, CN117417333A, CN118255757A, and CN117794925A disclose processes that address incomplete reactions by adding excessive metal catalysts, increasing the amount of hydrogen peroxide, or raising its concentration. However, the presence of excess hydrogen peroxide in the reaction system exacerbates reaction safety risks, complicates post-processing, requires more sodium sulfite and sodium thiosulfate for quenching of the mother liquor, increases waste, and is environmentally unfriendly. Furthermore, using sodium tungstate as a catalyst results in high production costs, making it unsuitable for industrial production.

[0007] In summary, given the existing technological problems, there is an urgent need to research and develop processes that are economically efficient and suitable for industrial production. Summary of the Invention

[0008] To address the shortcomings of existing processes in the synthesis of sulfonylpyrazine, such as high risk of oxidation reactions, long maturation times, low reaction efficiency, numerous impurities, and cumbersome post-processing, this invention provides a continuous synthesis method for sulfonylpyrazine. This method employs a continuous reaction, maintaining a low concentration of hydrogen peroxide throughout the oxidation process, thus reducing reaction risk. Furthermore, it features a short reaction time, minimal impurity generation, simple post-processing, and high operability, making it highly valuable for industrial applications.

[0009] The specific technical solution of the present invention is as follows:

[0010] A continuous synthesis method for sulfonylpyrazine includes the following steps: In the first stage, 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylthio]-4,5-dihydro-5,5-dimethyl-1,2-isooxazole solution (i.e., Compound 1 solution), hydrogen peroxide solution, and alkaline solution are continuously fed into a first continuous reactor for temperature-controlled reaction using a metering pump; In the second stage, the reaction solution from the first stage and hydrogen peroxide are continuously fed into a second continuous reactor for temperature-controlled reaction; After the reaction is completed, the mixture is transferred to a crystallization vessel for crystallization, filtration, washing, and drying to obtain sulfonylpyrazine.

[0011] Preferably, the continuous reactor is selected from one or a combination of microchannel reactors and tubular reactors.

[0012] In a preferred embodiment, the first continuous reactor is a microchannel reactor and the second continuous reactor is a tubular reactor, depending on the reaction characteristics.

[0013] Preferably, the alkali is one or a combination of sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphotungstate, sodium acetate, sodium hydroxide, and potassium hydroxide.

[0014] In a preferred embodiment, the base is a phosphate, more preferably one or a combination of sodium phosphate and potassium phosphate.

[0015] Furthermore, the reaction solvent is one or a combination of acetonitrile, ethanol, n-propanol, isopropanol, ethyl acetate, butyl acetate, and DMF.

[0016] Preferably, the temperature of the first continuous reactor is controlled at 30~50℃, more preferably 40~45℃; the temperature of the second continuous reactor is controlled at 60~80℃, more preferably 70~75℃.

[0017] Preferably, the residence time of the oxidation reaction in the first continuous reactor is 80-130 min, more preferably 100-130 min; the residence time of the oxidation reaction in the second continuous reactor is 100-150 min, more preferably 120-150 min.

[0018] Compared with the prior art, the present invention has the following advantages:

[0019] 1) The process of this invention uses an alkaline system, especially a phosphate system, to replace the traditional strong acid reaction media such as sulfuric acid and trifluoroacetic acid, which completely avoids the corrosion of equipment by strong acids and greatly reduces equipment investment costs. The reaction process of this system is exothermic and gentle, without the risk of violent decomposition of hydrogen peroxide in strong acid systems, and the safety redundancy of the process is significantly improved. In addition, the reaction process does not require the addition of transition metal catalysts such as sodium tungstate, which eliminates the risk of heavy metal residues from the source. The product can meet the heavy metal limit standards for the export of raw materials without additional impurity removal steps, which significantly reduces the subsequent refining costs.

[0020] 2) This invention adopts a two-stage continuous flow reaction configuration of “microchannel reactor + tubular reactor”, and achieves gradient regulation of the reaction process by precisely controlling the acceleration rate of hydrogen peroxide droplets; in the first stage, the rapid and highly selective conversion of sulfide to sulfoxide is achieved in the microchannel reactor, avoiding over-oxidation or insufficient reaction; in the second stage, the deep conversion of sulfoxide to sulfone is completed in the tubular reactor, and the total reaction time is significantly shortened compared with the traditional process.

[0021] 3) The process of this invention uses an alkaline system, especially a phosphate system, which does not require increasing the amount of hydrogen peroxide or increasing the concentration of hydrogen peroxide or adding extra transition metal catalysts to obtain high-yield and high-purity sulfonylpyrazol products. The reaction time is greatly shortened and the reaction efficiency is significantly improved. The low concentration and low amount of hydrogen peroxide significantly reduce the use of reducing agent, simplify post-treatment, reduce the amount of waste generated, and reduce production costs. Attached Figure Description

[0022] Figure 1 : Flowchart of the continuous synthesis of sulfonylpyrazole in this invention.

[0023] Figure 2 1H NMR spectrum of 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole.

[0024] Figure 3 1H NMR spectrum of 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfinyl]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole. Detailed Implementation

[0025] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the invention and not for limiting the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.

[0026] As analyzed in the background section of this application, the existing oxidation process for synthesizing sulfonylpyrazine suffers from severe equipment corrosion due to its strong acidic system and the risk of violent decomposition by hydrogen peroxide. However, the traditional alkaline system used for aging / reaction has excessively long maturation / reaction times. Using a short-time continuous flow reaction system results in yields far below expectations and low industrial production efficiency. Furthermore, the addition of transition metal catalysts such as sodium tungstate leads to high production costs and the risk of heavy metal residues. To overcome these problems, this application provides a continuous oxidation synthesis method for sulfonylpyrazine, comprising: a first stage: continuously feeding a solution of 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylthio]-4,5-dihydro-5,5-dimethyl-1,2-isooxazole (i.e., the compound 1 solution), an aqueous hydrogen peroxide solution, and an alkaline solution into a first continuous reactor under controlled temperature conditions via a metering pump; a second stage: continuously feeding the reaction solution from the first stage and hydrogen peroxide into a second continuous reactor under controlled temperature conditions; after the reaction is complete, the mixture is transferred to a crystallization vessel for crystallization, filtration, washing, and drying to obtain sulfonylpyrazine.

[0027] Furthermore, the continuous reactor is selected from one or a combination of microchannel reactors and tubular reactors.

[0028] In a preferred embodiment, the first continuous reactor is a microchannel reactor and the second continuous reactor is a tubular reactor, depending on the reaction characteristics.

[0029] Furthermore, the alkali is one or a combination of sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphotungstate, sodium acetate, sodium hydroxide, and potassium hydroxide.

[0030] Furthermore, the alkaline solution is an aqueous solution with an alkaline content of 10-30%wt; more preferably 10-20%.

[0031] In a preferred embodiment, the base is a phosphate, more preferably one or a combination of sodium phosphate and potassium phosphate.

[0032] Furthermore, the molar ratio of compound 1 to alkali is 1.0:0.05~0.5; more preferably 1:0.05~0.1.

[0033] Preferably, the molar concentration of the compound 1 solution is 0.3~1 mol / L, and further, the molar concentration of the compound 1 solution is 0.5~0.8 mol / L.

[0034] Furthermore, the concentration of the hydrogen peroxide aqueous solution is 10%~50%wt, preferably 20~30%wt, and particularly preferably 25~30%.

[0035] Furthermore, the amount of hydrogen peroxide used is 2.5 to 4.0 times the amount of 1 mole of the compound, and more preferably 2.5 to 3.0 times.

[0036] In a preferred embodiment, the amount of hydrogen peroxide used in the first stage is 1.5 to 2.0 times the amount of 1 mole of the compound, and the amount of hydrogen peroxide used in the second stage is 1.0 to 1.5 times the amount of 1 mole of the compound.

[0037] Further, the reaction solvent is one or a combination of acetonitrile, ethanol, n-propanol, isopropanol, ethyl acetate, butyl acetate, and DMF; more preferably, it is one or a combination of acetonitrile, ethanol, isopropanol, ethyl acetate, and butyl acetate.

[0038] Furthermore, the temperature of the first continuous reactor is controlled at 30~50℃, more preferably 40~45℃; the temperature of the second continuous reactor is controlled at 60~80℃, more preferably 70~75℃.

[0039] Furthermore, the residence time of the oxidation reaction in the first continuous reactor is 80-130 min, more preferably 100-130 min; the residence time of the oxidation reaction in the second continuous reactor is 100-150 min, more preferably 120-150 min.

[0040] The beneficial effects that this application can achieve will be further illustrated below with reference to embodiments and comparative examples.

[0041] All raw materials used in this invention are not particularly limited in their source; they can be purchased from the market or prepared using conventional methods well known to those skilled in the art. Unless otherwise specified, all concentrations used are mass percentages. In the following examples and comparative examples, the product yield is the molar yield, calculated using the formula: Yield = Product mass * Product content / (Product molecular weight * Molar amount of raw materials).

[0042] The raw material 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole used in this invention can be prepared according to the methods disclosed in patent CN116761802A and patent CN111777064B.

[0043] In the following examples, the tubular reactor / microchannel reactor models and sources are as follows: Tubular reactor: HOMAG MIC tubular reactor; Microchannel reactor: Corning G1 microchannel reactor.

[0044] Example 1

[0045] The process preparation flow of this embodiment is as follows: Figure 1The continuous reactors employ microchannel reactors and tubular reactors for continuous oxidation reactions, respectively, and the corresponding material conveying metering pumps are numbered as follows: Figure 1 As shown, the flow rate is adjusted according to the pump volume and residence time. The specific implementation steps are as follows:

[0046] 1) Material preparation: Mix compound 1 (85% purity, 422g, 1mol) with acetonitrile to prepare a 0.66mol / L acetonitrile solution of compound 1 for later use; prepare the first stage hydrogen peroxide (28.5%wt, 238g, 2mol) and place it in pump B for later use; prepare the second stage hydrogen peroxide (28.5%wt, 119g, 1mol) and place it in pump D for later use; prepare the potassium phosphate solution (10%wt, 214g, 0.1mol) and place it in pump C for later use.

[0047] 2) Continuous reactor setup: The reaction temperature of the microchannel reactor is set to 45℃, and the reaction temperature of the tubular reactor is set to 75℃; metering pump A is used to deliver the compound 1 solution at a flow rate of 12 mL / min; metering pump B is used to deliver hydrogen peroxide at a flow rate of 1.64 mL / min; metering pump C is used to deliver the alkaline solution at a flow rate of 2.43 mL / min; metering pump D is used to deliver hydrogen peroxide at a flow rate of 0.7 mL / min.

[0048] 3) Continuous reaction: Metering pumps A, B, and C were started, and the mixture of compound 1, hydrogen peroxide, and alkaline solution was reacted in a microchannel reactor for 125 min. HPLC analysis showed that the content of the raw material 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazole-4-ylmethylthio]-4,5-dihydro-5,5-dimethyl-1,2-isooxazole was <0.1% (HPLC area %). Metering pump D was started, and the mixture of the reaction solution and the newly pumped hydrogen peroxide was reacted in a tubular reactor for 147 min. HPLC analysis showed that the impurity sulfoxide 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazole-4-ylsulfinyl]-4,5-dihydro-5,5-dimethyl-1,2-isooxazole was <0.3% (HPLC area %). The mixture was transferred to a product crystallization vessel, water was added for crystallization, and the mixture was filtered, washed, and dried to obtain a white solid sulfonylpyrazolium, with a yield of 98.0% and a purity of 98.7%.

[0049] Examples 2-5

[0050] The difference from Example 1 lies in the concentration and amount of hydrogen peroxide used. The reaction results are shown in Table 1.

[0051] Table 1

[0052]

[0053] Examples 6-10

[0054] The difference from Example 1 lies in the type and amount of alkali used. The reaction results are shown in Table 2.

[0055] Table 2

[0056]

[0057] Examples 11-13

[0058] The difference from Example 1 lies in the temperature of the continuous reactor, and the reaction results are shown in Table 3.

[0059] Table 3

[0060]

[0061] Examples 14-16

[0062] The difference from Example 1 lies in the type of reaction solvent. The reaction results are shown in Table 4.

[0063] Table 4

[0064]

[0065] Comparative Example 1 Compound 1 (85% purity, 422 g, 1 mol) was mixed with acetonitrile to prepare a 0.66 mol / L acetonitrile solution of Compound 1 for later use; hydrogen peroxide (30% wt, 340 g, 3 mol) was prepared for later use; potassium phosphate solution (10% wt, 214 g, 0.1 mol) was prepared for later use; the reaction temperature of the microchannel reactor was set to 75℃, the flow rate of the Compound 1 solution was 5 mL / min, the flow rate of the hydrogen peroxide was 2 mL / min, and the flow rate of the alkaline solution was 1.02 mL / min; the mixture of Compound 1, hydrogen peroxide, and alkaline solution was reacted in the microchannel reactor for 3... After 00 min, the reaction solution was introduced into the product crystallization vessel, water was added for crystallization, filtration, washing, and drying to obtain a white solid sulfonylpyrazolium. HPLC analysis showed that the raw material contained 2.3% 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole and 6.2% sulfoxide. The yield was 85.4% and the purity was 90.3%.

Claims

1. A continuous synthesis method for sulfonylpyrazole, characterized in that, Includes the following steps: First stage: 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylthio]-4,5-dihydro-5,5-dimethyl-1,2-isooxazole solution (i.e., compound 1 solution), hydrogen peroxide solution, and alkaline solution are continuously fed into the first continuous reactor under metering pump control, and the reaction is carried out at a controlled temperature. Second stage: The reaction solution from the first stage and hydrogen peroxide are continuously fed into the second continuous reactor for temperature-controlled reaction. After the reaction is completed, the solution is transferred to a crystallization kettle for crystallization, filtration, washing, and drying to obtain sulfopyrazol.

2. The synthesis method according to claim 1, characterized in that, The continuous reactor is selected from one or a combination of microchannel reactors and tubular reactors.

3. The synthesis method as described in claim 2, characterized in that, The first-stage continuous reactor is a microchannel reactor, and the second-stage continuous reactor is a tubular reactor.

4. The synthesis method according to claim 1, characterized in that, The alkali is one or a combination of sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphotungstate, sodium acetate, sodium hydroxide, and potassium hydroxide.

5. The synthesis method according to claim 1, characterized in that, The alkali is a phosphate, selected from sodium phosphate, potassium phosphate, or a combination thereof.

6. The synthesis method according to claim 1, characterized in that, The molar ratio of compound 1 to alkali is 1.0:0.05~0.5; more preferably 1:0.05~0.

1.

7. The synthesis method according to claim 1, characterized in that, The concentration of the hydrogen peroxide solution is 10%~50%wt, preferably 20~30%wt, and particularly preferably 25~30%.

8. The synthesis method according to claim 1, characterized in that, The amount of hydrogen peroxide used is 2.5 to 4.0 times the amount of 1 mole of the compound, more preferably 2.5 to 3.0 times.

9. The synthesis method according to claim 1, characterized in that, The reaction solvent is one or a combination of acetonitrile, ethanol, n-propanol, isopropanol, ethyl acetate, butyl acetate, and DMF.

10. The synthesis method according to claim 1, characterized in that, The temperature of the first continuous reactor is controlled at 30~50℃, more preferably 40~45℃; the temperature of the second continuous reactor is controlled at 60~80℃, more preferably 70~75℃.

Images