2, 6-diethyl-4-methylbromobenzene full-continuous flow synthesis process and reaction device thereof

Abstract

The invention discloses a 2, 6-diethyl-4-methyl bromobenzene full-continuous flow synthesis process and a reaction device thereof, and relates to the technical field of compound synthesis. A reaction substrate and a sodium nitrite solution mixed with a catalyst are respectively input into a full-continuous flow shear reaction device through a feed port; after flowing through the temperature zone 1, the mixture is mixed with hydrobromic acid and enters a temperature zone 2 to complete a diazotization reaction, a diazotization reaction solution is obtained, the diazotization reaction solution flows out of the temperature zone 2, enters the bromination unit, reacts with a bromination reagent in the bromination unit, sequentially flows through a temperature zone 3 and is output from a discharge port, and a final product 2 is obtained after extraction, water washing, desolvation and distillation. The catalyst is 2, 6-diethyl-4-methyl bromobenzene. A continuous process is adopted, so that the difficulty of industrial application is greatly reduced; and during industrial amplification, the required production scale can be obtained through one-time amplification without tedious and complex multi-time step-by-step amplification and adjustment and optimization of process conditions and parameters, so that manpower, material resources and project development time are greatly saved.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of compound synthesis, in particular to a full-continuous-flow synthesis process of 2,6-diethyl-4-methylbromobenzene and a reaction device thereof. BACKGROUND

[0002] Fenquinotrifludioxime is a phenylpyrazoline herbicide with a novel structure developed by Syngenta Crop Protection Company for use in wheat fields. The mechanism of action is to inhibit acetyl-CoA carboxylase, reduce the synthesis of fatty acids of weeds, and has a close to 100% control effect on some gramineous weeds such as wild oats, brome, hard grass and so on which are resistant to oxime ethers of cyclohexanediones and aryloxyphenoxypropionic acid (APP) herbicides at an effective dose of 30-60 g / hm2. The application dose is low, the structure is novel, and it does not produce resistance to APP herbicides. The biggest feature is good safety to barley. It has a completely new chemical structure and a different action site, and can effectively control wild oats, ryegrass, hard grass, rice grass, foxtail grass, Japanese foxtail grass and dogtail grass, especially the weeds resistant to fluazifop-butyl and fenoxaprop-P-ethyl, and has a broad application prospect. At present, the main route for synthesizing fenquinotrifludioxime is to take 2,6-diethyl-4-methyl aniline as a starting material to undergo diazotization and Sandmeyer reaction to obtain an intermediate 2,6-diethyl-4-methyl bromobenzene. [1,4,5]-oxadiazole bromide hydrogen salt and malonyl chloride undergo nucleophilic substitution reaction to obtain tetrahydro-7H-pyrazole [1,2d][1,4,5] benzodiazepine-7,9(8H)-dione. 4-methyl-2,6-diethyl bromobenzene and tetrahydro-7H-pyrazole [1,2d][1,4,5] benzodiazepine-7,9(8H)-dione are cross-coupled under the catalysis of a catalyst to obtain 8-(2,6-diethyl-4-methylphenyl) 1,2,4,5-tetrahydro pyrazole [1,2-d][1,4,5] oxadiazole-7,9-dione. Finally, the final product fenquinotrifludioxime is obtained after acylation by pivaloyl chloride. The 2,6-diethyl-4-methyl bromobenzene is an important intermediate.

[0003] In the reaction device of Chinese patent CN116573986A, 2,6-diethyl-4-methyl aniline, o-dichlorobenzene and sodium bromide are stirred uniformly, HBr solution is added dropwise into the reaction system, then pentyl nitrite is added dropwise, after the dropwise addition is completed, stirring is continued, sodium carbonate solution is added into the reaction system to adjust pH to 7-8, and then the system is left to stand and separate into layers. The organic phase is washed with water again, then o-dichlorobenzene is removed from the organic phase by reduced pressure distillation, and 2,6-diethyl-4-methyl bromobenzene is obtained. The process uses expensive pentyl nitrite, and is not suitable for industrial production.

[0004] Chinese patent CN110117216A continuously adds diazotization reagent, acid and 2, 6-diethyl-4-methylaniline at the inlet of the continuous flow reactor, carries out diazotization reaction, the obtained diazonium salt further reacts with bromination reagent, and continuously obtains 2, 6-diethyl-4-methylbromobenzene crude product at the outlet of the integrated reactor, methylcyclohexane is added for extraction and phase separation, the organic phase is washed with water, saturated sodium carbonate, and then desolventized under reduced pressure to obtain 2, 6-diethyl-4-methylbromobenzene, in the process, hydrogen bromide and sodium nitrite are mixed first, and then react with the raw material to obtain diazonium salt, and sodium nitrite and acid are mixed and decomposed violently, so the reaction is uncontrollable.

[0005] Chinese patent CN114907181A is used for Sandmeyer reaction and continuously prepares 2, 6-diethyl-4-methylbromobenzene, 2, 6-diethyl-4-methylaniline toluene solution, hydrogen bromide aqueous solution and sodium nitrite aqueous solution are simultaneously introduced into the reactor to carry out diazotization reaction, and then are reversely contacted with bromine source aqueous solution and brominated to obtain 2, 6-diethyl-4-methylbromobenzene, the process requires high equipment and complex control.

[0006] Therefore, the present application is proposed to solve the above technical problems. SUMMARY

[0007] The present application aims to provide a full continuous flow synthesis process of 2, 6-diethyl-4-methylbromobenzene and a reaction device thereof, to solve the technical problems of high cost and difficulty in large-scale production of synthesizing 2, 6-diethyl-4-methylbromobenzene in the prior art.

[0008] The first object of the present application is to provide a full continuous flow synthesis process of 2, 6-diethyl-4-methylbromobenzene under the action of a catalyst, which uses a full continuous flow shearing reaction device, reaction raw materials are added into the inlet of the full continuous flow shearing reaction device, and the final product 2, 6-diethyl-4-methylbromobenzene is obtained from the outlet of the full continuous flow shearing reaction device, the reaction raw materials include a catalyst, a reaction substrate, hydrogen bromide and sodium nitrite; The full continuous flow synthesis process comprises the following steps: S1, the reaction substrate and the sodium nitrite solution mixed with the catalyst are respectively input into the full continuous flow shearing reaction device through the inlet, mixed with hydrogen bromide after flowing through temperature zone 1, and then enter temperature zone 2 to complete the diazotization reaction, and obtain a diazotization reaction solution; S2, the diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, reacts with the bromination reagent in the bromination unit, and then flows through temperature zone 3 in sequence, and is output from the outlet, and after extraction, water washing, desolventization and distillation, the final product 2, 6-diethyl-4-methylbromobenzene is obtained; The reaction substrate is 2, 6-diethyl-4-methylaniline.

[0009] Further, in step S1, a strong shearing process is accompanied in the temperature zone 1, for weakening or breaking the bond, and reducing the viscosity of the system.

[0010] Further, the catalyst is a phase transfer catalyst, selected from one or more of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), dodecyltrimethylammonium chloride (DTAC), tetradecyltrimethylammonium chloride (TTAC), etc.

[0011] Further, the mass ratio of the catalyst and the reaction substrate is preferably 0.1-0.5%.

[0012] Further, the molar ratio of hydrobromic acid and the reaction substrate is 2:1-2.8:1; The mass concentration of hydrobromic acid is 20%-48%.

[0013] Further, the molar ratio of sodium nitrite and the reaction substrate is 1:1-1.15:1; The mass concentration of sodium nitrite is 30%-44%.

[0014] Further, the bromination reagent is prepared by quantitatively mixing 48% HBr, 98% H2SO4 and ferrous sulfate heptahydrate at room temperature; Among them, the equivalent ratio of 48% HBr:98% H2SO4:ferrous sulfate heptahydrate:2,6-diethyl-4-methylaniline is 0.2:0.2:0.2:1.

[0015] Further, the temperature of the temperature zone 1 is 5-30°C; The temperature of the temperature zone 2 is -20-5°C; The temperature of the temperature zone 3 is 40-90°C.

[0016] Further, the yield of 2,6-diethyl-4-methylbromobenzene is ≥90%, and the content of 2,6-diethyl-4-methylbromobenzene is ≥95%.

[0017] The second object of the application is to provide a 2,6-diethyl-4-methylbromobenzene full continuous flow shearing reaction device, which is applied to the synthesis process of any of the above, comprising a shearing unit, a diazotization unit and a bromination unit connected in series, wherein the shearing unit is a temperature zone 1 for shearing the mixture of the reaction substrate and sodium nitrite, the diazotization unit is a temperature zone 2 for diazotization reaction of the reaction substrate, and the bromination unit is a temperature zone 3 for bromination reaction. The feeding port is located at the bottom of the shearing unit, and the discharging port is located at the top of the bromination unit. The shearing unit has a star-shaped reactor, and the diazotization unit and the bromination unit both have a fork-shaped reactor.

[0018] By adopting the technical scheme, the application has the following beneficial effects: 1、The production process of the application integrates diazotization and bromination process into a simple and easy-to-operate production process through one reactor, directly produces the product in a short time, and realizes high-quality and high-efficiency production.

[0019] 2、The production process is safe and efficient, the yield and content of the produced 2,6-diethyl-4-methylbromobenzene product are high, the production cost is greatly reduced, the safety of product production is improved, and high-efficiency, high-quality and large-scale production of 2,6-diethyl-4-methylbromobenzene is realized.

[0020] 3、The safety of the production process is greatly improved, the relatively small liquid holdup of the continuous flow reactor and the excellent heat transfer characteristics, combined with the short reaction time, make the process more safe.

[0021] 4、In the full continuous flow shear reaction device, the flow rate is stable, the production process is stable, and therefore the product quality is stable and the reproducibility is good. BRIEF DESCRIPTION OF DRAWINGS

[0022] The accompanying drawings are part of the present application and serve to provide a further understanding of the application, the schematic embodiments of the application and the description thereof serve to explain the application, but do not constitute an improper limitation on the application. Obviously, the drawings described below are only some embodiments, and other drawings can be obtained by those skilled in the art without creative labor. In the drawings: Fig. 1 The structure schematic diagram of the full continuous flow shear reaction device provided for the embodiments of the present application; Fig. 2 The full continuous flow process flowchart for synthesizing 2,6-diethyl-4-methylbromobenzene provided for the embodiments of the present application.

[0023] It should be noted that these drawings and written descriptions are not intended to limit the scope of the concept of the application in any way, but to illustrate the concept of the application to those skilled in the art by referring to specific embodiments. DETAILED DESCRIPTION

[0024] Referring to Figs. 1-2 The embodiments of the present application provide a full continuous flow synthesis process of 2,6-diethyl-4-methylbromobenzene, which adopts a full continuous flow shear reaction device, the reaction raw materials are added to the feed inlet of the full continuous flow shear reaction device, and the final product 2,6-diethyl-4-methylbromobenzene is obtained from the discharge outlet of the full continuous flow shear reaction device, the reaction raw materials include a catalyst, a reaction substrate, hydrobromic acid and sodium nitrite; The full continuous flow synthesis process includes the following steps: S1, the reaction substrate and the sodium nitrite solution mixed with the catalyst are respectively input into the full continuous flow shearing reaction device through the feeding port, after flowing through the temperature zone 1, mixed with hydrobromic acid to enter the temperature zone 2 to complete the diazotization reaction, and the diazotization reaction solution is obtained; S2, the diazotization reaction solution flows out of the temperature zone 2 and enters the bromination unit, after reacting with the bromination reagent in the bromination unit, it flows through the temperature zone 3 in turn, and is output through the discharge port, after extraction, water washing, desolventizing and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The reaction substrate is 2,6-diethyl-4-methylphenylamine.

[0025] It should be noted that the full continuous flow synthesis process time is ≤45s, preferably, the production time is 15-30s. The full continuous flow synthesis process time is the time experienced by the whole process of inputting the reaction raw materials from the feeding port, completing the diazotization and bromination two-step reactions in the integrated full continuous flow shearing reaction device, and outputting from the discharge port.

[0026] As a kind of continuous process, the full continuous flow synthesis process is a fast and efficient full-flow continuous process, which has the characteristics of short time, high efficiency and easy operation, and the raw materials are continuously and uninterruptedly added during the process, and the product is continuously and uninterruptedly produced. The material (i.e. the reaction mixture containing raw materials, intermediates, products and solvents) is continuously flowing, without interruption, waiting, etc. When the process operation reaches the steady state, the composition, temperature and other state parameters of the material at any position in the reactor do not change with time, which is a steady-state process, so the production process and product quality are stable.

[0027] In step S1, the temperature zone 1 is accompanied by a strong shearing process, which is used to weaken or break the bond. The shearing force directly acts on the chemical bond, weakens or breaks the bond, and reduces the reaction activation energy. On the other hand, in the fluid system, the shearing force reduces the viscosity of the system and enhances diffusion and mixing.

[0028] The catalyst is a phase transfer catalyst, which is selected from one or more of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), dodecyltrimethylammonium chloride (DTAC), and tetradecyltrimethylammonium chloride (TTAC), etc. Preferably, it is tetrabutylammonium chloride (TBAC).

[0029] The mass ratio of catalyst to reaction substrate is preferably 0.1-0.5%, preferably 0.2-0.3%. The catalyst dosage is less than 0.2%, which cannot achieve the effect of catalytic reaction, resulting in reduced product yield. Too much catalyst will cause imbalance between the reaction substrate and the catalyst, thereby affecting the reaction rate and reducing the yield. The catalyst is used to prepare the sodium nitrite solution with sodium nitrite aqueous solution.

[0030] The molar ratio of hydrobromic acid to the reaction substrate is 2:1 to 2.8:1, preferably 2.1:1 to 2.6:1, and more preferably 2.1:1 to 2.3:1. Too low an equivalent of hydrobromic acid leads to incomplete diazotization reaction, resulting in reduced product yield. When the equivalent is higher than 2.3, it leads to increased impurities in the subsequent bromination reaction, resulting in reduced product yield and content. The mass concentration of hydrobromic acid is 20% to 48%, preferably 30% to 48%, and more preferably 40% to 48%. Too low a concentration of hydrobromic acid leads to increased impurities in the subsequent bromination reaction, resulting in reduced product yield.

[0031] The molar ratio of sodium nitrite to the reaction substrate is 1:1 to 1.15:1, preferably 1.02:1 to 1.15:1, and more preferably 1.05:1 to 1.1:1. Too low an equivalent leads to incomplete diazotization reaction, resulting in reduced product yield. Too high an equivalent leads to increased impurities in the diazotization reaction, resulting in reduced product yield. The mass concentration of sodium nitrite is 30% to 44%, preferably 35% to 44%, and more preferably 40% to 44%. Too low a concentration of sodium nitrite leads to increased impurities in the subsequent bromination reaction, resulting in reduced product yield.

[0032] The bromination reagent is prepared by mixing 48% HBr, 98% H2SO4, and ferrous sulfate heptahydrate at room temperature. The equivalent ratio of 48% HBr:98% H2SO4:ferrous sulfate heptahydrate:2,6-diethyl-4-methylaniline is 0.2:0.2:0.2:1.

[0033] The temperature of warm zone 1 is 5 to 30°C, preferably 10 to 30°C, and more preferably 20 to 30°C. Too low a temperature leads to precipitation of sodium nitrite, incomplete diazotization reaction, and reduced product yield. The temperature of warm zone 2 is -20 to 5°C, preferably -15 to 5°C, and more preferably -10 to 0°C. Too high a temperature leads to decomposition of the diazonium salt, resulting in reduced product yield. Too low a temperature cannot further improve the yield and also increases energy consumption. The temperature of warm zone 3 is 40 to 90°C, preferably 50 to 90°C, and more preferably 60 to 80°C. Too high a temperature leads to increased impurities in the bromination reaction, resulting in reduced product yield. Too low a temperature leads to incomplete bromination reaction and also reduces the product yield.

[0034] The yield of 2,6-diethyl-4-methylbromobenzene is ≥90%, preferably ≥95%. The content of 2,6-diethyl-4-methylbromobenzene is ≥95%, preferably ≥96%, and more preferably ≥98%.

[0035] A 2,6-diethyl-4-methyl bromobenzene full continuous flow shearing reaction device is applied to the synthesis process, and comprises shearing units, diazotization units and bromination units connected in series, wherein the shearing units are warm zone 1 for shearing the mixture of the reaction substrate and sodium nitrite, the diazotization units are warm zone 2 for diazotization reaction of the reaction substrate, and the bromination units are warm zone 3 for bromination reaction; the feeding port is located at the bottom of the shearing unit, and the discharging port is located at the top of the bromination unit; the shearing unit has a star-shaped reactor, and the diazotization units and the bromination units have a fork-shaped reactor.

[0036] It should be noted that the material flow in the full continuous flow shearing reaction device is completed by the pressure of the reactor itself to transport the material from front to back; the star-shaped reactor has strong shearing function to disperse the mixture of the reaction substrate and sodium nitrite solution, weaken or break the bond, and reduce the reaction activation energy; the fork-shaped reactor is connected with heat exchange medium inside, has strong mixing and heat exchange effect, is beneficial to diazotization heat removal and bromination heat supply reaction, and continuously inputs various reaction raw materials into the full continuous flow shearing reaction device and continuously collects the reaction product; by selecting and using a suitable catalyst, the yield of the reaction product is improved; meanwhile, the unique internal structure design of the full continuous flow shearing reaction device, the division and temperature setting of the functional unit warm zone, the configuration optimization of the residence time of each warm zone and the synergistic effect of the functional units are combined to fully react in a short time, thereby greatly improving the efficiency of the process.

[0037] Through the synergistic effect of the division and temperature setting of each warm zone of the full continuous flow shearing reaction device and other factors, the full continuous flow process is realized. The full continuous flow reaction system can further match the reaction process by combining the temperature, material concentration, material ratio and material flow rate, so as to obtain better process effect.

[0038] The full continuous flow synthesis process adopts continuous process in the diazotization reaction stage and the bromination stage, has good stability and reliability, and thus the product quality is stable and reproducible, and the difficulty of industrial application is greatly reduced; when industrialization is scaled up, the process conditions and parameters do not need to be adjusted and optimized, and the production scale can be scaled up at one time, thereby greatly saving manpower, material resources and project development time; in industrial production, the production scale of the product can be flexibly changed, and the process conditions and parameters do not need to be re-adjusted and optimized, and the production process has good flexibility; the production process is stable and reliable, and the fluctuation of the process conditions and parameters will not affect the product quality, and the product quality is easy to control; and this greatly improves the safety of the production process.

[0039] It should be noted that the concentration in the embodiment of the present application is mass concentration, and the product is detected by gas chromatography (GC). As can be seen from the following embodiments of the present application, when the process parameters in the following embodiment tables are controlled in the appropriate range, the 2,6-diethyl-4-methylbromobenzene obtained from the target product meets the requirement that the content of 2,6-diethyl-4-methylbromobenzene is ≥95%.

[0040] In operation, raw material 1 (2,6-diethyl-4-methyl aniline solution), raw material 2 (sodium nitrite solution), raw material 3 (aqueous hydrobromic acid), and raw material 4 (bromination reagent) are sequentially fed into the full continuous flow shearing reaction device by constant flow pumps, and the feeding rates are shown in the following tables. Among them, feeding rate 1 represents the feeding rate of raw material 1, feeding rate 2 represents the feeding rate of raw material 2, feeding rate 3 represents the feeding rate of raw material 3, and feeding rate 4 represents the feeding rate of raw material 4. After shearing mixing in temperature zone 1, diazotization reaction is carried out in temperature zone 2, and the reaction is complete; the reaction liquid flowing out of temperature zone 2 enters temperature zone 3 for bromination to obtain 2,6-diethyl-4-methylbromobenzene crude product. Among them, the process temperature is controlled by temperature zone, the reaction time is controlled by the proportion of the flow time of each temperature zone and the total full continuous flow synthesis process time, and the full continuous flow synthesis process time of each embodiment is shown in the following tables. The various process parameters of each embodiment are shown in the following tables, wherein the catalyst dosage refers to the mass percentage of the catalyst to the reaction substrate.

[0041] Table 1: Screening of temperature zone 1 temperature in examples 1-4 ; Example 1 The 2,6-diethyl-4-methyl aniline solution is input into the full continuous flow shearing reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 5℃), it is mixed with 48% hydrobromic acid input at a rate of 112 g / min to enter temperature zone 2 (temperature 0℃) to complete the diazotization reaction, and obtain a diazotization reaction solution; After the diazotization reaction solution flows out of temperature zone 2, it enters the bromination unit, and after reacting with the bromination reagent input into the bromination unit at a rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60℃) and is output from the discharge port. The molar ratio of 2,6-diethyl-4-methyl aniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained, the production time is 30 s, the yield is 90%, and the content is 95%.

[0042] Example 2 The 2,6-diethyl-4-methylaniline solution was input into the full continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, flowed through temperature zone 1 (temperature 10°C), mixed with 48% hydrobromic acid input at 112 g / min into temperature zone 2 (temperature 0°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input into the bromination unit at 34.5 g / min, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 30 s, the yield was 90%, and the content was 95%.

[0043] Example 3 The 2,6-diethyl-4-methylaniline solution was input into the full continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, flowed through temperature zone 1 (temperature 20°C), mixed with 48% hydrobromic acid input at 112 g / min into temperature zone 2 (temperature 0°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input into the bromination unit at 34.5 g / min, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 30 s, the yield was 93%, and the content was 96%.

[0044] Example 4 The 2,6-diethyl-4-methylaniline solution was input into the full continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, flowed through temperature zone 1 (temperature 30°C), mixed with 48% hydrobromic acid input at 112 g / min into temperature zone 2 (temperature 0°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 95%, and the content is 98%.

[0045] Table 2: Screening of temperature zone 2 temperature for examples 5-9 ; Example 5 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shear reaction device at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -20°C) to complete the diazotization reaction, and the diazotization reaction solution is obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 95%, and the content is 96%.

[0046] Example 6 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shear reaction device at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -15°C) to complete the diazotization reaction, and the diazotization reaction solution is obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 95%, and the content is 98%.

[0047] Example 7 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the inlet at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), they were mixed with the 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input at 34.5 g / min in the bromination unit, and then flowed through temperature zone 3 (temperature 60°C) in turn and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 30 s, the yield was 95%, and the content was 96%.

[0048] Example 8 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the inlet at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), they were mixed with the 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature 0°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input at 34.5 g / min in the bromination unit, and then flowed through temperature zone 3 (temperature 60°C) in turn and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 30 s, the yield was 95%, and the content was 98%.

[0049] Example 9 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the inlet at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), they were mixed with the 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature 5°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input of 34.5 g / min, it successively flows through temperature zone 3 (temperature 40°C) and is output from the outlet, the molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1, and after extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained, the production time is 30 s, the yield is 90%, and the content is 96%.

[0050] Table 3: Screening of temperature zone 3 temperature of examples 10-14 ; Example 10 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shearing reaction device at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at 54.5 g / min, after flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and the diazotization reaction solution is obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input of 34.5 g / min, it successively flows through temperature zone 3 (temperature 40°C) and is output from the outlet, the molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1, and after extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained, the production time is 30 s, the yield is 90%, and the content is 96%.

[0051] Example 11 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shearing reaction device at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at 54.5 g / min, after flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and the diazotization reaction solution is obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input of 34.5 g / min, it successively flows through temperature zone 3 (temperature 40°C) and is output from the outlet, the molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1, and after extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained, the production time is 30 s, the yield is 90%, and the content is 96%.

[0052] Example 12 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the inlet at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), they were mixed with the 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input at 34.5 g / min in the bromination unit, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 30 s, the yield was 95%, and the content was 96%.

[0053] Example 13 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the inlet at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), they were mixed with the 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input at 34.5 g / min in the bromination unit, and then flowed through temperature zone 3 (temperature 80°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 30 s, the yield was 95%, and the content was 98%.

[0054] Example 14 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the inlet at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), they were mixed with the 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; The diazotization reaction solution flowed out of temperature zone 2 and entered the bromination unit, reacted with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, with a production time of 30 s, a yield of 90%, and a content of 95%.

[0055] Table 4: Catalyst dosage screening in examples 15-18 ; Example 15 The 2,6-diethyl-4-methylaniline solution was input into the full continuous flow shear reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.1% tetrabutylammonium chloride (TBAC) was input at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), the mixture was mixed with 48% hydrobromic acid input at a rate of 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, obtaining a diazotization reaction solution. The diazotization reaction solution flowed out of temperature zone 2 and entered the bromination unit, reacted with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, with a production time of 30 s, a yield of 90%, and a content of 96%.

[0056] Example 16 The 2,6-diethyl-4-methylaniline solution was input into the full continuous flow shear reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.1% tetrabutylammonium chloride (TBAC) was input at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), the mixture was mixed with 48% hydrobromic acid input at a rate of 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, obtaining a diazotization reaction solution. The diazotization reaction solution flowed out of temperature zone 2 and entered the bromination unit, reacted with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, with a production time of 30 s, a yield of 95%, and a content of 96%.

[0057] Example 17 The 2,6-diethyl-4-methylaniline solution was fed into the continuous flow shearing reactor at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.3% tetrabutylammonium chloride (TBAC) was fed into the continuous flow shearing reactor at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), the mixture was combined with 48% hydrobromic acid fed into the continuous flow shearing reactor at a rate of 112 g / min to complete the diazotization reaction in temperature zone 2 (temperature -10°C) to obtain a diazotization reaction solution. The diazotization reaction solution flowed out of temperature zone 2 and entered the bromination unit. After reacting with the bromination reagent fed into the bromination unit at a rate of 34.5 g / min, the mixture flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained. The production time was 30 s, the yield was 95%, and the content was 98%.

[0058] Example 18 The 2,6-diethyl-4-methylaniline solution was fed into the continuous flow shearing reactor at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.5% tetrabutylammonium chloride (TBAC) was fed into the continuous flow shearing reactor at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), the mixture was combined with 48% hydrobromic acid fed into the continuous flow shearing reactor at a rate of 112 g / min to complete the diazotization reaction in temperature zone 2 (temperature -10°C) to obtain a diazotization reaction solution. The diazotization reaction solution flowed out of temperature zone 2 and entered the bromination unit. After reacting with the bromination reagent fed into the bromination unit at a rate of 34.5 g / min, the mixture flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained. The production time was 30 s, the yield was 93%, and the content was 95%.

[0059] Table 5: Screening of catalyst types for Examples 19-23 ; Example 19 The 2,6-diethyl-4-methylaniline solution was fed into the continuous flow shearing reactor at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% benzyltriethylammonium chloride (TEBA) was fed into the continuous flow shearing reactor at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), the mixture was combined with 48% hydrobromic acid fed into the continuous flow shearing reactor at a rate of 112 g / min to complete the diazotization reaction in temperature zone 2 (temperature -10°C) to obtain a diazotization reaction solution. The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 90%, and the content is 95%.

[0060] Example 20 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shearing reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at a rate of 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, obtaining a diazotization reaction solution; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 95%, and the content is 98%.

[0061] Example 21 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shearing reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium bromide (TBAB) is input at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at a rate of 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, obtaining a diazotization reaction solution; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 90%, and the content is 95%.

[0062] Example 22 A solution of 2,6-diethyl-4-methylaniline was fed into the continuous flow shearing reactor at a rate of 51.4 g / min, and a 44% sodium nitrite solution mixed with 0.2% dodecyltrimethylammonium chloride (DTAC) was fed into the continuous flow shearing reactor at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), the solution was mixed with 48% hydrobromic acid fed into the continuous flow shearing reactor at a rate of 112 g / min, and flowed into temperature zone 2 (temperature -10°C) to complete the diazotization reaction, to obtain a diazotization reaction solution; After flowing out of temperature zone 2, the diazotization reaction solution flowed into the bromination unit, reacted with a bromination reagent fed into the bromination unit at a rate of 34.5 g / min, and then flowed through temperature zone 3 (temperature 60°C) in sequence, and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, with a production time of 30 s, a yield of 95%, and a content of 96%.

[0063] Example 23 A solution of 2,6-diethyl-4-methylaniline was fed into the continuous flow shearing reactor at a rate of 51.4 g / min, and a 44% sodium nitrite solution mixed with 0.2% dodecyltrimethylammonium chloride (DTAC) was fed into the continuous flow shearing reactor at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), the solution was mixed with 48% hydrobromic acid fed into the continuous flow shearing reactor at a rate of 112 g / min, and flowed into temperature zone 2 (temperature -10°C) to complete the diazotization reaction, to obtain a diazotization reaction solution; After flowing out of temperature zone 2, the diazotization reaction solution flowed into the bromination unit, reacted with a bromination reagent fed into the bromination unit at a rate of 34.5 g / min, and then flowed through temperature zone 3 (temperature 60°C) in sequence, and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, with a production time of 30 s, a yield of 95%, and a content of 96%.

[0064] Table 6: Screening of sodium nitrite equivalents for Examples 24-28 ; Example 24 A solution of 2,6-diethyl-4-methylaniline was fed into the continuous flow shearing reactor at a rate of 51.4 g / min, and a 44% sodium nitrite solution mixed with 0.2% dodecyltrimethylammonium chloride (DTAC) was fed into the continuous flow shearing reactor at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), the solution was mixed with 48% hydrobromic acid fed into the continuous flow shearing reactor at a rate of 112 g / min, and flowed into temperature zone 2 (temperature -10°C) to complete the diazotization reaction, to obtain a diazotization reaction solution; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 90%, and the content is 95%.

[0065] Example 25 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shearing reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at a rate of 50.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at a rate of 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and the diazotization reaction solution is obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.02:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 90%, and the content is 96%.

[0066] Example 26 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shearing reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at a rate of 50.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at a rate of 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and the diazotization reaction solution is obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.05:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 95%, and the content is 96%.

[0067] Example 27 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, flowed through temperature zone 1 (temperature 20°C), mixed with 48% hydrobromic acid input at 112 g / min into temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input into the bromination unit at 34.5 g / min, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 30 s, the yield was 95%, and the content was 98%.

[0068] Example 28 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, flowed through temperature zone 1 (temperature 20°C), mixed with 48% hydrobromic acid input at 112 g / min into temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input into the bromination unit at 34.5 g / min, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 30 s, the yield was 95%, and the content was 98%.

[0069] Table 7: Screening of sodium nitrite concentration in examples 29-32 ; Example 29 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, flowed through temperature zone 1 (temperature 20°C), mixed with 48% hydrobromic acid input at 112 g / min into temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 15 s, the yield is 90%, and the content is 95%.

[0070] Example 30 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shearing reaction device at a rate of 51.4 g / min, and the 35% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at a rate of 68.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at a rate of 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and the diazotization reaction solution is obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 20 s, the yield is 90%, and the content is 96%.

[0071] Example 31 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shearing reaction device at a rate of 51.4 g / min, and the 35% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at a rate of 68.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at a rate of 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and the diazotization reaction solution is obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 20 s, the yield is 90%, and the content is 96%.

[0072] Example 32 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), they were mixed with 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input at 34.5 g / min in the bromination unit, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 30 s, the yield was 95%, and the content was 98%.

[0073] Table 8: Screening of hydrobromic acid equivalents for examples 33-37 ; Example 33 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), they were mixed with 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input at 34.5 g / min in the bromination unit, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 30 s, the yield was 95%, and the content was 98%.

[0074] Example 34 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), they were mixed with 48% hydrobromic acid input at 112 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 95%, and the content is 98%.

[0075] Example 35 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shear reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at a rate of 122.7 g / min to complete the diazotization reaction in temperature zone 2 (temperature -10°C) to obtain a diazotization reaction solution. The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.3. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 95%, and the content is 96%.

[0076] Example 36 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shear reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at a rate of 138.7 g / min to complete the diazotization reaction in temperature zone 2 (temperature -10°C) to obtain a diazotization reaction solution. The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.6. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 20 s, the yield is 90%, and the content is 96%.

[0077] Example 37 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), it was mixed with 48% hydrobromic acid input at 149.3 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input at 34.5 g / min in the bromination unit, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.8. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 15 s, the yield was 90%, and the content was 96%.

[0078] Table 9: Screening of hydrobromic acid concentration in examples 38-41 ; Example 38 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), it was mixed with 20% hydrobromic acid input at 268.8 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; After the diazotization reaction solution flowed out of temperature zone 2, it entered the bromination unit, reacted with the bromination reagent input at 34.5 g / min in the bromination unit, and then flowed through temperature zone 3 (temperature 60°C) in sequence and was output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent was 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene was obtained, the production time was 15 s, the yield was 90%, and the content was 95%.

[0079] Example 39 The 2,6-diethyl-4-methylaniline solution was input into the continuous flow shearing reaction device through the feed port at 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) was input at 54.5 g / min, and after flowing through temperature zone 1 (temperature 20°C), it was mixed with 30% hydrobromic acid input at 179.2 g / min to enter temperature zone 2 (temperature -10°C) to complete the diazotization reaction, and a diazotization reaction solution was obtained; The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 20 s, the yield is 90%, and the content is 96%.

[0080] Example 40 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shear reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at a rate of 112 g / min to complete the diazotization reaction in temperature zone 2 (temperature -10°C) to obtain a diazotization reaction solution. The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 95%, and the content is 96%.

[0081] Example 41 The 2,6-diethyl-4-methylaniline solution is input into the full continuous flow shear reaction device at a rate of 51.4 g / min, and the 44% sodium nitrite solution mixed with 0.2% tetrabutylammonium chloride (TBAC) is input at a rate of 54.5 g / min. After flowing through temperature zone 1 (temperature 20°C), it is mixed with 48% hydrobromic acid input at a rate of 112 g / min to complete the diazotization reaction in temperature zone 2 (temperature -10°C) to obtain a diazotization reaction solution. The diazotization reaction solution flows out of temperature zone 2 and enters the bromination unit, and after reacting with the bromination reagent in the bromination unit at an input rate of 34.5 g / min, it successively flows through temperature zone 3 (temperature 60°C) and is output from the outlet. The molar ratio of 2,6-diethyl-4-methylaniline, sodium nitrite, and bromination reagent is 1:1.1:2.1. After extraction, water washing, desolventizing, and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained. The production time is 30 s, the yield is 95%, and the content is 96%.

[0082] The embodiments are only illustrative of the application and are not intended to limit the application. Those skilled in the art can make modifications to the embodiments without creative contribution after reading the specification, and the modifications are within the protection scope of the application and are protected by the patent law.

Claims

1. A fully continuous flow process for the synthesis of 2,6-diethyl-4-methylbromobenzene, characterized in that, The reaction raw materials are added into the feed inlet of the full continuous flow shearing reaction device, and the final product 2,6-diethyl-4-methylbromobenzene is obtained from the discharge outlet of the full continuous flow shearing reaction device, wherein the reaction raw materials include a catalyst, a reaction substrate, hydrobromic acid and sodium nitrite; The full continuous flow synthesis process comprises the following steps: S1, the reaction substrate and the sodium nitrite solution mixed with the catalyst are respectively input into the full continuous flow shearing reaction device through the feed inlet, mixed with the hydrobromic acid after flowing through the temperature zone 1, and then enter the temperature zone 2 to complete the diazotization reaction, thereby obtaining a diazotization reaction solution; S2, the diazotization reaction solution flows out of the temperature zone 2 and enters the bromination unit, reacts with the bromination reagent in the bromination unit, and then flows through the temperature zone 3 in sequence, and is output from the discharge outlet, and after extraction, water washing, desolventizing and distillation, the final product 2,6-diethyl-4-methylbromobenzene is obtained; The reaction substrate is 2,6-diethyl-4-methylaniline.

2. A continuous flow process for the synthesis of 2,6-diethyl-4-methylbromobenzene according to claim 1, characterized in that, In the step S1, the temperature zone 1 is accompanied by a strong shearing process for weakening or breaking the bond and reducing the viscosity of the system.

3. A continuous flow process for the synthesis of 2,6-diethyl-4-methylbromobenzene according to claim 1, characterized in that, The catalyst is a phase transfer catalyst, which is selected from one or more of benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), dodecyltrimethylammonium chloride (DTAC), and tetradecyltrimethylammonium chloride (TTAC).

4. A fully continuous flow process for the synthesis of 2,6-diethyl-4- methylbromobenzene according to claim 3, characterized in that, The mass ratio of the catalyst to the reaction substrate is preferably 0.1-0.5%.

5. A fully continuous flow process for the synthesis of 2,6-diethyl-4- methylbromobenzene according to claim 4, characterized in that, The molar ratio of the hydrobromic acid to the reaction substrate is 2:1-2.8:

1. The mass concentration of the hydrobromic acid is 20%-48%.

6. A fully continuous flow process for the synthesis of 2,6-diethyl-4- methylbromobenzene according to claim 5, characterized in that, The molar ratio of the sodium nitrite to the reaction substrate is 1:1-1.15:

1. The mass concentration of the sodium nitrite is 30%-44%.

7. A fully continuous flow process for the synthesis of 2,6-diethyl-4- methylbromobenzene according to claim 1, characterized in that, The bromination reagent is prepared by mixing 48% HBr, 98% H2SO4 and ferrous sulfate heptahydrate at room temperature. The equivalent ratio of 48% HBr:98% H2SO4:ferrous sulfate heptahydrate:2,6-diethyl-4-methylaniline is 0.2:0.2:0.2:

1.

8. A fully continuous flow process for the synthesis of 2,6-diethyl-4- methylbromobenzene according to claim 7, characterized in that, The temperature of the temperature zone 1 is 5-30°C. The temperature of the temperature zone 2 is -20-5°C. The temperature of the temperature zone 3 is 40-90°C.

9. A fully continuous flow process for the synthesis of 2,6-diethyl-4- methylbromobenzene according to claim 8, characterized in that, The yield of the 2,6-diethyl-4-methylbromobenzene is ≥90%, and the content of the 2,6-diethyl-4-methylbromobenzene is ≥95%.

10. A 2,6-diethyl-4-methylbromobenzene fully continuous flow shearing reaction apparatus for use in the synthesis process of any one of claims 1 to 9, characterized in that, The shearing unit is the temperature zone 1, which is used for shearing the mixture of the reaction substrate and sodium nitrite, the diazotization unit is the temperature zone 2, which is used for the diazotization reaction of the reaction substrate, and the bromination unit is the temperature zone 3, which is used for the bromination reaction. The feed inlet is located at the bottom of the shearing unit, and the discharge outlet is located at the top of the bromination unit. The shearing unit has a star-shaped structure reactor, and the diazotization unit and the bromination unit have a fork-shaped structure reactor.

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