A continuous flow catalytic hydrogenation synthesis of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone

Abstract

The application discloses a continuous flow catalytic hydrogenation synthesis method of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroacetone, and belongs to the technical field of fine chemical industry and continuous flow chemical synthesis. The preparation method comprises the following steps: taking an organic solvent solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroacetone as feed liquid A, taking hydrogen as feed B, uniformly mixing the feed liquid A and the feed B in a gas-liquid mixer, passing the mixture into a fixed bed reactor filled with a noble metal supported catalyst, performing continuous catalytic hydrogenation reaction under a set temperature and pressure, obtaining a reaction mixture, adjusting the back pressure of the reaction mixture, performing gas-liquid separation, performing crystallization, filtration and washing on the separated liquid, drying the filtered and washed liquid to obtain a target product, and recycling the separated solvent after purification. The application solves the problems of low production efficiency, high safety risk and unstable yield of the traditional batch process, realizes the recycling of the solvent, and improves the purity and yield of the target product.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical engineering and continuous flow chemical synthesis technology, specifically relating to a continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone. Background Technology

[0002] 1-(2-Amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone is a key structural unit in the synthesis of various fluorinated pharmaceutical, pesticide, and material intermediates. Traditional synthetic methods often employ a batch autoclave catalytic hydrogenation process, using noble metals such as platinum and palladium as catalysts, to reduce the nitro group under hydrogen pressure.

[0003] Intermittent operation can easily lead to uneven material mixing and localized overheating, resulting in runaway reactions and safety hazards. Catalyst separation requires filtration, which can cause catalyst loss and dust hazards, and continuous regeneration is difficult to achieve. Post-processing of products is cumbersome, involving multiple steps such as distillation, crystallization, washing, and centrifugation, resulting in high energy consumption, large solvent consumption, and significant yield fluctuations. Continuous flow chemistry technology has advantages such as high mass and heat transfer efficiency, precise control of reaction parameters, good safety, and ease of scale-up, making it particularly suitable for catalytic hydrogenation processes involving highly exothermic, high-pressure, and hazardous reagents. Summary of the Invention

[0004] This invention provides a continuous flow catalytic hydrogenation synthesis method and system for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone, to solve the problems of long reaction cycle and low production efficiency in the synthesis of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in the prior art.

[0005] A continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone includes the following steps: S1. Dissolve 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in an organic solvent to obtain feed liquid A, and use hydrogen gas as feed B; S2. Feed liquid A is delivered to the preheater via a high-pressure pump and heated to 30~45℃ before being introduced into the gas-liquid mixer. Feed B is introduced into the gas-liquid mixer through a flow meter, so that feed liquid A and feed B are uniformly mixed in the gas-liquid mixer to obtain a gas-liquid mixture. S3. The gas-liquid mixture obtained in S2 is fed into a fixed-bed reactor packed with a noble metal supported catalyst, and a continuous catalytic hydrogenation reaction is carried out under the set temperature, pressure and residence time conditions to obtain a reaction mixture; S4. After adjusting the back pressure of the reaction mixture obtained in S3, it is passed into a gas-liquid separator to separate the unreacted feed B. The separated unreacted feed B is recycled or vented. The separated liquid product is continuously crystallized by adjusting the temperature and adding the antisolvent water. The crystallized solid-liquid mixture is then filtered in a continuous solid-liquid separator and washed with a methanol-water mixed solvent to obtain a wet product. The wet product is continuously dried to obtain high-purity 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone. The separated solution is recycled and purified and returned to S1 to prepare feed liquid A.

[0006] Furthermore, in S1, the mass concentration of 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in feed liquid A is 17~25%.

[0007] Furthermore, in S1, the organic solvent is methanol.

[0008] Furthermore, in S1, the hydrogen is industrial grade with a purity of ≥99.5%.

[0009] Furthermore, the gas-liquid mixer is any one of a micro mixer, a T-connector, or a Y-connector.

[0010] Furthermore, the noble metal supported catalyst is either Pt / C or Pd / C, the loading of noble metal in the noble metal supported catalyst is 3-5%, and the particle size of the noble metal supported catalyst is 140 mesh to 2 mm.

[0011] Furthermore, in S3, the set temperature is 30~80℃, the pressure condition is 1~3.5MPa, and the residence time is 5~8min.

[0012] Furthermore, in S3, the molar ratio of feed B to 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in feed liquid A during the continuous catalytic hydrogenation reaction is 5:1.

[0013] Furthermore, in S4, the continuous solid-liquid separator is any one of a belt filter, a centrifuge, or a hydrocyclone separator.

[0014] Furthermore, in S4, the continuous drying is either vacuum belt drying or spiral drying.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: Safe and efficient: The continuous flow system is compact with low liquid holdup, and hydrogen is consumed in real time, significantly reducing the risks associated with storing and handling high-pressure hydrogen; the gas-liquid mixer and fixed-bed catalytic reactor have high heat transfer efficiency, avoiding localized overheating. Stable product quality: The plug flow reactor has no backmixing, a narrow residence time distribution, fewer side reactions, and significantly improved product purity and yield. Green and economical process: No filtration or recovery is required, resulting in a long lifespan and low loss; solvent can be designed for online recovery and recycling; automated continuous operation reduces manual intervention and solvent consumption. Easy to scale up and integrate: Production can be rapidly scaled up through numerical amplification or parallel stacking. Attached Figure Description

[0016] Figure 1 This is a flow chart of the continuous flow catalytic hydrogenation synthesis of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone according to the present invention. Detailed Implementation

[0017] The present invention will be further illustrated below with reference to embodiments. These embodiments are for illustrative purposes only and are not intended to limit the invention in any way. It should be understood that the described embodiments are merely some, not all, of the embodiments described in this application. All other embodiments obtained by those skilled in the art based on the embodiments in this application without inventive effort are within the scope of protection of this application.

[0018] Example 1 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone was dissolved in methanol to prepare feed solution A with a mass concentration of 20%; industrial-grade hydrogen was used as feed B. Feed liquid A is delivered to a preheater at a flow rate of 10 mL / min using a high-pressure pump and heated to 30-45°C. The preheated liquid is then introduced into a micromixer. Feed liquid B, with a flow rate controlled by a flow meter at 50 mL / min, is also introduced into the micromixer, ensuring uniform mixing of feed liquid A and feed liquid B to obtain a gas-liquid mixture. The flow rate of feed liquid B is coordinated with the flow rate of feed liquid A using the high-pressure pump, ensuring that the mixture of feed liquid B and 1-(2-nitro-5-chlorophenyl)-2,2,2- in feed liquid A is homogeneous. The molar ratio of trifluoroethyl ketone is 5:1. The gas-liquid mixture is passed into a 50 mL fixed-bed reactor packed with 3% Pt / C catalyst (140 mesh ~ 2 mm). The fixed-bed reactor is equipped with a temperature monitoring system and an external circulation temperature control system to maintain the set temperature of the catalytic hydrogenation reaction and ensure the stability of the continuous reaction. The reaction temperature is controlled at 50 °C and the pressure at 1.5 MPa. The residence time in the fixed-bed reactor is 5 min to carry out the continuous catalytic hydrogenation reaction and obtain the reaction mixture. The reaction mixture was adjusted to atmospheric pressure via a back pressure regulating valve and then introduced into a gas-liquid separator to separate unreacted feed B. The resulting liquid product entered an online crystallization / quenching module, where crystallization was induced by continuous dropwise addition of deionized water. The crystallized solid-liquid mixture was then continuously centrifuged through a belt filter and washed with a methanol-water mixed solvent to obtain a wet product. The wet product was continuously vacuum belt dried to obtain a white solid of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone. The separated methanol solution was purified by vacuum distillation and returned to S1 for preparing feed solution A. Liquid chromatography analysis showed that the purity of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone was >99%, and the yield was 89%.

[0019] Example 2 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone was dissolved in methanol to prepare feed solution A with a mass concentration of 20%; industrial-grade hydrogen was used as feed B. A high-pressure infusion pump delivers feed liquid A to the preheater at a flow rate of 20 mL / min. After heating to 30-45°C, it is introduced into a T-connector. Feed liquid B, with a flow rate controlled by a flow meter at 50 mL / min, is then introduced into the T-connector to ensure uniform mixing of feed liquid A and feed liquid B within the T-connector, resulting in a gas-liquid mixture. The flow rate of feed liquid B is coordinated with the flow rate of feed liquid A delivered by the high-pressure infusion pump to control the molar ratio of 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in the gas-liquid mixture. The gas-liquid mixture is introduced into a 100 mL fixed-bed reactor containing 5% Pd / C catalyst (140 mesh to 2 mm) at a ratio of 5:1. The fixed-bed reactor is equipped with a temperature monitoring system and an external circulation temperature control system to maintain the set temperature of the catalytic hydrogenation reaction and ensure the stability of the continuous reaction. The reaction temperature is controlled at 60 °C and the pressure at 2 MPa. The residence time of the material in the fixed-bed reactor is 4.5 to 5 min for continuous catalytic hydrogenation reaction. The nitro group is reduced to amino group to obtain the reaction mixture. The reaction mixture was adjusted to atmospheric pressure via a back pressure regulating valve and then introduced into a gas-liquid separator to separate unreacted feed B. The resulting liquid product entered an online crystallization module, where deionized water was continuously added to induce crystallization. The resulting solid-liquid mixture was centrifuged and washed with a methanol-water mixture to obtain a wet product. The wet product was continuously spiral-dried to obtain a white solid of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone. The separated methanol solution was purified by vacuum distillation and returned to S1 for preparing feed solution A. The conversion efficiency was 91%, and the selectivity was >99.5%.

[0020] Example 3 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone was dissolved in methanol to prepare feed solution A with a mass concentration of 25%; industrial-grade hydrogen was used as feed B. A reaction system employing an integrated online infrared spectroscopy monitoring module monitors the decrease in nitro characteristic peaks during the reaction process in real time. Feed liquid A is delivered to the preheater at a flow rate of 8 mL / min via a high-pressure pump, heated to 30-45°C, and then introduced into a micro-mixer. Feed liquid B, with a flow rate controlled by a flow meter at 50 mL / min, is introduced into the micro-mixer, ensuring uniform mixing of feed liquid A and feed liquid B within the T-connector to obtain a gas-liquid mixture. The flow rate of feed liquid B is coordinated with the flow rate of feed liquid A delivered by the high-pressure pump to control the mixing of 1-(2-)-nitro ... The molar ratio of (-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone is 5:1. The gas-liquid mixture is passed into a 50 mL fixed-bed reactor packed with 3% Pt / C catalyst (140 mesh ~ 2 mm). The fixed-bed reactor is equipped with a temperature monitoring system and an external circulation temperature control system to maintain the set temperature of the catalytic hydrogenation reaction and ensure the stability of the continuous reaction. The reaction temperature is controlled at 80 °C and the pressure at 3.1 MPa. The residence time of the gas-liquid mixture in the fixed-bed reactor is 6 min to carry out the continuous catalytic hydrogenation reaction and obtain the reaction mixture. The reaction mixture was adjusted to atmospheric pressure via a back pressure regulating valve and then introduced into a gas-liquid separator to separate unreacted feed B. The resulting liquid product entered an online crystallization / quenching module, where crystallization was induced by continuous dropwise addition of deionized water. The crystallized solid-liquid mixture was centrifuged using a hydrocyclone separator and washed with a methanol-water mixed solvent to obtain a wet product. The wet product was then continuously vacuum belt-dried to obtain a white solid of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone. The separated methanol solution was purified by vacuum distillation and returned to prepare feed solution A. The results showed a raw material conversion rate >99.8%, a yield of 91%, and a purity >99%.

[0021] Example 4 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone was dissolved in methanol to prepare feed solution A with a mass concentration of 20%; industrial-grade hydrogen was used as feed B. Feed liquid A is delivered to the preheater at a flow rate of 178 mL / min using a high-pressure pump. After being heated to 30-45°C, it is introduced into a micro-mixer. Feed liquid B is then introduced into the micro-mixer at a flow rate of 50 mL / min, controlled by a flow meter. This ensures that feed liquid A and feed liquid B are uniformly mixed within the T-connector, resulting in a gas-liquid mixture. The flow rate of feed liquid B is controlled in conjunction with the flow rate of feed liquid A from the high-pressure pump, thereby controlling the molar ratio of 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in the gas-liquid mixture. The gas-liquid mixture was introduced into a 1500 mL fixed-bed reactor containing 5% Pt / C catalyst (140 mesh to 2 mm) at a ratio of 5:1. The fixed-bed reactor was equipped with a temperature monitoring system and an external circulation temperature control system to maintain the set temperature of the catalytic hydrogenation reaction and ensure the stability of the continuous reaction. The reaction temperature was controlled at 77°C and the pressure at 3.5 MPa. The residence time of the material in the fixed-bed reactor was 7.5 min for continuous catalytic hydrogenation. The nitro group was reduced to amino group to obtain the reaction mixture. The reaction mixture was adjusted to atmospheric pressure via a back pressure regulating valve and then introduced into a gas-liquid separator to separate unreacted feed B. The resulting liquid product entered an online crystallization module, where deionized water was continuously added to induce crystallization. The resulting solid-liquid mixture was continuously centrifuged and washed with a methanol-water mixture to obtain a wet product. The wet product was continuously spiral-dried to obtain a white solid of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroacetone. The separated methanol solution was purified by vacuum distillation and returned to prepare feed solution A. The conversion efficiency was 91%, and the selectivity was >99.5%.

[0022] Example 5 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone was dissolved in methanol to prepare feed solution A with a mass concentration of 25%; industrial-grade hydrogen was used as feed B. A reaction system employing an integrated online infrared spectroscopy monitoring module monitors the decrease of nitro characteristic peaks in real time during the reaction. Feed liquid A is delivered to the preheater at a flow rate of 8 mL / min via a high-pressure pump, heated to 30–45°C, and then introduced into a micromixer. Feed liquid B, with a flow rate controlled by a flow meter at 50 mL / min, is also introduced into the micromixer, ensuring uniform mixing of feed liquids A and B to obtain a gas-liquid mixture. The flow rate of feed liquid B is monitored by the flow meter, and the flow rate of feed liquid A is monitored by the high-pressure pump. The flow rate was controlled to maintain a molar ratio of 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in the gas-liquid mixture at 5:1. The gas-liquid mixture was then introduced into a 50 mL fixed-bed reactor packed with 3% Pt / C catalyst (140 mesh ~ 2 mm). The system reaction temperature was controlled at 70 °C, the pressure at 2.5 MPa, and the residence time of the gas-liquid mixture in the fixed-bed reactor was 8 min. A continuous catalytic hydrogenation reaction was carried out to obtain a reaction mixture. The reaction mixture was adjusted to atmospheric pressure via a back pressure regulating valve and then introduced into a gas-liquid separator to separate unreacted feed B. The resulting liquid product entered an online crystallization / quenching module, where crystallization was induced by continuous dropwise addition of deionized water. The crystallized solid-liquid mixture was then continuously centrifuged through a belt filter and washed with a methanol-water mixed solvent to obtain a wet product. The wet product was continuously vacuum belt dried to obtain a white solid of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone. The separated methanol solution was purified by vacuum distillation and returned to prepare feed solution A. The solvent methanol was recovered online by vacuum distillation, and no decrease in reaction efficiency was observed after five cycles. The conversion rate was >99.8%, and the yield was 90%.

[0023] Example 6 30 kg of 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone was dissolved in 143 kg of methanol and stirred until homogeneous to prepare feed solution A with a mass concentration of 17.3%; industrial-grade hydrogen was used as feed B. Feed liquid A is pumped at a high-pressure pump at a flow rate of 10 mL / min to a preheater and heated to 30-45°C. It is then introduced into a micromixer, with feed liquid B introduced at a flow rate of 50 mL / min controlled by a flow meter. This ensures uniform mixing of feed liquid A and feed liquid B, resulting in a gas-liquid mixture. The flow rate of feed liquid B is coordinated with the flow rate of feed liquid A from the high-pressure pump to maintain a molar ratio of 5:1 between feed liquid B and 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in the gas-liquid mixture. This gas-liquid mixture is then introduced into a 500 mL fixed-bed reactor containing 0.6 kg of 3% Pt / C catalyst (140 mesh to 2 mm particle size). The reaction pressure is controlled at 1.0 MPa. The reactor is equipped with a multi-point temperature monitoring system and an external circulation system. A ring-type heat transfer oil temperature control system maintains the reaction temperature stably at 40-50℃. The feed flow rate is adjusted to ensure the gas-liquid mixture resides in the fixed-bed reactor for 8 minutes, yielding a reaction mixture. The reaction mixture is then adjusted to atmospheric pressure via a back pressure regulating valve and introduced into a gas-liquid separator. Unreacted feed B is recycled back to the micro-mixer for reuse. The resulting liquid product enters a continuous distillation-crystallization integrated device. Distillation removes some methanol and adjusts the system concentration. Cooling and the addition of deionized water induce continuous crystallization. The resulting solid-liquid mixture is filtered in a centrifuge and washed with a methanol-water mixture to obtain a wet product. The wet product is continuously vacuum belt-dried to obtain a white solid, 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone. The separated methanol solution is purified by distillation and returned to prepare feed solution A. Testing showed a product yield of 87%, with a purity >99% and selectivity >99.5% as determined by liquid chromatography.

[0024] Of course, the above description is not intended to limit the present invention, and the present invention is not limited to the examples given above. Any changes, modifications, additions or substitutions made by those skilled in the art within the scope of the present invention should also fall within the protection scope of the present invention.

Claims

1. A continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone, comprising the following steps: S1. Dissolve 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in an organic solvent to obtain feed liquid A, and use hydrogen gas as feed B; S2. Feed liquid A is delivered to the preheater via a high-pressure pump and heated to 30~45℃ before being introduced into the gas-liquid mixer. Feed B is introduced into the gas-liquid mixer through a flow meter, so that feed liquid A and feed B are uniformly mixed in the gas-liquid mixer to obtain a gas-liquid mixture. S3. The gas-liquid mixture obtained in S2 is fed into a fixed-bed reactor packed with a noble metal supported catalyst, and a continuous catalytic hydrogenation reaction is carried out under the set temperature, pressure and residence time conditions to obtain a reaction mixture; S4. After adjusting the back pressure of the reaction mixture obtained in S3, it is passed into a gas-liquid separator to separate the unreacted feed B. The separated unreacted feed B is recycled or vented. The separated liquid product is continuously crystallized by adjusting the temperature and adding the antisolvent water. The crystallized solid-liquid mixture is then filtered in a continuous solid-liquid separator and washed with a methanol-water mixed solvent to obtain a wet product. The wet product is continuously dried to obtain high-purity 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone. The separated solution is recycled and purified and returned to S1 to prepare feed liquid A.

2. The continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone according to claim 1, characterized in that, In S1, the mass concentration of 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in feed liquid A is 17~25%.

3. The continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone according to claim 1, characterized in that, In S1, the organic solvent is methanol.

4. The continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone according to claim 1, characterized in that, In S1, the hydrogen is industrial grade with a purity of ≥99.5%.

5. The continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone according to claim 1, characterized in that, The gas-liquid mixer can be any one of a micro mixer, a T-connector, or a Y-connector.

6. The continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone according to claim 1, characterized in that, The noble metal supported catalyst is either Pt / C or Pd / C, the loading of noble metal in the noble metal supported catalyst is 3-5%, and the particle size of the noble metal supported catalyst is 140 mesh to 2 mm.

7. The continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone according to claim 1, characterized in that, In S3, the set temperature is 30~80℃, the pressure is 1~3.5MPa, and the residence time is 5~8min.

8. The continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone according to claim 1, characterized in that, In S3, the molar ratio of feed B to 1-(2-nitro-5-chlorophenyl)-2,2,2-trifluoroethyl ketone in feed liquid A during the continuous catalytic hydrogenation reaction is 5:

1.

9. The continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone according to claim 1, characterized in that, In S4, the continuous solid-liquid separator is any one of a belt filter, a centrifuge, or a hydrocyclone separator.

10. The continuous flow catalytic hydrogenation synthesis method for 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethyl ketone according to claim 1, characterized in that, In step S4, continuous drying is either vacuum belt drying or spiral drying.

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