Synthesis process of p-chlorophenylboronic acid

Abstract

The invention relates to a synthesis process of p-chlorophenylboronic acid, which comprises the following steps: by taking tetrahydrofuran as a solvent and p-dichlorobenzene as an initial raw material, firstly preparing p-chlorophenylmagnesium chloride through Grignard reaction, then reacting the p-chlorophenylmagnesium chloride with boric acid ester in a microchannel reactor to obtain a p-chlorophenylboronic acid ester crude product, and then hydrolyzing, layering and carrying out oil-phase azeotropic distillation to obtain the p-chlorophenylboronic acid ester. And finally, recrystallizing by adopting a mixed system of an alcohol solvent and a benzene solvent to obtain p-chlorophenylboronic acid with the content of 98% or above. The synthetic process of the p-chlorophenylboronic acid is mild in reaction condition, simple and convenient to operate, low in cost, high in safety, high in product content and very suitable for being applied to industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemicals, and particularly relates to a synthesis process of p-chlorophenylboronic acid. Background Art

[0002] p-Chlorophenylboronic acid is an important synthetic intermediate used in the preparation of the pharmaceutical carbinoxamine and the pesticides boscalid and tetrazolinone. Literature also reports that this compound can be used in the synthesis of organic electroluminescent materials. Due to its arylboronic acid structure, p-chlorophenylboronic acid can be used in the Suzuki reaction to form C-C, C-N, and C-S bonds. Currently, there are three common methods for preparing p-chlorophenylboronic acid: the first involves diazotizing p-chloroaniline to form a diazonium salt, which is then reacted with boric acid to produce p-chlorophenylboronic acid; the second involves treating p-chlorobromobenzene with butyllithium to form an aryllithium salt, followed by the addition of a boric acid ester for condensation and hydrolysis to produce p-chlorophenylboronic acid. This reaction typically requires a harsh temperature of -78°C, and the lithium reagent used is highly flammable, posing significant safety risks and making it unsuitable for industrial production. The third method involves the Grignard reagent method, in which p-chlorobromobenzene is reacted with magnesium to form a Grignard reagent, which is then added dropwise to the boric acid ester for condensation, followed by hydrolysis to produce p-chlorophenylboronic acid.

[0003] p-Chlorophenylboric acid is a key intermediate in the pesticide boscalid. Literature review and recent environmental impact assessments related to boscalid reveal that the synthesis of p-chlorophenylboric acid primarily uses p-chlorobromobenzene as a starting material. This material is first reacted with magnesium to produce p-chlorophenylmagnesium bromide, which is then reacted with a borate ester and hydrolyzed to produce p-chlorophenylboric acid. Examples include "Study on the Synthesis Process of p-Chlorophenylboric Acid" in Volume 46, Issue 2 of Fine Chemical Intermediates, "Synthesis of the Fungicide Boscalid" in Issue 32 of 2011, and the 2000 ton / year boscalid project described in the 2023 "Environmental Impact Report on the Expansion Project of Hebei Lansheng Biotechnology Co., Ltd. for an Annual Production of 25,005 Tons of High-Efficiency and Low-Toxicity Pesticides." All of these methods use p-chlorobromobenzene as a starting material to produce p-chlorophenylboric acid. The current market price of p-chlorobromobenzene is over 10 times that of p-dichlorobenzene, making the production of p-chlorophenylboric acid via this route prohibitively expensive. Furthermore, the brominated product is highly polluting to the environment and generates a significant amount of magnesium salt solid waste.

[0004] Therefore, reducing production costs, simplifying the process, improving conversion rates, and minimizing solid pollution have always been a series of technical challenges in the industrial production of p-chlorophenylboronic acid. Although there are many patents and literature reporting the preparation of arylboronic acid compounds, there are few reports using p-dichlorobenzene as a raw material and tetrahydrofuran as a solvent.

[0005] Patent CN104530106A uses p-dichlorobenzene as a raw material to prepare p-chlorophenylboronic acid with a yield of 85.6%, and a purity of 98.5% without purification. Extensive experimental verification revealed that the reaction was difficult to carry out, the yield was low, and the impurities were excessive, with a content of only approximately 85%, failing to meet the quality requirements of boscalid. Furthermore, because p-chlorophenylboronic acid is a highly polar substance with very low solubility in non-polar solvents, the patent's use of toluene to extract p-chlorophenylboronic acid was particularly ineffective.

[0006] Invention patent CN106946915A uses p-dichlorobenzene as a raw material to prepare p-chlorophenylboronic acid with a yield of 93% and a purity of 99.8% without purification. Extensive experimental verification and gas chromatography-mass spectrometry (GC-MS) analysis of the Grignard reaction solution from the Grignard reaction stage revealed the presence of numerous di-Grignard and coupled impurities in p-dichlorobenzene during the Grignard reaction. Furthermore, complete conversion of the raw material p-dichlorobenzene was difficult. Liquid chromatography-mass spectrometry (LC-MS) analysis revealed the presence of significant amounts of terephthalic acid, biphenylboric acid, and dichlorophenylboric acid after reaction with borate esters. Recrystallization from water removed only the highly polar p-terephthalic acid, while biphenylboric acid and dichlorophenylboric acid remained. The resulting p-chlorophenylboric acid content was only approximately 80%, failing to meet the quality requirements for boscalid production. Summary of the Invention

[0007] In view of the defects of the prior art, the object of the present invention is to provide a method for synthesizing p-chlorophenylboronic acid with mild conditions, simple operation, low cost, high safety and high product content, which is suitable for industrial expansion production.

[0008] The technical solution adopted by the present invention to solve the above problems is: a synthesis process of p-chlorophenylboronic acid, comprising the following steps: S1: dissolving p-dichlorobenzene in tetrahydrofuran to obtain a p-dichlorobenzene tetrahydrofuran solution; S2: dissolving an initiator alkyl halide in tetrahydrofuran to obtain an initiator tetrahydrofuran solution; S3: Put magnesium into a Grignard reactor and add tetrahydrofuran to obtain an initial Grignard solution; S4: under certain temperature conditions, the initiator tetrahydrofuran solution is dropped into the initial Grignard solution of S3; S5: under certain temperature conditions, adding the tetrahydrofuran solution of p-dichlorobenzene to S4 to carry out Grignard reaction. After the Grignard reaction is completed, a portion of the obtained Grignard reaction solution is used for the next reaction, and the other portion is retained as an initiator for the next batch reaction; S6: continuously introducing a portion of the Grignard reaction solution and the borate ester into a microchannel reactor according to a certain molar ratio to react; S7: The boronation reaction liquid from the microchannel reactor is dripped into dilute hydrochloric acid for hydrolysis. After hydrolysis, the reaction mixture is allowed to stand for separation and the water layer is removed to obtain an oil phase containing p-chlorophenylboronic acid. S8: adding the oil phase containing p-chlorophenylboronic acid to water for azeotropic distillation to remove the low-boiling point solvent, then cooling and filtering to obtain a crude p-chlorophenylboronic acid product; S9: Recrystallize the crude p-chlorophenylboronic acid to obtain a p-chlorophenylboronic acid product.

[0009] Preferably, the water content of the tetrahydrofuran is ≤200 ppm; more preferably, it is 50 to 200 ppm; and even more preferably, it is 100 to 200 ppm.

[0010] Preferably, the molar ratio of the total amount of tetrahydrofuran to p-dichlorobenzene in the Grignard reaction is 4-8:1, that is, the molar ratio of the total amount of tetrahydrofuran used in steps S1 to S3 to p-dichlorobenzene is 4-8:1; more preferably, it is 4-6:1; further preferably, it is 4-5:1.

[0011] Preferably, the mass concentration of the p-dichlorobenzene tetrahydrofuran solution in step S1 is 10-50%; more preferably, 20-40%; and even more preferably, 25-30%.

[0012] Preferably, the initiator alkyl halide in step S2 is one of ethyl bromide, propyl bromide, and isopropyl bromide, more preferably propyl bromide and isopropyl bromide; even more preferably, isopropyl bromide.

[0013] Preferably, the mass concentration of the initiator tetrahydrofuran solution is 10-30%; more preferably, it is 20-30%; and even more preferably, it is 20-25%.

[0014] Preferably, the molar ratio of the initiator alkyl halide to p-dichlorobenzene is 0.01 to 0.1:1, more preferably 0.01 to 0.05:1; further preferably 0.03 to 0.05:1.

[0015] Preferably, the molar ratio of magnesium to p-dichlorobenzene is 0.9 to 1:1; more preferably, it is 0.9 to 0.95:1; and even more preferably, it is 0.9 to 0.92:1.

[0016] Preferably, the mass ratio of magnesium to tetrahydrofuran in step S3 is 1:3-6; more preferably, it is 1:4-6; and even more preferably, it is 1:4-5.

[0017] Preferably, the reaction temperature in step S4 is 10-60°C; more preferably, 20-40°C; even more preferably, 20-30°C.

[0018] Preferably, the dripping time of the initiator tetrahydrofuran solution is 0.5 to 3 hours; more preferably, it is 0.5 to 2 hours; further preferably, it is 0.5 to 1 hour.

[0019] Preferably, the reaction temperature in step S5 is 55-75°C; more preferably, 55-65°C; even more preferably, 60-65°C.

[0020] Preferably, the dropwise addition time of the p-dichlorobenzene tetrahydrofuran solution is 4 to 8 hours, and the reaction is continued for 1 hour after the dropwise addition is completed; further preferably, the dropwise addition time of the p-dichlorobenzene tetrahydrofuran solution is 5 to 7 hours; further preferably, the dropwise addition time of the p-dichlorobenzene tetrahydrofuran solution is 5 to 6 hours.

[0021] Preferably, the reaction temperature in step S6 is -10 to -30°C; more preferably, it is -10 to -20°C; and even more preferably, it is -10 to -15°C.

[0022] Preferably, the borate ester is one of trimethyl borate, triethyl borate, triisopropyl borate, tri-n-butyl borate, and triisobutyl borate; more preferably, it is one of trimethyl borate, triisopropyl borate, and triisobutyl borate; and even more preferably, it is trimethyl borate and triisobutyl borate.

[0023] Preferably, the molar ratio of the borate ester to p-dichlorobenzene is 0.8 to 1:1; more preferably, it is 0.8 to 0.9:1; and even more preferably, it is 0.8 to 0.85:1.

[0024] Preferably, the hydrolysis temperature in step S7 is 0-60°C; more preferably, 20-50°C; even more preferably, 25-45°C.

[0025] Preferably, the molar ratio of the dilute hydrochloric acid to the boric acid ester is 0.95 to 1.5:1; more preferably, it is 0.95 to 1.2:1; and even more preferably, it is 0.95 to 1:1.

[0026] Preferably, the mass concentration of the dilute hydrochloric acid is 5-15%; more preferably, it is 5-15%; even more preferably, it is 10-15%.

[0027] Preferably, the volume ratio of the oil phase to water during azeotropic distillation in step S8 is 1:1-5; more preferably, it is 1:2-4; and even more preferably, it is 1:2-3.

[0028] Preferably, the recrystallization solvent used for recrystallization in step S9 is a mixed component of an alcohol and a benzene solvent, the alcohol solvent is one of methanol, ethanol, propanol, and butanol, and the benzene solvent is one of benzene, chlorobenzene, toluene, and xylene. Further preferably, the alcohol solvent is one of n-butanol and isobutanol, and the benzene solvent is one of chlorobenzene and xylene; further preferably, the alcohol solvent is isobutanol and the benzene solvent is chlorobenzene. The volume ratio of the alcohol solvent to the benzene solvent is 1:10 to 30; further preferably, it is 1:15 to 25; further preferably, it is 1:20 to 25.

[0029] Preferably, the weight ratio of the recrystallization solvent to the crude p-chlorophenylboric acid is 5 to 15:1, more preferably 5 to 10:1; and even more preferably 8 to 10:1.

[0030] Compared with the prior art, the advantages of the present invention are: (1) The synthesis process of p-chlorophenylboronic acid of the present invention uses cheap and readily available p-dichlorobenzene as a raw material, which greatly reduces the production cost of p-chlorophenylboronic acid. In addition, the Grignard reaction is carried out at a temperature of 55 to 75°C, and the addition time of the p-dichlorobenzene tetrahydrofuran solution is controlled to be 4 to 8 hours, so that the final yield and the content of p-chlorophenylboronic acid are optimized.

[0031] (2) In the present invention, the molar ratio of magnesium to p-dichlorobenzene is 0.9 to 1:1, so that the cheap p-dichlorobenzene is excessive in the Grignard reaction, thereby consuming all the magnesium chips and allowing the magnesium to be completely converted, making the Grignard reaction solution clear and avoiding the problem of magnesium blockage in the subsequent process.

[0032] (3) The present invention continuously introduces the Grignard reaction solution and borate ester into a microchannel reactor in a certain molar ratio to carry out boronation reaction, thereby reducing the side reaction impurities generated by the local exothermic temperature rise caused by the reaction of the Grignard reagent and the borate ester, avoiding the need to maintain the reaction temperature below -30°C in a conventional reactor, thereby reducing production energy consumption and being more suitable for industrial production.

[0033] (4) In the post-treatment process of the synthesis process of p-chlorophenylboronic acid of the present invention, the oil phase containing p-chlorophenylboronic acid is added to water for azeotropic distillation, which can better remove tetrahydrofuran, alcohol solvents, and benzene solvents from the system, prevent the solvents from entering the recrystallization solvent system, and enable the recrystallization solvent to be recycled. In addition, by using a mixed system of alcohol solvents and benzene solvents for recrystallization, p-chlorophenylboronic acid with a content of more than 98% can be obtained, which meets the quality requirements for the synthesis of boscalid. DETAILED DESCRIPTION

[0034] The present invention is described in further detail below with reference to the examples. Example 1

[0035] A synthesis process for p-chlorophenylboronic acid comprises the following steps: S1: Dissolve 594 g (4 mol) of p-dichlorobenzene in 1500 g of tetrahydrofuran and set aside; S2: Dissolve 19.8 g (0.16 mol) of isopropyl bromide in 70 g of tetrahydrofuran and set aside; S3: Add 89.4 g (3.64 mol) of magnesium chips to the Grignard reactor, followed by 400 g of tetrahydrofuran; S4: At 20-30°C, add the solution prepared in S2 to S3. After 3 minutes of dripping, there is a clear exothermic temperature rise. The dripping is completed in 0.5 hours. After the dripping is completed, continue stirring for 0.5 hours. S5: The reaction solution from the previous step was heated to 60°C, and the temperature was controlled at 60-65°C. The tetrahydrofuran solution of p-dichlorobenzene was added dropwise. An obvious exothermic temperature rise occurred after 5 minutes of addition. The addition was completed after 5.5 hours. After the addition was completed, the temperature was kept at room temperature for 1 hour, and then the temperature was lowered to room temperature. The content of p-chlorophenylmagnesium chloride was 19.22% after sampling and analysis. S6: The Grignard reaction solution and triisobutyl borate were introduced into a Corning G1 microchannel reactor at 10.51 ml / min and 3.65 ml / min, respectively (molar ratio of p-dichlorobenzene to triisobutyl borate was 1:0.83). The external circulation temperature of the microchannel reactor was maintained at -20°C, and the temperature of the material in the reactor was controlled between -10°C and -15°C. HPLC analysis of the sample revealed a concentration of 0.33% of the key impurity, diphenylboric acid. S7: The boronization reaction liquid from the microchannel reactor was added dropwise to 1143 g (3.92 mol) of 12.5% dilute hydrochloric acid for hydrolysis at a temperature of 30-35°C. After the hydrolysis was complete, the mixture was allowed to stand at 30-35°C to separate the layers. The lower layer of 1734.5 g of the magnesium chloride aqueous solution was removed to obtain 2849.6 g (3131.4 ml) of an oil phase containing p-chlorophenylboronic acid. S8: Add 3131.4 ml of the oil phase obtained in the previous step into an azeotropic distillation kettle (equipped with a 1 m packed tower and glass spring packing), then add 6889.4 ml of water, and slowly distill and azeotropically distill. When the top gas phase reaches 100°C, stop distillation, cool to 30-35°C, and filter to obtain 550.6 g of crude wet product of p-chlorophenylboronic acid; S9: Add 215.5 ml of isobutanol and 4740.8 ml of chlorobenzene to the refining kettle, add 550.6 g of crude p-chlorophenylboric acid from the previous step, heat and reflux for 1 hour, slowly cool to 30-35 ° C and crystallize for 1 hour, then filter and dry the wet product to obtain 436.3 g of p-chlorophenylboric acid with a yield of 68.5% (based on p-dichlorobenzene) and a content of 98.2%. Example 2

[0036] A synthesis process for p-chlorophenylboronic acid comprises the following steps: S1: Dissolve 594 g (4 mol) of p-dichlorobenzene in 1500 g of tetrahydrofuran and set aside; S2: Dissolve 22 g (0.2 mol) of ethyl bromide in 70 g of tetrahydrofuran and set aside; S3: Add 89.4 g (3.64 mol) of magnesium chips to the Grignard reactor, followed by 390 g of tetrahydrofuran; S4: At 30-35°C, add the solution prepared in S2 to S3. After 5 minutes of dripping, there is a clear exothermic temperature rise. The dripping is completed in 0.5 hours. After the dripping is completed, continue stirring for 0.5 hours. S5: The reaction solution from the previous step was heated to 60°C, and the temperature was controlled at 60-65°C. The tetrahydrofuran solution of p-dichlorobenzene was added dropwise. The temperature was exothermic for 6 minutes and the temperature was completely increased after 5 hours. After the temperature was completely increased, the solution was kept warm for 1 hour and then cooled to room temperature. The content of p-chlorophenylmagnesium chloride was 18.68% after sampling and analysis. S6: The Grignard reaction solution and triisobutyl borate were introduced into a Corning G1 microchannel reactor at 21.02 ml / min and 7.48 ml / min, respectively (the molar ratio of p-dichlorobenzene to triisobutyl borate was 1:0.85). The external circulation temperature of the microchannel reactor was maintained at -20°C, and the temperature of the material in the reactor was controlled between -10°C and -15°C. HPLC analysis of the sample revealed a concentration of 0.35% diphenylboric acid, a key impurity. S7: The boronization reaction liquid from the microchannel reactor was added dropwise to 1024.8 g (3.88 mol) of 13.8% dilute hydrochloric acid for hydrolysis at a temperature of 30-35°C. After hydrolysis, the mixture was allowed to stand at 30-35°C to separate the layers. The lower layer (1740.8 g of the magnesium chloride aqueous solution) was removed to obtain 2743.6 g (2998.5 ml) of an oil phase containing p-chlorophenylboronic acid. S8: Add 2998.5 ml of the oil phase obtained in the previous step into an azeotropic distillation kettle (equipped with a 1 m packed tower and glass spring packing), then add 5997.8 ml of water, and slowly distill and azeotropically distill. When the top gas phase reaches 100°C, stop distillation, cool to 30-35°C, and filter to obtain 532.5 g of crude wet product of p-chlorophenylboronic acid; S9: Add 166.4 ml of n-butanol and 2510.6 ml of xylene to the refining kettle, add 532.5 g of crude p-chlorophenylboric acid from the previous step, heat and reflux for 1 hour, slowly cool to 30-35 ° C and crystallize for 1 hour, then filter and dry the wet product to obtain 393.8 g of p-chlorophenylboric acid with a yield of 62.2% (based on p-dichlorobenzene) and a content of 98.8%. Example 3

[0037] A synthesis process for p-chlorophenylboronic acid comprises the following steps: S1: Dissolve 594 g (4 mol) of p-dichlorobenzene in 1570 g of tetrahydrofuran and set aside; S2: Add 89.4 g (3.64 mol) of magnesium chips, 390 g of tetrahydrofuran, and 40 ml of Grignard reaction solution to the Grignard reactor; S3: At 30-35°C, add the solution prepared in S2 to S3. After 5 minutes of dripping, there is a clear exothermic temperature rise. The dripping is completed in 0.5 hours. After the dripping is completed, continue stirring for 0.5 hours. S4: The reaction solution in the previous step was heated to 60°C, and the material temperature was controlled at 60-65°C. The p-dichlorobenzene tetrahydrofuran solution was added dropwise. There was a significant exothermic temperature rise after 6 minutes of addition. The addition was completed in 5 hours. After the addition was completed, the temperature was kept at 40°C for 1 hour, and then the temperature was lowered to room temperature. The p-chlorophenylmagnesium chloride content was detected by sampling and analysis, and was 18.75% (40 ml of the Grignard reaction solution was taken out as the initiator for the next batch of Grignard reaction); S5: The Grignard reaction solution and triisobutyl borate were introduced into a Corning G1 microchannel reactor at 21.02 ml / min and 7.48 ml / min, respectively (molar ratio of p-dichlorobenzene to triisobutyl borate was 1:0.85). The external circulation temperature of the microchannel reactor was maintained at -20°C, and the temperature of the material in the reactor was controlled between -10°C and -15°C. HPLC analysis of the sample revealed a concentration of 0.31% diphenylboric acid, a key impurity. S6: The boronization reaction liquid from the microchannel reactor was added dropwise to 1166.8 g (3.9 mol) of 12.2% dilute hydrochloric acid for hydrolysis at a temperature of 30-35°C. After the hydrolysis was complete, the mixture was allowed to stand at 30-35°C to separate the layers. The lower layer (1855.8 g of the magnesium chloride aqueous solution) was removed to obtain 2740.8 g (2994.4 ml) of an oil phase containing p-chlorophenylboronic acid. S7: Add 2994.4 ml of the oil phase obtained in the previous step into an azeotropic distillation kettle (equipped with a 1 m packed tower and glass spring packing), then add 5988.8 ml of water, and slowly distill and azeotropically distill. When the top gas phase reaches 100°C, stop distillation, cool to 30-35°C, and filter to obtain 542.2 g of crude wet product of p-chlorophenylboronic acid; S8: Add 166.4 ml of n-butanol and 2510.6 ml of xylene to the refining kettle, add 542.2 g of crude p-chlorophenylboronic acid from the previous step, heat and reflux for 1 hour, slowly cool to 30-35 ° C and crystallize for 1 hour, then filter and dry the wet product to obtain 396.5 g of p-chlorophenylboronic acid with a yield of 62.5% (based on p-dichlorobenzene) and a content of 98.6%.

[0038] Comparative Example 1 The only difference from Example 1 is that the microchannel reactor is replaced by a low-temperature reactor.

[0039] A synthesis process for p-chlorophenylboronic acid comprises the following steps: S1: Dissolve 594 g (4 mol) of p-dichlorobenzene in 1500 g of tetrahydrofuran and set aside; S2: Dissolve 19.8 g (0.16 mol) of isopropyl bromide in 70 g of tetrahydrofuran and set aside; S3: Add 89.4 g (3.64 mol) of magnesium chips to the Grignard reactor, followed by 400 g of tetrahydrofuran; S4: At 20-30°C, add the solution prepared in S2 to S3. After 3 minutes of dripping, there is a clear exothermic temperature rise. The dripping is completed in 0.5 hours. After the dripping is completed, continue stirring for 0.5 hours. S5: The reaction solution from the previous step was heated to 60°C, and the temperature was controlled at 60-65°C. The tetrahydrofuran solution of p-dichlorobenzene was added dropwise. An obvious exothermic temperature rise occurred after 5 minutes of addition. The addition was completed after 5.5 hours. After the addition was completed, the temperature was kept at room temperature for 1 hour, and then the temperature was lowered to room temperature. The content of p-chlorophenylmagnesium chloride was 19.22% after sampling and analysis. S6: 767.9 g (3.32 mol) of triisobutyl borate was added to the jacketed reactor, and a -30°C cooling circulating fluid was introduced into the jacket to cool the contents to -25°C. S7: Add the Grignard reaction solution obtained in S5 dropwise to S6, maintaining the temperature between -20°C and -25°C during the addition. Allow the solution to complete within 3 hours, then maintain the temperature for 15 minutes. Sampling and HPLC analysis revealed a concentration of 0.49% diphenylboric acid, a key impurity. S8: 1143 g (3.92 mol) of 12.5% dilute hydrochloric acid was added dropwise to S7 for hydrolysis at a temperature of 30-35°C. After the hydrolysis was complete, the mixture was allowed to stand at 30-35°C to separate the layers. The lower layer (1734.3 g of the magnesium chloride aqueous solution) was removed to obtain 2849.8 g (3131.9 ml) of an oil phase containing p-chlorophenylboronic acid. S8: Add 3131.9 ml of the oil phase obtained in the previous step into an azeotropic distillation kettle (equipped with a 1 m packed tower and glass spring packing), then add 6889.4 ml of water, and slowly distill and azeotropically distill. When the top gas phase reaches 100°C, stop distillation, cool to 30-35°C, and filter to obtain 548.8 g of crude wet product of p-chlorophenylboronic acid; S9: Add 215.5 ml of isobutanol and 4740.8 ml of chlorobenzene to the refining kettle, add 550.6 g of crude p-chlorophenylboric acid from the previous step, heat and reflux for 1 hour, slowly cool to 30-35 ° C and crystallize for 1 hour, then filter and dry the wet product to obtain 430.6 g of p-chlorophenylboric acid with a yield of 67.6% (based on p-dichlorobenzene) and a content of 98.2%.

[0040] Comparative Example 2 The only difference from Example 1 is that: S5: The reaction solution in the previous step is heated to 40°C, and the material temperature is controlled at 40-45°C and p-dichlorobenzene tetrahydrofuran solution is added dropwise. There is a significant exothermic temperature rise phenomenon after 8 minutes of dripping, and the dripping is completed in 5.5 hours. After the dripping is completed, the temperature is continued to be kept for 1 hour, and then the temperature is reduced to room temperature.

[0041] The yield is 51.5% (calculated based on p-dichlorobenzene), and the p-chlorophenylboric acid content is 98.2%.

[0042] Comparative Example 3 The only difference from Example 1 is that: S5: The reaction solution in the previous step is heated to 80°C, and the material temperature is controlled at 80-85°C and p-dichlorobenzene tetrahydrofuran solution is added dropwise. There is an obvious exothermic temperature rise phenomenon after 5 minutes of dripping, and the dripping is completed in 3 hours. After the dripping is completed, the temperature is continued to be kept for 1 hour, and then the temperature is reduced to room temperature.

[0043] The yield is 56.1% (calculated based on p-dichlorobenzene), and the p-chlorophenylboric acid content is 98.0%.

[0044] Comparative Example 4 The only difference from Example 1 is that in step S9, only chlorobenzene (4956.3 ml) is added for recrystallization.

[0045] The yield is 66.8% (calculated based on p-dichlorobenzene), and the p-chlorophenylboric acid content is 96.4%.

[0046] Comparative Example 5 The only difference from Example 1 is that in step S9, only isobutanol (4956.3 ml) is added for recrystallization.

[0047] The yield is 32.8% (calculated based on p-dichlorobenzene), and the p-chlorophenylboric acid content is 98.1%.

[0048] In addition to the above embodiments, the present invention also includes other implementation methods. Any technical solutions formed by equivalent transformation or equivalent replacement should fall within the scope of protection of the claims of the present invention.

Claims

1. A synthesis process for p-chlorophenylboronic acid, characterized in that, The following steps are involved: S1: dissolving p-dichlorobenzene in tetrahydrofuran to obtain a p-dichlorobenzene tetrahydrofuran solution; S2: dissolving an initiator alkyl halide in tetrahydrofuran to obtain an initiator tetrahydrofuran solution; S3: Put magnesium into a Grignard reactor and add tetrahydrofuran to obtain an initial Grignard solution; S4: under certain temperature conditions, the initiator tetrahydrofuran solution is dropped into the initial Grignard solution of S3; S5: Under certain temperature conditions, the tetrahydrofuran solution of p-dichlorobenzene is added dropwise to S4 to carry out a Grignard reaction. After the Grignard reaction is completed, a portion of the Grignard reaction solution is used for the next reaction, and the other portion is retained as an initiator for the next batch reaction; S6: continuously introducing a portion of the Grignard reaction solution and the borate ester into a microchannel reactor according to a certain molar ratio to react; S7: The boronation reaction liquid from the microchannel reactor is dripped into dilute hydrochloric acid for hydrolysis. After hydrolysis, the reaction mixture is allowed to stand for separation and the water layer is removed to obtain an oil phase containing p-chlorophenylboronic acid. S8: adding the oil phase containing p-chlorophenylboronic acid to water for azeotropic distillation to remove the low-boiling point solvent, then cooling and filtering to obtain a crude p-chlorophenylboronic acid product; S9: Recrystallize the crude p-chlorophenylboronic acid to obtain a p-chlorophenylboronic acid product.

2. The synthesis process of p-chlorophenylboronic acid according to claim 1, wherein: The molar ratio of the total amount of tetrahydrofuran used in steps S1 to S3 to p-dichlorobenzene is 4 to 8:1, and the mass concentration of the p-dichlorobenzene tetrahydrofuran solution in step S1 is 10 to 50%.

3. The synthesis process of p-chlorophenylboronic acid according to claim 1, wherein: The initiator alkyl halide in step S2 is one of ethyl bromide, propyl bromide, and isopropyl bromide, and the mass concentration of the initiator tetrahydrofuran solution is 10-30%.

4. The synthesis process of p-chlorophenylboronic acid according to claim 1, wherein: The molar ratio of the initiator alkyl halide to p-dichlorobenzene is 0.01-0.1:1, and the molar ratio of the magnesium to p-dichlorobenzene is 0.9-1:

1.

5. The synthesis process of p-chlorophenylboronic acid according to claim 1, wherein: The mass ratio of magnesium to tetrahydrofuran in step S3 is 1:3-5.

6. The synthesis process of p-chlorophenylboronic acid according to claim 1, wherein: In step S4, the reaction temperature is 10-60° C., and the initiator tetrahydrofuran solution is added dropwise for 0.5-3 h.

7. The synthesis process of p-chlorophenylboronic acid according to claim 1, wherein: In step S5, the reaction temperature is 55-75° C., the time for adding the p-dichlorobenzene tetrahydrofuran solution is 4-8 hours, and the reaction is continued by keeping the temperature for 1 hour after the addition is completed.

8. The synthesis process of p-chlorophenylboronic acid according to claim 1, wherein: In step S6, the reaction temperature is -10 to -30°C, the borate ester is one of trimethyl borate, triethyl borate, triisopropyl borate, tri-n-butyl borate, and triisobutyl borate, and the molar ratio of the borate ester to p-dichlorobenzene is 0.8 to 1:

1.

9. The synthesis process of p-chlorophenylboronic acid according to claim 1, wherein: In step S7, the hydrolysis temperature is 0-60° C., the molar ratio of the dilute hydrochloric acid to the borate ester is 0.95-1.5:1, and the mass concentration of the dilute hydrochloric acid is 5-15%. In step S8, the volume ratio of the oil phase to water during azeotropic distillation is 1:1-5.

10. The synthesis process of p-chlorophenylboronic acid according to claim 1, wherein: The recrystallization solvent used for recrystallization in step S9 is a mixed component of an alcohol and a benzene solvent, the alcohol solvent is one of methanol, ethanol, propanol, and butanol, the benzene solvent is one of benzene, chlorobenzene, toluene, and xylene, and the volume ratio of the alcohol solvent to the benzene solvent is 1:10 to 30; the weight ratio of the recrystallization solvent to the crude p-chlorophenylboric acid is 5 to 15:1.