Method for continuously preparing pyroxasulfone intermediate by serially connecting dynamic tubular reactors

Abstract

The invention provides a method for continuously preparing a pyroxasulfone intermediate by serially connecting dynamic tubular reactors. The method comprises the following steps: reacting an organic solvent solution of a compound IV with an inorganic acid solution of thiourea in a dynamic tubular reactor I to obtain a reaction solution of a compound III; reacting the reaction solution of the compound III with an alkali solution of a compound II in a dynamic tubular reactor II to obtain a mixed solution; and mixing the mixed solution with hydrochloric acid in a kettle, filtering, centrifuging and drying to obtain the pyroxasulfone intermediate I. The problems of violent heat release and easy generation of impurities in the mixing process of the intermediate III and the intermediate II are solved; a small amount of solids are generated in the reaction process, and compared with a tubular reactor, the series dynamic tubular reactor is adopted, so that the problem that a reaction channel is easy to block is avoided.

Description

Technical Field

[0001] This invention relates to the chemical industry, and mainly to a method for the continuous preparation of sulfonylpyrazol intermediates using a series dynamic tubular reactor. Background Technology

[0002] Sulfonazole is a pre-emergence soil-applied herbicide developed by Japanese companies Combinatorial Chemicals and Anbara Chemicals, applicable to most crop fields. Overall, sulfonazole is essentially harmless to organic matter in the environment and has low water solubility, thus reducing the likelihood of groundwater contamination.

[0003] Studying the important synthetic intermediates I and III of sulfonylpyrazole and developing a synthetic process with high product content, good quality, high yield and environmental friendliness is of great significance for the further development of subsequent sulfonylpyrazole synthesis methods.

[0004] Currently, there are two main routes for synthesizing sulfonylpyrazole, one of which, with a shorter synthetic route, is shown below:

[0005]

[0006] This route uses intermediate 1 as a raw material, which undergoes hydroxymethylation to obtain intermediate 2, then reacts with key intermediate III to obtain intermediate I, followed by difluoromethylation to obtain intermediate 3, and finally oxidation with hydrogen peroxide to obtain sulfonylpyrazine technical grade. This route has relatively short steps and is more advantageous for industrialization; however, the post-processing of intermediate III is complex, the product is easily decomposed, and the purchase cost is too high. The reaction between intermediate 2 and key intermediate III requires a large amount of acid and alkali, the reaction process is highly exothermic, and it is easy to generate dimer impurities. The yield and purity of intermediate I are both low. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a method for the continuous preparation of sulfopyrazol intermediate I using a series of dynamic tubular reactors. By connecting two dynamic tubular reactors in series, a solution is achieved to obtain intermediate I with high yield and purity without separating the intermediate products. This effectively solves the problems of complex post-processing of intermediate III and easy product decomposition, as well as the issues of intense exothermic reaction and high impurity content in the traditional process of intermediate I, making it more suitable for industrial production.

[0008] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: A method for the continuous preparation of sulfonylpyrazine intermediates using a series dynamic tubular reactor includes the following steps: (1) The acetonitrile solution of compound IV and the hydrochloric acid solution of thiourea were reacted in dynamic tubular reactor I to obtain the reaction solution of compound III; (2) The reaction solution of compound III was reacted directly with the alkaline solution of compound II in dynamic tubular reactor II without separation and purification to obtain a mixed solution; (3) The mixture obtained in step (2) is mixed with hydrochloric acid in a reactor, filtered, centrifuged and dried to obtain sulfopyrazole intermediate I; the specific reaction structure and operation flow chart are as follows. Figure 1 As shown: .

[0009] An acetonitrile solution of compound IV and a hydrochloric acid solution of thiourea were mixed in a certain proportion in a dynamic tubular reactor I. The resulting reaction solution did not require separation and purification. It was directly mixed with an alkaline solution of compound II in a certain proportion in dynamic tubular reactor II. The resulting reaction solution entered an acidification vessel, was mixed with hydrochloric acid for acidification, and finally centrifuged, washed, and dried to obtain sulfonylpyrazine intermediate I. It should be noted that the organic solvent used in step (1) has good solubility for sulfonylpyrazine intermediate I. Since the product in this step was not purified, the organic solvent carried into the next step would theoretically lead to the loss of the final product, sulfonylpyrazine intermediate I. However, the presence of a large amount of water in the system would promote the precipitation of the product, and intermediate I would not be lost.

[0010] Preferably, the organic solvent in step (1) is acetonitrile; the mass ratio of compound IV to solvent acetonitrile is 1:5.0~1:7.0.

[0011] Preferably, the inorganic acid described in step (1) is hydrochloric acid, and the mass fraction of hydrochloric acid is 20%~30%; the molar ratio of thiourea to hydrochloric acid aqueous solution is 1:0.7~1:0.9.

[0012] Preferably, the molar ratio of compound IV to thiourea in step (1) is 1:1.4 to 1:1.6.

[0013] Preferably, the reaction temperature in step (1) is 20~100℃; further, the reaction temperature in step (1) is 30~50℃; preferably, the retention time in the dynamic tubular reactor in step (1) is 0.1~60 minutes; further, the retention time in step (1) is 1.0~10 minutes.

[0014] Preferably, the material of the dynamic tubular reactor in step (1) is 316L, Hastelloy, or polytetrafluoroethylene; further, the material of the dynamic tubular reactor in step (1) is Hastelloy.

[0015] Preferably, the stirring paddle inside the dynamic tubular reactor in step (1) is an axial flow stirring paddle, a radial flow stirring paddle, or a mixed flow stirring paddle; further, the stirring paddle inside the dynamic tubular reactor in step (1) is a radial flow stirring paddle; preferably, the stirring method of the dynamic tubular reactor in step (1) is unidirectional rotation, and the stirring speed is 160~180 revolutions per minute. It should be noted that the stirring speed should not be too slow or too fast. If the stirring is too slow, the raw material will not react sufficiently, and if the stirring is too fast, cavities will be generated, which will lead to uneven feeding in the next step.

[0016] Preferably, the inorganic base described in step (2) is a liquid base with a mass fraction of 20% to 30%; the molar ratio of compound II to liquid base in step (2) is 1:4.0 to 1:6.0.

[0017] Preferably, in step (2), the molar ratio of compound II to compound IV is 1:1.0 to 1:1.5.

[0018] Preferably, the reaction temperature in step (2) is -10~30℃; further, the reaction temperature in step (2) is 0~15℃; preferably, the retention time of the dynamic tubular reactor in step (2) is 0.1~60 minutes; further, the retention time in step (1) is 1.0~4.0 minutes.

[0019] Preferably, the material of the dynamic tubular reactor in step (1) is 316L, Hastelloy, or polytetrafluoroethylene; further, the material of the dynamic tubular reactor in step (1) is Hastelloy.

[0020] Preferably, the stirring paddle inside the dynamic tubular reactor in step (1) is an axial flow stirring paddle, a radial flow stirring paddle, or a mixed flow stirring paddle; further, the stirring paddle inside the dynamic tubular reactor in step (1) is a radial flow stirring paddle; preferably, the stirring mode of the dynamic tubular reactor in step (1) is unidirectional rotation, and the stirring speed is 180~220 revolutions per minute.

[0021] Preferably, the pH value of the acidification solution in the acidification tank in step (3) needs to be less than 2.

[0022] The two-step continuous flow tandem synthesis of intermediate I can achieve a yield of up to 98% and a purity of up to 94%. Intermediate III synthesized without separation and purification solves the problem of easy decomposition during post-processing of this product (intermediate III), while simplifying the process flow and making it more suitable for industrial production. It also solves the problems of intense exothermic reactions and impurity generation during the mixing of intermediates III and II. A small amount of solids is generated during the reaction; however, the use of a tandem dynamic tubular reactor avoids the problem of easy blockage of the reaction channels compared to a traditional tubular reactor. In summary, this invention shortens the reaction time, improves single-batch reaction efficiency, increases yield and purity, reduces reaction risks, and is more suitable for industrial production. Attached Figure Description

[0023] Figure 1 This is a process flow diagram of the present invention. Detailed Implementation

[0024] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0025] The dynamic tubular reactors used in this invention are all made of Hastelloy, and the liquid holding capacity of both dynamic tubular reactors is 100 mL.

[0026] Example 1 Compound IV was mixed with acetonitrile until homogeneous, and a 1 mol / L compound IV acetonitrile solution was prepared for later use. Thiourea was mixed with 30% hydrochloric acid aqueous solution and stirred until clear, and a 5 mol / L thiourea hydrochloric acid solution was prepared. Compound II was mixed with alkali to prepare a 1 mol / L compound II alkali solution. According to the operation flow chart, metering pump 1 delivered the compound IV acetonitrile solution at a flow rate of 20 mL / min, metering pump 2 delivered the thiourea hydrochloric acid solution at a flow rate of 6 mL / min, and metering pump 3 delivered the compound II alkali solution at a flow rate of 20 mL / min. Dynamic tubular reactor I was set to a temperature of 40℃ and a rotation speed of 160 rpm, while dynamic tubular reactor II was set to a temperature of 0℃ and a rotation speed of 180 rpm. Metering pumps 1, 2, and 3 were started, and intermediate IV and thiourea were reacted in dynamic tubular reactor I for 3.8 minutes to obtain intermediate III. Intermediate II was then reacted in dynamic tubular reactor II for 2.2 minutes. The reaction solution was then acidified in an acidification kettle (pH less than 2). Finally, the solution was centrifuged, washed, and dried to obtain product intermediate I, a pale yellow powder with a pungent odor, with a yield of 98.42% and a purity of 95.13%.

[0027] Example 2 Compound IV was mixed thoroughly with acetonitrile to prepare a 1 mol / L compound IV acetonitrile solution for later use; thiourea was mixed with 30% hydrochloric acid aqueous solution and stirred until clear to prepare a 5 mol / L thiourea hydrochloric acid solution; compound II was mixed with liquid alkali to prepare a 1 mol / L compound II alkali solution; according to the operation flow chart, metering pump 1 delivered compound IV acetonitrile solution at a flow rate of 20 mL / min, metering pump 2 delivered thiourea hydrochloric acid solution at a flow rate of 6 mL / min, and metering pump 3 delivered compound II alkali solution at a flow rate of 20 mL / min. Dynamic tubular reactor I was set to a temperature of 30℃ and a rotation speed of 170 rpm, while dynamic tubular reactor II was set to a temperature of 0℃ and a rotation speed of 210 rpm. Metering pumps 1, 2, and 3 were started, and intermediate IV and thiourea were reacted in dynamic tubular reactor I for 3.8 minutes to obtain intermediate III. Intermediate II was then reacted in dynamic tubular reactor II for 2.2 minutes. The reaction solution was then acidified in an acidification kettle (pH less than 2). Finally, the solution was centrifuged, washed, and dried to obtain product intermediate I, a pale yellow powder with a pungent odor, with a yield of 98.28% and a purity of 96.32%.

[0028] Example 3 Compound IV was mixed thoroughly with acetonitrile to prepare a 1 mol / L compound IV acetonitrile solution for later use; thiourea was mixed with 30% hydrochloric acid aqueous solution and stirred until clear to prepare a 5 mol / L thiourea hydrochloric acid solution; compound II was mixed with liquid alkali to prepare a 1 mol / L compound II alkali solution; according to the operation flow chart, metering pump 1 delivered the compound IV acetonitrile solution at a flow rate of 20 mL / min, metering pump 2 delivered the thiourea hydrochloric acid solution at a flow rate of 6 mL / min, and metering pump 3 delivered the compound II alkali solution at a flow rate of 20 mL / min. Dynamic tubular reactor I was set to a temperature of 40℃ and a rotation speed of 180 rpm, while dynamic tubular reactor II was set to a temperature of 10℃ and a rotation speed of 200 rpm. Metering pumps 1, 2, and 3 were started, and intermediate IV and thiourea were reacted in dynamic tubular reactor I for 3.8 minutes to obtain intermediate III. Intermediate II was then reacted in dynamic tubular reactor II for 2.2 minutes. The reaction solution was then acidified in an acidification kettle (pH less than 2). Finally, the solution was centrifuged, washed, and dried to obtain product intermediate I, a pale yellow powder with a pungent odor, with a yield of 98.47% and a purity of 95.11%.

[0029] Example 4 Compound IV was mixed thoroughly with acetonitrile to prepare a 1 mol / L compound IV acetonitrile solution for later use; thiourea was mixed with 30% hydrochloric acid aqueous solution and stirred until clear to prepare a 5 mol / L thiourea hydrochloric acid solution; compound II was mixed with liquid alkali to prepare a 1 mol / L compound II alkali solution; according to the operation flow chart, metering pump 1 delivered the compound IV acetonitrile solution at a flow rate of 20 mL / min, metering pump 2 delivered the thiourea hydrochloric acid solution at a flow rate of 6 mL / min, and metering pump 3 delivered the compound II alkali solution at a flow rate of 20 mL / min. Dynamic tubular reactor I was set to a temperature of 40℃ and a rotation speed of 200 rpm, while dynamic tubular reactor II was set to a temperature of 10℃ and a rotation speed of 200 rpm. Metering pumps 1, 2, and 3 were started, and intermediate IV and thiourea reacted in dynamic tubular reactor I for 4.2 minutes to obtain intermediate III. Intermediate II was then reacted in dynamic tubular reactor II for 2.3 minutes. The reaction solution was then acidified in an acidification kettle (pH less than 2). Finally, the solution was centrifuged, washed, and dried to obtain product intermediate I, a pale yellow powder with a pungent odor, with a yield of 90.20% and a purity of 90.79%.

[0030] Example 5 Compound IV was mixed thoroughly with acetonitrile to prepare a 1 mol / L compound IV acetonitrile solution for later use; thiourea was mixed with 30% hydrochloric acid aqueous solution and stirred until clear to prepare a 5 mol / L thiourea hydrochloric acid solution; compound II was mixed with potassium hydroxide to prepare a 1 mol / L compound II alkaline solution; according to the operation flow chart, metering pump 1 delivered the compound IV acetonitrile solution at a flow rate of 20 mL / min, metering pump 2 delivered the thiourea hydrochloric acid solution at a flow rate of 6 mL / min, and metering pump 3 delivered the compound II alkaline solution at a flow rate of 20 mL / min. Dynamic tubular reactor I was set to a temperature of 40℃ and a rotation speed of 300 rpm, while dynamic tubular reactor II was set to a temperature of 10℃ and a rotation speed of 200 rpm. Metering pumps 1, 2, and 3 were started, and intermediate IV and thiourea were reacted in dynamic tubular reactor I for 4.2 minutes to obtain intermediate III. Intermediate II was then reacted in dynamic tubular reactor II for 2.3 minutes. The reaction solution was then acidified in an acidification kettle (pH less than 2). Finally, the solution was centrifuged, washed, and dried to obtain product intermediate I, a pale yellow powder with a pungent odor, with a yield of 85.73% and a purity of 88.72%.

[0031] Comparative Example 1 700g of acetonitrile was added to a 1L round-bottom flask and stirred. Then 114g of thiourea was added, followed by 146g of 30% hydrochloric acid aqueous solution. After stirring until clear, 133.58g (1mol) of intermediate IV was added dropwise. After the addition was complete, the temperature was raised to 40℃ and the reaction was carried out for 4 hours. In another 2L round-bottom flask, 196.13g (1mol) of intermediate II and 1000g of 20% liquid alkali were added and stirred until clear. Then, the reaction solution of intermediate III from the previous step was added dropwise to the 2L round-bottom flask. During the addition, the reaction temperature was controlled at 10~15℃. After the addition was complete, the reaction was carried out for 20 minutes. Then, 30% hydrochloric acid aqueous solution was added dropwise until the pH of the reaction solution was <2. Finally, the product intermediate I was obtained by centrifugation, washing, and drying. It was a pale yellow powder with a small amount of lumpy solids and a pungent odor. The yield was 79.89% and the purity was 76.31%. Unlike the comparative example, the products in this example are all in powder form and there are no lumpy solids. This is because a series dynamic tubular reactor is used, which keeps the reaction liquid in a well-stirred state at all times, making it difficult for clumping to occur. At the same time, the dynamic tubular reactor effectively isolates air, avoiding the generation of other solid impurities and making it less likely for impurities to be trapped.

Claims

1. A method for the continuous preparation of sulfonylpyrazol intermediates using a series dynamic tubular reactor, characterized in that, Includes the following steps: (1) The organic solvent solution of compound IV reacts with the inorganic acid solution of thiourea in dynamic tubular reactor I to obtain the reaction solution of compound III; (2) The reaction solution of compound III and the alkaline solution of compound II react in dynamic tubular reactor II to obtain a mixed solution; (3) The mixture obtained in step (2) is mixed with hydrochloric acid in a reactor, filtered, centrifuged, and dried to obtain sulfonylpyrazine intermediate I; the reaction structure and operation process are shown below: 。 2. The method for continuous preparation of sulfonylpyrazol intermediate using a series dynamic tubular reactor according to claim 1, characterized in that, The organic solvent solution of compound IV and the inorganic acid solution of thiourea are mixed and reacted in a certain proportion in dynamic tubular reactor I. The resulting reaction solution does not need to be separated and purified. It is directly mixed and reacted with the alkaline solution of compound II in a certain proportion in dynamic tubular reactor II. The resulting reaction solution enters the acidification vessel, is mixed with hydrochloric acid for acidification, and finally centrifuged, washed and dried to obtain sulfopyrazine intermediate I.

3. The method for continuous preparation of sulfonylpyrazol intermediate using a series dynamic tubular reactor according to claim 2, characterized in that, The organic solvent in step (1) is acetonitrile; the mass ratio of compound IV to solvent acetonitrile is 1:5.0~1:7.

0.

4. The method for continuous preparation of sulfonylpyrazol intermediate using a series dynamic tubular reactor according to claim 2, characterized in that, The inorganic acid mentioned in step (1) is hydrochloric acid, with a mass fraction of 20% to 30%; the molar ratio of thiourea to hydrochloric acid aqueous solution is 1:0.7 to 1:0.

9. The molar ratio of compound IV to thiourea is 1:1.4 to 1:1.

6.

5. The method for continuous preparation of sulfonylpyrazol intermediate using a series dynamic tubular reactor according to claim 2, characterized in that, The reaction temperature in step (1) is 20~100℃; the reaction temperature in step (1) is 30~50℃; The retention time of the dynamic tubular reactor is 0.1 to 60 minutes; the retention time is 1.0 to 10 minutes.

6. The method for continuous preparation of sulfonylpyrazol intermediate using a series dynamic tubular reactor according to claim 2, characterized in that, The dynamic tubular reactor in step (1) is made of 316L, Hastelloy, and polytetrafluoroethylene. The internal stirring impeller of the dynamic tubular reactor is an axial flow stirring impeller, a radial flow stirring impeller, or a mixed flow stirring impeller. The dynamic tubular reactor is stirred in one direction at a speed of 160-180 revolutions per minute.

7. The method for continuous preparation of sulfonylpyrazol intermediate using a series dynamic tubular reactor according to claim 2, characterized in that, The alkali mentioned in step (2) is liquid alkali, and the mass fraction of liquid alkali is 20%~30%; the molar ratio of compound II to liquid alkali is 1:4.0~1:6.

0. The molar ratio of compound II to compound IV is 1:1.0 to 1:1.

5.

8. The method for continuous preparation of sulfonylpyrazol intermediate using a series dynamic tubular reactor according to claim 2, characterized in that, The reaction temperature in step (2) is -10~30℃; The reaction temperature is 0~15℃; The retention time of the dynamic tubular reactor is 0.1 to 60 minutes; further, the retention time is 1.0 to 4.0 minutes.

9. The method for continuous preparation of sulfonylpyrazol intermediate using a series dynamic tubular reactor according to claim 2, characterized in that, The dynamic tubular reactor in step (2) is made of 316L, Hastelloy, and polytetrafluoroethylene. The internal stirring impeller of the dynamic tubular reactor is an axial flow stirring impeller, a radial flow stirring impeller, or a mixed flow stirring impeller. The dynamic tubular reactor is stirred in one direction at a speed of 180-220 revolutions per minute.

10. The method for continuous preparation of sulfonylpyrazol intermediate using a series dynamic tubular reactor according to claim 2, characterized in that, In step (3), the pH value of the acidification solution in the acidification kettle needs to be less than 2.

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