A continuous flow microchannel synthesis of o-hydroxybenzoic acid and derivatives thereof

Abstract

This application relates to the technical field of organic synthesis, specifically disclosing a continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives. The continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives disclosed in this application employs an integrated microchannel reactor and includes the following steps: using phenol or its derivatives as raw materials, a phenolate reaction is carried out with an alkali metal hydroxide solution in a first microchannel to obtain intermediate 1; CO2 is introduced into intermediate 1, and a carboxylation reaction is carried out in a second microchannel to obtain intermediate 2; intermediate 2 is reacted with a dilute acid solution in a third microchannel to obtain a crude solution; the crude solution is carried into a fourth microchannel for crystallization to obtain the target crystalline form; and the target crystalline form is carried into a fifth microchannel for post-processing to obtain the target product. The synthesis method employed in this application, through continuous reaction, significantly improves the synthesis efficiency and allows for online control of the crystal form.

Description

Technical Field

[0001] This application relates to the technical field of organic synthesis, specifically to a continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives. Background Technology

[0002] o-hydroxybenzoic acid (salicylic acid) and its derivatives are key intermediates in the fields of pharmaceuticals, antioxidants, and toner charge control agents, and their market demand continues to grow. However, the batch reactor process commonly used in current industrial production has a series of technical bottlenecks that restrict the improvement of product quality and cost optimization, specifically in the following three aspects: (1) The process flow is dispersed, and efficiency and purity are limited. Traditional processes usually complete key steps such as carboxylation, acidification, and crystallization in multiple independent devices, and materials need to be frequently transferred between reactors, acidification tanks, and crystallizers. This process not only increases the complexity of operation, but also significantly introduces the risk of contamination by foreign impurities, affecting the purity of the product. At the same time, each step of the reaction cycle is long, and the reaction time is usually more than 2 hours, resulting in low equipment utilization and low overall production efficiency, making it difficult to meet the large-scale and continuous market demand. (2) Crystal form control is difficult, and product performance is unstable. The application performance of the target product is highly dependent on its crystal form. In the crystallization process of batch production, the control precision of key parameters such as temperature curves and stirring rates is insufficient, which easily causes fluctuations in crystallization conditions between batches. This directly leads to poor crystal form consistency in products, such as a difference of 0.5-1.0° in the characteristic peak shift in X-ray diffraction patterns. Fluctuations in crystal form and particle size will seriously affect downstream applications, ultimately resulting in unstable performance of end products. (3) Lagging process control leads to high energy consumption and costs. Batch reactions are batch operations, and the control of key process parameters such as temperature and pressure has obvious lag, making it impossible to achieve instantaneous and precise following of set values. This control defect not only affects the selectivity and yield of the reaction, but also leads to energy waste. Related studies have shown that the comprehensive energy consumption of batch reactions in the process of heating, cooling, and pressure maintenance is usually more than 30% higher than that of advanced continuous production processes, which greatly weakens the cost competitiveness of products in the context of high energy prices.

[0003] In summary, existing batch processes face severe challenges in terms of production efficiency, product quality stability, and energy costs. Developing continuous, automated, and precisely controllable new production processes has become an inevitable direction for improving the technological level and enhancing the core competitiveness of the o-hydroxybenzoic acid and its derivatives industry. Summary of the Invention

[0004] To address the aforementioned technical problems, this application provides a continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives.

[0005] In a first aspect, this application provides a continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives, employing an integrated microchannel reactor to sequentially complete phenolation reaction, carboxylation reaction, acidification reaction, crystallization treatment, and post-treatment, including the following steps: (1) Using phenol or its derivatives as raw materials, a phenolate reaction is carried out by introducing an alkali metal hydroxide solution into the first microchannel. The temperature is controlled at 63-77℃, the pressure at 0.3-0.5MPa, and the reaction time at 2-3min to obtain intermediate 1. (2) CO2 is introduced into intermediate 1 and carboxylation reaction is carried out in the second microchannel. The temperature is controlled at 78-92℃, the pressure is 1.2-1.6MPa, and the reaction time is 3-4min to obtain intermediate 2. (3) Pass intermediate 2 and dilute acid solution into the third microchannel for acidification reaction, control the temperature at 38-52℃, the pressure at 0.2-0.3MPa, and the reaction time at 2-3min to obtain crude product solution; (4) The crude product solution is passed into the fourth microchannel for crystallization treatment, and the target crystalline substance is obtained by cooling. (5) The target crystalline material is passed into the fifth microchannel for post-processing. After separation, washing and drying, the target product is obtained.

[0006] The purpose of this application is to provide a continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives, which realizes continuous phenolation, carboxylation, acidification and crystallization through an integrated microchannel reactor, and simultaneously controls the crystal form online, thereby solving the problems of low efficiency and large crystal form fluctuation in existing processes.

[0007] Preferably, in step (1), the alkali metal hydroxide solution is a sodium hydroxide solution with a mass concentration of 15-25%.

[0008] Preferably, in step (1), the temperature is controlled at 65-75℃, the pressure at 0.35-0.45MPa, and the flow rate at 5-8mL / min.

[0009] In a specific implementation scheme, in step (1), the temperature can be 65℃, 70℃, 75℃, the pressure can be 0.35MPa, 0.4MPa, 0.45MPa, and the flow rate can be 5mL / min, 6mL / min, 7mL / min, 8mL / min.

[0010] Preferably, in step (2), the temperature is controlled at 80-90℃, the pressure at 1.3-1.5MPa, the flow rate at 3-5mL / min, and the CO2 flow rate at 5-20mL / min.

[0011] In a specific implementation scheme, in step (2), the temperature can be 80℃, 85℃, or 90℃; the pressure can be 1.3MPa, 1.4MPa, or 1.5MPa; the flow rate can be 3mL / min, 4mL / min, or 5mL / min; and the CO2 flow rate can be 5mL / min, 10mL / min, 15mL / min, or 20mL / min.

[0012] Preferably, in step (3), the dilute acid solution is a hydrochloric acid solution with a mass concentration of 10-15%.

[0013] Preferably, in step (3), the temperature is controlled at 40-50℃, the pressure at 0.22-0.28MPa, and the flow rate at 4-6mL / min.

[0014] In a specific implementation, in step (3), the temperature can be 40℃, 45℃, or 50℃, the pressure can be 0.22MPa, 0.25MPa, or 0.28MPa, and the flow rate can be 4mL / min, 5mL / min, or 6mL / min.

[0015] Preferably, when the target product is 3,5-di-tert-butylsalicylic acid, the raw material is 2,4-di-tert-butylphenol; in the method for preparing the target product 3,5-di-tert-butylsalicylic acid, the process parameters for crystallization treatment in step (4) are: the temperature is gradually reduced from 40-50℃ to 5-8℃ at a cooling rate of 0.5-3℃ / min, while the flow rate is controlled at 2-3mL / min and the stirring frequency is 500-800rpm.

[0016] Secondly, this application provides a 3,5-di-tert-butylsalicylic acid, prepared using the aforementioned synthesis method; the X-ray diffraction characteristic peaks of the 3,5-di-tert-butylsalicylic acid are: 2θ=9.8±0.2°, 17.2±0.2°, 21.5±0.2°; or the X-ray diffraction characteristic peaks of the 3,5-di-tert-butylsalicylic acid are: 2θ=10.1±0.2°, 18.3±0.2°, 19.1±0.2°; the 3,5-di-tert-butylsalicylic acid has a crystallinity ≥95%, a thermal decomposition temperature ≥230℃, and a solubility rate ≥0.8g / min in water at 25℃.

[0017] Thirdly, this application provides an integrated microchannel reactor for the synthesis of o-hydroxybenzoic acid and its derivatives, characterized in that the integrated microchannel reactor comprises a phenolation module, a carboxylation module, an acidification module, a crystallization module, and a post-treatment module connected in series, wherein the inner diameter of the microchannel in each module is 200-300 μm and the channel length is 1.2-1.5 m, and the parameters between modules are independently controlled by corrosion-resistant valves; the temperature, pressure, and flow rate of each module are independently controlled by a PLC system.

[0018] Preferably, the crystallization module incorporates a temperature sensor and an online XRD detector to achieve real-time feedback control of the crystal form. The technical solution of this application utilizes modular integration: the phenolic salting, carboxylation, acidification, crystallization, and post-treatment modules are connected in series, and the materials flow and react continuously in the microchannel, with a total process time of ≤15min.

[0019] The technical solution of this application can achieve precise parameter control: the temperature, pressure and flow rate of each microchannel module are independently adjusted by the PLC system, with a control accuracy of ±0.5℃ and ±0.01MPa; The technical solution of this application can realize online control of crystal form: the crystallization module has a built-in XRD detector to provide real-time feedback of crystal form characteristic peaks, and the target crystal form (new crystal form or conventional crystal form) can be precisely controlled by adjusting the cooling rate and stirring frequency.

[0020] In summary, the technical solution of this application has the following effects: The continuous flow microchannel synthesis method used in this application greatly improves the synthesis efficiency: the total reaction time is shortened from 2 hours in the traditional batch process to less than 15 minutes, and the production efficiency is increased by 8 times.

[0021] The synthesis method used in this application makes the crystal form controllable: by adjusting the crystallization parameters online, the crystal form can be controlled in real time; among them, 3,5-di-tert-butylsalicylic acid can achieve precise switching between the novel crystal form and the conventional crystal form with small crystal form consistency error.

[0022] The synthesis method used in this application optimizes the performance: the product purity of 3,5-di-tert-butylsalicylic acid is ≥99.6%, the crystallinity is ≥95%, the thermal stability is improved by 12%, and the performance fluctuation of downstream applications (such as toner charge control agents) is ≤5%.

[0023] The synthesis method used in this application has the advantages of being green and energy-saving: the energy consumption of the microchannel process is reduced by 35%, the solvent recovery rate is ≥95%, and it meets the requirements of clean production. Attached Figure Description

[0024] Figure 1 The image shows the XRD pattern of the novel crystal form of the target product 3,5-di-tert-butylsalicylic acid in Example 1.

[0025] Figure 2 The image shows the XRD pattern of the conventional crystal form of the target product 3,5-di-tert-butylsalicylic acid in Example 2. Detailed Implementation

[0026] The present application will be further described in detail below with reference to embodiments, comparative examples and performance test results. These embodiments should not be construed as limiting the scope of protection claimed in this application.

[0027] Example

[0028] Example 1

[0029] Example 1 provides a continuous flow microchannel synthesis method for o-hydroxybenzoic acid derivatives.

[0030] In this embodiment, the target product is 3,5-di-tert-butylsalicylic acid, and the raw material is 2,4-di-tert-butylphenol.

[0031] This embodiment uses an integrated microchannel reactor for the synthesis of o-hydroxybenzoic acid derivatives (3,5-di-tert-butylsalicylic acid), comprising a phenolation module, a carboxylation module, an acidification module, a crystallization module, and a post-treatment module connected in series. Each module has a microchannel inner diameter of 250 μm and a channel length of 1.5 m. Parameters between modules are independently controlled via corrosion-resistant valves. The temperature, pressure, and flow rate of each module are independently controlled by a PLC system. The crystallization module incorporates a temperature sensor and an online XRD detector to achieve real-time feedback control of the crystal form.

[0032] The continuous flow microchannel synthesis method of o-hydroxybenzoic acid derivative (3,5-di-tert-butylsalicylic acid) in this embodiment is as follows.

[0033] (1) Phenolization reaction: 2,4-di-tert-butylphenol (purity 99.0%) and 20% sodium hydroxide solution were introduced into the first microchannel phenolization module at a molar ratio of 1:1.2. The temperature was controlled at 70℃, the pressure at 0.4MPa and the flow rate at 6mL / min. The reaction was carried out for 2.5min to obtain sodium 2,4-di-tert-butylphenol solution intermediate 1.

[0034] (2) Carboxylation reaction: CO2 (flow rate 10 mL / min) was introduced into intermediate 1 and carboxylation reaction was carried out in the second microchannel carboxylation module. The temperature was controlled at 85℃, the pressure at 1.3 MPa, the flow rate at 4 mL / min, and the reaction time at 3.5 min to obtain sodium 3,5-di-tert-butylsalicylate solution intermediate 2. The carboxylation rate was ≥98.5% as detected by HPLC.

[0035] (3) Acidification reaction: The above intermediate 2 and 12% hydrochloric acid were introduced into the third microchannel acidification module at a molar ratio of 1:1.1 for acidification reaction. The temperature was controlled at 45℃, the pressure at 0.25MPa, the flow rate at 5mL / min, and the reaction time at 2.5min to obtain a crude solution of 3,5-di-tert-butylsalicylic acid.

[0036] (4) Crystallization treatment: The crude product solution was passed into the fourth microchannel crystallization module for crystallization treatment. The temperature was gradually reduced from 45℃ to 6℃ at a cooling rate of 1.5℃ / min, while the flow rate was controlled at 2.5mL / min and the stirring frequency at 600rpm. The target crystalline substance (novel crystalline form) was obtained. The characteristic peaks detected by online XRD were 2θ=9.8°, 17.2°, and 21.5°. The XRD pattern of the novel crystalline form of 3,5-di-tert-butylsalicylic acid is shown below. Figure 1 As shown.

[0037] (5) Post-processing: The target crystalline material was passed into the fifth microchannel post-processing module for post-processing. After separation, washing twice with deionized water, and vacuum drying at 60℃ for 10 min, the target product 3,5-di-tert-butylsalicylic acid was obtained; the yield was 94.2% and the purity was 99.7%.

[0038] Example 2

[0039] Example 2 provides a continuous flow microchannel synthesis method for o-hydroxybenzoic acid derivatives.

[0040] The difference between this embodiment and Embodiment 1 is that in step (4), the cooling rate is 0.8℃ / min, the stirring frequency is 800rpm, and the characteristic peaks detected online by XRD are 2θ=10.1°, 18.3°, and 19.1° (conventional crystal form). The XRD pattern of the conventional crystal form of 3,5-di-tert-butylsalicylic acid is as follows: Figure 2 As shown.

[0041] In this embodiment, the yield of the target product 3,5-di-tert-butylsalicylic acid was 92.8%, and the purity was 99.6%.

[0042] Example 3

[0043] Example 3 provides a continuous flow microchannel synthesis method for o-hydroxybenzoic acid derivatives.

[0044] The continuous flow microchannel synthesis method of o-hydroxybenzoic acid derivatives in this embodiment is as follows.

[0045] (1) Phenolization reaction: 3,5-dimethylphenol (purity 99.2%) and 25% sodium hydroxide solution were introduced into the first microchannel phenolization module at a molar ratio of 1:1.3. The temperature was controlled at 65℃, the pressure at 0.35MPa and the flow rate at 5mL / min. The reaction was carried out for 2min to obtain 3,5-dimethylphenol sodium solution intermediate 1.

[0046] (2) Carboxylation reaction: CO2 (flow rate 12 mL / min) was introduced into intermediate 1 and carboxylation reaction was carried out in the second microchannel carboxylation module. The temperature was controlled at 90℃, the pressure at 1.5 MPa, and the flow rate at 3.5 mL / min. The reaction was carried out for 4 min to obtain sodium salicylate solution intermediate 2. The carboxylation rate was ≥98.2% as detected by HPLC. (3) Acidification reaction: The above intermediate 2 and 15% hydrochloric acid solution were introduced into the third microchannel acidification module at a molar ratio of 1:1.15 for acidification reaction. The temperature was controlled at 40℃, the pressure at 0.25MPa, and the flow rate at 4.5mL / min. The reaction was carried out for 3min to obtain crude 2-hydroxy-4,6-dimethylbenzoic acid solution.

[0047] (4) Crystallization treatment: The crude product solution was passed into the fourth microchannel crystallization module for crystallization treatment. The temperature was gradually reduced from 45℃ to 4℃ at a cooling rate of 1.2℃ / min. The flow rate was controlled at 2mL / min and the stirring frequency at 650rpm to obtain the target crystalline substance. The characteristic peaks detected by XRD online were 2θ=10.3°, 18.5°, and 20.1°.

[0048] (5) Post-processing: The target crystalline material was passed into the fifth microchannel post-processing module for post-processing. After separation and washing with deionized water twice, the product was vacuum dried at 55°C for 12 min to obtain the target product. The product yield was 92.5% and the purity was 99.6%.

[0049] Examples 4-9

[0050] Examples 4-9 provide a continuous flow microchannel synthesis method for o-hydroxybenzoic acid derivatives.

[0051] The specific differences between the above embodiments and Embodiment 1 are as follows.

[0052] In Example 4: In step (1) phenolation reaction, the reaction temperature is 63℃.

[0053] In Example 5: In step (1) phenolation reaction, the reaction temperature is 77°C.

[0054] In Example 6: In step (2) carboxylation reaction, the reaction temperature is 78°C.

[0055] In Example 7: In step (2) carboxylation reaction, the reaction temperature is 92℃.

[0056] In Example 8: In step (3) acidification reaction, the reaction temperature is 38°C.

[0057] In Example 9: In step (3) acidification reaction, the reaction temperature is 52℃.

[0058] All other process parameters in the above embodiments are the same as those in Embodiment 1.

[0059] The yield and purity of the target product 3,5-di-tert-butylsalicylic acid (novel crystal form) in the above embodiments are shown below.

[0060] In Example 4, the yield of the target product 3,5-di-tert-butylsalicylic acid was 90.1%, and the purity was 99.6%.

[0061] In Example 5, the yield of the target product 3,5-di-tert-butylsalicylic acid was 91.0%, and the purity was 99.8%.

[0062] In Example 6, the yield of the target product 3,5-di-tert-butylsalicylic acid was 89.6%, and the purity was 99.7%.

[0063] In Example 7, the yield of the target product 3,5-di-tert-butylsalicylic acid was 88.9%, and the purity was 99.7%.

[0064] In Example 8, the yield of the target product 3,5-di-tert-butylsalicylic acid was 90.6%, and the purity was 99.6%.

[0065] In Example 9, the yield of the target product 3,5-di-tert-butylsalicylic acid was 90.3%, and the purity was 99.7%.

[0066] By comparing the target product 3,5-di-tert-butylsalicylic acid prepared in Examples 1 and 4-9, it can be seen that the temperature of the phenolation reaction, carboxylation reaction, and acidification reaction has a significant impact on the yield of the target product 3,5-di-tert-butylsalicylic acid. In this application, the optimized temperatures of the phenolation reaction, carboxylation reaction, and acidification reaction are 65-75℃, 80-90℃, and 40-50℃, respectively, which can further improve the yield of the target product.

[0067] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives, characterized in that, An integrated microchannel reactor was used to sequentially complete the phenolation reaction, carboxylation reaction, acidification reaction, crystallization treatment, and post-treatment, including the following steps: (1) Using phenol or its derivatives as raw materials, a phenolate reaction is carried out by introducing an alkali metal hydroxide solution into the first microchannel. The temperature is controlled at 63-77℃, the pressure at 0.3-0.5MPa, and the reaction time at 2-3min to obtain intermediate 1. (2) CO2 is introduced into intermediate 1 and carboxylation reaction is carried out in the second microchannel. The temperature is controlled at 78-92℃, the pressure is 1.2-1.6MPa, and the reaction time is 3-4min to obtain intermediate 2. (3) Pass intermediate 2 and dilute acid solution into the third microchannel for acidification reaction, control the temperature at 38-52℃, the pressure at 0.2-0.3MPa, and the reaction time at 2-3min to obtain crude product solution; (4) The crude product solution is passed into the fourth microchannel for crystallization treatment, and the target crystalline substance is obtained by cooling. (5) The target crystalline material is passed into the fifth microchannel for post-processing. After separation, washing and drying, the target product is obtained.

2. The continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives according to claim 1, characterized in that, In step (1), the alkali metal hydroxide solution is a sodium hydroxide solution with a mass concentration of 15-25%.

3. The continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives according to claim 1, characterized in that, In step (1), the temperature is controlled at 65-75℃, the pressure at 0.35-0.45MPa, and the flow rate at 5-8mL / min.

4. The continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives according to claim 1, characterized in that, In step (2), the temperature is controlled at 80-90℃, the pressure at 1.3-1.5MPa, the flow rate at 3-5mL / min, and the CO2 flow rate at 5-20mL / min.

5. The continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives according to claim 1, characterized in that, In step (3), the dilute acid solution is a hydrochloric acid solution with a mass concentration of 10-15%.

6. The continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives according to claim 1, characterized in that, In step (3), the temperature is controlled at 40-50℃, the pressure at 0.22-0.28MPa, and the flow rate at 4-6mL / min.

7. The continuous flow microchannel synthesis method for o-hydroxybenzoic acid and its derivatives according to any one of claims 1-6, characterized in that, When the target product is 3,5-di-tert-butylsalicylic acid, the raw material is 2,4-di-tert-butylphenol; in the method for preparing the target product 3,5-di-tert-butylsalicylic acid, the process parameters for crystallization treatment in step (4) are: the temperature is gradually reduced from 40-50℃ to 5-8℃ at a cooling rate of 0.5-3℃ / min, while the flow rate is controlled at 2-3mL / min and the stirring frequency is 500-800rpm.

8. A 3,5-di-tert-butylsalicylic acid, characterized in that, The 3,5-di-tert-butylsalicylic acid was prepared using the synthesis method described in any one of claims 1-7; the X-ray diffraction characteristic peaks of the 3,5-di-tert-butylsalicylic acid were: 2θ = 9.8 ± 0.2°, 17.2 ± 0.2°, 21.5 ± 0.2°; or the X-ray diffraction characteristic peaks of the 3,5-di-tert-butylsalicylic acid were: 2θ = 10.1 ± 0.2°, 18.3 ± 0.2°, 19.1 ± 0.2°; the 3,5-di-tert-butylsalicylic acid had a crystallinity ≥ 95%, a thermal decomposition temperature ≥ 230°C, and a solubility rate ≥ 0.8 g / min in water at 25°C.

9. An integrated microchannel reactor for the synthesis of o-hydroxybenzoic acid and its derivatives, characterized in that, The integrated microchannel reactor includes a phenolation module, a carboxylation module, an acidification module, a crystallization module, and a post-treatment module connected in series. The inner diameter of the microchannel in each module is 200-300 μm and the channel length is 1.2-1.5 m. The parameters between modules are independently controlled through corrosion-resistant valves. The temperature, pressure, and flow rate of each module are independently controlled by a PLC system.

10. The integrated microchannel reactor for the synthesis of o-hydroxybenzoic acid and its derivatives according to claim 9, characterized in that, The crystallization module incorporates a temperature sensor and an online XRD detector to enable real-time feedback control of the crystal form.

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