Continuous synthesis method of pyroxasulfone intermediate

Abstract

The invention relates to a continuous synthesis method of a pyroxasulfone intermediate. The method comprises the following steps: continuously pumping an intermediate 1 alkali solution and a formaldehyde solution into a micro-channel reactor 1 according to a certain ratio, and reacting; reacting the compound 5 solution with an alkali solution in the micro-channel reactor 2; materials at outlets of the micro-channel reactor 1 and the micro-channel reactor 2 directly pass through a mixer and then enter the micro-channel reactor 3 for reaction; continuously pumping acid into the tubular reactor 1, and mixing the acid with the material at the outlet of the micro-channel reactor 3 for reaction; and feeding a solid-liquid mixture from the tubular reactor into a product receiving kettle, further fully mixing, centrifuging, washing, and drying to obtain the pyroxasulfone intermediate. The method solves the problems of instability, many impurities and low yield and purity of the existing synthesis process, improves the utilization rate of the raw materials, shortens the reaction time, reduces the generation of three wastes, and lowers the production cost of the product.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and in particular relates to a continuous synthesis method of a sulfonepyraclostrobin intermediate. Background Art Pyroxasulfone, commonly known as pyroxasulfone in English, is a new type of broad-spectrum, highly active pre-emergence soil treatment agent developed by Kumizu Chemical Co., Ltd. of Japan. It belongs to the isoxazole herbicide. As an excellent pre-emergence soil treatment agent, pyroxasulfone has the same mechanism of action as the classic soil treatment agents acetochlor and S-isopropylamine, but the dosage is only about 1 / 10 of them. In addition, the product has a wide control spectrum and can be safely used in crops such as corn, cotton, peanuts, wheat, and sunflowers; it can effectively control grass weeds such as Setaria, Digitaria, and Echinochloa, as well as broad-leaved weeds such as Amaranthus, Datura, Solanum, and Abutilon. Pyroxasulfone is considered the best agent for controlling resistant weeds such as rigid ryegrass in countries such as Australia. It is expected that it may replace chloroacetamide herbicides in the future and become a new benchmark for soil treatment agents, so it has a good market development prospect.

[0002] At present, the two main routes for synthesizing sulfonepyraclostrobin are as follows:

[0003] Route 1 uses key intermediate 1 as raw material, undergoes hydroxymethylation, difluoromethoxylation, chlorination, and then docks with key intermediate 5 to obtain intermediate 6, and finally oxidizes with hydrogen peroxide to obtain sulfonepyraclostrobin. Route 2 uses key intermediate 1 as raw material, undergoes hydroxymethylation, then docks with key intermediate 5, and then undergoes difluoromethoxylation to obtain intermediate 6, and finally oxidizes with hydrogen peroxide to obtain sulfonepyraclostrobin. From the comparison of routes alone, route 2 has one less chlorination step than route 1, and industrialization should have more advantages; but since the process of docking intermediate 2 and intermediate 5 to synthesize intermediate 7 in route 2 uses a large excess of base, the reaction process is highly exothermic, the process is difficult to control, and more intermediate 5 and intermediate 1 dimer impurities are produced, which are difficult to remove, resulting in low yield and purity of intermediate 7 (yield is usually about 85%, purity is about 88%), affecting subsequent reactions, and the production cost is high, and there is not much advantage in actual industrialization.

[0004] The synthetic route of intermediate 7 is as follows: intermediate 1 reacts with formaldehyde in the presence of a base to obtain intermediate 2, which is then mixed with an alkaline solution of compound 5 and then acidified to obtain compound 7. Intermediate 2 can only remain stable under strong alkalinity, otherwise more impurity 1 will be generated; in order to reduce the generation of impurity 1, an excess of compound 5 will be added, and the excess compound 5 will produce impurities 2 and impurity 3, which are difficult to purify, resulting in low product purity. Secondly, intermediate 2 and compound 5 will not generate compound 7 after mixing under alkaline conditions. It must be converted into compound 7 after adjusting the pH to acidic. Therefore, how to reduce or avoid the generation of impurity 1 during the pH adjustment process is the key to improving yield and purity. Summary of the invention

[0005] To solve the above problems, the present invention provides a continuous synthesis method of sulfonepyraclostrobin intermediates. The method solves the problems of instability, high impurities, low yield and purity of the existing synthesis process by changing the traditional preparation process, and provides a method for continuously synthesizing sulfonepyraclostrobin intermediate 7 with high yield and high purity. The utilization rate of raw materials and reaction efficiency are improved, the reaction time is shortened from the original 3 hours to less than 20 minutes, the generation of three wastes is reduced, and the production cost of the product is reduced.

[0006] A continuous synthesis method of a sulfonepyraclostrobin intermediate, characterized in that the intermediate is: , The following compounds were used in the synthesis method: , , , The synthesis method is as follows: ; The method comprises the following steps: 1) Intermediate 1 and a base are prepared into a base solution of intermediate 1, and compound 5 is prepared into a solution of a certain molar concentration; 2) The intermediate 1 alkaline solution and the formaldehyde solution are continuously pumped into the microchannel reactor 1 through the metering pump 1 and the metering pump 2 according to a certain ratio, and reacted at a certain temperature for a certain time; 3) Compound 5 solution and alkaline solution are continuously pumped into microchannel reactor 2 through metering pump 3 and metering pump 4 according to a certain ratio, and reacted at a certain temperature for a certain time; 4) The materials at the outlets of microchannel reactor 1 and microchannel reactor 2 directly pass through the mixer and then enter microchannel reactor 3 to react at a certain temperature for a certain time; 5) According to a certain ratio, the acid is continuously pumped into the tubular reactor 1 through the metering pump 5 to mix with the material at the outlet of the microchannel reactor 3, and reacted at a certain temperature for a certain time; the solid-liquid mixture coming out of the tubular reactor enters the product receiving kettle, and after further sufficient mixing, enters the centrifugation, washes the material, and dries to obtain the sulfonepyraclostrobin intermediate 7.

[0007] As one of the technical solutions of the present invention, the molar ratio of the intermediate 1 to the base in the step (1) is 1:(1.0-4.0), preferably 1:(1.0-1.5); the molar concentration of the intermediate 1 alkaline solution is 0.1 mol / L-5 mol / L (based on the intermediate 1), preferably 0.5 mol / L-2 mol / L; the base is one or more of NaOH, KOH, Na2CO3, K2CO3, sodium methoxide, potassium methoxide, sodium ethoxide, preferably NaOH, KOH, sodium methoxide, potassium methoxide; the solution is water, methanol, acetonitrile, preferably water or methanol.

[0008] As one of the technical solutions of the present invention, the molar ratio of the intermediate 1 alkaline solution to formaldehyde in the step (2) is 1:(1.0-4.0), preferably 1:(1.0-1.5); the molar concentration of formaldehyde is 0.1 mol / L-20 mol / L, preferably 5 mol / L-15 mol / L; the formaldehyde solution is one of formaldehyde aqueous solution, formaldehyde methanol solution and formaldehyde ethanol solution.

[0009] As one of the technical solutions of the present invention, the reaction temperature in step (2) is -20°C to 50°C, preferably -10°C to 20°C; the reaction time is 0.1 to 30 min, preferably 10 to 20 min.

[0010] As one of the technical solutions of the present invention, the molar ratio of the intermediate 5 to the base in the step (3) is 1:(1.0~4.0), preferably 1:(2.0~3.0); the molar concentration of the compound 5 solution is 0.1mol / L~5mol / L, preferably 0.5mol / L~2mol / L; the base is one of NaOH, KOH, Na2CO3, K2CO3, sodium methoxide, potassium methoxide, sodium ethoxide, preferably NaOH, KOH, sodium methoxide or potassium methoxide; the solution is water, methanol, acetonitrile, preferably water or methanol; The structure of the intermediate 5 is: .

[0011] As one of the technical solutions of the present invention, the reaction temperature in step (3) is -20°C to 50°C, preferably -10°C to 20°C; the reaction time is 0.1 to 30 min, preferably 5 to 10 min.

[0012] As one of the technical solutions of the present invention, the reaction temperature in step (4) is -20°C to 50°C, preferably -10°C to 20°C; the reaction time is 0.1 to 30 min, preferably 1 to 10 min.

[0013] As one of the technical solutions of the present invention, the molar ratio of the intermediate 1 to the compound 5 and the acid in the step (5) is 1: (1-3.0): (2.0-5.0); preferably 1: (1-1.2): (2.0-4.0); the acid is one of hydrochloric acid, sulfuric acid and phosphoric acid, preferably hydrochloric acid; the molar concentration of the acid is 0.1 mol / L-5 mol / L.

[0014] As one of the technical solutions of the present invention, the molar ratio of the intermediate 1 to formaldehyde and the compound 5 in the steps (1) to (5) is 1: (1~3.0): (1.0~3.0); preferably 1: (1.0~1.2): (1.0~1.2).

[0015] As one of the technical solutions of the present invention, whether the structures of the microchannel reactor 1, microchannel reactor 2, and microchannel reactor 3 need to be limited, or whether there are any special features.

[0016] The beneficial effects of the present invention are as follows: 1) The present invention adopts a continuous method to synthesize the key intermediate 7 of sulfonepyraclostrobin, which overcomes the shortcomings of the prior art. The thio intermediate 5 is easily decomposed during the autoclave alkalization process, the reaction operation process is cumbersome, the process is unstable, and the yield and purity fluctuate greatly.

[0017] 2) The present invention utilizes continuous flow technology in the synthesis of sulfonepyraclostrobin, which reduces the risk factor of reaction amplification; reduces the instability and easy decomposition of intermediates; has less online materials and strong controllability; and significantly improves the yield (yield increased to 95%~98%) and purity (liquid phase purity is 90%~99%). BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The present invention is a flow chart of the continuous synthesis of the sulfonepyraclostrobin intermediate. DETAILED DESCRIPTION

[0019] The technical solutions in the present invention are described clearly and completely below in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0020] The structure of the full continuous flow preparation technology used in the embodiment is shown in the attached Figure 1 As shown, metering pumps 1 and 2 are connected to microchannel reactor 1 through a pipeline, metering pumps 3 and 4 are connected to microchannel reactor 2 through a pipeline, microchannel reactor 1 and microchannel reactor 2 are connected to microchannel reactor 3 through a pipeline, metering pump 5 and tubular reactor 1 are connected to tubular reactor 1 through a pipeline, and tubular reactor 1 is connected to the product receiving kettle and the centrifuge in sequence through a pipeline.

[0021] The microchannel reactor or tubular reactor is made of silicon carbide, Hastelloy, PTE hose or glass. The process of continuous flow reaction is realized in the microchannel reactor or tubular reactor of the present invention. In the embodiment of the present invention, the reaction of the material is taken as an example of a microchannel reactor, and its material is Hastelloy.

[0022] Example 1 Add NaOH (288 g, 7.2 mol) and water to intermediate 1 (1-methyl-3-trifluoromethyl-1H-pyrazole-5-ol) (996 g, 6 mol) to prepare a 2 mol / L alkaline solution of intermediate 1 for use; prepare formaldehyde into a 10 mol / L aqueous solution for use; prepare intermediate 5 into a 2 mol / L aqueous solution for use, and prepare NaOH into a 10 mol / L aqueous solution for use; as shown in the legend, metering pump 1 is used to transport the alkaline solution of intermediate 1 at a flow rate of 10 mL / min; metering pump 2 is used to transport the formaldehyde aqueous solution at a flow rate of 2.4 mL / min; metering pump 3 is used to transport the aqueous solution of intermediate 5 at a flow rate of 11 mL / min; metering pump 4 is used to transport the 10 mol / L NaOH aqueous solution at a flow rate of 5.5 mL / min; metering pump 5 is used to transport 30% hydrochloric acid at a flow rate of 2 mL / min; set the reaction temperature of microchannel reactor 1 to 0℃, the reaction temperature of microchannel reactor 2 to 10℃, the reaction temperature of microchannel reactor 3 to 0℃, and the reaction temperature of tubular reactor 1 to 0℃; start metering pumps 1, 2, 3, and 4, intermediate 1 and formaldehyde react in the microchannel reactor for 10 minutes, intermediate 5 and liquid alkali react in the microchannel reactor for 5 minutes, the two materials are mixed and then enter microchannel reactor 3 to react for 5 minutes, and then continuously enter tubular reactor 1 to mix with hydrochloric acid, react for 2 minutes and enter the product receiving kettle, centrifuge after mixing, wash the material, and dry to obtain the product sulfone pyrazoline intermediate 7, which is a light yellow solid. The yield is 93%, the purity is 94%, the impurity 1 content is 1.1%, the impurity 2 content is 1.1%, and the impurity 3 content is 0.7%.

[0023] Example 2 The operation was the same as in Example 1, except that the reaction temperature of tubular reactor 1 was set to 20° C. The product yield after the reaction was 90%, the purity was 90%, the content of impurity 1 was 3%, the content of impurity 2 was 1.2%, and the content of impurity 3 was 1.3%.

[0024] Example 3 The operation was the same as in Example 1, except that the reaction temperature of tubular reactor 1 was set to -10°C. The product yield after the reaction was 96%, the purity was 95%, the content of impurity 1 was 0.5%, the content of impurity 2 was 1.2%, and the content of impurity 3 was 0.6%.

[0025] Example 4 The operation was the same as in Example 1, except that hydrochloric acid was replaced by 3.5 mol / L phosphoric acid aqueous solution. The yield of the product after the reaction was 95%, the purity was 94%, the content of impurity 1 was 0.7%, the content of impurity 2 was 1.2%, and the content of impurity 3 was 0.8%.

[0026] Example 5 Add sodium methoxide (389 g, 7.2 mol) and methanol to intermediate 1 (1-methyl-3-trifluoromethyl-1H-pyrazole-5-ol) (996 g, 6 mol) to prepare a 2 mol / L methanol solution of intermediate 1 for use; prepare formaldehyde into a 10 mol / L methanol solution for use; prepare intermediate 5 into a 2 mol / L methanol solution for use, and prepare sodium methoxide into a 5 mol / L methanol solution for use; as shown in the legend, metering pump 1 is used to transport the methanol solution of intermediate 1 at a flow rate of 10 mL / min; metering pump 2 is used to transport the methanol solution of formaldehyde at a flow rate of 2.4 mL / min; metering pump 3 is used to transport the methanol solution of intermediate 5 at a flow rate of 11 mL / min; metering pump 4 is used to transport the 5 mol / L methanol solution of sodium methoxide at a flow rate of 11 mL / min; metering pump 5 is used to transport 30% hydrochloric acid at a flow rate of 2 mL / min; set the reaction temperature of microchannel reactor 1 to 0℃, the reaction temperature of microchannel reactor 2 to 10℃, the reaction temperature of microchannel reactor 3 to 0℃, and the reaction temperature of tubular reactor 1 to 0℃; start metering pumps 1, 2, 3, and 4, intermediate 1 and formaldehyde react in the microchannel reactor for 10 minutes, intermediate 5 and sodium methoxide react in the microchannel reactor for 5 minutes, the two materials are mixed and then enter the microchannel reactor 3 to react for 5 minutes, and then continuously enter the tubular reactor 1 to mix with hydrochloric acid, react for 2 minutes and enter the product receiving kettle, remove methanol after mixing, centrifuge, wash the material, and dry to obtain the product sulfone pyrazoline intermediate 7, which is a light yellow solid. The yield is 96%, the purity is 95%, the impurity 1 content is 0.3%, the impurity 2 content is 1.1%, and the impurity 3 content is 0.9%.

[0027] Comparative Example 1 In a 2 L three-necked round-bottom flask with a stirring jacket, add 1166 g of intermediate 1 (166 g, 1 mol), add 200 mL of water, control the internal temperature at 0℃~10℃, and add 120 mL (1.2 mol) of 10 mol / L sodium hydroxide solution dropwise while stirring. After stirring to clarify, add 120 mL (1.2 mol) of 10 mol / L formaldehyde solution dropwise. After the addition is complete, continue to stir and react at 0℃~10℃ for 30 min, continue to add 250 mL (2.5 mol) of 10 mol / L sodium hydroxide solution, and slowly add 510 mL (1.1 mol) of 2 mol / L aqueous solution of intermediate 5 dropwise at this temperature. After the addition is complete, continue to stir and react at 0℃~10℃ for 30 min, then control the internal temperature not to exceed 15℃, add 30% hydrochloric acid dropwise, adjust pH = 2~3, continue stirring for half an hour, filter, wash, and dry to obtain a light yellow solid 260 g, yield 84%, purity 90%, impurity 1 content 2.3%, impurity 2 content 3.2%, impurity 3 content 4%.

[0028] Comparative Example 2 In a 2 L three-necked round-bottom flask with a stirring jacket, add 1166 g of intermediate 1 (166 g, 1 mol) and 200 mL of methanol. Control the internal temperature at 0℃~10℃, and add 216 g (1.2 mol) of 30% sodium methoxide methanol solution dropwise while stirring. After stirring to clarify, add 120 mL (1.2 mol) of 10 mol / L formaldehyde methanol solution dropwise. After the addition is complete, continue to stir and react at 0℃~10℃ for 30 min. Continue to add 450 g (2.5 mol) of 30% sodium methoxide methanol solution. At this temperature, slowly add 510 mL (1.1 mol) of 2 mol / L methanol solution of intermediate 5 dropwise. After the addition is complete, continue to stir and react at 0℃~10℃ for 30 min. Then control the internal temperature not to exceed 15℃, add 30% hydrochloric acid dropwise, adjust the pH to 2~3, continue stirring for half an hour, evaporate the methanol, filter, wash and dry to obtain a light yellow solid 269 g, yield 87%, purity 91%, impurity 1 content 2.4%, impurity 2 content 2.9%, impurity 3 content 3.6%. By comparing the embodiments and comparative examples, it can be seen that the present invention can greatly simplify the reaction operation and shorten the reaction time through a continuous synthesis method; at the same time, it can greatly reduce the generation of impurities, improve the utilization rate of raw materials, effectively improve the reaction yield and product purity, and reduce production costs.

[0029] The foregoing description is primarily for illustrative purposes. Although the present invention has been shown and described with respect to exemplary embodiments thereof, it will be appreciated by those skilled in the art that the foregoing and various other changes, omissions and additions may be made in its form and details without departing from the spirit and scope of the present invention.

Claims

1. A continuous synthesis method of a sulfonepyraclostrobin intermediate, characterized in that: The intermediate is: ， The following compounds were used in the synthesis method: 、 、 ， The synthesis method is as follows: ； The method comprises the following steps: 1) Intermediate 1 and a base are prepared into a base solution of intermediate 1, and compound 5 is prepared into a solution of a certain molar concentration; 2) The intermediate 1 alkaline solution and the formaldehyde solution are continuously pumped into the microchannel reactor 1 through the metering pump 1 and the metering pump 2 according to a certain ratio, and reacted at a certain temperature for a certain time; 3) Compound 5 solution and alkaline solution are continuously pumped into microchannel reactor 2 through metering pump 3 and metering pump 4 according to a certain ratio, and reacted at a certain temperature for a certain time; 4) The materials at the outlets of microchannel reactor 1 and microchannel reactor 2 directly pass through the mixer and then enter microchannel reactor 3 to react at a certain temperature for a certain time; 5) According to a certain ratio, the acid is continuously pumped into the tubular reactor 1 through the metering pump 5 to mix with the material at the outlet of the microchannel reactor 3, and reacted at a certain temperature for a certain time; the solid-liquid mixture coming out of the tubular reactor enters the product receiving kettle, and after further sufficient mixing, enters the centrifugation, washes the material, and dries to obtain the sulfonepyraclostrobin intermediate 7.

2. The continuous synthesis method of a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The molar ratio of the intermediate 1 to the base in the step (1) is 1:(1.0-4.0), preferably 1:(1.0-1.5); the molar concentration of the intermediate 1 alkaline solution is 0.1 mol / L-5 mol / L (based on the intermediate 1), preferably 0.5 mol / L-2 mol / L; the base is one or more of NaOH, KOH, Na2CO3, K2CO3, sodium methoxide, potassium methoxide, sodium ethoxide, preferably NaOH, KOH, sodium methoxide, potassium methoxide; the solution is water, methanol, acetonitrile, preferably water or methanol.

3. The continuous synthesis method of a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The molar ratio of the intermediate 1 alkaline solution to formaldehyde in step (2) is 1:(1.0-4.0), preferably 1:(1.0-1.5); the molar concentration of formaldehyde is 0.1 mol / L-20 mol / L, preferably 5 mol / L-15 mol / L; the formaldehyde solution is one of formaldehyde aqueous solution, formaldehyde methanol solution and formaldehyde ethanol solution.

4. The continuous synthesis method of a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The reaction temperature in step (2) is -20°C to 50°C, preferably -10°C to 20°C; the reaction time is 0.1 to 30 min, preferably 10 to 20 min.

5. The continuous synthesis method of a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The molar ratio of the intermediate 5 to the base in step (3) is 1:(1.0-4.0), preferably 1:(2.0-3.0); the molar concentration of the compound 5 solution is 0.1 mol / L-5 mol / L, preferably 0.5 mol / L-2 mol / L; the base is one of NaOH, KOH, Na2CO3, K2CO3, sodium methoxide, potassium methoxide, and sodium ethoxide, preferably NaOH, KOH, sodium methoxide or potassium methoxide; the solution is water, methanol, and acetonitrile, preferably water or methanol; The structure of the intermediate 5 is: 。 6. The continuous synthesis method of a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The reaction temperature in step (3) is -20°C to 50°C, preferably -10°C to 20°C; the reaction time is 0.1 to 30 min, preferably 5 to 10 min.

7. The continuous synthesis method of a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The reaction temperature in step (4) is -20°C to 50°C, preferably -10°C to 20°C; the reaction time is 0.1 to 30 min, preferably 1 to 10 min.

8. The continuous synthesis method of a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The molar ratio of the intermediate 1 to the compound 5 and the acid in the step (5) is 1: (1-3.0): (2.0-5.0); preferably 1: (1-1.2): (2.0-4.0); the acid is one of hydrochloric acid, sulfuric acid and phosphoric acid, preferably hydrochloric acid; the molar concentration of the acid is 0.1 mol / L-5 mol / L.

9. The continuous synthesis method of a sulfonepyraclostrobin intermediate according to claim 1, characterized in that: The molar ratio of the intermediate 1 to formaldehyde and the compound 5 in the steps (1) to (5) is 1: (1-3.0): (1.0-3.0); preferably 1: (1.0-1.2): (1.0-1.2).

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