Method for continuously synthesizing 2-thiophenecarboxaldehyde by using continuous flow reactor

Abstract

The invention provides a method for continuously synthesizing 2-thiophenecarboxaldehyde by using a continuous flow reactor, and relates to the technical field of organic synthesis, and the method comprises the following steps: mixing thiophene and N, N-dimethylformamide (DMF) to form a material A; continuously inputting the material A and phosphorus oxychloride (POCl3) into a micro-channel continuous flow reactor through a high-pressure feeding pump, and controlling the reaction temperature to be 60-150 DEG C and the retention time to be 0.5-5 minutes; synchronously inputting the reaction liquid output by the micro-channel reactor and a sodium hydroxide aqueous solution into a dynamic tubular reactor, and carrying out hydrolysis reaction at 10-70 DEG C for 0.5-5 minutes; according to the method, the 2-thiophenecarboxaldehyde is obtained by extracting the 2-thiophenecarboxaldehyde by using dichloromethane (DCM), and a continuous flow reactor technology is adopted, so that the reaction efficiency is remarkably improved. Compared with the traditional batch reaction, the continuous flow reactor has higher mass transfer and heat transfer efficiency, can realize rapid reaction, shortens the reaction time, and improves the product yield at the same time.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and more specifically, particularly relates to a method for continuously synthesizing 2-thiophenecarboxaldehyde by using a continuous flow reactor. Background Art

[0002] 2-Thiophenecarboxaldehyde is an important organic compound, which is widely used in the fields of medicine, material chemistry, etc. For example, it is used as a key intermediate in the synthesis of BACE1 inhibitors, anti-inflammatory drugs, anti-HIV PR inhibitors and anti-breast cancer drugs. Traditional synthesis methods have problems such as harsh reaction conditions, low efficiency and serious environmental pollution.

[0003] 2-Thiophenecarboxaldehyde, as a unique sulfur-containing heterocyclic aromatic aldehyde compound, has shown broad application potential in many fields such as medicine (especially key raw materials for the synthesis of anti-HIV drugs, anti-tumor drugs and antibacterial agents), pesticides (synthesis of highly effective insecticides and fungicidal active intermediates), dyes (necessary components of high-performance dyes) and polymer materials (monomers of new functional polymer materials) due to its extraordinary chemical structure and properties.

[0004] The journal (Zhou Weiping. "Production and Application of Thiophene Carboxaldehyde." Fine Chemical Intermediates 35.5 (2005): 2) reported a synthetic route for 2-thiophene carboxaldehyde. The process involves the initial mixing of N,N-dimethylformamide and thiophene, followed by the slow addition of phosphorus oxychloride at 20-30°C and the completion of the reaction at 80-95°C for 4 hours, during which the temperature must be carefully controlled and the tail gas must be treated. Although the article reported the innovativeness of this synthetic route, it did not mention the potential shortcomings. In fact, the process involves precise temperature control requirements, complex tail gas treatment processes, and cumbersome extraction and washing steps, which not only increase the difficulty of operation and energy consumption, but may also have a negative impact on the purity and yield of the final product, and is accompanied by higher safety and environmental challenges. Therefore, it is particularly important to further optimize the process to overcome the above-mentioned defects.

[0005] Traditional 2-thiophenecarboxaldehyde synthesis technologies, such as chemical oxidation, electrochemical oxidation and catalytic oxidation, are generally limited by harsh reaction conditions (high temperature and high pressure), lengthy reaction cycles, low yields and serious environmental pollution problems. In particular, the chemical oxidation method uses a large amount of oxidants, which leads to high production costs and environmental burdens, which is not conducive to sustainable development.

[0006] In recent years, the rise of continuous flow reaction technology has opened up new paths in the field of organic synthesis. With its highly controllable reaction conditions, efficient mass and heat transfer performance, and the convenience of automated and continuous production, continuous flow reactors have significantly improved reaction efficiency, reduced costs, and alleviated environmental pressure. Applying this technology to the synthesis of 2-thiophenecarboxaldehyde is expected to fundamentally solve the problems existing in traditional methods and achieve efficient, environmentally friendly, and continuous industrial production.

[0007] Although the application of continuous flow technology in the synthesis of some organic compounds has been reported, continuous synthesis strategies for 2-thiophenecarboxaldehyde are still relatively rare. Therefore, developing a new method for the synthesis of 2-thiophenecarboxaldehyde based on a continuous flow reactor not only makes a significant academic contribution but also has profound practical significance for accelerating its industrialization process and meeting diverse application needs, which is a crucial step in promoting the development of this field. Summary of the Invention

[0008] To solve the above technical problems, the present invention provides a method for continuously synthesizing 2-thiophenecarboxaldehyde using a continuous flow reactor to solve the above problems.

[0009] A method for continuously synthesizing 2-thiophenecarboxaldehyde based on a continuous flow reactor, comprising the following steps: mixing thiophene with N,N-dimethylformamide (DMF) to form material A; continuously inputting material A and phosphorus oxychloride (POCl3) into a microchannel continuous flow reactor through high-pressure feed pumps respectively, controlling the reaction temperature at 60 - 150 °C and the residence time at 0.5 - 5 minutes; synchronously inputting the reaction solution output from the microchannel reactor and an aqueous sodium hydroxide solution into a dynamic tubular reactor for hydrolysis reaction at 10 - 70 °C with a residence time of 0.5 - 5 minutes; collecting the hydrolysis solution and extracting it with dichloromethane (DCM) to obtain 2-thiophenecarboxaldehyde. The reaction temperature of the continuous flow reaction is 60 - 150 °C, preferably 85 - 135 °C. For example, specific reaction temperatures that can be listed are 60 °C, 80 °C, 90 °C, 100 °C, 115 °C, 125 °C, 135 °C, 145 °C, etc. The reaction temperature of the continuous flow hydrolysis reaction is 10 - 70 °C, preferably 20 - 50 °C. For example, specific hydrolysis reaction temperatures that can be listed are 20 °C, 30 °C, 40 °C, 50 °C, etc.

[0010] Preferably, the reaction temperature of the microchannel continuous flow reactor is 85 - 135°C, and the residence time is 3 - 5 minutes; the hydrolysis temperature of the dynamic tubular reactor is 20 - 50°C, and the residence time is 1 - 4 minutes. The molar ratio of thiophene to DMF in the material A is 1:1.1 - 1.5, and the molar ratio of thiophene to POCl3 is 1:1.1 - 1.5. The mass concentration of the sodium hydroxide aqueous solution is 20% - 40%, and the molar ratio of NaOH to POCl3 in the hydrolysis reaction is 1:1 - 1.5. The reaction time of the reaction solution in the continuous flow reactor is 0.5 - 5 min, preferably 3 - 5 min. For example, the reaction times that can be listed are 1 min, 2 min, 3 min, 4 min, 5 min, etc.

[0011] Preferably, the channel diameter of the microchannel continuous flow reactor is 0.5 - 2 mm, and the material is corrosion-resistant alloy or silicon carbide ceramic. The design pressure ≤ 5 MPa. The dynamic tubular reactor adopts a spiral tube design, the tube diameter is 10 - 50 mm, and a static mixer is built-in. The mixing efficiency ≥ 90%. In the DCM extraction step, the organic phase recovers the solvent by distillation, the purity of 2-thiophenecarboxaldehyde ≥ 98%, and the yield ≥ 95%. The reaction time of the reaction solution hydrolyzed in the continuous flow reactor is 0.5 - 5 min, preferably 1 - 4 min. For example, the reaction times that can be listed are 1 min, 2 min, 3 min, 4 min, etc.

[0012] A 2-thiophenecarboxaldehyde synthesis system based on a continuous flow reactor, comprising: a microchannel continuous flow reactor equipped with a temperature sensor and a pressure controller; a dynamic tubular reactor integrated with a static mixing unit and a pH on-line monitoring module; a high-pressure feed pump for precisely controlling the flow rates of material A and POCl3 (0.1 - 5 mL / min); an automated control system for adjusting the temperature, pressure and residence time in real time. The microchannel continuous flow reactor and the dynamic tubular reactor are connected by a corrosion-resistant pipeline, and the overall system sealing meets the IP65 standard. The automated control system is embedded with a digital twin model to optimize the process parameters based on the reaction kinetic data, with an error range of ±1°C and ±0.1 min.

[0013] Compared with the prior art, the present invention has the following beneficial effects:

[0014] 1. High efficiency: By adopting the continuous flow reactor technology, the reaction efficiency is significantly improved. Compared with the traditional batch reaction, the continuous flow reactor has higher mass transfer and heat transfer efficiencies, can achieve rapid reactions, shorten the reaction time, and improve the product yield at the same time.

[0015] 2. Environmental friendliness: The continuous flow reactor can precisely control the reaction conditions, reducing side reactions and the generation of harmful waste. Compared with traditional chemical oxidation methods, the present invention reduces the usage amount of oxidants, reduces environmental pollution, and meets the requirements of green chemistry and sustainable development.

[0016] 3. Continuous production: The present invention realizes the continuous synthesis of 2-thiophenecarboxaldehyde, overcoming the limitations of batch production in traditional methods. The continuous flow reactor can achieve automated operation, reduce manual intervention, improve production stability and consistency, and is suitable for large-scale industrial production.

[0017] 4. Mild reaction conditions: Compared with traditional methods, the present invention realizes milder reaction conditions in the continuous flow reactor, reducing energy consumption and equipment requirements, while improving operation safety.

[0018] 5. Cost reduction: The present invention significantly reduces the production cost. The high efficiency and repeatability of the continuous flow reactor further reduce resource consumption in the production process, enhancing economic benefits.

[0019] 6. Innovation: The present invention first applies continuous flow reaction technology to the synthesis of 2-thiophenecarboxaldehyde, filling the technical gap in this field and having important academic value and industrial application prospects.

[0020] 7. Scalability: The modular design of the continuous flow reactor makes the present invention easy to scale up and expand, and can flexibly adapt to production requirements of different scales, providing reliable technical support for the industrial production of 2-thiophenecarboxaldehyde.

[0021] In summary, the present invention has made significant technological progress in terms of high efficiency, environmental friendliness, continuous production, reaction conditions, cost control, innovation, and scalability, providing an efficient, environmentally friendly, and economical solution for the synthesis of 2-thiophenecarboxaldehyde. Brief Description of the Drawings

[0022] Figure 1 is the GC schematic diagram of 2-thiophenecarboxaldehyde of the present invention;

[0023] Figure 2 is the schematic diagram of experimental data of 2-thiophenecarboxaldehyde of the present invention. Detailed Embodiments

[0024] The following further describes in detail the embodiments of the present invention with reference to the drawings and examples. The following examples are used to illustrate the present invention, but cannot be used to limit the scope of the present invention.

[0025] Please refer to Figure 1 - Figure 2, the present invention provides a continuous synthesis method of 2-thiophenecarboxaldehyde based on a continuous flow reactor, comprising the following steps: mixing thiophene with N,N-dimethylformamide (DMF) to form material A; continuously inputting material A and phosphorus oxychloride (POCl3) into a microchannel continuous flow reactor respectively through high-pressure feeding pumps, controlling the reaction temperature at 60 - 150 °C and the residence time at 0.5 - 5 minutes; synchronously inputting the reaction solution output from the microchannel reactor and an aqueous sodium hydroxide solution into a dynamic tubular reactor for hydrolysis reaction at 10 - 70 °C with a residence time of 0.5 - 5 minutes; collecting the hydrolysis solution and extracting it with dichloromethane (DCM) to obtain 2-thiophenecarboxaldehyde.

[0026] The reaction temperature of the microchannel continuous flow reactor is 85 - 135 °C and the residence time is 3 - 5 minutes; the hydrolysis temperature of the dynamic tubular reactor is 20 - 50 °C and the residence time is 1 - 4 minutes. The molar ratio of thiophene to DMF in material A is 1:1.1 - 1.5, the molar ratio of thiophene to POCl3 is 1:1.1 - 1.5, the mass concentration of the aqueous sodium hydroxide solution is 20% - 40%, and the molar ratio of NaOH to POCl3 in the hydrolysis reaction is 1:1 - 1.5.

[0027] The channel diameter of the microchannel continuous flow reactor is 0.5 - 2 mm, and the material is corrosion-resistant alloy or silicon carbide ceramic, with a design pressure ≤ 5 MPa. The dynamic tubular reactor adopts a spiral tube design with a pipe diameter of 10 - 50 mm and a built-in static mixer, and the mixing efficiency ≥ 90%. In the DCM extraction step, the organic phase is distilled to recover the solvent, and the purity of 2-thiophenecarboxaldehyde ≥ 98% and the yield ≥ 95%.

[0028] A 2-thiophenecarboxaldehyde synthesis system based on a continuous flow reactor, comprising: a microchannel continuous flow reactor configured with a temperature sensor and a pressure controller; a dynamic tubular reactor integrated with a static mixing unit and a pH on-line monitoring module; high-pressure feeding pumps for precisely controlling the flow rates of material A and POCl3 (0.1 - 5 mL / min); an automated control system for real-time adjustment of temperature, pressure and residence time. The microchannel continuous flow reactor and the dynamic tubular reactor are connected by corrosion-resistant pipes, and the overall system sealing meets the IP65 standard. The automated control system is embedded with a digital twin model to optimize process parameters based on reaction kinetic data, with an error range of ±1 °C and ±0.1 min.

[0029] For the first time, the present invention continuously synthesizes 2-thiophenecarboxaldehyde by using a continuous flow reactor, changing the traditional batch process to a continuous process, solving a series of problems such as long reaction time and high safety risk in batch reactions, and optimizing the reaction parameters of 2-thiophenecarboxaldehyde. It has the advantages of simple operation, environmental friendliness, mild reaction, short reaction time, higher reaction safety compared with conventional methods, high conversion rate, few impurities, simple post-treatment and full automation, which is beneficial to industrial production and has made obvious technological progress compared with the prior art.

[0030] A method for continuously synthesizing 2-thiophenecarboxaldehyde by using a continuous flow reactor, which performs a continuous flow reaction by using the continuous flow reactor, specifically including the following steps:

[0031]

[0032] Configure materials:

[0033] 1. Take 200 g of DMF (N,N-dimethylformamide) and pour it into a 500 ml conical flask, add the raw material (thiophene), stir and mix evenly for later use (abbreviated as material A);

[0034] 2. Continuously input the prepared material A and POCI3 (material B) into the continuous flow reactor through two high-pressure feed pumps, and control the reaction conditions such as temperature, residence time, molar ratio, etc. to carry out the reaction;

[0035] 3. The reaction solution (containing compound 2) flowing out of the microchannel is directly transported to a dynamic tubular reactor, and an aqueous sodium hydroxide solution is pumped into the dynamic tubular reactor through another feed pump for hydrolysis reaction to obtain 2-thiophenecarboxaldehyde;

[0036] 4. The collected hydrolysis solution is extracted with DCM, and the organic phase is sent for GC analysis.

[0037] The present invention will be described in detail below with specific examples / comparative examples.

[0038] Comparative Example 1

[0039] The steps for synthesizing 2-thiophenecarboxaldehyde by a batch reaction process are as follows:

[0040] In a 100 L reactor, low-temperature circulation was carried out. First, thiophene (3000 g, 35.65 mol, 1.0 eq) and DMF (2867 g, 39.22 mol, 1.1 eq) were added. After stirring, the external bath was heated to 90 °C to start gentle reflux. After 1 hour, the system was in gentle reflux, and the temperature was controlled not to exceed 95 °C. POCl3 (6287 g, 41.00 mol, 1.15 eq) was added dropwise. An alkaline tail gas absorption device was required to treat the acid gas emitted. After 1.5 hours of dropping, the temperature was raised to 100 °C in the external bath, and the internal temperature was stirred at 85 - 95 °C for 4 hours. After the reaction was completed, the temperature was lowered to 20 °C. The reaction solution was dropped into 9 L of pure water, and then the pH was adjusted to neutral with 30% NaOH. Extraction was carried out with dichloromethane, and the organic phase was sent for GC analysis. The purity of 2-thiophenecarboxaldehyde was 95.35%.

[0041] Example 1

[0042] The pre-prepared solution (Material A) and phosphorus oxychloride (B) (thiophene:DMF:POCl3 = 1:1.15:1.1) were continuously injected into the continuous flow reactor through high-pressure piston pumps respectively. During the reaction process, a high-precision control system was used to ensure precise control of the reaction conditions. The temperature was strictly maintained at 85 °C, and the reaction residence time was 2 minutes. The reaction solution flowing out of the microchannel was transported to a dynamic tubular reactor. A 30% aqueous sodium hydroxide solution was pumped into the dynamic tubular reactor through another feed pump. The temperature was controlled at 30 °C, and the residence time was 2 minutes for hydrolysis reaction to obtain the crude product. After the reaction was completed, extraction was carried out with DCM. The purity of 2-thiophenecarboxaldehyde in the organic phase was 65.35%;

[0043] Example 2

[0044] Further, on the basis of Example 1, only the reaction temperature was changed to 95 °C, and other conditions remained unchanged, including the reaction time still being 2 minutes. The reaction solution flowing out of the microchannel was transported to a dynamic tubular reactor. A 30% aqueous sodium hydroxide solution was pumped into the dynamic tubular reactor through another feed pump. The temperature was controlled at 30 °C, and the residence time was 2 minutes for hydrolysis reaction to obtain the crude product. After the reaction was completed, extraction was carried out with DCM. The purity of 2-thiophenecarboxaldehyde in the organic phase was further increased to 71.97%;

[0045] Example 3

[0046] On the basis of maintaining the same experimental apparatus and operation process as in Example 2, only the reaction time was adjusted to 3 minutes, and other conditions remained unchanged, including the reaction temperature still being 95°C. The reaction solution flowing out of the microchannel was transported to a dynamic tubular reactor, and 30% aqueous sodium hydroxide solution was pumped into the dynamic tubular reactor through another feed pump, controlling the temperature at 30°C and the residence time at 2 minutes for hydrolysis reaction to obtain the crude product. After the reaction ended, extraction was carried out with DCM, and the purity of 2-thiophenecarboxaldehyde in the organic phase was increased to 78.70%;

[0047] Example 4

[0048] Further on the basis of Example 3, only the reaction temperature was changed to 125°C, and other conditions remained unchanged, including the reaction time still being 3 minutes. The reaction solution flowing out of the microchannel was transported to a dynamic tubular reactor, and 30% aqueous sodium hydroxide solution was pumped into the dynamic tubular reactor through another feed pump, controlling the temperature at 30°C and the residence time at 2 minutes for hydrolysis reaction to obtain the crude product. After the reaction ended, extraction was carried out with DCM, and the purity of 2-thiophenecarboxaldehyde in the organic phase was further increased to 85.08%;

[0049] Example 5

[0050] Further on the basis of Example 4, only the reaction temperature was changed to 135°C, and other conditions remained unchanged, including the reaction time still being 3 minutes. The reaction solution flowing out of the microchannel was transported to a dynamic tubular reactor, and 30% aqueous sodium hydroxide solution was pumped into the dynamic tubular reactor through another feed pump, controlling the temperature at 30°C and the residence time at 2 minutes for hydrolysis reaction to obtain the crude product. After the reaction ended, extraction was carried out with DCM, and the purity of 2-thiophenecarboxaldehyde in the organic phase was further increased to 91.21%;

[0051] Example 6

[0052] On the basis of Example 5, the equivalent ratio of the raw material to phosphorus oxychloride was adjusted to 1:1.5 to explore more optimal reaction conditions. Other conditions remained unchanged, including the reaction temperature still being 135°C and the reaction residence time still being 3 minutes. The reaction solution flowing out of the microchannel was transported to a dynamic tubular reactor, and 30% aqueous sodium hydroxide solution was pumped into the dynamic tubular reactor through another feed pump, controlling the temperature at 30°C and the residence time at 2 minutes for hydrolysis reaction to obtain the crude product. After the reaction ended, extraction was carried out with DCM, and the purity of 2-thiophenecarboxaldehyde in the organic phase was 98.36%;

[0053] In summary, the method for continuously synthesizing 2-thiophenecarboxaldehyde using a continuous flow reactor proposed by the present invention provides strong support and impetus for industrial production with many advantages such as high efficiency, safety, and environmental friendliness.

[0054] The embodiments of the present invention are given for purposes of illustration and description, and are not exhaustive or limit the invention to the disclosed forms. Many modifications and variations are obvious to those of ordinary skill in the art. The embodiments are chosen and described in order to best explain the principles of the invention and its practical application, and to enable those of ordinary skill in the art to understand the invention and design various embodiments with various modifications suitable for a particular purpose.

Claims

1. A continuous synthesis method of 2-thiophenecarboxaldehyde based on a continuous flow reactor, characterized in that, The following steps are involved: Mixing thiophene with N,N-dimethylformamide (DMF) to form material A; Material A and phosphorus oxychloride (POCl3) are continuously fed into the microchannel continuous flow reactor through a high-pressure feed pump, respectively, and the reaction temperature is controlled to be 60-150°C and the residence time is 0.5-5 minutes; The reaction liquid output from the microchannel reactor and the sodium hydroxide aqueous solution are synchronously input into the dynamic tubular reactor for hydrolysis reaction at 10-70° C. with a residence time of 0.5-5 minutes; The hydrolyzate was collected and extracted with dichloromethane (DCM) to obtain 2-thiophenecarboxaldehyde.

2. The method for continuously synthesizing 2-thiophenecarboxaldehyde by using a continuous flow reactor as claimed in claim 1, wherein The reaction temperature of the microchannel continuous flow reactor is 85-135° C., and the residence time is 3-5 minutes; the hydrolysis temperature of the dynamic tubular reactor is 20-50° C., and the residence time is 1-4 minutes.

3. The method for continuously synthesizing 2-thiophenecarboxaldehyde by using a continuous flow reactor according to claim 1, characterized in that, The molar ratio of thiophene to DMF in the material A is 1:1.1-1.5, and the molar ratio of thiophene to POCl3 is 1:1.1-1.

5.

4. The method for continuously synthesizing 2-thiophenecarboxaldehyde by using a continuous flow reactor as claimed in claim 1, wherein, The mass concentration of the sodium hydroxide aqueous solution is 20% to 40%, and the molar ratio of NaOH to POCl3 in the hydrolysis reaction is 1:1-1.

5.

5. The method for continuously synthesizing 2-thiophenecarboxaldehyde by using a continuous flow reactor as claimed in claim 1, wherein The channel diameter of the microchannel continuous flow reactor is 0.5-2 mm, the material is corrosion-resistant alloy or silicon carbide ceramic, and the design pressure is ≤5 MPa.

6. The method for continuously synthesizing 2-thiophenecarboxaldehyde by using a continuous flow reactor according to claim 1, wherein The dynamic tubular reactor adopts a spiral tubular design, has a tube diameter of 10-50 mm, and has a built-in static mixer with a mixing efficiency of ≥90%.

7. The method for continuously synthesizing 2-thiophenecarboxaldehyde by using a continuous flow reactor according to claim 1, wherein In the DCM extraction step, the organic phase is distilled to recover the solvent, and the purity of 2-thiophenecarboxaldehyde is ≥98%, and the yield is ≥95%.

8. A 2-thiophenecarboxaldehyde synthesis system based on a continuous flow reactor, characterized in that, include: Microchannel continuous flow reactor, equipped with temperature sensor and pressure controller; Dynamic tubular reactor, integrating static mixing unit and pH online monitoring module; High-pressure feed pump, used to accurately control the flow rate of material A and POCl3 (0.1-5mL / min); Automatic control system to adjust temperature, pressure and residence time in real time.

9. The 2-thiophenecarboxaldehyde synthesis system based on a continuous flow reactor according to claim 8, wherein, The microchannel continuous flow reactor is connected to the dynamic tubular reactor via a corrosion-resistant pipeline, and the sealing performance of the overall system meets the IP65 standard.

10. The 2 - thiophenecarboxaldehyde synthesis system based on a continuous - flow reactor according to claim 8, wherein, The automated control system is embedded in a digital twin model and optimizes process parameters based on reaction kinetics data, with an error range of ±1°C and ±0.1min.

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