Method and system for continuously preparing 2-(methylthio) phenylboronic acid by using microchannel reactor

Abstract

The invention discloses a method and a system for continuously preparing 2-(methylthio) phenylboronic acid by a microchannel reactor, and belongs to the technical field of synthesis and preparation of 2-(methylthio) phenylboronic acid. According to the technical scheme, the preparation method comprises the following steps: S1, preparing raw materials: respectively dissolving reactants including 2-methylthio bromobenzene, boric acid ester, hydrochloric acid and n-butyllithium into a solvent, and respectively preparing a 2-methylthio bromobenzene solution, a boric acid ester solution, an acid solution and an n-butyllithium solution; s2, micro-channel reaction: respectively conveying the 2-methylthio bromobenzene solution, the n-butyllithium solution, the borate solution and the acid solution prepared in the step S1 into a micro-channel reactor through a flow rate pump, and carrying out the micro-channel reaction on the 2-methylthio bromobenzene solution, the n-butyllithium solution, the borate solution and the acid solution. And S3, separation and purification: carrying out separation and purification on the reaction liquid obtained in S2 to obtain the required product 2-methylthio phenylboronic acid. According to the invention, simultaneous three-step cascade reaction is carried out in the microchannel reactor to synthesize 2-methylthio phenylboronic acid. The reaction efficiency is improved; and the production energy consumption is reduced.

Description

Technical Field

[0001] This invention belongs to the field of synthesis and preparation technology of 2-methylthiophenylboronic acid, specifically relating to a method and system for the continuous preparation of 2-methylthiophenylboronic acid using a microchannel reactor. Background Technology

[0002] Arylboronic acids are important intermediates in organic chemistry, widely used in Suzuki coupling reactions, diol protection, Diels-Alder reactions, selective aldehyde oxidation, asymmetric amino acid synthesis, and amidation catalysts. In biomedicine, organoboronic acids serve not only as carbohydrate recognition sensors but also as selective carriers for sugars and nucleotides, and as enzyme inhibitors. In organic electroluminescent materials, arylboronic acid derivatives have attracted considerable attention due to their easily modifiable structures, wide band gaps, high luminous efficiency, and good thermal, photostability, and chemical stability. Furthermore, thiomethyl groups, as auxochromes, can enhance the optical properties of compounds, and 2-methylthiophenylboronic acid, as a fundamental monomer raw material for OLED synthesis, has also garnered significant interest.

[0003] The market demand for 2-methylthiophenylboronic acid is increasing year by year, and the requirements for product quality are gradually improving. Therefore, developing a safe, efficient, and continuous process for synthesizing high-purity, high-yield 2-methylthiophenylboronic acid is of practical significance. There are two main methods for synthesizing arylboronic acid compounds. One method involves reacting a halogenated aromatic hydrocarbon (usually brominated) with a butyllithium reagent to prepare an aryllithium intermediate, which then undergoes an addition reaction with a borate ester, followed by hydrolysis to obtain arylboronic acid (Chem. Commun. 2010, 46, 6380–6381). The other method involves reacting a halogenated aromatic hydrocarbon with magnesium shavings to prepare an aryl Grignard reagent, which then undergoes an addition reaction with a borate ester, followed by hydrolysis to obtain arylboronic acid.

[0004] .

[0005] However, both of the above methods require extremely stringent process conditions. The reaction system needs to be strictly controlled to be anhydrous and oxygen-free, with nitrogen protection throughout the process, making the operation quite cumbersome. Reagents need to be added dropwise in steps, typically over 5-6 hours, resulting in long processing times and low production efficiency. In particular, the use of butyllithium reagent generally requires temperatures around -78°C, necessitating liquid nitrogen temperature control. Conventional batch reactors inevitably suffer from problems such as localized overheating due to uneven mixing. The reaction process also generates numerous side reactions, resulting in low purity and yield of the target product, and significant waste and energy consumption. Therefore, a method for preparing 2-methylthiophenylboronic acid needs to be developed to shorten the reaction time, improve production efficiency, and be suitable for industrial production. Summary of the Invention

[0006] This invention provides a method for the continuous preparation of 2-methylthiophenylboronic acid using a microchannel reactor, which effectively solves the aforementioned problems and has practical significance. Specifically, the method involves using 2-methylthiobromobenzene, butyllithium reagent, borate ester, and hydrochloric acid as reactants, and carrying out a three-step cascade reaction in a microchannel reactor in a specific ratio to synthesize the target product, 2-methylthiophenylboronic acid. This improves reaction efficiency, reduces production energy consumption, and is suitable for industrial-scale production.

[0007] The technical solution of this invention is as follows: In one aspect, a method for the continuous preparation of 2-methylthiophenylboronic acid using a microchannel reactor is disclosed, comprising the following steps: S1 Raw material preparation: Dissolve the reactants 2-methylthiobromobenzene, borate ester, hydrochloric acid and n-butyllithium in solvents respectively to prepare 2-methylthiobromobenzene solution, borate ester solution, acid solution and n-butyllithium solution respectively; S2 Microchannel Reaction: The 2-methylthiobromobenzene solution and n-butyllithium solution prepared in S1 are respectively transported to the microchannel reactor for butyllithium reaction to obtain reaction solution one; reaction solution one undergoes ester addition reaction with the transported borate ester solution to obtain reaction solution two; reaction solution two undergoes quenching reaction with the transported acid solution to obtain 2-methylthiophenylboronic acid mother liquor. S3 Separation and Purification: The 2-methylthiophenylboronic acid mother liquor obtained in S2 is separated and purified to obtain the desired product, 2-methylthiophenylboronic acid.

[0008] Preferably, the borate ester is trimethyl borate, triethyl borate, tripropyl borate, or tributyl borate.

[0009] Preferably, the solvent is one or a combination of two or more of the following solvents: n-hexane, cyclohexane, toluene, tetrahydrofuran, diethyl ether, and methanol.

[0010] Preferably, the concentration of the 2-methylthiobromobenzene solution is 0.05-4 mol / L, the concentration of the n-butyllithium solution is 2-3 mol / L, the concentration of the borate ester solution is 1-5 mol / L, and the concentration of the acid solution is 1-5 mol / L.

[0011] Preferably, the flow rate of the 2-methylthiobromobenzene solution is 30-60 mL / min, the flow rate of the n-butyllithium solution is 20-30 mL / min, the flow rate of the borate ester solution is 15-40 mL / min, and the flow rate of the acid solution is 20-30 mL / min.

[0012] Preferably, in step S2, the temperature for both the butyllithium reaction and the ester addition reaction is -15 to (-35) °C, the quenching reaction temperature is -5 to 5 °C, the pressure is 0 to 2 MPa, and the total residence time is 30 to 100 s.

[0013] Secondly, the system used in the method is disclosed. The system used in the continuous preparation of 2-methylthiophenylboronic acid by the microchannel reactor includes a reaction zone M1, a reaction zone M2, a quenching zone M3 and a controller connected in sequence by pipelines. The outer sides of the reaction zone M1, the reaction zone M2 and the quenching zone M3 are all covered with heat exchange zones. The heat exchange zones are provided with heat exchange medium outlet pipelines and heat exchange medium inlet pipelines. The heat exchange medium outlet pipelines and heat exchange medium inlet pipelines are connected to external heat exchange equipment. The M1 reaction zone, M2 reaction zone, and M3 quenching zone are each equipped with a first feed inlet, a second feed inlet, a discharge outlet, and a mixing unit. The first feed inlet and the second feed inlet are each equipped with a flow rate pump, which is electrically connected to the controller. The discharge outlet is equipped with a back pressure valve, which is electrically connected to the controller. Both the first and second feed inlets are connected to the mixing unit. Several mixing units are interconnected to form reaction channel one. The outlet of reaction channel one is connected to several reaction channels two in sequence through pipelines. Each reaction channel two includes two sets of several mixing units arranged in parallel in the horizontal direction. The vertically corresponding mixing units in the two sets of parallel mixing units are connected through pipeline one. Several blocking protrusions are provided in the pipelines connecting reaction channel one and reaction channel two, as well as in the pipelines connecting two adjacent reaction channels two. The last reaction channel two is connected to the discharge port.

[0014] Preferably, two adjacent mixing units are connected by a sub-channel, and each mixing unit is provided with a "V"-shaped flow splitting structure and a flow bypass area.

[0015] Preferably, the "human" shaped diversion structure is a centrally symmetrical structure, and the width of the "human" shaped diversion structure is half the width of the sub-channel.

[0016] Preferably, the flow-around region is cylindrical, and the diameter of the flow-around region is the same as the width of the sub-channel.

[0017] Compared with the prior art, the present invention has the following advantages: 1. The microchannel reactor of this invention exhibits high mass transfer and heat exchange efficiency, excellent performance in terms of equipment and process piping airtightness, and realizes a three-step series continuous preparation process of 2-methylthiophenylboronic acid. Based on its superior mass transfer and heat exchange efficiency, the reaction can be carried out at temperatures lower than the traditional -78°C reaction process, increasing the reaction temperature by 53°C to -25°C, eliminating the need for liquid nitrogen temperature control and significantly reducing energy consumption. Furthermore, the entire reaction system has excellent sealing, avoiding the potential danger of n-butyllithium coming into contact with air. Only one nitrogen purging is required at the initial stage of the reaction, eliminating the need for repeated purging operations, enabling continuous production and greatly simplifying the operation process. After the microchannel reaction pilot-scale process is developed, no pilot-scale process is required; it can be directly scaled up to industrial scale without any scale-up effect, significantly shortening the research and development cycle.

[0018] 2. This invention utilizes a microchannel reactor to prepare 2-methylthiophenylboronic acid, enabling complete reaction in each reaction unit and control over residence time, reducing side reactions, improving reaction selectivity, and realizing the three-step cascade reaction of butyllithium, ester addition, and hydrolysis quenching. This reduces solvent consumption, significantly improves production efficiency, and lowers production costs. The entire reaction process, from feeding to heat exchange, can be fully automated, eliminating cumbersome manual operations. After the reaction, liquid chromatography analysis shows a conversion rate of over 99.9%, making it suitable for industrial-scale production.

[0019] 3. The microchannel reactor of this invention, through its "human"-shaped flow splitting structure and central symmetry, combined with multi-channel splitting and jetting structures, reduces fluid resistance, thereby lowering pressure drop, extending the service life of the equipment, and achieving the goal of reducing operating costs; the setting of the blocking protrusion further increases the mass transfer efficiency of two-phase mixing, making the temperature more stable and improving the mixing effect.

[0020] 4. The microchannel reactor structure described in this invention enhances material mass transfer and heat transfer through multi-dimensional design, specifically as follows: The outlet of reaction channel one is connected in series with multiple reaction channels two via pipelines, forming a staged processing path. Each reaction channel two contains two sets of parallel mixing units, with corresponding mixing units in each set interconnected via pipeline one. This expands the material contact area and allows for thorough separation and convergence of materials in the parallel flow channels, improving mixing uniformity. Simultaneously, the connecting pipelines between reaction channels one and two, as well as the connecting pipelines between adjacent reaction channels two, are equipped with several obstructing protrusions. As the material flows through these protrusions, it is disturbed, breaking the laminar flow and creating turbulent flow, reducing the thickness of the mass and heat transfer boundary layer. Finally, the material is collected at the outlet via the last reaction channel two. Throughout the process, the material not only reacts gradually between multiple channels, but also, thanks to the parallel interconnection structure of the mixing units and the disturbance effect of the pipeline protrusions, achieves more thorough contact and more efficient energy transfer, thus significantly enhancing mass and heat transfer effects. Attached Figure Description

[0021] Figure 1 This is a schematic diagram of the reaction process of the present invention.

[0022] Figure 2 This is a schematic diagram of the microchannel reactor of the present invention.

[0023] In the diagram, 1 is the first feed inlet; 2 is the second feed inlet; 3 is the discharge outlet; 4 is the mixing unit; 5 is the first reaction channel; 6 is the second reaction channel; 7 is the first pipeline; 8 is the sub-channel; 9 is the "V"-shaped flow divider structure; 10 is the flow bypass area; and 11 is the blocking protrusion. Detailed Implementation

[0024] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions will be clearly and completely described below in conjunction with the embodiments of this invention.

[0025] like Figure 1-2 As shown, the system used for the continuous preparation of 2-methylthiophenylboronic acid using a microchannel reactor includes reaction zones M1, M2, and M3 quenching zones connected sequentially by pipelines. Each of the reaction zones is surrounded by a heat exchange zone, which uses commercially available materials and will not be described in detail here. The heat exchange zone is equipped with a heat exchange medium outlet pipeline and a heat exchange medium inlet pipeline, which are connected to an external heat exchange device. This external heat exchange device can be a commercially available integrated heating and cooling unit. The M1 reaction zone, M2 reaction zone and M3 quenching zone are each equipped with a first feed inlet 1, a second feed inlet 2, a discharge outlet 3 and a mixing unit 4. The first feed inlet 1 and the second feed inlet 2 are each equipped with a flow rate pump, which is electrically connected to the controller. The discharge outlet 3 is equipped with a back pressure valve, which is electrically connected to the controller. Both the first feed inlet 1 and the second feed inlet 2 are connected to the mixing unit 4. Several mixing units 4 are interconnected to form a reaction channel 1 5. The outlet of the reaction channel 1 5 is connected to several reaction channels 2 6 in sequence through pipelines. Each reaction channel 2 6 includes two sets of several mixing units 4 arranged in parallel in the horizontal direction. The vertically corresponding mixing units 4 in the two sets of parallel mixing units 4 are connected through pipeline 1 7. Several blocking protrusions 11 are provided in the pipelines connecting the reaction channel 1 5 and the reaction channel 2 6, as well as in the pipelines connecting two adjacent reaction channels 2 6. The last reaction channel 2 6 is connected to the discharge port 3.

[0026] Two adjacent mixing units 4 are connected by a sub-channel 8. Each mixing unit 4 is equipped with a "human"-shaped flow splitting structure 9 and a flow bypass zone 10.

[0027] The "human" shaped diversion structure 9 is a centrally symmetrical structure. The width of the "human" shaped diversion structure 9 is half the width of the sub-channel 8. It should be noted that the width of the "human" shaped diversion structure 9 is the thickness of each side of the "human" shape.

[0028] The flow-around region 10 is cylindrical, and the diameter of the flow-around region 10 is the same as the width of the sub-channel 8.

[0029] Example 1 A method for the continuous preparation of 2-methylthiophenylboronic acid using a microchannel reactor includes the following steps: S1 Raw material preparation: Dissolve the reactants 2-methylthiobromobenzene, borate ester, hydrochloric acid and n-butyllithium in solvents respectively to prepare 2-methylthiobromobenzene solution, borate ester solution, acid solution and n-butyllithium solution respectively; Preparation of 2-methylthiobromobenzene solution (phase A): Prepare a 1 mol / L solution (phase A) of the main raw material 2-methylthiobromobenzene using tetrahydrofuran as solvent; Preparation of n-butyllithium solution (phase B): Prepare a 2.0 mol / L n-butyllithium solution (phase B) using tetrahydrofuran as the solvent. Preparation of concentrated tributyl borate solution (phase C): Prepare a 1.0 mol / L tributyl borate solution (phase C) using tetrahydrofuran as solvent. Preparation of acid solution: Add 200 mL of methanol and 50 mL of concentrated hydrochloric acid to a 500 mL three-necked flask to prepare an acid solution (phase D), and let the temperature drop to room temperature for later use.

[0030] S2 microchannel reaction: The 2-methylthiobromobenzene solution (phase A) prepared in S1 was pumped into the M1 reaction zone of the microchannel reactor at a flow rate of 39 mL / min. At the same time, a 2.0 mol / L n-butyllithium solution (phase B) was pumped into the M1 reaction zone at a flow rate of 24 mL / min to fully mix and induce the butyllithium reaction. The residence time was 14 seconds, the reaction temperature was controlled at -30℃, and the pressure was kept stable at 0.5 MPa. After the reaction of butyllithium, the reaction solution flows out of the M1 reaction zone at the same flow rate. After the reaction solution flows out of the M1 reaction zone and into the inlet of the M2 reaction zone, a concentrated solution of tributyl borate (C phase) is simultaneously introduced into the M2 reaction zone of the microchannel reactor at a flow rate of 15.6 mL / min for ester addition reaction. The residence time of this step is 16 seconds, the reaction temperature of the M2 reaction zone is controlled at -30℃, and the pressure is controlled to be stable at 0.5 MPa. After the ester addition reaction, the reaction solution II flows out of the M2 reaction zone at the same flow rate. After the reaction solution II flows out of the M2 reaction zone and into the inlet of the M3 quenching zone, the acid solution (D phase) is pumped into the M3 quenching zone of the microchannel reactor at a flow rate of 22 mL / min. It is mixed with the reaction solution II flowing out of the M2 reaction zone and reacted. The residence time of this reaction step is 5 seconds, and the reaction temperature is controlled at 0℃. After the reaction solution flows out of the M3 quenching zone, 100 mL of the solution flowing out of the M3 quenching zone is continuously collected, washed with water, and then the phases are separated using a separatory funnel. The upper organic phase is taken as the 2-methylthiophenylboronic acid mother liquor.

[0031] S3 separation and purification: The 2-methylthiophenylboronic acid mother liquor was first filtered under reduced pressure to remove impurities. The filtrate was transferred to a separatory funnel, deionized water was added and shaken thoroughly. After standing until the aqueous and organic phases were completely separated, the aqueous phase was discarded. The organic phase was then transferred to a distillation flask and concentrated to recover the solvent. The distillation product was then distilled to collect the target fraction. Finally, a desiccant was used for drying. After standing to adsorb residual moisture, the desiccant was removed by filtration to obtain the desired product, 2-methylthiophenylboronic acid.

[0032] A small amount of 2-methylthiophenylboronic acid product was analyzed by liquid chromatography. The conversion rate of the main raw material 2-methylthiobromobenzene was as high as 99.7%, and the total yield was 87%.

[0033] Example 2 A method for the continuous preparation of 2-methylthiophenylboronic acid using a microchannel reactor includes the following steps: S1 Raw material preparation: Dissolve the reactants 2-methylthiobromobenzene, borate ester, hydrochloric acid and n-butyllithium in solvents respectively to prepare 2-methylthiobromobenzene solution, borate ester solution, acid solution and n-butyllithium solution respectively; Preparation of 2-methylthiobromobenzene solution (phase A): Prepare a 1.5 mol / L 2-methylthiobromobenzene solution (phase A) using tetrahydrofuran as solvent; Preparation of n-butyllithium solution (phase B): Prepare a 2.0 mol / L n-butyllithium solution (phase B) using tetrahydrofuran as the solvent. Preparation of concentrated tributyl borate solution (phase C): Prepare a 1.5 mol / L tributyl borate solution (phase C) using tetrahydrofuran as solvent. Preparation of acid solution: Add 300 mL of methanol and 80 mL of concentrated hydrochloric acid to a 500 mL three-necked flask to prepare an acid solution (phase D), and let the temperature drop to room temperature for later use.

[0034] S2 microchannel reaction: The 2-methylthiobromobenzene solution (phase A) prepared in S1 was pumped into the M1 reaction zone of the microchannel reactor at a flow rate of 60 mL / min. At the same time, a 2.0 mol / L n-butyllithium solution (phase B) was pumped into the M1 reaction zone at a flow rate of 28 mL / min to fully mix and induce the butyllithium reaction. The residence time was 12 seconds, the reaction temperature was controlled at -25℃, and the pressure was kept stable at 0.5 MPa. After the reaction of butyllithium, the reaction solution flows out of the M1 reaction zone at the same flow rate. After the reaction solution flows out of the M1 reaction zone and into the inlet of the M2 reaction zone, the concentrated solution of the raw material tributyl borate (C phase) is simultaneously flowed into the M2 reaction zone of the microchannel reactor at a flow rate of 36 mL / min to carry out the ester addition reaction. The residence time of this step is 15 seconds, the reaction temperature of the M2 reaction zone is controlled at -25℃, and the pressure is controlled to be stable at 0.5 MPa. After the ester addition reaction, the reaction solution II flows out of the M2 reaction zone at the same flow rate. After the reaction solution II flows out of the M2 reaction zone and into the inlet of the M3 quenching zone, the acid solution (D phase) is pumped into the M3 quenching zone of the microchannel reactor at a flow rate of 25 mL / min. It is then mixed with the reaction solution flowing out of the M2 reaction zone. The residence time of this step is 7 seconds, and the reaction temperature is controlled at 0℃. After the reaction solution flows out of the M3 quenching zone, 100 mL of the solution flowing out of the M3 quenching zone is continuously collected, washed with water, and then the phases are separated using a separatory funnel. The upper organic phase is taken as the 2-methylthiophenylboronic acid mother liquor.

[0035] S3 separation and purification: The 2-methylthiophenylboronic acid mother liquor was first filtered under reduced pressure to remove impurities. The filtrate was transferred to a separatory funnel, deionized water was added and shaken thoroughly. After standing until the aqueous and organic phases were completely separated, the aqueous phase was discarded. The organic phase was then transferred to a distillation flask and concentrated to recover the solvent. The distillation product was then distilled to collect the target fraction. Finally, a desiccant was used for drying. After standing to adsorb residual moisture, the desiccant was removed by filtration to obtain the desired product, 2-methylthiophenylboronic acid.

[0036] A small amount of 2-methylthiophenylboronic acid product was analyzed by liquid chromatography. The conversion rate of the main raw material 2-methylthiobromobenzene was as high as 99.9%, and the total yield was 85%.

[0037] Comparative Example 1 The preparation of 2-methylthiophenylboronic acid using a conventional batch reactor includes the following steps: S1 Raw Material Preparation: The raw material preparation is consistent with step S1 in Example 1; S2 Butyllithium reaction: Slowly add n-butyllithium solution to 2-methylthiobromobenzene solution for 5 hours while maintaining the temperature at -78℃. After the addition is complete, continue stirring for 1 hour. S3 ester addition reaction: Tributyl borate was slowly added dropwise over 2 hours while maintaining the temperature at -78℃. After the addition was complete, stirring was continued for another 2 hours. S4 hydrolysis reaction: Slowly add hydrochloric acid solution for 1 hour, then heat to room temperature and stir for 1 hour; S5 Separation and Purification: The reaction solution is first filtered under reduced pressure to remove impurities. The filtrate is transferred to a separatory funnel, deionized water is added and shaken thoroughly. After standing until the aqueous and organic phases are completely separated, the aqueous phase is discarded. The organic phase is then transferred to a distillation flask and concentrated to recover the solvent. The distillation product is then distilled to collect the target fraction. Finally, the product is dried with a desiccant. After standing to adsorb residual moisture, the desiccant is removed by filtration to obtain 2-methylthiophenylboronic acid.

[0038] A small amount of the product was analyzed by liquid chromatography. The conversion rate of the main raw material 2-methylthiobromobenzene was 95%, and the overall yield was 65%.

[0039] Comparative Example 2 Unlike Example 1, the reaction temperature in reaction zones M1 and M2 of this comparative example was controlled at -12°C, while other conditions were exactly the same as in Example 1. The desired product, 2-methylthiophenylboronic acid, was finally obtained. Liquid chromatography analysis of the sample showed a 99.3% conversion rate of the 2-methylthiobromobenzene raw material and an overall yield of 80%. The decrease in yield due to increased reaction temperature is primarily due to the initiation of multiple side reactions and the impairment of reaction selectivity by high temperatures. Excessively high temperatures accelerate the self-coupling reaction of butyllithium, consuming the activity of the target reaction. Furthermore, excessively high temperatures reduce the reactivity of butyllithium with 2-methylthiobromobenzene, inducing side reactions, accelerating the decomposition rate of butyllithium, and reducing the concentration of the effective active component in the system. Ultimately, this leads to a decrease in the conversion rate of 2-methylthiobromobenzene and a reduction in the formation efficiency of 2-methylthiophenylboronic acid, resulting in a lower yield.

[0040] Comparative Example 3 Phase A was pumped into reaction zone M1 of the microchannel reactor at a flow rate of 55 mL / min, while phase B was pumped into reaction zone M1 at a flow rate of 33.6 mL / min for thorough mixing to induce a butyllithium reaction. The residence time was 8 seconds. Phase C was then pumped into reaction zone M2 of the microchannel reactor at a flow rate of 22 mL / min for an ester addition reaction. The residence time for this step was 10 seconds. Phase D was then pumped into quenching zone M3 of the microchannel reactor at a flow rate of 30.8 mL / min to mix with the reaction solution flowing out of reaction zone M2. The residence time for this step was 5 seconds. Other conditions were exactly the same as in Example 1. The desired product, 2-methylthiophenylboronic acid, was finally obtained. Liquid chromatography analysis of the sample showed a conversion rate of 95.3% for the 2-methylthiobromobenzene raw material and an overall yield of 78.5%. The decrease in the conversion rate of 2-methylthiobromobenzene and the yield of 2-methylthiophenylboronic acid was mainly due to incomplete reaction and impaired selectivity. The reaction between butyllithium and 2-methylthiobromobenzene requires a certain amount of time to complete the collision of active species and the formation of chemical bonds. When the residence time is insufficient, a large amount of raw materials leave the reaction system without participating in the target reaction, which directly leads to a decrease in conversion rate. At the same time, the reaction system does not reach dynamic equilibrium under short residence time, the activity of butyllithium is not fully utilized, and the proportion of side reactions may increase due to incomplete local reactions, further reducing the formation of the target product, ultimately resulting in a simultaneous decrease in conversion rate and yield.

[0041] Although the present invention has been described in detail by way of preferred embodiments, the 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 invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. Process for the continuous preparation of 2-methylthiophenylboronic acid in a microchannel reactor, characterized in that, The method comprises the following steps: S1 raw material preparation: the reactants 2-methylthiobromobenzene, borate ester, hydrochloric acid and n-butyllithium are respectively dissolved in solvents to prepare 2-methylthiobromobenzene solution, borate ester solution, acid solution and n-butyllithium solution; S2 micro-channel reaction: the prepared 2-methylthiobromobenzene solution and n-butyllithium solution in S1 are respectively delivered to a micro-channel reactor for butyllithium reaction to obtain reaction liquid one; the reaction liquid one is subjected to ester addition reaction with the delivered borate ester solution to obtain reaction liquid two; the reaction liquid two is subjected to quenching reaction with the delivered acid solution to obtain 2-methylthiophenyl boronic acid mother liquor; S3 separation and purification: the 2-methylthiophenyl boronic acid mother liquor obtained in S2 is subjected to separation and purification to obtain the desired product 2-methylthiophenyl boronic acid.

2. The process of claim 1 for the continuous production of 2-methylthiophenylboronic acid in a microchannel reactor, wherein, The borate ester is trimethyl borate, triethyl borate, tripropyl borate or tributyl borate.

3. The process for the continuous production of 2-methylthiophenylboronic acid according to claim 1, wherein, The solvent is n-hexane, cyclohexane, toluene, tetrahydrofuran, diethyl ether or methanol, or a combination of two or more thereof.

4. The process for the continuous production of 2-methylthiophenylboronic acid according to claim 1, characterized in that, The concentration of the 2-methylthiobromobenzene solution is 0.05-4 mol / L, the concentration of the n-butyllithium solution is 2-3 mol / L, the concentration of the borate ester solution is 1-5 mol / L, and the concentration of the acid solution is 1-5 mol / L.

5. The process of claim 1 for the continuous production of 2-methylthiophenylboronic acid in a microchannel reactor, wherein, The flow rate of the 2-methylthiobromobenzene solution is 30-60 mL / min, the flow rate of the n-butyllithium solution is 20-30 mL / min, the flow rate of the borate ester solution is 15-40 mL / min, and the flow rate of the acid solution is 20-30 mL / min.

6. The process of claim 1 for the continuous production of 2-methylthiophenylboronic acid in a microchannel reactor, wherein, The temperature of the butyllithium reaction and the ester addition reaction in step S2 is-15 to-35℃, the quenching reaction temperature is-5 to 5℃, the pressure is 0-2 MPa, and the total residence time is 30 s-100 s.

7. System for use in a method according to any one of claims 1-6, characterized in that The system for continuously preparing 2-methylthiophenyl boronic acid by using a micro-channel reactor comprises M1 reaction zone, M2 reaction zone, M3 quenching zone and a controller connected in sequence through pipelines, and the outer sides of the M1 reaction zone, the M2 reaction zone and the M3 quenching zone are each coated with a heat exchange zone, the heat exchange zone is provided with a heat exchange medium outlet pipeline and a heat exchange medium inlet pipeline, and the heat exchange medium outlet pipeline and the heat exchange medium inlet pipeline are connected to an external heat exchange device; The M1 reaction zone, the M2 reaction zone and the M3 quenching zone are each provided with a first feeding port (1), a second feeding port (2), a discharging port (3) and a mixing unit (4), the first feeding port (1) and the second feeding port (2) are each provided with a flow rate pump, the flow rate pump is electrically connected to the controller, the discharging port (3) is provided with a back pressure valve, and the back pressure valve is electrically connected to the controller; The first feeding port (1) and the second feeding port (2) are communicated with the mixing units (4), the mixing units (4) are communicated with each other to form a reaction channel one (5), the outlet of the reaction channel one (5) is connected with a plurality of reaction channel twos (6) in sequence through pipelines, each reaction channel two (6) comprises two groups of mixing units (4) which are arranged in parallel in the horizontal direction, the mixing units (4) corresponding in the vertical direction in the two groups of parallel mixing units (4) are communicated through a pipeline one (7), a plurality of blocking protrusions (11) are arranged in the pipeline connecting the reaction channel one (5) and the reaction channel two (6) and the pipeline connecting two adjacent reaction channel twos (6), and the last reaction channel two (6) is connected with a discharge port (3).

8. The system of claim 7, wherein, The adjacent two mixing units (4) are communicated through a sub-channel (8), and the "person" type shunt structure (9) and the flow around area (10) are arranged in each mixing unit (4).

9. The system of claim 8, wherein, The "person" type shunt structure (9) is a central symmetric structure, and the width of the "person" type shunt structure (9) is half of the width of the sub-channel (8).

10. The system of claim 8, wherein, The flow around area (10) is a cylinder, and the diameter of the flow around area (10) is the same as the width of the sub-channel (8).

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