A method for the continuous production of p-chlorophenylboronic acid

Abstract

This invention belongs to the field of organic synthesis technology, specifically relating to a continuous method for preparing p-chlorophenylboronic acid. This method optimizes reaction conditions and reactor configuration, achieving continuous Grignard reaction, esterification reaction, and acidolysis reaction. Finally, the p-chlorophenylboronic acid intermediate is obtained through separation, solvent removal, and crystallization. This method not only greatly improves production efficiency but also solves the problems of the dangers of the Grignard reaction, as well as the poor stability of the Grignard intermediate and the violent exothermic reaction. It significantly improves reaction yield and product quality. The p-chlorophenylboronic acid product prepared by this method has a content of over 99% and a yield of over 90%, far exceeding the industry level. This preparation method is easy to scale up for industrial production and can use p-dichlorobenzene and p-chlorobromobenzene together, significantly reducing production costs.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for the continuous preparation of p-chlorophenylboronic acid. Background Technology

[0002] p-Chlorophenylboronic acid is an important pharmaceutical intermediate, a key intermediate in the synthesis of the novel pesticide fungicide boscalid. It can also be used in the synthesis of tetrazolinone, carbizaramine, and other drugs, possessing broad market potential and application prospects. The main synthetic methods for p-chlorophenylboronic acid include catalytic boration, organolithium reagent method, and Grignard reagent method. However, the first two methods have high raw material costs and complex operations, making them unsuitable for industrial production. Currently, the Grignard reagent method is the most widely used method in industry.

[0003] Grignard reaction is an important method for constructing carbon-carbon bonds in organic synthesis and is widely used in the fields of medicine and fine chemicals. Its core is the reaction of organic halides with metallic magnesium to generate organometallic compounds. The strong exothermic characteristics of this reaction and the high reactivity of the products make it accompanied by significant safety risks in industrial production. Specifically, it is manifested in the following four aspects: (1) Risk of runaway reaction: If the initial temperature is too low or the reaction is insufficient, the reaction cannot start, resulting in the accumulation of halogenated hydrocarbons. Once the reaction is accidentally triggered, the accumulated material will react violently in an instant, generating uncontrollable and violent exothermic reactions, causing the temperature and pressure inside the reactor to rise rapidly, which may lead to material overflow and explosion accidents; (2) Risk of quenching caused by impurities: If water or other compounds containing active hydrogen are mixed into the reaction system, it will not only inhibit the normal progress of the reaction and cause the reaction to be quenched, but also cause the Grignard reagent to decompose and release flammable and explosive gases; (3) Risk of explosion due to solvent accumulation: Ether solvents may generate peroxides during use, which may explode when heated or vibrated; (4) Risk of magnesium raw material handling: Magnesium metal reacts with water to generate hydrogen and exotherm, which may also easily cause risks. Therefore, according to the requirements of safety production management, Grignard reactions are key hazardous chemical processes under supervision, and developing safe processes is an urgent need for production safety.

[0004] In traditional production methods, Grignard reactions are mostly produced using batch reactor processes. For example, patent CN110054642A describes a process using p-dichlorobenzene as a raw material, iodine as an initiator, and tetrahydrofuran and toluene as solvents. Under nitrogen protection, the reaction is heated and stirred to initiate the Grignard reaction. After successful initiation, a mixed solution of p-dichlorobenzene, tetrahydrofuran, and toluene is slowly added dropwise to prepare a Grignard reagent. The Grignard reagent is then cooled to -15°C to -20°C, and trimethyl borate or tributyl borate is added dropwise to initiate a condensation reaction. The product is then acidified with hydrochloric acid, washed with water to separate the layers, the solvent is distilled under negative pressure, and water is added to obtain p-chlorophenylboronic acid. This preparation method is a typical batch reactor process. To achieve large-scale industrial production, a large reactor with a high liquid holding capacity is required. The Grignard reaction is vigorous, posing a significant risk of overheating and material spillage, resulting in substantial safety hazards. Furthermore, adding excessive amounts of borate esters to the Grignard reagent can easily form multiple Grignard impurities, affecting product quality.

[0005] Patent CN120441604A uses tetrahydrofuran as a solvent and p-dichlorobenzene as a starting material. First, p-chlorophenyl magnesium chloride is prepared via a Grignard reaction. Then, the magnesium chloride reacts with borate esters in a microchannel reactor to obtain crude p-chlorophenylboronic acid ester. This crude product is then hydrolyzed, separated, and subjected to azeotropic distillation in the oil phase. Finally, recrystallization using a mixture of alcohol and benzene solvents yields p-chlorophenylboronic acid with a purity of over 98%. While this preparation method avoids the formation of multiple Grignard impurities by modifying the reaction mechanism with borate esters, it does not address the safety hazards of the Grignard reaction and is unsuitable for the needs of safe production.

[0006] Furthermore, the reactivity of p-dichlorobenzene is significantly lower than that of p-chlorobromobenzene. Therefore, the p-chlorophenylboronic acid synthesized from p-dichlorobenzene is inferior to that from the p-chlorobromobenzene process in terms of yield and product quality, especially during scale-up. Improving the reactivity of p-dichlorobenzene is also an urgent problem in industrial conversion.

[0007] Therefore, a method for the continuous preparation of p-chlorophenylboronic acid is needed. Summary of the Invention

[0008] To address the aforementioned problems in existing technologies, this invention provides a continuous method for preparing Grignard reagents. A tubular reactor is used to achieve continuous Grignard reaction, esterification reaction, and acidolysis reaction. This significantly improves process safety while substantially increasing reaction yield and product quality. The p-chlorophenylboronic acid product prepared by this method has a content of over 99% and a yield of over 90%, far exceeding industry standards and demonstrating a clear competitive advantage. It is also suitable for industrial-scale production. Furthermore, while ensuring safe production, the mixed use of p-dichlorobenzene and p-chlorobromobenzene significantly reduces production costs.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A continuous method for preparing p-chlorophenylboronic acid, comprising the following steps: (1) Initiation was carried out in a Grignard tubular reactor using magnesium shavings, tetrahydrofuran, p-chlorohalobenzene and bromoethane; (2) After successful initiation, p-chlorohalobenzene is continuously fed into the Grignard tubular reactor while magnesium shavings are intermittently added. When the area normalization content of p-chlorohalobenzene is ≤1% as detected by gas chromatography, the reaction is qualified. The feed liquid containing the Grignard intermediate is then sent into the esterification tubular reactor. (3) While receiving the above-mentioned feed liquid in the esterification tubular reactor, trimethyl borate solution is continuously introduced. When the area normalization content of the Grignard intermediate is ≤0.5% as detected by liquid chromatography, the reaction is qualified. The feed liquid containing the esterification intermediate is then sent to the acid hydrolysis tubular reactor. (4) While receiving the above-mentioned liquid, the acid hydrolysis tubular reactor continuously introduces hydrochloric acid solution. The surface normalization content of the esterification intermediate is ≤0.3% as detected by liquid chromatography. The reaction is qualified, and the liquid is sent to the receiving vessel. (5) After the organic phase is separated by standing in the receiving vessel, an ether solvent is added to crystallize the product and the product is obtained by filtration.

[0010] The aforementioned Grignard tubular reactor is a vertical, jacketed, dynamic tubular reactor, while the esterification tubular reactor and acid hydrolysis tubular reactor are horizontal, jacketed, dynamic tubular reactors.

[0011] Furthermore, the above steps are as follows: (1) Magnesium shavings are added from the top of the Grignard tube reactor, and then a mixture of tetrahydrofuran, p-chlorohalobenzene and initiator bromoethane is pumped from the bottom of the reactor through a metering pump. The stirring is turned on and the speed is controlled at 300-400 rpm. Wait for initiation and observe whether the reaction system has obvious temperature rise. When the system temperature rises to above 45°C, the initiation is successful.

[0012] In step (1), the magnesium chips are flake-shaped magnesium chips with a length of 2-4 mm, a width of 0.8-2 mm, and a thickness of 0.2-0.5 mm.

[0013] In step (1), the p-chlorohalobenzene is p-chlorobromobenzene or a mixture of p-dichlorobenzene and p-chlorobromobenzene, preferably a mixture of p-dichlorobenzene and p-chlorobromobenzene; preferably, when a mixture of the two is used, the molar ratio of p-dichlorobenzene and p-chlorobromobenzene is 1:1-4:1; preferably, the molar ratio of the magnesium shavings to p-chlorohalobenzene is 3-4:1; preferably, the mass ratio of the p-chlorohalobenzene, bromoethane and tetrahydrofuran is 1:(0.01-0.03):3-4.

[0014] Step (1) is mainly the initiation of the Grignard reaction. The initiation operation has the risk of getting out of control and is a relatively dangerous step in the Grignard reaction process. Therefore, a small amount of raw material must be added during initiation. The bottom layer of stirring should just be enough to stir the material. If the ambient temperature is low, the temperature should be raised to 15-25℃ and wait for initiation. During the initiation process, the temperature change of the reaction system should be observed at all times.

[0015] (2) After successful initiation, the pre-prepared p-chlorohalobenzene solution is continuously pumped into the bottom feed port of the Grignard tubular reactor at a constant flow rate of 10-30 mL / min using a metering pump. At the same time, magnesium shavings are continuously fed into the top feed port of the reactor intermittently. The reaction produces a liquid containing Grignard intermediates. A sample is taken and the area normalization content of p-chlorohalobenzene is ≤1% by gas chromatography. The reaction is qualified. The liquid flows out from the upper side outlet of the Grignard tubular reactor and enters the esterification tubular reactor.

[0016] In step (2), the p-chlorohalobenzene solution is dissolved in tetrahydrofuran or a mixture of tetrahydrofuran and toluene to ensure that the system is dissolved into a uniform and transparent solution, thereby preventing solid impurities from clogging the metering pump; the volume ratio of tetrahydrofuran to toluene in the mixed solvent is 1:1-2, and the mass ratio of p-chlorohalobenzene to the solvent is 1:2-5.

[0017] Preferably, in step (2), the molar ratio of p-chlorohalobenzene to the added magnesium chips is 1:1-4; preferably, the intermittent addition of magnesium chips means adding 2-6g every 5-10 minutes until the above molar ratio range is reached.

[0018] Preferably, in step (2), the reaction temperature is controlled at 10-40℃ by adjusting the temperature and circulation volume of the jacket cooling medium.

[0019] The Grignard intermediate is p-chlorophenyl magnesium bromide, p-chlorophenyl magnesium chloride, or a mixture thereof. Specifically, when p-dichlorobenzene is selected as the p-chlorohalobenzene, the Grignard intermediate is p-chlorophenyl magnesium chloride; when p-chlorobromobenzene is selected as the p-chlorohalobenzene, the Grignard intermediate is p-chlorophenyl magnesium bromide; and when a mixture of p-dichlorobenzene and p-chlorobromobenzene is selected as the p-chlorohalobenzene, the Grignard intermediate is a mixture of p-chlorophenyl magnesium bromide and p-chlorophenyl magnesium chloride.

[0020] (3) While receiving the reaction liquid overflowing from the Grignard tubular reactor, the esterification tubular reactor continuously pumps the trimethyl borate solution into the reactor from the top feed port at a constant flow rate of 10-20 mL / min according to the stoichiometric ratio. The reaction produces a feed liquid containing esterification intermediates. The sample is taken and the area normalization content of the Grignard intermediates is ≤0.5% by liquid chromatography. The reaction is qualified. The feed liquid flows out from the top outlet of the esterification tubular reactor and enters the acid hydrolysis tubular reactor.

[0021] In step (3), the trimethyl borate solution is dissolved in tetrahydrofuran or toluene, and the mass ratio of trimethyl borate to solvent is 1:3-5; the molar ratio of Grignard intermediate to trimethyl borate is 1:1-3; the reaction temperature in this step is -30℃ to 0℃, because the esterification reaction is a very fast reaction on the order of seconds, and the reaction occurs immediately upon contact. Therefore, it is necessary to control the esterification reaction temperature by adjusting the temperature of the jacket cooling medium and the circulation volume; the final esterification intermediate obtained in this step is (4-chlorophenyl)-dimethoxyborane.

[0022] (4) While receiving the reaction liquid overflowing from the esterification tubular reactor, the hydrochloric acid aqueous solution is continuously pumped into the feed port above the acid hydrolysis tubular reactor at a constant flow rate of 5-15 mL / min through a metering pump according to the stoichiometric ratio. The acid hydrolysis reaction generates a feed liquid containing p-chlorophenylboronic acid. The sample is taken and the area normalization content of the esterification intermediate is ≤0.3% by liquid chromatography. The reaction is qualified. The feed liquid flows out from the discharge port at the top of the acid hydrolysis tubular reactor and enters the receiving vessel.

[0023] In step (4), the mass concentration of the hydrochloric acid aqueous solution is 5%-15%; the molar ratio of the esterification intermediate to hydrochloric acid is 1:1-1.5.

[0024] Preferably, the reaction temperature in step (4) is 0℃-20℃. The acid hydrolysis reaction is a very rapid reaction on the order of seconds, and the reaction occurs immediately upon contact. During the process, the acid hydrolysis temperature needs to be controlled by adjusting the temperature and circulation of the jacket cooling medium.

[0025] (5) The liquid in the acid hydrolysis tubular reactor overflows into the receiving vessel, is allowed to stand and separate, the organic phase is desolvated, an ether solvent is added to crystallize, and the product of p-chlorophenylboronic acid is obtained by filtration.

[0026] Preferably, the organic phase desolvation in step (5) refers to distilling off the toluene and tetrahydrofuran solvents used in the reaction by vacuum distillation; the ether solvent used for crystallization is any one of petroleum ether, methyl tert-butyl ether, and cyclopentyl ether with a boiling range of 90-120℃; the mass ratio of the ether solvent to the p-chlorohalobenzene in step (2) is 2-3:1.

[0027] Compared with the traditional batch reaction process, the advantages of this invention are: (1) Grignard reaction is carried out in a continuous process using a tubular reactor, with a small liquid holdup, which significantly reduces the severity of accidents.

[0028] (2) After the tandem esterification is made continuous, the storage of Grignard intermediates is avoided, which not only reduces safety hazards, but also eliminates the problem of deterioration of intermediates during storage, and significantly improves the yield of esterification reaction.

[0029] (3) Continuous esterification and continuous acid hydrolysis solve the problem of violent exothermic reaction, making the process more stable and reliable.

[0030] (4) After adopting a continuous operation process, the degree of automation is high, and the "separation of man and machine" is realized to a greater extent, making the process more stable and safer.

[0031] (5) After the Grignard triggering is completed, production can continue continuously, avoiding secondary triggering and further mitigating safety risks.

[0032] (6) The use of p-dichlorobenzene and p-chlorobromobenzene in combination significantly improves the utilization rate of p-dichlorobenzene. While achieving the same product quality as p-chlorobromobenzene, the production cost is significantly reduced.

[0033] In summary, the technical solution of this invention optimizes the reaction conditions and reactor configuration, enabling continuous Grignard reaction, esterification reaction, and acidolysis reaction. Finally, the intermediate p-chlorophenylboronic acid is obtained through separation, solvent removal, and crystallization. This method not only significantly improves production efficiency but also solves the problems of the Grignard reaction's inherent dangers, poor stability of the Grignard intermediate, and the violent exothermic reaction. It greatly improves the reaction yield and product quality, achieving continuous production of p-chlorophenylboronic acid. The p-chlorophenylboronic acid product prepared by this method has a purity of over 99% and a yield of over 90%, far exceeding industry standards. Furthermore, the use of p-dichlorobenzene and p-chlorobromobenzene significantly reduces production costs. Therefore, this preparation method has a clear competitive advantage and is suitable for industrial-scale production. Attached Figure Description

[0034] Figure 1 This is a simplified process flow diagram of the present invention.

[0035] In the diagram, 1 is the metering pump for the Grignard reaction feedstock, 2 is the Grignard tubular reactor, 3 is the metering pump for the trimethyl borate solution, 4 is the esterification tubular reactor, 5 is the metering pump for the hydrochloric acid solution, 6 is the acid hydrolysis tubular reactor, and 7 is the receiving vessel. Detailed Implementation

[0036] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention. A simplified process flow diagram of the continuous preparation of p-chlorophenylboronic acid of the present invention is shown below. Figure 1 .

[0037] The magnesium shavings used in the following examples are flake magnesium shavings with a length of 2-4 mm, a width of 0.8-2 mm, and a thickness of 0.2-0.5 mm; the vertical tubular reactor and the horizontal tubular reactor were both purchased from Jiangsu Shiliu Chemical Technology Co., Ltd.

[0038] Example 1 A method for continuous preparation of p-chlorophenylboronic acid, the specific steps of which are as follows: (1) Add 25g of magnesium shavings from the top of a 2L vertical jacketed Grignard tube reactor, and then pump a mixture of 200g of tetrahydrofuran, 50g of p-chlorobromobenzene and 1g of bromoethane from the bottom using a metering pump. Turn on the stirring and control the speed at 400 rpm. Heat the mixture to 25°C and wait for initiation. After about 5 minutes, the reaction temperature is observed to start to rise. After about 3 minutes, the temperature rises rapidly from 25°C to 50°C, and the Grignard reaction is successfully initiated. (2) After successful initiation, a 20% tetrahydrofuran solution of p-chlorobromobenzene was continuously pumped into the bottom feed port of the Grignard tubular reactor at a rate of 20 mL / min using a metering pump. At the same time, 6 g of magnesium shavings were added from the top feed port of the reactor every 10 min. The molar ratio of p-chlorohalobenzene to the added magnesium shavings was 1:1.2. The reaction temperature was controlled at 25 °C. (3) After feeding for about 87 minutes, the reaction liquid in the Grignard tubular reactor was sampled. The area normalization content of p-chlorohalobenzene was 0.4% by gas chromatography, which was qualified for the reaction. The liquid containing Grignard intermediate flowed out from the outlet at the upper side of the Grignard tubular reactor and into a 2L horizontal jacketed esterification tubular reactor. At the same time, a 20% mass fraction of toluene solution of trimethyl borate was continuously pumped into the inlet of the esterification tubular reactor through a metering pump at a rate of 20 mL / min. The molar ratio of Grignard intermediate to trimethyl borate was 1:1.8, and the reaction temperature was controlled at -20℃. (4) After feeding for about 50 minutes, the reaction liquid in the esterification tubular reactor was sampled. The surface normalization content of the Grignard intermediate p-chlorophenyl magnesium bromide was 0.2% by liquid chromatography. The reaction was qualified. The liquid containing the esterification intermediate flowed out from the upper outlet of the esterification tubular reactor into a 2L horizontal jacketed acid hydrolysis tubular reactor. At the same time, a 10% hydrochloric acid aqueous solution was continuously pumped into the feed port of the acid hydrolysis tubular reactor at a flow rate of 10 mL / min through a metering pump. The molar ratio of esterification intermediate to hydrochloric acid was 1:1.3. The reaction temperature was controlled at 15℃. (5) After about 40 minutes, the reaction liquid in the acid hydrolysis tubular reactor was sampled. The surface normalization content of the esterification intermediate (4-chlorophenyl)-dimethoxyborane was 0.1% by liquid chromatography, indicating that the reaction was qualified. The liquid flowed out from the upper outlet of the acid hydrolysis tubular reactor into the receiving vessel. After standing and separating, tetrahydrofuran and toluene were distilled off from the organic phase under reduced pressure. Cyclopentyl ether was added for crystallization. The mass ratio of cyclopentyl ether to p-chlorohalobenzene in step (2) was 2.5:1. The product of p-chlorophenylboronic acid was obtained by filtration. The p-chlorophenylboronic acid content was 99.5% and the yield was 95.8% by HPLC.

[0039] Example 2 A method for continuous preparation of p-chlorophenylboronic acid, the specific steps of which are as follows: (1) Add 25g of magnesium shavings from the top of a 2L vertical jacketed Grignard tube reactor, and then pump a mixture of 200g of tetrahydrofuran, 21.7g of p-dichlorobenzene, 28.3g of p-chlorobromobenzene and 1g of bromoethane from the bottom using a metering pump. Turn on the stirrer and control the speed at 400 rpm. Heat the mixture to 20°C and wait for initiation. After about 5 minutes, observe that the reaction temperature begins to rise. After about 5 minutes, the temperature rises rapidly from 20°C to 52°C, indicating that the Grignard reaction has been successfully initiated. (2) After successful initiation, a 20% tetrahydrofuran solution of p-dichlorobenzene and p-chlorobromobenzene (p-dichlorobenzene and p-chlorobromobenzene are mixed in a 1:1 molar ratio) is continuously pumped into the bottom feed port of the Grignard tubular reactor at a rate of 15 mL / min using a metering pump. At the same time, 5.1 g of magnesium shavings are added from the top feed port of the reactor every 10 min. The molar ratio of p-chlorohalobenzene to the added magnesium shavings is 1:1.2. The reaction temperature is controlled at 40 °C. (3) After feeding for about 116 minutes, the reaction liquid in the Grignard tubular reactor was sampled. The area normalization content of p-chlorobromobenzene and p-dichlorobenzene was 0.5% by gas chromatography, indicating that the reaction was qualified. The liquid containing Grignard intermediates flowed out from the outlet at the upper side of the Grignard tubular reactor into a 2L horizontal jacketed esterification tubular reactor. At the same time, a 20% mass fraction of trimethyl borate toluene solution was continuously pumped into the inlet of the esterification tubular reactor through a metering pump at a rate of 18 mL / min. The molar ratio of Grignard intermediates to trimethyl borate was 1:1.6, and the reaction temperature was controlled at -20℃. (4) After feeding for about 60 minutes, the reaction liquid in the esterification tubular reactor was sampled. The surface normalization content of the Grignard intermediates p-chlorophenyl magnesium chloride and p-chlorophenyl magnesium bromide was 0.3% by liquid chromatography. The reaction was qualified. The liquid containing the esterification intermediates flowed out from the upper outlet of the esterification tubular reactor into a 2L horizontal jacketed acid hydrolysis tubular reactor. At the same time, a 10% hydrochloric acid aqueous solution was continuously pumped into the feed port of the acid hydrolysis tubular reactor through a metering pump at a flow rate of 7 mL / min. The molar ratio of esterification intermediates to hydrochloric acid was 1:1.1. The reaction temperature was controlled at 20℃. (5) After about 50 minutes, the reaction liquid in the acid hydrolysis tubular reactor was sampled. The surface normalization content of the esterification intermediate (4-chlorophenyl)-dimethoxyborane was 0.1% by liquid chromatography. The reaction was qualified. The liquid flowed out from the upper outlet of the acid hydrolysis tubular reactor into the receiving vessel. After standing and separating, tetrahydrofuran and toluene were distilled off from the organic phase under reduced pressure. Then, petroleum ether with a boiling range of 90-120℃ was added for crystallization. The mass ratio of petroleum ether to p-chlorohalobenzene in step (2) was 2.5:1. The p-chlorophenylboronic acid product was obtained by filtration. The p-chlorophenylboronic acid content was 99.4% and the yield was 95.5% by HPLC.

[0040] Based on Example 2, the inventors verified the effect of adjusting and optimizing the molar ratio of p-dichlorobenzene and p-chlorobromobenzene on the content and yield of p-chlorophenylboronic acid in the product. The experimental results are shown in Table 1.

[0041] Table 1. Content and yield of p-chlorophenylboronic acid at different molar ratios of p-dichlorobenzene and p-chlorobromobenzene

[0042] The experimental data in the table above show that when the amount of p-dichlorobenzene mixed is too large and the molar ratio exceeds 4:1, the yield and quality of the product decrease significantly.

[0043] Comparative Example 1: A continuous method for preparing p-chlorophenylboronic acid, the specific steps of which are as follows: (1) Add 30g of magnesium shavings from the top of a 2L vertical jacketed Grignard tube reactor, and then pump 200g of tetrahydrofuran, 50g of p-dichlorobenzene and 1g of bromoethane from the bottom using a metering pump. Turn on the stirring and control the speed at 400 rpm. Wait for the reaction to start. After about 5 minutes, the reaction temperature is observed to start to rise. After about 4 minutes, the temperature rises rapidly from 25℃ to 55℃. The Grignard reaction is successfully initiated. (2) After successful initiation, a 20% tetrahydrofuran solution of p-dichlorobenzene was continuously pumped into the bottom feed port of the Grignard tubular reactor at a rate of 10 mL / min using a metering pump. At the same time, 4 g of magnesium shavings were added from the top feed port of the reactor every 10 min. The molar ratio of p-chlorohalobenzene to the added magnesium shavings was 1:1.2. The reaction temperature was controlled at 30 °C. (3) After feeding for about 174 minutes, the reaction liquid in the Grignard tubular reactor was sampled. The area normalization content of p-chlorohalobenzene was 0.7% by gas chromatography, indicating that the reaction was qualified. The liquid containing the Grignard intermediate flowed out from the outlet at the upper side of the Grignard tubular reactor and into a 2L horizontal jacketed esterification tubular reactor. At the same time, a 20% mass fraction of trimethyl borate toluene solution was continuously pumped into the inlet of the esterification tubular reactor through a metering pump at a rate of 15 mL / min. The molar ratio of Grignard intermediate to trimethyl borate was 1:2.1, and the reaction temperature was controlled at -30℃. (4) After feeding for 80 minutes, the reaction liquid in the esterification tubular reactor was sampled. The surface normalization content of the Grignard intermediate p-chlorophenyl magnesium chloride was 0.4% by liquid chromatography. The reaction was qualified. The liquid containing the esterification intermediate flowed out from the upper outlet of the esterification tubular reactor into a 2L horizontal jacketed acid hydrolysis tubular reactor. At the same time, a 10% hydrochloric acid aqueous solution was continuously pumped into the feed port of the acid hydrolysis tubular reactor at a flow rate of 5 mL / min through a metering pump. The molar ratio of esterification intermediate to hydrochloric acid was 1:1. The reaction temperature was controlled at 20℃. (5) After about 65 minutes, the reaction liquid in the acid hydrolysis tubular reactor was sampled. The surface normalization content of the esterification intermediate (4-chlorophenyl)-dimethoxyborane was 0.2% by liquid chromatography. The reaction was qualified. The liquid flowed out from the upper outlet of the acid hydrolysis tubular reactor into the receiving vessel. After standing and separating, the organic phase was distilled off tetrahydrofuran and toluene under reduced pressure. Then, petroleum ether with a boiling range of 90-120℃ was added for crystallization. The mass ratio of petroleum ether to p-chlorohalobenzene in step (2) was 2.5:1. The product of p-chlorophenylboronic acid was obtained by filtration. The p-chlorophenylboronic acid content was 98.1% by HPLC and the yield was 88.1%.

[0044] Comparative Example 2: A batch method for preparing p-chlorophenylboronic acid, the specific steps of which are as follows: To a 2000mL four-necked reaction flask, first add 25g of p-dichlorobenzene, 100g of tetrahydrofuran, 30g of magnesium shavings, and 0.5g of bromoethane. Under nitrogen protection, heat to 25°C and stir until Grignard initiation occurs. The reaction system gradually changes from colorless to pale yellow, accompanied by a 20°C increase in temperature, indicating successful initiation. After successful initiation, slowly add a mixed solution of 122g of p-dichlorobenzene and 488g of tetrahydrofuran to the successfully initiated Grignard reagent, controlling the temperature at 25°C during the addition. After the addition is complete, maintain the temperature at 25°C for 1 hour to prepare the Grignard reagent. Then, cool the Grignard reagent to -15°C and add 124.8g of trimethyl borate to the Grignard reagent to initiate the esterification reaction. After the esterification reaction is complete, add 365g of... A 10% hydrochloric acid solution was used to acidify the p-chlorophenylboronic acid. After standing and separating the layers, the organic phase was distilled under negative pressure to remove tetrahydrofuran. Then, 300g of petroleum ether was added to crystallize the mixture. The filtered product yielded p-chlorophenylboronic acid. HPLC analysis showed a purity of 97.1% and a yield of 80.2%.

[0045] Compared with traditional batch processing, the present invention adopts a continuous process, which is simple to operate and significantly improves the reaction yield and product content. In Comparative Example 2, the use of p-dichlorobenzene resulted in significantly lower product yield and content. Even after using a continuous process in Comparative Example 1, the yield of p-chlorophenylboronic acid improved, but it was still difficult to exceed 90%. In Example 2, by using a mixture of p-dichlorobenzene and p-chlorobromobenzene, the product quality almost reached the level of the p-chlorobromobenzene process, significantly improving the reaction effect of p-dichlorobenzene. Since the cost of p-dichlorobenzene is significantly lower than that of p-chlorobromobenzene, the production cost of p-chlorophenylboronic acid is significantly reduced.

[0046] In summary, the technical solution of this invention optimizes the reaction conditions and reactor configuration, achieving continuous Grignard reaction, continuous esterification reaction, and continuous acidolysis reaction. Finally, the p-chlorophenylboronic acid intermediate is obtained by separation, desolvation, and crystallization. This method not only greatly improves production efficiency but also solves the problems of the dangers of Grignard reaction, as well as the poor stability of Grignard intermediates and the violent exothermic reaction. It significantly improves the reaction yield and product quality. The p-chlorophenylboronic acid product prepared by this method has a content of over 99% and a yield of over 90%, far exceeding the industry level. Furthermore, it can be mixed with p-dichlorobenzene. Therefore, this preparation method has a clear competitive advantage and is easy to scale up for industrial production.

[0047] The same type of Grignard boric acid can be prepared by referring to and using this method. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

Claims

1. A method for the continuous production of p-chlorophenylboronic acid, characterized in that, The specific steps are as follows: (1) Initiation was carried out in a Grignard tubular reactor using magnesium shavings, tetrahydrofuran, p-chlorohalobenzene and bromoethane; (2) After successful initiation, p-chlorohalobenzene is continuously fed into the Grignard tubular reactor while magnesium shavings are intermittently added. When the area normalization content of p-chlorohalobenzene is ≤1% as detected by gas chromatography, the reaction is qualified. The feed liquid containing the Grignard intermediate is then sent into the esterification tubular reactor. (3) While receiving the above-mentioned feed liquid in the esterification tubular reactor, trimethyl borate solution is continuously introduced. When the area normalization content of the Grignard intermediate is ≤0.5% as detected by liquid chromatography, the reaction is qualified. The feed liquid containing the esterification intermediate is then sent to the acid hydrolysis tubular reactor. (4) While receiving the above-mentioned liquid, the acid hydrolysis tubular reactor continuously introduces hydrochloric acid solution. The surface normalization content of the esterification intermediate is ≤0.3% as detected by liquid chromatography. The reaction is qualified, and the liquid is sent to the receiving vessel. (5) After the organic phase is separated by standing in the receiving vessel, an ether solvent is added to crystallize the product and the product is obtained by filtration.

2. The method of claim 1, wherein the method is continuous. The specific steps (1) are as follows: magnesium shavings are added from the top of the Grignard tubular reactor, and then a mixture of tetrahydrofuran, p-chlorohalobenzene and initiator bromoethane is pumped from the bottom of the reactor through a metering pump. The stirring speed is turned on and controlled at 300-400 rpm. The reaction is allowed to proceed until initiation is achieved. The reaction system is observed to show a significant temperature increase. When the system temperature rises to above 45°C, the initiation is successful.

3. The method of claim 1 or 2, wherein the method is characterized by, In step (1), the magnesium shavings are flake-shaped magnesium shavings, and the p-chlorohalobenzene is p-chlorobromobenzene or a mixture of p-dichlorobenzene and p-chlorobromobenzene; preferably, when a mixture of the two is used, the molar ratio of p-dichlorobenzene and p-chlorobromobenzene is 1:1-4:1; preferably, the molar ratio of the magnesium shavings and p-chlorohalobenzene in step (1) is 3-4:1; preferably, the mass ratio of p-chlorohalobenzene, bromoethane and tetrahydrofuran in step (1) is 1:0.01-0.03:3-4.

4. The method of claim 1, wherein the method is continuous. The specific steps (2) are as follows: After successful initiation, the pre-prepared p-chlorohalobenzene solution is continuously pumped into the bottom feed port of the Grignard tubular reactor at a constant flow rate of 10-30 mL / min using a metering pump. At the same time, magnesium shavings are continuously fed into the top feed port of the reactor intermittently. The reaction generates a liquid containing Grignard intermediates. A sample is taken, and the area normalization content of p-chlorohalobenzene is ≤1% by gas chromatography. The reaction is qualified, and the liquid flows out from the upper side outlet of the Grignard tubular reactor and enters the esterification tubular reactor.

5. The method of claim 1 or 4, wherein the method is continuous. In step (2), the p-chlorohalogenated benzene solution is dissolved in tetrahydrofuran or a mixed solvent of tetrahydrofuran and toluene, wherein the volume ratio of tetrahydrofuran to toluene in the mixed solvent is 1:1-2, and the mass ratio of p-chlorohalogenated benzene to solvent is 1:2-5; preferably, the molar ratio of p-chlorohalogenated benzene to added magnesium shavings in step (2) is 1:1-4; preferably, the intermittent addition of magnesium shavings means adding 2-6g every 5-10min until the above molar ratio range is reached; preferably, the reaction temperature in step (2) is 10-40℃.

6. The method for continuous preparation of p-chlorophenylboronic acid according to claim 1, characterized in that, The specific steps (3) are as follows: While receiving the reaction liquid overflowing from the Grignard tubular reactor, the esterification tubular reactor continuously pumps the trimethyl borate solution into the reactor from the top feed port at a constant flow rate of 10-20 mL / min according to the stoichiometric ratio. The reaction generates a liquid containing esterification intermediates. The sample is taken and the area normalization content of the Grignard intermediates is detected by liquid chromatography to be ≤0.5%. The reaction is qualified. The liquid flows out from the top outlet of the esterification tubular reactor and enters the acid hydrolysis tubular reactor.

7. The method for continuous preparation of p-chlorophenylboronic acid according to claim 1 or 6, characterized in that, In step (3), the trimethyl borate solution is dissolved in tetrahydrofuran or toluene, and the mass ratio of trimethyl borate to solvent is 1:3-5; the molar ratio of Grignard intermediate to trimethyl borate is 1:1-3; the reaction temperature in this step is -30℃ to 0℃; the esterification intermediate finally obtained in this step is (4-chlorophenyl)-dimethoxyborane.

8. The method of claim 1, wherein the method is continuous. The specific steps (4) are as follows: While receiving the reaction liquid overflowing from the esterification tubular reactor, the hydrochloric acid aqueous solution is continuously pumped into the feed port above the acid hydrolysis tubular reactor at a constant flow rate of 5-15 mL / min through a metering pump according to the stoichiometric ratio. The acid hydrolysis reaction generates a feed liquid containing p-chlorophenylboronic acid. A sample is taken, and the area normalization content of the esterification intermediate is detected by liquid chromatography to be ≤0.3%. The reaction is qualified, and the feed liquid flows out from the upper outlet of the acid hydrolysis tubular reactor into the receiving vessel.

9. The method of claim 1 or 8, wherein the method is continuous. In step (4), the mass concentration of the hydrochloric acid aqueous solution is 5%-15%; the molar ratio of the esterification intermediate to hydrochloric acid is 1:1-1.5; preferably, the reaction temperature in step (4) is 0℃-20℃.

10. The method of claim 1, wherein the method is continuous. The specific steps (5) are as follows: the feed liquid in the acid hydrolysis tubular reactor overflows into the receiving vessel, is allowed to stand and separate, the organic phase is desolvated, an ether solvent is added to crystallize, and the product of p-chlorophenylboronic acid is obtained by filtration. Preferably, the organic phase desolvation refers to distilling off the toluene and tetrahydrofuran solvents used in the reaction by vacuum distillation; the ether solvent used for crystallization is any one of petroleum ether, methyl tert-butyl ether, and cyclopentyl ether with a boiling range of 90-120℃; the mass ratio of the ether solvent to the p-chlorohalobenzene in step (2) is 2-3:1.

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