Method for synthesizing 2-fluoro-6-trifluoromethylpyridine by adopting tubular reactor

Abstract

The invention discloses a method for synthesizing 2-fluoro-6-trifluoromethylpyridine by using hydrogen fluoride as a fluorinating agent and applying a tubular reactor, and belongs to the technical field of organic synthesis. The method specifically comprises the following steps: A, conveying raw materials: pumping liquid 2-chloro-6-trichloromethylpyridine and hydrogen fluoride into a primary tubular reactor; b, reacting in a first-stage tubular reactor: controlling the temperature to be 140 + / -5 DEG C / pressure to be 3MPa; c, gas-liquid primary separation: tightly connecting an outlet of the reactor with a gas-liquid separator; and D, reaction in a second-stage tubular reactor: raising the pressure of the material to 3.8 MPa, and feeding the material into the second-stage tubular reactor at 175 + / -5 DEG C. E, gas-liquid secondary separation, wherein an outlet pressure reducing valve is connected with a gas-liquid separator, and the pressure is 0.3 MPa; and F, product purification: carrying out water washing rectification on the product to obtain a high-purity 2-fluoro-6-trifluoromethylpyridine product. Compared with a traditional tank reactor, the yield of the method is greatly increased to 98% or above, the utilization rate of raw materials is greatly increased, and the raw material cost of each ton of products can be reduced by about 20-25%.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 2-fluoro-6-trifluoromethylpyridine by using hydrogen fluoride as a fluorinating agent and applying a tubular reactor. Background Art

[0002] As an important organic intermediate, 2-fluoro-6-trifluoromethylpyridine is an important component of the molecular structures of many drugs in the pharmaceutical field and plays a key role in enhancing the activity, specificity, and pharmacokinetic properties of drugs. In the pesticide field, pesticides developed based on its structure have characteristics such as high efficiency, low toxicity, and environmental friendliness, and are widely used in the prevention and control of crop pests and diseases.

[0003] However, most traditional synthesis methods rely on batch reactors. A large amount of reaction materials are accommodated inside the batch reactor. When facing high-temperature and high-pressure reaction conditions, once accidents such as leakage and runaway reactions occur, accidents involving a large amount of materials will pose a serious safety threat, such as possible violent explosions and large-scale leakage of toxic and harmful gases. Moreover, due to the complex mixing state of the materials inside the batch reactor, there is a large lag in heat transfer and mass transfer, making it extremely difficult to precisely control the temperature and pressure. The inaccurate control of temperature and pressure makes it difficult for the reaction to maintain the optimal conditions, resulting in the conversion rate and yield of the reaction remaining at a relatively low level for a long time.

[0004] According to the statistical data of past relevant research, when synthesizing 2-fluoro-6-trifluoromethylpyridine using a batch reactor, the average conversion rate is only in the range of 70%-80%, and the yield is in the range of 65%-75%. At the same time, most of the operations of the batch reactor rely on manual labor. From raw material addition, reaction process monitoring to product separation, the degree of automation is extremely low. This not only limits the improvement of production efficiency, but also causes significant fluctuations in product quality due to the differences in manual operations, ultimately significantly increasing the production cost.

[0005] Therefore, there is an urgent need to develop a new method for synthesizing 2-fluoro-6-trifluoromethylpyridine with a high safety factor, precise controllability during the reaction process, and capable of achieving highly automated production. Summary of the Invention

[0006] The present invention aims to construct a method for synthesizing 2-fluoro-6-trifluoromethylpyridine using hydrogen fluoride as a fluorinating agent and a tubular reactor, comprising: A. Raw material transportation: pumping liquid 2-chloro-6-trichloromethylpyridine and hydrogen fluoride into a first-stage tubular reactor; B. First-stage tubular reactor reaction: controlling 140±5℃ / pressure 3MPa; C. First-stage gas-liquid separation: the reactor outlet is closely connected to the gas-liquid separator; D. Second-stage tubular reactor reaction: the material is raised to 3.8MPa and enters a 175±5℃ second-stage tubular reactor. E. Secondary gas-liquid separation: the outlet pressure reducing valve is connected to the gas-liquid separator, with a pressure of 0.3MPa; F. Product purification: the product is washed and distilled to obtain a high-purity 2-fluoro-6-trifluoromethylpyridine product. The process of the present invention solves a series of key problems existing in the existing kettle reactor synthesis technology, such as high safety risk, difficult temperature and pressure control, low production efficiency and high cost, and promotes the 2-fluoro-6-trifluoromethylpyridine synthesis technology to achieve a qualitative leap.

[0007] The method for synthesizing 2-fluoro-6-trifluoromethylpyridine using a tubular reactor of the present invention comprises the following steps:

[0008] G. Raw material transportation: Use pipeline pumps to pump liquid 2-chloro-6-trichloromethylpyridine (CTC) and liquid hydrogen fluoride into the primary tubular reactor at a stable and accurate flow rate, and measure the flow rate with a flow meter.

[0009] Furthermore, in the above technical solution, this process uses the DCS flow control system to accurately adjust the input ratio of the two raw materials according to the reaction kinetics model, and strictly control the molar ratio of hydrogen fluoride to CTC in the range of 6 to 12: 1. At the initial stage of the reaction, the raw materials can be evenly distributed and fully contacted in the tubular reactor, laying a solid foundation for the efficient development of subsequent reactions.

[0010] H. Primary tubular reactor reaction: The temperature of the primary tubular reactor is controlled at 140±5°C and the pressure is stably maintained at 3MPa through the heat transfer oil circulation system.

[0011] Furthermore, in the above technical solution, 2-chloro-6-trichloromethylpyridine (CTC) reacts with hydrogen fluoride to first generate 2-fluoro-6-difluoromonochloromethylpyridine and produce a large amount of hydrogen chloride. The temperature and pressure conditions can overcome the reaction activation energy and promote the rapid start of the reaction. For example, in the early experimental research, when the temperature was lower than 135°C, the reaction rate was too slow and the conversion rate could only reach about 60%; when the temperature was higher than 145°C, the by-product content increased significantly and the yield was reduced to about 85%.

[0012] I. Primary gas-liquid separation: The outlet of the primary tubular reactor is closely connected to a well-designed gas-liquid separator.

[0013] Further, in the above technical solution, in the gas-liquid separator, by using the principles of gravity sedimentation and phase equilibrium, the preliminary separation of the hydrogen chloride generated by the reaction from the reaction system is achieved. The generated hydrogen chloride and a small amount of unreacted hydrogen fluoride are discharged from the top in the gas phase, and the liquid phase containing the unreacted raw materials and part of the target product flows out from the liquid phase outlet at the bottom and is connected to the secondary tubular reactor through a pipeline booster pump.

[0014] J. Reaction in the secondary tubular reactor: The pressure of the material from the liquid phase outlet of the primary gas-liquid separator is increased to 3.8 MPa by a pipeline booster pump and then sent into the secondary tubular reactor. The temperature of the secondary tubular reactor is set at 175 ± 5 °C.

[0015] Further, in the above technical solution, in this enhanced environment of high temperature and high pressure, the unreacted raw materials further react, promoting a significant increase in the conversion rate and purity of the target product 2-fluoro-6-(trifluoromethyl)pyridine. The reaction conditions at this stage have been systematically optimized. When the pressure is lower than 3.6 MPa or the temperature is lower than 170 °C, the final conversion rate and yield of the product do not reach the ideal level; while when the pressure or temperature is too high, problems such as increased equipment corrosion and more side reactions will occur.

[0016] K. Secondary gas-liquid separation: The outlet of the secondary tubular reactor is connected to the gas-liquid separator through a specially designed pressure reducing valve, and the pressure in the gas-liquid separator is stabilized at 0.3 MPa after decompression.

[0017] Further, in the above technical solution, the gas phase part in the gas-liquid separator is mainly unreacted hydrogen fluoride and a small amount of hydrogen chloride. The gas phase is liquefied by a 7 °C condenser. The unreacted hydrogen fluoride is successfully liquefied and recovered, which can be recycled for subsequent reaction processes to improve the utilization rate of raw materials. The remaining hydrogen chloride gas after condensation is discharged to a dedicated water absorption device through a pressure reducing valve for treatment to avoid environmental pollution.

[0018] Further, in the above technical solution, the liquid phase in the gas-liquid separator is the 2-fluoro-6-(trifluoromethyl)pyridine generated by the reaction. After detection, its content is ≥ 98%, the conversion rate is ≥ 99%, and the yield is ≥ 97% at this time.

[0019] L. Product purification: The liquid phase product obtained from the gas-liquid separator is washed with water, and then the product is rectified to obtain high-purity 2-fluoro-6-(trifluoromethyl)pyridine.

[0020] Further, in the above technical solution, when washing the liquid phase product with water, the residual hydrogen fluoride is removed by utilizing the property that hydrogen fluoride is easily soluble in water.

[0021] Further, in the above technical solution, the washing process adopts multi-stage countercurrent washing to ensure the best removal effect of hydrogen fluoride.

[0022] Furthermore, in the above technical solution, during rectification, the temperature of the rectification still and the reboiler is controlled at 110-120 °C, the vacuum is 35-45 Kpa, and the reflux ratio is 1:2 for harvesting. The harvesting stops when there is no distillate, and 2-fluoro-6-trifluoromethylpyridine with a purity of over 99.5% is obtained.

[0023] Advantages of the invention

[0024] Improved safety performance: The amount of materials in the tubular reactor system is significantly reduced compared to the kettle reactor, being less than one-thousandth of that of the kettle reactor. The sharp reduction in the amount of materials greatly reduces the harm of accidents during the reaction process in case of sudden situations such as pipeline rupture or abnormal exothermic reaction, as the total amount of materials participating in the reaction is extremely small. Moreover, due to the small amount of materials in the tubular reactor, the heat capacity of its reaction system is small, and it responds extremely quickly to changes in temperature and pressure. When there are minor fluctuations in the reaction temperature or pressure, it can be quickly adjusted through the automated control system, making the temperature and pressure control simpler and more precise, thus significantly reducing the safety risks during the production process.

[0025] Automated production: The entire tubular reactor system is equipped with an advanced automated control system. From the raw material transportation link, the flow control of the pipeline pump, the temperature and pressure regulation of the first-stage and second-stage tubular reactors, to the operation of the gas-liquid separator and the separation and purification of products, all processes can be precisely operated through the automated control system. This not only greatly improves the production efficiency, with the production efficiency being 5-8 times higher than that of the traditional manual operation mode of the kettle reactor, but also effectively reduces the errors caused by manual operation and the safety hazards caused by human factors, ensuring the stability of the production process and the consistency of product quality.

[0026] Fine reaction control: The reaction in the present invention belongs to the micro-reaction mode. With its unique structure and operation mode, the tubular reactor can achieve fine control of temperature and pressure. In the first-stage tubular reactor, the temperature can be precisely controlled at 140 ± 2 °C, and in the second-stage tubular reactor, the temperature can be stably controlled at 175 ± 5 °C. This precise temperature control enables the reaction to always proceed under the optimal thermodynamic and kinetic conditions. Compared with the traditional kettle reactor, the yield of the method of the present invention has been greatly increased from the original relatively low level to over 98%, and the conversion rate also reaches over 99%, greatly improving the utilization rate of raw materials and significantly reducing the production cost. After calculation, compared with the traditional kettle reactor synthesis method, when producing 2-fluoro-6-trifluoromethylpyridine using the method of the present invention, the raw material cost per ton of product can be reduced by about 20-25%. Brief description of the drawings

[0027] Figure 1Process equipment flow chart for synthesizing 2-fluoro-6-trifluoromethylpyridine using a tubular reactor; wherein: 1. CTC storage tank; 2. Hydrogen fluoride storage tank; 3. CTC pipeline pump; 4. Hydrogen fluoride pipeline pump; 5. First-stage tubular reactor; 6. First-stage gas-liquid separator; 7. Condenser; 8. Pressure reducing valve A; 9. Hydrogen fluoride recovery tank; 10. Booster pump; 11. Check valve; 12. Second-stage tubular reactor; 13. Second-stage gas-liquid separator; 14. Condenser; 15. Pressure reducing valve B; 16. Hydrogen fluoride recovery tank; 17. Pressure reducing valve C; 18. Flowmeter A; 19. Flowmeter B. Detailed implementation mode

[0028] Example 1

[0029] Raw material preparation: Carefully prepare sufficient amounts of liquid 2-chloro-6-trichloromethylpyridine (CTC) and liquid hydrogen fluoride. During the preparation process, gas chromatography analysis technology is used to strictly detect the purity of the raw materials to ensure that their purity meets the reaction requirements. Among them, the purity of 2-chloro-6-trichloromethylpyridine (CTC) reaches more than 99.5%, and the purity of liquid hydrogen fluoride reaches more than 99.8%.

[0030] Reaction in the first-stage tubular reactor: Start the high-precision pipeline pump, and pump liquid 2-chloro-6-trichloromethylpyridine (CTC) (1) and liquid hydrogen fluoride (2) into the first-stage tubular reactor (5) stably through pipeline pumps (3) and (4) respectively according to the preset flow ratio of 1:8.62 (molar ratio). With the help of constant-temperature heat-conducting oil, the temperature is stably maintained at 140 °C and the pressure is kept at 3 MPa. The reaction materials stay in the first-stage tubular reactor (5) for the predetermined residence time. The first-stage tubular reactor is made of carbon steel, with an inner diameter of 0.05 m and a length of 164 m. The residence time is determined by precise flow control and the length and inner diameter of the tubular reactor to be 300 ± 20 minutes. 40 kg (173.21 mol) of CTC and 30 kg (1492.52 mol) of hydrogen fluoride are pumped in per hour.

[0031] Gas-liquid separation (first stage): The reaction materials flow smoothly from the outlet of the first-stage tubular reactor (5) into the gas-liquid separator (6). Inside the gas-liquid separator (6), based on the principles of gravity and phase equilibrium, hydrogen chloride generated by the reaction and a small amount of unreacted hydrogen fluoride are efficiently discharged in the gas phase, and the liquid-phase materials enter the second-stage tubular reactor through the pipeline booster pump (10) at a stable flow rate.

[0032] Results of the first-stage reaction: 2-fluoro-6-difluorochloromethylpyridine 92.4%, 2-fluoro-6-trifluoromethylpyridine 6.5%, 2-fluoro-6-monofluorodichloromethylpyridine 0.5%.

[0033] Reaction in the secondary tubular reactor: The pressure of the liquid-phase material is increased to 3.8 MPa by the pipeline booster pump (10) and then fed into the secondary tubular reactor (12). With the constant-temperature heat-conducting oil equipped in the secondary tubular reactor (12), its temperature is stably controlled at 175 °C. The material continues to react in the secondary tubular reactor to further improve the product purity and yield, and the reaction residence time is set to 300 ± 20 minutes.

[0034] Results of the secondary reaction: 2-fluoro-6-difluorochloromethylpyridine 0.01%, 2-fluoro-6-trifluoromethylpyridine 99.3%, 2-fluoro-6-monofluorodichloromethylpyridine 0%, other impurities < 0.01%.

[0035] Gas-liquid separation (secondary): The material at the outlet of the secondary tubular reactor (12) smoothly enters the gas-liquid separator (13) through the pressure-reducing valve (17), and the pressure is reduced to 0.3 MPa. In the gas-liquid separator (13), hydrogen fluoride and hydrogen chloride with relatively low pressure exist in the gas phase and pass through the condenser (14) supplied with 7 °C condensed water. During this process, the unreacted hydrogen fluoride is efficiently liquefied and recovered, and the purity of the recovered hydrogen fluoride is detected to be above 99%. The hydrogen chloride gas cannot be liquefied and is discharged to the water absorption treatment device through the pressure-reducing valve. The liquid phase of the gas-liquid separator is collected and detected by gas chromatography analysis technology. The content of 2-fluoro-6-trifluoromethylpyridine is 99.3%, and the conversion rate is 99.8%.

[0036] Product purification: The liquid-phase product of the gas-liquid separator is fed into a multi-stage countercurrent water washing device for continuous water washing operation to remove residual hydrogen fluoride. Every 7000 kg of the washed product enters the batch distillation column to distill and remove impurities. At this time, 9790.6 kg of CTC is consumed, and the reaction yield is 99.8%. Distillation further increases the content of 2-fluoro-6-trifluoromethylpyridine and removes impurities. In the above technical solution, the temperature of the distillation kettle and the reboiler is controlled at 110 - 120 °C, the vacuum is 35 - 45 Kpa, and the reflux ratio is 1:2 for harvesting. The harvesting stops when there is no distillate, and 6905.2 kg of 2-fluoro-6-trifluoromethylpyridine is obtained, with a GC purity of 99.8% and a distillation yield of 99.1%; the total yield is 98.9%.

[0037] Example 2

[0038] Raw material preparation: Repeat the raw material preparation steps of Example 1, strictly control the raw material purity, and ensure that the purity of 2-chloro-6-trichloromethylpyridine (CTC) and liquid hydrogen fluoride reaches above 99.5% and above 99.8% respectively.

[0039] Reaction in the primary tubular reactor: The temperature of the primary tubular reactor (5) is controlled at 142 °C, the pressure is maintained at 3 MPa, and the rest of the operations are the same as in Example 1. The parameters such as the flow rates of the pipeline pumps (3) and (4) and the material residence time are all kept consistent.

[0040] Gas-liquid separation (primary): Same as the gas-liquid separation (6) step in Example 1, using the same gas-liquid separator equipment and operating parameters, and the residence time of the material is still set to 300 ± 20 minutes.

[0041] Primary reaction result: 2-Fluoro-6-difluorochloromethylpyridine 93.1%, 2-Fluoro-6-trifluoromethylpyridine 5.7%, 2-Fluoro-6-monofluorodichloromethylpyridine 0.6%.

[0042] Secondary tubular reactor reaction: Control the temperature of the secondary tubular reactor (12) at 172 °C and the pressure at 3.8 MPa. Other operations are the same as in Example 1, and the residence time of the material is still set to 300 ± 20 minutes.

[0043] Secondary reaction result: 2-Fluoro-6-difluorochloromethylpyridine 0.01%, 2-Fluoro-6-trifluoromethylpyridine 99.4%, 2-Fluoro-6-monofluorodichloromethylpyridine 0%.

[0044] Gas-liquid separation (secondary): Same as the gas-liquid separation (13) step in Example 1, and parameters such as the temperature of the condenser (14) and the pressure of the gas-liquid separator (13) remain unchanged.

[0045] Product purification: Same as the product purification step in Example 1, using the same water washing and rectification equipment and operating parameters. Finally, 6918.3 kg of 2-Fluoro-6-trifluoromethylpyridine is obtained, with a GC purity of 99.7% and a total yield of 98.5%.

[0046] It can be clearly seen from Example 1 and Example 2 that the method for synthesizing 2-Fluoro-6-trifluoromethylpyridine using a tubular reactor according to the present invention can stably prepare products with high purity, and has high conversion rate and yield. When appropriately fine-tuning different operating conditions such as temperature, it can still maintain good reaction effects, fully demonstrating the reliability and stability of this method. In actual industrial applications, it can provide an efficient, safe and low-cost technical solution for the production of 2-Fluoro-6-trifluoromethylpyridine.

Claims

1. A method for synthesizing 2-fluoro-6-trifluoromethylpyridine using a tubular reactor, characterized in that, It includes the following steps: A. Feedstock transportation: Using a high-precision pipeline pump, pump liquid 2-chloro-6-trichloromethylpyridine and liquid hydrogen fluoride into a primary tubular reactor; B. Reaction in the primary tubular reactor: Through a heat transfer oil circulation system, control the temperature of the primary tubular reactor at 140 ± 5 °C and maintain the pressure stably at 3 MPa; C. Primary gas-liquid separation: The outlet of the primary tubular reactor is closely connected to a gas-liquid separator; D. Reaction in the secondary tubular reactor: Use a pipeline booster pump to increase the pressure of the material from the liquid phase outlet of the primary gas-liquid separator to 3.8 MPa, and then send it into the secondary tubular reactor; E. Secondary gas-liquid separation: The outlet of the secondary tubular reactor is connected to a gas-liquid separator through a specially designed pressure reducing valve, and the pressure in the gas-liquid separator is stably at 0.3 MPa after decompression; F. Product purification: Wash the liquid phase product obtained from the gas-liquid separator, and then carry out product rectification to obtain high-purity 2-fluoro-6-trifluoromethylpyridine.

2. The synthesis method of 2-fluoro-6-trifluoromethylpyridine using a tubular reactor according to claim 1, characterized in that: In step A, the molar ratio of hydrogen fluoride to CTC is controlled at 6 - 10:

1.

3. The synthesis method of 2-fluoro-6-trifluoromethylpyridine using a tubular reactor according to claim 1, characterized in that: In step C, in the gas-liquid separator, using the principle of gravity sedimentation and phase equilibrium, achieve the preliminary separation of the hydrogen chloride generated by the reaction and the reaction system. The generated hydrogen chloride and a small amount of unreacted hydrogen fluoride are discharged from the top in gaseous form, and the liquid phase containing the unreacted raw materials and part of the target product flows out from the bottom liquid phase outlet and is connected to the secondary tubular reactor through a pipeline booster pump.

4. The synthesis method of 2-fluoro-6-trifluoromethylpyridine using a tubular reactor according to claim 1, characterized in that: In step D, the temperature of the secondary tubular reactor is set at 175 ± 5 °C.

5. The synthesis method of 2-fluoro-6-trifluoromethylpyridine using a tubular reactor according to claim 1, characterized in that: In step E, the gas phase part in the gas-liquid separator is mainly unreacted hydrogen fluoride and a small amount of hydrogen chloride; the gas phase is liquefied through a 7 °C condenser, and the unreacted hydrogen fluoride is successfully liquefied and recycled for subsequent reaction processes to improve the raw material utilization rate; while the remaining hydrogen chloride gas after condensation is discharged through a pressure reducing valve to a special water absorption device for treatment.

6. The synthesis method of 2-fluoro-6-trifluoromethylpyridine using a tubular reactor according to claim 1, characterized in that: In step F, the washing process adopts a multi-stage countercurrent washing method to ensure the best removal effect of hydrogen fluoride.

7. The synthesis method of 2-fluoro-6-trifluoromethylpyridine using a tubular reactor according to claim 1, characterized in that: In step F, during rectification, control the temperature of the rectification kettle and reboiler at 110 - 120 °C, the vacuum degree at 35 - 45 Kpa, and the reflux ratio at 1:2 for harvesting. Stop harvesting when there is no distillate, and obtain 2-fluoro-6-trifluoromethylpyridine with a purity of over 99.5%.

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