Method for synthesizing 5-bromo-2-chlorobenzoic acid by adopting microchannel reaction device

Abstract

The invention relates to the fields of chemistry and chemical engineering, organic synthesis and medicinal chemistry, in particular to a method for synthesizing 5-bromo-2-chlorobenzoic acid by adopting a microchannel reaction device. The method comprises the following steps: I, mixing 2-chlorobenzoic acid and sulfuric acid to obtain a reaction solution A; mixing bromine, sodium periodate, liquid organic acid and water to obtain a reaction solution B; and II, feeding the reaction liquid A and the reaction liquid B into a micro mixer of a micro-channel reaction device for mixing, then feeding the mixture into a micro reactor of the micro-channel reaction device for contact reaction, and carrying out post-treatment on contact reaction effluent to obtain the 5-bromo-2-chlorobenzoic acid. The method has the advantages of high product selectivity, high yield, high purity, convenient process, low production cost, and less by-product and three-waste pollution.

Description

Technical Field

[0001] This invention relates to the fields of chemical engineering, organic synthesis, and medicinal chemistry, and specifically to a method for synthesizing 5-bromo-2-chlorobenzoic acid using a microchannel reaction apparatus. Background Technology

[0002] 5-Bromo-2-chlorobenzoic acid is an important structural intermediate for many drugs, such as etagliflozin, dapagliflozin, and empagliflozin. Dapagliflozin, as the first pharmaceutically significant sodium-dependent glucose transporter 2 (SGLT2) inhibitor, targets the reabsorption of glucose in the renal tubules and is a novel drug for treating type 2 diabetes. It boasts advantages such as good tolerability, high safety, sustained and stable blood glucose control, and few side effects, showing broad application prospects. 5-Bromo-2-chlorobenzoic acid, as a common upstream raw material for the synthesis of SGLT2 inhibitors like dapagliflozin, has a huge market demand.

[0003] Currently, there are numerous reports and patents regarding the preparation of 5-bromo-2-chlorobenzoic acid. The most atom-economical and cost-effective route is the site-selective bromination of 2-chlorobenzoic acid to obtain the target product. However, due to the presence of strong electron-withdrawing groups on the benzene ring, the bromination process often suffers from low substrate activity and uncontrollable side reactions. This inevitably leads to the formation of isomers such as 3-bromo-2-chlorobenzoic acid, 4-bromo-2-chlorobenzoic acid, and disubstituted 2-chlorobenzoic acid, resulting in demanding reaction conditions and cumbersome post-processing, significantly increasing synthesis costs and hindering industrial-scale production.

[0004] CN104744227A reports a method for obtaining 5-bromo-2-chlorobenzoic acid by monobromination in an N-bromosuccinimide (NBS) / sulfuric acid system. This method has a simple reaction process, readily available raw materials, and improves the selectivity of the bromination process of 2-chlorobenzoic acid. However, the selectivity of 5-bromo-2-chlorobenzoic acid is generally only 60-70%, and about 10% of 4-bromo-2-chlorobenzoic acid impurities are still generated. These impurities have similar polarity to the product and are difficult to remove by conventional methods. Often, multiple recrystallizations are required to obtain a product with ideal purity, resulting in a low product yield and affecting production applications.

[0005] CN110002989B also uses 2-chlorobenzoic acid as a raw material to prepare 5-bromo-2-chlorobenzoic acid by bromination in an NBS / sulfuric acid system. The difference is that a reducing sulfur salt is added during the reaction to inhibit the production of 4-bromo-2-chlorobenzoic acid, thereby improving the regioselectivity of bromination. However, the process generates a large amount of solid waste salt.

[0006] CN110590541A discloses a method for preparing 5-bromo-2-chlorobenzoic acid using 2-chlorobenzoic acid and bromine as raw materials, with the participation of one or more catalysts such as metallic iron, aluminum, zinc, niobium, or boron trifluoride and trifluoromethanesulfonate, as well as organic solvents. This synthesis method is time-consuming, often requiring more than 48 hours, and the post-processing requires the introduction of hydrochloric acid and other organic solvents. The yield is less than 80%, the synthesis process is relatively complex, and the cost of treating the three wastes is high.

[0007] CN112979448B uses 2-chlorobenzoic acid as a raw material, a haloalkane as a solvent system, ferric trifluoromethanesulfonate as a catalyst, and dibromoamino silica gel as a brominating agent to prepare 5-bromo-2-chlorobenzoic acid. In this method, the dibromoamino silica gel can be recycled, with a recovery rate of 98% after six cycles. However, the synthesis method of dibromoamino silica gel is relatively complex, increasing production costs and making it unsuitable for process scale-up.

[0008] The preparation methods for 5-bromo-2-chlorobenzoic acid disclosed in CN110105193B, CN110590541A, CN111620778A, and CN111925289A do not show substantial improvement compared to the aforementioned disclosed technologies. The defects such as large emissions of waste, low yield, and low product purity during the process have not been completely resolved. Summary of the Invention

[0009] The purpose of this invention is to overcome the problems of low selectivity, numerous byproducts, low product purity, harsh reaction conditions, complex processes, and large amounts of waste in existing technologies, and to provide a method for synthesizing 5-bromo-2-chlorobenzoic acid using a microchannel reaction device, which has high product selectivity, yield, and purity, convenient process, low production cost, and less byproducts and waste pollution.

[0010] Microreactors offer advantages such as large specific surface area, small real-time online flow rate, continuous fluid flow, high mass and heat transfer efficiency, easy process control, and fewer side reactions. This invention utilizes the advantages of microreactors by applying the reaction system to a microreactor, thereby reducing byproducts in the synthesis of 5-bromo-2-chlorobenzoic acid and facilitating industrial-scale production.

[0011] According to a first aspect of the present invention, a method for synthesizing 5-bromo-2-chlorobenzoic acid using a microchannel reaction apparatus is provided, comprising the following steps:

[0012] Step I: Mix 2-chlorobenzoic acid with sulfuric acid to obtain reaction solution A; mix bromine, sodium periodate, liquid organic acid, and water to obtain reaction solution B;

[0013] Step II: Reactant solution A and reactant solution B are fed into the micromixer of the microchannel reaction device for mixing, and then into the microreactor of the microchannel reaction device for contact reaction. The effluent from the contact reaction is post-treated to obtain 5-bromo-2-chlorobenzoic acid.

[0014] The method for synthesizing 5-bromo-2-chlorobenzoic acid provided by this invention has the advantages of high product selectivity, high yield and purity, simple, fast and economical production, and low by-products and environmental pollution. Attached Figure Description

[0015] Figure 1 This is a schematic diagram of the synthesis route using a microchannel reaction device;

[0016] Figure 2 This is a diagram of an actual microchannel reaction device;

[0017] Figure 3 This is the 1H NMR spectrum of 5-bromo-2-chlorobenzoic acid in Example 1;

[0018] Figure 4 This is the carbon spectrum of 5-bromo-2-chlorobenzoic acid in Example 1;

[0019] Figure 5 This is a liquid phase diagram of the synthesis of 5-bromo-2-chlorobenzoic acid in Example 1.

[0020] Explanation of reference numerals in the attached figures

[0021] A1—Pump A1; B2—Pump B2; 3—Micromixer; 4—Microreactor; 5—Receiving device. Detailed Implementation

[0022] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the invention. The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values; these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0023] This invention provides a method for synthesizing 5-bromo-2-chlorobenzoic acid using a microchannel reaction apparatus, comprising the following steps:

[0024] Step I: Mix 2-chlorobenzoic acid with sulfuric acid to obtain reaction solution A; mix bromine, sodium periodate, liquid organic acid, and water to obtain reaction solution B;

[0025] Step II: Reactant solution A and reactant solution B are fed into the micromixer of the microchannel reaction device for mixing, and then into the microreactor of the microchannel reaction device for contact reaction. The effluent from the contact reaction is post-treated to obtain 5-bromo-2-chlorobenzoic acid.

[0026] The method for synthesizing 5-bromo-2-chlorobenzoic acid with the above characteristics has the advantages of high product selectivity, high yield and purity, convenient process, low production cost, and less by-products and pollution.

[0027] In this invention, the concentration of 2-chlorobenzoic acid in reaction solution A can be selected within a wide range. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the concentration of 2-chlorobenzoic acid in reaction solution A is 0.1 to 1 mol / L, preferably 0.15 to 0.5 mol / L, for example, it can be 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, 0.5 mol / L, 0.6 mol / L, 0.7 mol / L, 0.8 mol / L, or 0.9 mol / L.

[0028] In this invention, the concentration of bromine in reaction solution B can be selected within a wide range. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the concentration of bromine in reaction solution B is 0.05–0.5 mol / L, preferably 0.1–0.25 mol / L, for example, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, or 0.4 mol / L.

[0029] In this invention, the concentration of sodium periodate in reaction solution B can be selected within a wide range. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the concentration of sodium periodate in reaction solution B is 0.05–0.5 mol / L, preferably 0.1–0.25 mol / L, for example, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, or 0.4 mol / L.

[0030] In this invention, the molar ratio of 2-chlorobenzoic acid, bromine, and sodium periodate can be selected within a wide range. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the molar ratio of 2-chlorobenzoic acid, bromine, and sodium periodate is 1:0.5 to 2:0.25 to 1, preferably 1:0.5 to 1:0.25 to 0.5.

[0031] In this invention, the amount of liquid organic acid used can be selected within a wide range. The following is an illustrative description, but it does not limit the scope of this invention. According to a preferred embodiment of the invention, the molar ratio of 2-chlorobenzoic acid to liquid organic acid is 1:50 to 70, preferably 1:50 to 60, for example, it can be 1:53, 1:56, 1:59, 1:62, 1:65, or 1:68.

[0032] In this invention, the amount of sulfuric acid used can be selected within a wide range. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the concentration of sulfuric acid, based on the total mass of reaction solution A and reaction solution B, is 62.4–69.8 wt%, preferably 64.5–68 wt%.

[0033] The amount and ratio of raw materials with the above characteristics can further improve product selectivity, yield and purity, and reduce by-products and pollution from waste.

[0034] In this invention, a wide range of liquid organic acids can be selected. The following examples are illustrative but do not limit the scope of the invention. According to a preferred embodiment of the invention, the liquid organic acid is selected from one or more of acetic acid and formic acid.

[0035] Liquid organic acids with the above characteristics can improve product selectivity, yield and purity, reduce by-products and pollution from waste, and at the same time reduce pipeline pressure and improve equipment safety in the synthesis process.

[0036] In this invention, the flow rate of reaction solution A entering the microchannel reaction device can be selected over a wide range. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the flow rate of reaction solution A entering the microchannel reaction device is 0.2 to 1.5 mL / min, preferably 0.47 to 1.01 mL / min.

[0037] In this invention, the flow rate of reaction solution B entering the microchannel reaction device can be selected over a wide range. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the flow rate of reaction solution B entering the microchannel reaction device is 0.2 to 1 mL / min, preferably 0.38 to 0.8 mL / min.

[0038] In this invention, the model of the micro mixer in step II is not particularly required and can be selected by those skilled in the art as needed. According to a preferred embodiment of the invention, the model of the micro mixer is selected from T-type, Y-type, or inverted Y-type, preferably Y-type.

[0039] In this invention, the tubing diameter of the micromixer in step II can be selected from a wide range, as illustrated below, but this does not limit the scope of the invention. According to a preferred embodiment of the invention, the tubing diameter of the micromixer is 0.5–4 mm, preferably 0.5–2 mm.

[0040] In this invention, the reaction temperature of the contact reaction in the microreactor in step II can be selected over a wide range, as illustrated below, but this does not limit the scope of the invention. According to a preferred embodiment of the invention, the reaction temperature of the contact reaction in the microreactor is 25–80°C, preferably 40–50°C.

[0041] In this invention, in step II, the residence time of the reaction solution in the microreactor for the contact reaction can be selected within a wide range. The following is an illustrative example, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the residence time of the reaction solution in the microreactor for the contact reaction is 5–15 min, preferably 9.4–13.8 min.

[0042] In this invention, the type of microreactor in step II is not particularly required and can be selected by those skilled in the art as needed. According to a preferred embodiment of this invention, the type of microreactor is selected from a tubular reactor or a heart-shaped reactor, preferably a tubular reactor.

[0043] In this invention, the volume of the microreactor in step II can be selected from a wide range, as illustrated below, but this does not limit the scope of the invention. According to a preferred embodiment of the invention, the volume of the microreactor is 4–40 mL, preferably 8–25 mL.

[0044] In this invention, the diameter of the microreactor's tubing in step II can be selected within a wide range. The following is an illustrative example, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the tubing diameter of the microreactor is 0.5–4 mm, preferably 0.5–2 mm. While microreactors with tubing diameters smaller than the above range can effectively increase the specific surface area, they can lead to an increase in liquid flow pressure, causing blockages, tubing ruptures, and other adverse conditions.

[0045] In this invention, the post-treatment method in step II has a wide range of options. Any post-treatment that can separate 5-bromo-2-chlorobenzoic acid from the contact reaction effluent can achieve the purpose of this invention. According to a preferred embodiment of this invention, the post-treatment includes: cooling, solid-liquid separation, drying, and recrystallization.

[0046] In this invention, a wide range of cooling methods can be selected. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the cooling method is to directly flow the contact reaction effluent into ice water to quench the precipitation, wherein the amount of ice water used per gram of contact reaction effluent is 15-20 mL.

[0047] In this invention, the range of solvent combinations used for recrystallization is relatively wide. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the solvent combination used for recrystallization is selected from one or more of acetic acid and water, toluene and water, methanol and water, and ethanol and water. Preferably, it is selected from one or more of the following: acetic acid and water in a volume ratio of 1:1.4 to 1.6, toluene and water in a volume ratio of 1:1.4 to 1.6, methanol and water in a volume ratio of 1:1.4 to 1.6, and ethanol and water in a volume ratio of 1:1.4 to 1.6.

[0048] In this invention, there are no special requirements for the number of recrystallizations, which can be determined by those skilled in the art based on the required purity of the product, and are not limited in this invention. In the embodiments and comparative examples of this invention, the number of recrystallizations is 1.

[0049] In this invention, the connection methods of the microchannel reaction device have a wide range of options, and those skilled in the art can design the connection methods according to their needs. According to a preferred embodiment of the invention, the microchannel reaction device includes pump A1, pump B2, a micromixer, and a microreactor. Pump A1 and pump B2 are connected in parallel to the micromixer via connecting pipes, and the micromixer and microreactor are connected in series via connecting pipes. Preferably, raw material storage tanks are connected before pump A1 and pump B2, and a product receiving device 5 is connected after the microreactor. The microchannel reaction device with the above features can achieve continuous operation.

[0050] In this invention, the types of pumps A1 and B2 can be selected from a wide range. The following is an illustrative description, but it does not limit the scope of this invention. According to a preferred embodiment of the invention, pumps A1 and B2 are low-pulsation and acid- and corrosion-resistant pumps, preferably PTFE injection pumps.

[0051] In this invention, the diameter of the connecting tube can be selected from a wide range. The following is an illustrative description, but it does not limit the scope of the invention. According to a preferred embodiment of the invention, the diameter of the connecting tube is 0.5 to 4 mm, preferably 0.5 to 2 mm.

[0052] In this invention, the length of the connecting tube can be selected from a wide range, as illustrated below, but this does not limit the scope of the invention. According to a preferred embodiment of the invention, the length of the connecting tube is 10–70 cm, preferably 10–40 cm.

[0053] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various specific technical features in any suitable manner. To avoid unnecessary repetition, the present invention will not describe the various possible combinations separately. However, these simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

[0054] The present invention will be described in detail below through embodiments. It should be noted that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above description.

[0055] For any experimental steps or conditions not specified in the examples and comparative examples, the procedures and conditions described in the literature in this field can be followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0056] A. Source of raw materials for the example

[0057] 2-Chlorobenzoic acid, purity ≥99%, from Shanghai Bid Pharmaceutical Technology Co., Ltd.;

[0058] Concentrated sulfuric acid, analytical grade, from Nanjing Wanqing Chemical Glassware Co., Ltd.

[0059] Bromine, purity ≥99.5%, from Nanjing Wanqing Chemical Glassware Co., Ltd.

[0060] Sodium periodate, purity ≥99%, from Shanghai Bid Pharmaceutical Technology Co., Ltd.;

[0061] Acetic acid, purity ≥99%, from Nanjing Haitai Scientific Instruments Co., Ltd.

[0062] B. Reaction apparatus

[0063] The microchannel reaction device used in this embodiment is shown in the schematic diagram. Figure 1 Among them, pumps A1 and B1 are PTFE injection pumps; micromixer 3 is a Y-type with a pipe diameter of 0.8 mm; microreactor 4 is a tubular reactor with a volume of 15 mL, a pipe diameter of 0.8 mm, a connecting pipe diameter of 0.8 mm, and a length of 40 mm; the actual diagram is shown below. Figure 2 Raw material A is fed by feed pump 1, and raw material B is fed by feed pump 2. The two raw materials enter the micro mixer through the mixing three-way valve, and then enter the micro reactor, and are collected by the product collector.

[0064] C. Effectiveness Evaluation Methods

[0065] The instruments used for proton and carbon NMR spectroscopy were both NMR spectrometers from Bruker GmbH, Germany. Sample preparation method: 20–50 mg of the product was dissolved in deuterated chloroform. The dissolved product was transferred to an NMR tube and placed in the NMR spectrometer. Automated analysis was performed using the built-in detection methods of the NMR spectrometer, followed by NMR analysis using MestReNova software. The yield was calculated as follows:

[0066] Product yield = Actual product mass / Theoretical mass * 100%.

[0067] The instrument for the liquid chromatography test was from Agilent Technologies, Inc., USA. The test method was as follows: a certain amount of reaction solution was taken, diluted with acetonitrile and water (volume ratio 1:1), filtered through an organic filter head using a 1mL syringe, and injected into a 2mL vial. The test was performed according to the detection method provided with the instrument.

[0068] Example 1

[0069] Reaction solution A: 0.78 g (5 mmol) of 2-chlorobenzoic acid, 25 mL of concentrated sulfuric acid. Reaction solution B: 0.39 g (2.5 mmol) of bromine, 0.54 g (2.5 mmol) of sodium periodate, 15 mL of acetic acid, 5 mL of water.

[0070] In the microchannel reaction device, according to Figure 1 As shown in the process, reaction solution A is pumped into micromixer 3 by pump A1 at a flow rate of 0.84 mL / min, and reaction solution B is pumped into micromixer 3 by pump B2 at a flow rate of 0.67 mL / min. After thorough mixing, the reaction solutions enter microreactor 4, where the reaction temperature is 50°C and the residence time is 10 min. The reaction solution is collected in receiving device 5, which is a container filled with ice water. The amount of ice water used is 13.3 mL per gram of reaction effluent. After filtration and drying, 3.9 mL of acetic acid and 5.9 mL of water are added. The solution is heated until it becomes clear, then allowed to cool naturally, filtered, and dried to obtain 5-bromo-2-chlorobenzoic acid. The yield is 95.2%. Figure 3 This is the 1H NMR spectrum of 5-bromo-2-chlorobenzoic acid from Example 1. Figure 4 This is the carbon spectrum of 5-bromo-2-chlorobenzoic acid from Example 1. Figure 3 , Figure 4 The product synthesized in Example 1 is 5-bromo-2-chlorobenzoic acid; Figure 5 This is the liquid phase diagram of the synthesis of 5-bromo-2-chlorobenzoic acid in Example 1. Figure 5 This indicates that the purity of the synthesized 5-bromo-2-chlorobenzoic acid is 99.774%. The proton NMR, carbon NMR, and liquid chromatography results of the following examples are similar to those of Example 1 and will not be repeated.

[0071] Example 2

[0072] The method was followed in Example 1, except that the flow rate of pump A1 was 0.47 mL / min and the flow rate of pump B2 was 0.38 mL / min. The yield was 90.8%.

[0073] Example 3

[0074] The method was followed in Example 1, except that the flow rate of pump A1 was 1.01 mL / min and the flow rate of pump B2 was 0.80 mL / min. The yield was 91.7%.

[0075] Example 4

[0076] The method was followed as in Example 1, except that the 3.9 mL of acetic acid and 5.9 mL of water in the recrystallization were replaced with 3.9 mL of methanol and 5.9 mL of water. The yield was 85.0%.

[0077] Example 5

[0078] The method was followed as in Example 1, except that the 3.9 mL of acetic acid and 5.9 mL of water in the recrystallization were replaced with 3.9 mL of ethanol and 5.9 mL of water. The yield was 83.2%.

[0079] Example 6

[0080] The method was followed as in Example 1, except that the 3.9 mL of acetic acid and 5.9 mL of water in the recrystallization were replaced with 3.9 mL of toluene and 5.9 mL of water. The yield was 78.6%.

[0081] Example 7

[0082] The method was followed in Example 1, except that the amount of bromine used was 0.78 g (5 mmol), and the amount of sodium periodate used was 0.30 g (1.4 mmol). The yield was 76.2%.

[0083] Example 8

[0084] The method was followed in Example 1, except that 30 mL of concentrated sulfuric acid was used. The yield was 77.3%.

[0085] Example 9

[0086] The method was followed as in Example 1, except that 15 mL of acetic acid was replaced with 15 mL of formic acid. The yield was 83.1%.

[0087] Example 10

[0088] The method was followed as in Example 1, except that 15 mL of acetic acid was replaced with 7.5 mL of acetic acid and 7.5 mL of formic acid. The yield was 87.4%.

[0089] Example 11

[0090] The method was followed in Example 1, except that the reaction temperature of the reaction solution in microreactor 4 was 70°C. The yield was 77.1%.

[0091] Example 12

[0092] The method was followed in Example 1, except that the residence time of the reaction solution in microreactor 4 was 5 minutes. The yield was 78.6%.

[0093] Comparative Example 1

[0094] This comparative experiment was conducted in a round-bottom flask. 15 mL of acetic acid and 5 mL of water were added to the round-bottom flask, and stirring was started. Then, 0.78 g (5 mmol) of 2-chlorobenzoic acid, 0.39 g (2.5 mmol) of bromine, and 0.54 g (2.5 mmol) of sodium periodate were added to the round-bottom flask. After heating to 50 °C, 25 mL of concentrated sulfuric acid was slowly added dropwise to the round-bottom flask, and the mixture was kept at this temperature for 3 hours after the addition was complete. After the reaction was complete, the mixture was quenched with 13.3 mL of ice water, filtered, and dried. 3.9 mL of acetic acid and 5.9 mL of water were added to the crude product, and the mixture was heated until the solution became clear. After natural cooling, the solution was filtered, dried, and 5-bromo-2-chlorobenzoic acid was obtained. The yield was 75.8%.

[0095] Comparative Example 2

[0096] The method was followed as in Example 1, except that 15 mL of acetic acid in reaction solution B was replaced with reaction solution A. The yield was 40.3%.

Claims

1. A method for synthesizing 5-bromo-2-chlorobenzoic acid using a microchannel reaction apparatus, characterized in that, Includes the following steps: Step I: Mix 2-chlorobenzoic acid with sulfuric acid to obtain reaction solution A; mix bromine, sodium periodate, liquid organic acid, and water to obtain reaction solution B; Step II: Reactant solution A and reactant solution B are fed into the micromixer of the microchannel reaction device for mixing, and then into the microreactor of the microchannel reaction device for contact reaction. The effluent from the contact reaction is post-treated to obtain 5-bromo-2-chlorobenzoic acid.

2. The method according to claim 1, wherein, In step I, The concentration of 2-chlorobenzoic acid in the reaction solution A is 0.1–1 mol / L, preferably 0.15–0.5 mol / L; and / or The concentration of bromine in the reaction solution B is 0.05–0.5 mol / L, preferably 0.1–0.25 mol / L; and / or The concentration of sodium periodate in the reaction solution B is 0.05–0.5 mol / L, preferably 0.1–0.25 mol / L; and / or The molar ratio of 2-chlorobenzoic acid, bromine, and sodium periodate is 1:0.5–2:0.25–1, preferably 1:0.5–1:0.25–0.5; and / or The molar ratio of 2-chlorobenzoic acid to liquid organic acid is 1:50–70, preferably 1:50–60; and / or The concentration of sulfuric acid is 62.4–69.8 wt%, preferably 64.5–68 wt%, based on the total mass of reaction solution A and reaction solution B.

3. The method according to claim 1 or 2, wherein, In step I, the liquid organic acid is selected from one or more of acetic acid and formic acid.

4. The method according to any one of claims 1-3, wherein, In step II, The flow rate of the reaction solution A input to the microchannel reaction device is 0.2–1.5 mL / min, preferably 0.47–1.01 mL / min; and / or The flow rate of the reaction solution B input into the microchannel reaction device is 0.2–1 mL / min, preferably 0.38–0.8 mL / min.

5. The method according to any one of claims 1-4, wherein, In step II, the mixing conditions in the micro mixer include: The micro mixer model is selected from T-type, Y-type, or inverted Y-type, preferably Y-type; and / or The pipe diameter of the micro mixer is 0.5–4 mm, preferably 0.5–2 mm.

6. The method according to any one of claims 1-5, wherein, In step II, the reaction conditions for the contact reaction include: The reaction temperature in the microreactor is 25–80 °C, preferably 40–50 °C; and / or The residence time of the reaction solution in the microreactor is 5–15 min, preferably 9.4–13.8 min; and / or The microreactor model is selected from either a tubular reactor or a heart-shaped reactor, preferably a tubular reactor; and / or The volume of the microreactor is 4–40 mL, preferably 8–25 mL; and / or When the microreactor is a tubular reactor, the diameter of the tubing is 0.5–4 mm, preferably 0.5–2 mm.

7. The method according to any one of claims 1-6, wherein, In step II, the post-processing includes: cooling, solid-liquid separation, drying, and recrystallization.

8. The method according to claim 7, wherein, The cooling method involves directly quenching the effluent from the contact reaction in ice water to quench the precipitation. The amount of ice water used per gram of contact reaction effluent is 15-20 mL.

9. The method according to claim 7, wherein, The combined solvent used for recrystallization is one or more of the following: acetic acid and water, toluene and water, methanol and water, and ethanol and water. Preferably, The volume ratio of acetic acid to water is 1:1.4–1.6; and / or The volume ratio of toluene to water is 1:1.4–1.6; and / or The volume ratio of methanol to water is 1:1.4 to 1.6; and / or The volume ratio of ethanol to water is 1:1.4 to 1.

6.

10. The method according to any one of claims 1-9, wherein, The microchannel reaction device includes a pump (A1), a pump (B2), a micro mixer (3), and a microreactor (4). The pump (A1) and the pump (B2) are connected in parallel to the micro mixer (3) via connecting pipes, and the micro mixer (3) and the microreactor (4) are connected in series via connecting pipes. Preferably, Pump (A1) and / or pump (B2) are low-pulsation and acid / corrosion resistant pumps, more preferably PTFE injection pumps; and / or The diameter of each of the aforementioned connecting pipes is 0.5–4 mm, more preferably 0.5–2 mm; and / or The length of each of the connecting tubes is 10 to 70 cm, more preferably 10 to 40 cm.

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