A production system and method for preparing an indoxacarb intermediate

Abstract

The present application relates to a kind of production system and method for preparing indoxacarb intermediate, belong to the technical field of pesticide.The present application is mixed uniformly after (5-chloro-2,3-dihydro-2-hydroxy-2-methoxycarbonyl-1H-indene) hydrazine carboxylic acid benzyl ester, diethoxymethane and catalyst in benzene solvent, and is reacted in pipeline reactor;After reaction liquid enters evaporator one gas-liquid separation, the unreacted raw material continues to react in pipeline, simultaneously enters evaporator two again gas-liquid separation;Residual raw material is reacted and separated again in evaporator one, sequentially form a cycle;When raw material in reaction system is less than 1%, reaction liquid is discharged from product pipeline.The present application formulates improvement scheme to the separation of by-product ethanol, so that it can be quickly separated, solves the drawbacks that ester impurity is generated due to ethanol cannot be removed in time in traditional process, improves the yield and ring compound quality of ring closing reaction.

Description

Technical Field

[0001] This invention relates to the technical field of pesticides, and specifically to a production system and method for preparing indoxacarb intermediates. Background Technology

[0002] Indoxacarb, CAS number 144171-61-9, English name: Indoxacarb, Chinese name: S-7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)-phenyl]amino]carbonyl]indo[1,2-e][1,3,4]oxadiazine-4(3H)-carboxylic acid methyl ester, chemical structural formula: ; Indoxacarb is a highly effective, safe, and low-toxicity oxadiazine insecticide developed by DuPont in 1992. It was the first commercially available sodium channel blocker oxadiazine insecticide and was registered and marketed as a "risk-reducing product" in many countries worldwide, including the United States, France, and China, starting in 2001. Indoxacarb is effective against almost all lepidopteran pests and is safe for humans, the environment, crops, and non-target organisms. Furthermore, indoxacarb has a short application restriction period before harvest, making it an ideal alternative to organophosphate insecticides.

[0003] 2-Benzyloxycarbonyl-7-chloroindo[1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-4a-carboxylic acid methyl ester (abbreviated as cyclic compound B) is an important intermediate in the synthesis of indoxacarb, and its structure is as follows: ; There are many existing methods for preparing cyclocomplex B, most of which use 5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone and diethoxymethane as reactants to generate cyclocomplex B via a cyclization reaction. However, in actual production, the problem of difficult removal of the byproduct ethanol leads to increased side reactions and low yield. Existing technology CN111825632A discloses a method for preparing a key intermediate of indoxacarb. This method first mixes the raw material 5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone with diethoxymethane, then adds the mixture dropwise into refluxed solvent and reacts in a reactor. The generated byproduct ethanol and the raw material diethoxymethane form an azeotropic mixture, which escapes from the top of the reactor and enters a distillation column for separation. The generated ethanol is collected, while the diethoxymethane is returned to the reactor for further reaction. The separation of ethanol promotes the forward reaction. However, in actual production, this method is problematic because the ethanol produced in the reaction vessel is difficult to separate out quickly and in large quantities, leading to an increase in ethyl ester impurities and affecting the yield of the cyclization reaction and the purity of the cyclized compound. Summary of the Invention

[0004] To address the problems of slow reaction rate and untimely separation of by-product ethanol in the preparation of cyclamate B using batch distillation in existing technologies, this invention provides a production system and method for preparing indoxacarb intermediates. From an engineering perspective, this method solves the problem of difficult removal of by-product ethanol in the cyclization reaction, reduces the generation of ethyl ester impurities, improves product content and yield, and is suitable for industrial conversion, laying the foundation for the production of high-quality indoxacarb.

[0005] The technical solution of this invention is as follows: A production system for preparing indoxacarb intermediates includes a pipeline reactor; the inlet of the pipeline reactor is connected to a preheater; a mixer is provided at the front end of the preheater; the mixer consists of a dynamic mixer and a static mixer; the dynamic mixer has R1 solution pipeline and R2 solution pipeline; each pipeline is equipped with a pump and a flow meter; the outlet of the pipeline reactor is connected to an evaporator, which has an evaporation chamber and an ethanol recovery port; the evaporation chamber is connected to a second evaporator via a transfer pump; the outlet of the transfer pump is equipped with an online detector; the second evaporator is connected to an evaporation chamber; the second evaporation chamber has an ethanol recovery port; the second evaporation chamber is connected to the first evaporator; a product pipeline is provided between the online chromatographic detector and the second evaporator.

[0006] Furthermore, the static mixer is one of the SK, SV, and SL types, with the SK type being preferred.

[0007] A method for preparing indoxacarb intermediates using the above-mentioned production system involves mixing a benzene-based solution (R1 solution) of (5-chloro-2,3-dihydro-2-hydroxy-2-methoxycarbonyl-1H-indene)hydrazine carboxylic acid methyl ester (intermediate A) / catalyst with a benzene-based solution of diethoxymethane (R2 solution) at specific flow rates in a mixer. The mixed solution is preheated to a certain temperature by a preheater and then enters a pipeline reactor. The mixture reacts in the pipeline reactor, whose outlet is connected to an evaporator. The reaction solution enters the evaporator and, under the action of a distributor, forms a uniform film. Under the action of a heat source, it boils and vaporizes. The vaporized gas and the reaction solution enter an evaporation chamber for gas-liquid separation. The gas phase (acetylene) is separated from the reaction solution. Alcohol and diethoxymethane are separated from ethanol recovery port one, condensed, and then recovered. The liquid phase enters the circulation pipeline and is pumped into evaporation chamber two. Since the liquid phase contains some unreacted raw materials, it continues to react and vaporize in the circulation pipeline, evaporator two, and evaporation chamber two. After secondary gas-liquid separation, the generated byproduct ethanol is promptly separated from ethanol recovery port two, condensed, and the solvent is recovered. This process promotes the cyclization reaction towards the reaction product. After online chromatographic detection confirms its quality, the qualified product is collected to obtain methyl 2-benzyloxycarbonyl-7-chloroindenzo[1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-4a-carboxylic acid. The reaction formula is as follows: ; The specific preparation steps are as follows: (1) Take (5-chloro-2,3-dihydro-2-hydroxy-2-methoxycarbonyl-1H-indene)hydrazine carboxylic acid benzyl ester (intermediate A) and catalyst, dissolve them in benzene-based solvents, and record the mixture as solution R1; take diethoxymethane, dissolve it in benzene-based solvents, and record the mixture as solution R2; pump solution R1 and solution R2 into a mixer at a certain flow rate, mix them, and then preheat them in a preheater before entering a pipeline reactor for reaction. The pipeline reactor is controlled at a certain temperature to ensure that the cyclization reaction proceeds smoothly. (2) After the reaction liquid is reacted in the pipeline reactor, it enters the evaporator to remove the by-product ethanol produced by the reaction and promote the forward reaction. (3) The unreacted intermediate A continues to react in the circulation pipeline under the circulation action of the transfer pump. The by-product ethanol is separated from the reaction material system again in time through evaporator II. The liquid phase flows into evaporator I for recirculation reaction and evaporation. (4) When the residue of intermediate A is less than 1% as detected by the online chromatograph at the outlet of the delivery pump, open the product collection line valve to collect the qualified cyclic material liquid from the product pipeline; (5) The qualified cyclized material liquid was washed with water to remove the acidic catalyst, and then the benzene solvent was recovered by negative pressure distillation. After the benzene solvent was removed, a crystallization solvent was added for crystallization and filtration to obtain the target product 2-benzyloxycarbonyl-7-chloroindo[1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-4a-carboxylic acid methyl ester (cyclized compound B).

[0008] Furthermore, the catalyst in step (1) is one of p-toluenesulfonic acid, methanesulfonic acid, and oxalic acid, preferably p-toluenesulfonic acid.

[0009] Furthermore, in the benzene-based solution in step (1), the solvent is one of toluene, xylene, ethylbenzene, or cumene, preferably ethylbenzene.

[0010] Furthermore, in step (1) R1 solution, the mass ratio of intermediate A, catalyst, and benzene series is 1:0.02~0.12:2~6.

[0011] Furthermore, in step (1) R2 solution, the mass ratio of diethoxymethane to benzene is 1:3.3~14.3.

[0012] Furthermore, the mass flow rate ratio of the extracted R1 solution, R2 solution, and cyclizer B solution is controlled at 1:0.46~1.44:1.34~2.24.

[0013] Furthermore, in step (1), a continuous reaction was carried out in a pipeline, which reduced the liquid holding capacity of the reaction, accelerated the internal mass transfer and heat transfer, and improved the reaction efficiency.

[0014] Furthermore, the evaporator selected in step (2) is one of the following: falling film evaporator, rising film evaporator, scraped film evaporator, or distillation separation column, with falling film evaporator being preferred.

[0015] Furthermore, the evaporator selected in step (3) is one of the following: forced circulation evaporator, external heating natural circulation evaporator, or central circulation tube evaporator, with forced circulation evaporator being preferred.

[0016] Furthermore, in step (2), the reaction temperature of the pipeline reactor is 88~95℃.

[0017] Furthermore, in step (2), the temperature of evaporator one is 74~85℃.

[0018] Furthermore, in step (3), the temperature of evaporator 2 is 100-120℃.

[0019] Furthermore, the crystallization solvent selected in step (5) is one of methanol, ethanol, and petroleum ether, with petroleum ether being preferred.

[0020] The beneficial effects of this invention are as follows: Compared with traditional processes, this invention first utilizes a dynamic mixer and a static mixer with a specific structure to uniformly mix the reaction raw materials, improving the mixing degree and effect of the reactants. Secondly, it improves the conventional batch distillation reaction into a continuous pipeline reaction, accelerating internal mass and heat transfer. Furthermore, through analysis of the reaction mechanism, an improved scheme for separating the by-product ethanol is developed. Membrane evaporation separation technology is used to increase the specific surface area of ​​the evaporating liquid, improving heat transfer efficiency and enabling rapid separation of the by-product ethanol. Moreover, the reaction liquid continues to react during pipeline circulation, passing through two evaporators after each cycle, ensuring that the generated by-product ethanol can be promptly discharged from the reaction system. This solves the drawback of traditional processes where the inability to remove ethanol in time leads to the formation of ethyl ester impurities, improving the yield of the cyclization reaction and the quality of the cyclized product. Furthermore, due to the significantly reduced liquid holdup in the pipeline reaction, this invention significantly improves safety compared to conventional batch reactions and batch distillations. In summary, this invention has the advantages of high reaction and separation efficiency, simple and easy operation, high safety and reliability, high yield, high content, and easy continuous operation, making it suitable for industrial production. Attached Figure Description

[0021] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0022] Figure 1 This is a schematic diagram of the connection of the production device of the present invention.

[0023] Figure 2 This is the HPLC chromatogram of the product prepared in Example 5 of the present invention.

[0024] Figure 3 This is the HPLC chromatogram of the product prepared in the comparative example of this invention.

[0025] In the diagram, 1-R1 solution pipeline, 2-R2 solution pipeline, 3-dynamic mixer, 4-static mixer, 5-preheater, 6-pipeline reactor, 7-evaporator one, 8-evaporation chamber one, 9-ethanol recovery port one, 10-online chromatograph, 11-transfer pump, 12-evaporator two, 13-evaporation chamber two, 14-ethanol recovery port two, 15-product pipeline. Detailed Implementation

[0026] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0027] Example 1 A production system for indoxacarb intermediates includes a tubular reactor 6, an evaporator 7, and an evaporator 2 12. The inlet of the tubular reactor 6 is connected to a preheater 5. A mixer is installed upstream of the preheater 5. The mixer consists of a dynamic mixer 3 and a static mixer 4. The dynamic mixer 3 has an R1 solution pipe 1 and an R2 solution pipe 2. Pumps and flow meters are installed on each pipe. The outlet of the tubular reactor 6 is connected to the evaporator 7, which is a falling film evaporator. Evaporation chamber 7 is equipped with evaporation chamber 8, which has an ethanol recovery port 9. Evaporation chamber 8 is connected to evaporator 2 12 via a transfer pump 11. Evaporator 2 12 is a forced circulation evaporator. An online chromatographic analyzer 10 is installed at the outlet of the transfer pump 11. Evaporator 2 12 is connected to evaporation chamber 2 13. Evaporation chamber 2 13 has an ethanol recovery port 14. Evaporation chamber 2 13 is connected to evaporator 7. A product pipeline 15 is provided between the online chromatographic analyzer 10 and evaporator 2 12.

[0028] Example 2 The indoxacarb intermediate was prepared using the production system described in Example 1, as follows: ; (1) R1 solution (intermediate A / p-toluenesulfonic acid / xylene = 1:0.02:2) and R2 solution (diethoxymethane / xylene = 1:6.25) are pumped into a dynamic mixer at flow rates of 60.4 kg / h and 58.0 kg / h respectively (R1 solution / R2 solution flow rate ratio 1:0.96). After preliminary mixing, the mixture is further mixed in a static mixer (SV type). The enhanced mixed liquid is preheated by a preheater and then enters a pipeline reactor for reaction. The pipeline reactor uses hot water to control the temperature at 90℃.

[0029] (2) The reaction liquid coming out of the pipeline reactor enters the evaporator one. Hot water is introduced into the jacket of the evaporator one to ensure that the material temperature is about 85°C. Under the action of the heat source, part of the liquid vaporizes and enters the evaporation chamber one along with the unvaporized liquid for gas-liquid separation. The gas phase is mainly ethanol (containing some diethoxymethane) which is separated from the ethanol recovery port one and then condensed for solvent recovery.

[0030] (3) The unreacted intermediate A continues to react in the pipeline under the action of the delivery pump. When it is delivered to the second evaporator, it is heated to 100°C. Some of the material is vaporized by the heat and enters the second evaporation chamber along with the unvaporized liquid for gas-liquid separation again. The gas phase is mainly ethanol (containing some diethoxymethane), which is separated from the second ethanol recovery port and then condensed for solvent recovery. The liquid phase enters the first evaporator to repeat the heating, reaction and evaporation.

[0031] (4) An online chromatographic detector is installed at the outlet of the delivery pump to monitor the content of intermediate A in real time during the reaction. When the residual content of intermediate A is less than 1%, the product collection line valve is opened to continuously collect the qualified product liquid at a flow rate of 106.4 kg / h (R1 solution / product liquid collection flow rate ratio 1:1.76).

[0032] (5) The collected qualified cyclized material liquid was washed with water and distilled to remove the solvent. Then, 36 kg of crystallization solvent ethanol was added to dissolve it and the mixture was transferred to a crystallization kettle. The temperature was lowered to 0-5℃ and centrifuged to obtain the target product methyl 2-benzyloxycarbonyl-7-chloroindo[1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-4a-carboxylic acid (cyclized compound B). The dry weight was 20.30 kg, the content was 98.0%, the yield was 96.5%, and the ethyl ester impurity content was 1.82%.

[0033] Example 3 The indoxacarb intermediate was prepared using the production system described in Example 1, as follows: ; (1) R1 solution (intermediate A / methanesulfonic acid / toluene = 1:0.05:3.4) and R2 solution (diethoxymethane / toluene = 1:14.3) are pumped into a dynamic mixer at flow rates of 89.0 kg / h and 128.4 kg / h respectively (R1 solution / R2 solution flow rate ratio 1:1.44). After preliminary mixing, they are further mixed in a static mixer (SV type). The enhanced mixed liquid is preheated by a preheater and then enters a pipeline reactor for reaction. The pipeline reactor uses hot water to control the temperature at 88℃.

[0034] (2) The reaction liquid coming out of the pipeline reactor enters the evaporator one. Hot water is introduced into the jacket of the evaporator one to ensure that the material temperature is about 80°C. Under the action of the heat source, part of the liquid vaporizes and enters the evaporation chamber one along with the unvaporized liquid for gas-liquid separation. The gas phase is mainly ethanol (containing some diethoxymethane) which is separated from the ethanol recovery port one and then condensed for solvent recovery.

[0035] (3) The unreacted intermediate A continues to react in the pipeline under the action of the delivery pump. When it is delivered to the second evaporator, it is heated to 116°C. Some of the material is vaporized by the heat and enters the second evaporation chamber along with the unvaporized liquid for gas-liquid separation again. The gas phase is mainly ethanol (containing some diethoxymethane), which is separated from the second ethanol recovery port and then condensed for solvent recovery. The liquid phase enters the first evaporator to repeat the heating, reaction and evaporation.

[0036] (4) An online chromatographic detector is installed at the outlet of the delivery pump to monitor the content of intermediate A in real time during the reaction. When the residue of intermediate A is less than 1%, the product collection line valve is opened to continuously collect the qualified product liquid at a flow rate of 199.4 kg / h (R1 solution / product liquid collection flow rate ratio 1:2.24).

[0037] (5) The collected qualified cyclized material liquid was washed with water and distilled to remove the solvent. Then, 36 kg of methanol, the crystallization solvent, was added to dissolve the liquid and transferred to a crystallization kettle. The temperature was lowered to 0-5℃, and centrifugation was performed to obtain the target product, methyl 2-benzyloxycarbonyl-7-chloroindo[1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-4a-carboxylic acid (cyclized compound B). The dry weight was 20.39 kg, the content was 98.3%, the yield was 97.2%, and the ethyl ester impurity content was 1.30%.

[0038] Example 4 The indoxacarb intermediate was prepared using the production system described in Example 1, as follows: ; (1) R1 solution (intermediate A / methanesulfonic acid / toluene = 1:0.12:6) and R2 solution (diethoxymethane / toluene = 1:4.1) are pumped into a dynamic mixer at flow rates of 142.4 kg / h and 82.0 kg / h respectively (R1 solution / R2 solution flow rate ratio 1:0.58). After preliminary mixing, the mixture is further mixed in a static mixer (SK type). The enhanced mixed liquid is preheated by a preheater and then enters a pipeline reactor for reaction. The pipeline reactor uses hot water to control the temperature at 95℃.

[0039] (2) The reaction liquid coming out of the pipeline reactor enters the evaporator one. Hot water is introduced into the jacket of the evaporator one to ensure that the material temperature is about 74°C. Under the action of the heat source, part of the liquid vaporizes and enters the evaporation chamber one along with the unvaporized liquid for gas-liquid separation. The gas phase is mainly ethanol (containing some diethoxymethane) which is separated from the ethanol recovery port one and then condensed for solvent recovery.

[0040] (3) The unreacted intermediate A continues to react in the pipeline under the action of the delivery pump. When it is delivered to the second evaporator, it is heated to 120°C. Some of the material is vaporized by the heat and enters the second evaporation chamber along with the unvaporized liquid for gas-liquid separation again. The gas phase is mainly ethanol (containing some diethoxymethane), which is separated from the second ethanol recovery port and then condensed for solvent recovery. The liquid phase enters the first evaporator to repeat the heating, reaction and evaporation.

[0041] (4) An online chromatographic detector is installed at the outlet of the delivery pump to monitor the content of intermediate A in real time during the reaction. When the residual content of intermediate A is less than 1%, the product collection line valve is opened to continuously collect the qualified product liquid at a flow rate of 204.4 kg / h (R1 solution / product liquid collection flow rate ratio 1:1.44).

[0042] (5) The collected qualified cyclized material liquid was washed with water and distilled to remove the solvent. Then, 36 kg of methanol, the crystallization solvent, was added to dissolve the liquid and transferred to a crystallization kettle. The temperature was lowered to 0-5℃, and centrifugation was performed to obtain the target product, methyl 2-benzyloxycarbonyl-7-chloroindo[1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-4a-carboxylic acid (cyclized compound B). The dry weight was 20.51 kg, the content was 98.2%, the yield was 97.7%, and the ethyl ester impurity content was 1.45%.

[0043] Example 5 The indoxacarb intermediate was prepared using the production system described in Example 1, as follows: ; (1) R1 solution (intermediate A / p-toluenesulfonic acid / ethylbenzene = 1:0.09:4.6) and R2 solution (diethoxymethane / ethylbenzene = 1:3.3) are pumped into a dynamic mixer at flow rates of 113.8 kg / h and 52.0 kg / h respectively (R1 solution / R2 solution flow rate ratio 1:0.46). After preliminary mixing, the mixture is further mixed in a static mixer (SK type). The enhanced mixed liquid is preheated by a preheater and then enters a pipeline reactor for reaction. The pipeline reactor uses hot water to control the temperature at 93℃.

[0044] (2) The reaction liquid coming out of the pipeline reactor enters the evaporator one. Hot water is introduced into the jacket of the evaporator one to ensure that the material temperature is about 78°C. Under the action of the heat source, part of the liquid vaporizes and enters the evaporation chamber one along with the unvaporized liquid for gas-liquid separation. The gas phase is mainly ethanol (containing some diethoxymethane) which is separated from the ethanol recovery port one and then condensed for solvent recovery.

[0045] (3) The unreacted intermediate A continues to react in the pipeline under the action of the delivery pump. When it is delivered to the second evaporator, it is heated to 112°C. Some of the material is vaporized by the heat and enters the second evaporation chamber along with the unvaporized liquid for gas-liquid separation again. The gas phase is mainly ethanol (containing some diethoxymethane), which is separated from the second ethanol recovery port and then condensed for solvent recovery. The liquid phase enters the first evaporator to repeat the heating, reaction and evaporation.

[0046] (4) An online chromatographic detector is installed at the outlet of the delivery pump to monitor the content of intermediate A in real time during the reaction. When the residual content of intermediate A is less than 1%, the product collection line valve is opened to continuously collect the qualified product liquid at a flow rate of 152.8 kg / h (R1 solution / product liquid collection flow rate ratio 1:1.34).

[0047] (5) The collected qualified cyclized material liquid was washed with water, distilled to remove the solvent, and then dissolved in 36 kg of petroleum ether, the crystallization solvent. The solution was then transferred to a crystallization vessel, cooled to 0-5℃, and centrifuged to obtain the target product, methyl 2-phenylmethoxycarbonyl-7-chloroindo[1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-4a-carboxylic acid (cyclized compound B). The dry weight was 20.49 kg, the content was 98.6%, the yield was 98.0%, and the ethyl ester impurity content was 1.15%. See the detailed detection chromatogram for details. Figure 2 . Figure 2 The main peak at RT=6.678 min is the target product, and the peak at RT=5.986 min is the ethyl ester impurity peak.

[0048] Comparative Example The indoxacarb intermediate was prepared according to the method disclosed in patent CN111825632A, as follows: ; (1) Mix 20.00 kg of intermediate A, 17.30 kg of diethoxymethane and 37.5 kg of toluene evenly for later use.

[0049] (2) Add 62.5 kg of toluene to the reactor and reflux it into the column. Set the reaction temperature to 110°C. After reaching 110°C, slowly add the mixture from step (1) into the toluene. After 6 hours, when the temperature at the top of the distillation column reaches 78°C, start collecting ethanol.

[0050] (3) After the ethanol collection was completed, the reaction system was desolvated under negative pressure. 75 kg of petroleum ether was added to the concentrate, and then the temperature was lowered to 0-5℃. After centrifugation and drying, the target product methyl 2-benzyloxycarbonyl-7-chloroindenzo[1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-4a-carboxylic acid was obtained. The dry weight was 20.38 kg, the content was 96.2%, the yield was 95.1%, and the content of ethyl ester impurity was 3.18%. For the detection chromatogram, please refer to [link to chromatogram]. Figure 3 . Figure 3 The main peak at RT=6.915min is the target product, and the peak at RT=6.169min is the ethyl ester impurity peak.

[0051] Through comparison with examples and comparative examples, it is evident that the preparation of methyl 2-benzyloxycarbonyl-7-chloroindenzo[1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-4a-carboxylic acid according to the process described in this invention reduces the ethyl ester impurity from the byproduct ethanol to below 2%, with an optimal reduction to 1.15%. The target product content is increased to over 98%, and the yield can be increased to over 96.5%, with an optimal yield of 98.0%. Furthermore, the use of microchannels and continuous separation operations allows for rapid and efficient separation of byproducts, reducing the amount of impurities generated. The process of this invention is simple to operate, safe, and reliable, making it more suitable for industrial production applications.

[0052] The comparative example, after scaling up the feed amount compared to patent CN111825632A, showed slightly lower product content and yield. This is because the ethyl ester impurities increased during the scaling-up process due to the slower ethanol removal rate. This, in turn, further demonstrates the advantage of this invention in controlling ethyl ester impurities.

[0053] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.

Claims

1. A method for preparing an intermediate of indoxacarb, characterized in that, The reaction formula is as follows: ； The specific preparation steps are as follows: (1) Dissolve (5-chloro-2,3-dihydro-2-hydroxy-2-methoxycarbonyl-1H-indene)hydrazine carboxylic acid benzyl ester and catalyst in a benzene-based solvent, and the mixture is recorded as solution R1; dissolve diethoxymethane in a benzene-based solvent, and the mixture is recorded as solution R2; pump solution R1 and solution R2 into a mixer for mixing, and then preheat them in a preheater before entering the pipeline reactor for reaction; (2) After the reaction liquid is reacted in the pipeline reactor, it enters the evaporator to remove the by-product ethanol produced in the reaction; (3) The unreacted intermediate A continues to react in the pipeline under the circulation of the transfer pump. The by-product ethanol is separated from the reaction material system again in time through evaporator II. The liquid phase flows into evaporator I for recirculation reaction and evaporation. (4) When the residue of intermediate A is less than 1% as detected by the online chromatograph at the outlet of the delivery pump, open the product collection line valve to collect the qualified cyclic material liquid from the product pipeline; (5) The qualified cyclized material liquid was washed with water to remove the acidic catalyst, and then the benzene solvent was recovered by negative pressure distillation. After the benzene solvent was removed, a crystallization solvent was added for crystallization and filtration to obtain the target product methyl 2-benzyloxycarbonyl-7-chloroindo[1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-4a-carboxylic acid. The method for preparing indoxacarb intermediates uses the following production system: The production system includes a pipeline reactor, the inlet of which is connected to a preheater; a mixer is installed before the preheater; the mixer consists of a dynamic mixer and a static mixer; the dynamic mixer has R1 solution pipelines and R2 solution pipelines; each pipeline is equipped with a pump and a flow meter; the outlet of the pipeline reactor is connected to evaporator one, which has an evaporation chamber one and an ethanol recovery port one; evaporation chamber one is connected to evaporator two via a transfer pump; the outlet of the transfer pump is equipped with an online chromatograph; evaporator two is connected to evaporation chamber two; evaporation chamber two has an ethanol recovery port two; evaporation chamber two is connected to evaporator one; a product pipeline is provided between the online chromatograph and evaporator two.

2. The method as described in claim 1, characterized in that, The static mixer is one of the SK, SV, or SL types.

3. The method as described in claim 1, characterized in that, The catalyst in step (1) is one of p-toluenesulfonic acid, methanesulfonic acid or oxalic acid.

4. The method as described in claim 1, characterized in that, The benzene solvent in step (1) is one of toluene, xylene, ethylbenzene or cumene.

5. The method as described in claim 1, characterized in that, In step (1), the mass ratio of intermediate A, catalyst and benzene solvent in solution R1 is 1:0.02~0.12:2~6.

6. The method as described in claim 1, characterized in that, In step (1), the mass ratio of diethoxymethane to benzene solvent in solution R2 is 1:3.3~14.

3.

7. The method as described in claim 1, characterized in that, The mass flow rate ratio of R1 solution, R2 solution, and cyclized material liquid was controlled at 1:0.46~1.44:1.34~2.

24.

8. The method as described in claim 1, characterized in that, The reaction temperature of the pipeline reactor in step (2) is 88~95℃.

9. The method as described in claim 1, characterized in that, In step (2), the temperature of evaporator one is 74~85℃; in step (3), the temperature of evaporator two is 100~120℃.

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