WO2022011732A1 - Continuous hydrogenation method for ethyl pyrazine-2-carboxylate and use thereof - Google Patents

Continuous hydrogenation method for ethyl pyrazine-2-carboxylate and use thereof Download PDF

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WO2022011732A1
WO2022011732A1 PCT/CN2020/103308 CN2020103308W WO2022011732A1 WO 2022011732 A1 WO2022011732 A1 WO 2022011732A1 CN 2020103308 W CN2020103308 W CN 2020103308W WO 2022011732 A1 WO2022011732 A1 WO 2022011732A1
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reaction
temperature control
bed reactor
control section
carboxylate
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PCT/CN2020/103308
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French (fr)
Chinese (zh)
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洪浩
洪亮
陶建
胡忠
张岩
朱建林
王波辉
戴瑞智
王俊强
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凯莱英生命科学技术(天津)有限公司
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Publication of WO2022011732A1 publication Critical patent/WO2022011732A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the invention relates to the field of organic synthesis, in particular to a continuous hydrogenation method of pyrazine-2-ethyl carboxylate and application thereof.
  • Pyrazine-2-carboxylic acid ethyl ester is a white or pale yellow solid.
  • the existing hydrogenation process of pyrazine-2-carboxylate is carried out in a catalytic hydrogenation reduction reactor, and the whole process is a batch reaction.
  • the above-mentioned catalytic hydrogenation reaction process has high requirements on the safety of hydrogen and reaction devices, large labor and high operation requirements for autoclave operation, catalyst needs to be filtered, it is difficult to control the spontaneous combustion of the catalyst, the hydrogenation reaction time is long, the conversion rate is low, and excessive reduction cannot be controlled. and product issues.
  • the present application provides a continuous hydrogenation method of ethyl pyrazine-2-carboxylate.
  • the main purpose of the present invention is to provide a continuous hydrogenation method of ethyl pyrazine-2-carboxylate and its application, so as to solve the problem that the existing catalytic hydrogenation reaction process of ethyl pyrazine-2-carboxylate is safe for hydrogen and reaction devices
  • High performance requirements, high labor and high operating requirements for autoclave operation, catalyst need to be filtered, difficult to control catalyst spontaneous combustion, long hydrogenation reaction time, low conversion rate and uncontrollable excessive reduction and other problems.
  • a continuous hydrogenation method of pyrazine-2-carboxylic acid ethyl ester comprising: carrying out a mixture of pyrazine-2-carboxylic acid ethyl ester and hydrogen Disperse to form a gas-liquid mixture containing small droplets of 50 nm to 5 mm as the reaction raw material; the reaction raw material is continuously input into the fixed bed reactor for catalytic hydrogenation, and the piperazine-2-ethyl carboxylate is continuously discharged, and at the same time along the The flow direction of the material divides the fixed bed reactor into at least two temperature control sections, and the temperature of the latter temperature control section is lower than the temperature of the former temperature control section.
  • the fixed-bed reactor is divided into a first temperature control section and a second temperature control section, and the temperature of the first temperature control section is 80-320 ° C, the reaction pressure is 0.1-10 MPa, and the volume The space velocity is 0.1-3h -1 ; the temperature of the second temperature control section is 70-310° C., the reaction pressure is 0.1-10MPa, and the volume space velocity is 0.1-3h -1 .
  • gas-liquid ratio in the dispersion process is 1:(1-100).
  • the particle size of the small droplets in the reaction raw material is 100 nm ⁇ 30 ⁇ m.
  • the fixed bed reactor is loaded with a catalyst, and the catalyst is selected from one or more of the group consisting of Ru/C, Pd/C, Rh/C and Ru/Al 2 O 3 .
  • the particle size of the catalyst is 0.1 to 5 mm.
  • the bed pressure drop of the fixed bed reactor is less than 0.01 MPa/m.
  • the method of the dispersion process is selected from the atomization method, the jet method or the Venturi method;
  • the fixed bed reactor is selected from the axial adiabatic fixed reaction bed, the radial adiabatic fixed reaction bed or the tubular fixed bed.
  • the continuous hydrogenation method further comprises: dispersing ethyl pyrazine-2-carboxylate with hydrogen and an organic solvent.
  • the organic solvent is one or more selected from the group consisting of ethanol, water, methanol and dichloromethane.
  • Another aspect of the present application also provides an application of the above-mentioned continuous hydrogenation method in the synthesis of sedative drugs or antiarrhythmic drugs.
  • pyrazine-2-ethyl carboxylate and hydrogen are dispersed to form a gas-liquid mixture containing 50nm-5mm droplets, which are used as reaction raw materials for continuous catalytic hydrogenation.
  • the above-mentioned forced dispersion process can enable the reaction raw materials to perform high-performance mass transfer in the catalytic hydrogenation reaction process, improve the sufficient reaction degree of the reaction raw materials, and shorten the reaction time.
  • the fixed-bed reactor is divided into at least two temperature control sections, and the temperature of the latter temperature control section is lower than the temperature of the previous temperature control section, and the heat accumulation can be effectively removed through the staged temperature control.
  • the reaction state in the reactor which can greatly increase the reaction efficiency, reduce the risk of impurity generation, and improve the yield, purity and product performance stability of the target product.
  • the catalyst does not need to be filtered, which reduces the risk of spontaneous combustion of the catalyst, and the recovered catalyst can also be recycled.
  • the above continuous hydrogenation method has the advantages of low cost, high yield of ethyl piperidine-4-carboxylate and high purity.
  • FIG. 1 shows a schematic structural diagram of a continuous hydrogenation device for pyrazine-2-carboxylic acid ethyl ester used in a typical embodiment of the present invention.
  • the existing catalytic hydrogenation of pyrazine-2-carboxylate has high requirements on the safety of hydrogen and reaction equipment, large labor and high operating requirements for autoclave operations, catalysts need to be filtered, difficult to Control the spontaneous combustion of the catalyst, long hydrogenation reaction time, low conversion rate and inability to control excessive reduction.
  • the present application provides a continuous hydrogenation method of pyrazine-2-ethyl carboxylate, the continuous hydrogenation method comprising: dispersing a mixture of pyrazine-2-ethyl carboxylate and hydrogen to form The gas-liquid mixture containing 50nm-50 ⁇ m droplets is used as the reaction raw material; the reaction raw material is continuously input into the fixed-bed reactor for catalytic hydrogenation, and the piperazine-2-ethyl carboxylate is continuously discharged, and at the same time along the flow direction of the material , the fixed bed reactor is divided into at least two temperature control sections, and the temperature of the latter temperature control section is lower than the temperature of the former temperature control section.
  • the ethyl pyrazine-2-carboxylate and hydrogen are dispersed to form a gas-liquid mixture containing small droplets of 50 nm to 50 ⁇ m, and the mixture is used as a reaction raw material for continuous catalytic hydrogenation reaction.
  • the above-mentioned forced dispersion process can enable the reaction raw materials to perform high-performance mass transfer in the catalytic hydrogenation reaction process, improve the sufficient reaction degree of the reaction raw materials, and shorten the reaction time.
  • the fixed-bed reactor is divided into at least two temperature control sections, and the temperature of the latter temperature control section is lower than the temperature of the previous temperature control section, and the heat accumulation can be effectively removed through the staged temperature control.
  • the reaction state in the reactor which can greatly increase the reaction efficiency, reduce the risk of impurity generation, and improve the yield, purity and product performance stability of the target product.
  • the catalyst does not need to be filtered, which reduces the risk of spontaneous combustion of the catalyst, and the recovered catalyst can also be recycled.
  • the above continuous hydrogenation method has the advantages of low cost, high yield of ethyl piperidine-4-carboxylate and high purity.
  • the above-mentioned continuous synthesis method has less reaction raw materials per unit time, which effectively reduces the risk of excessive reduction. It has great advantages and can successfully realize the modularization of the reaction device; this can greatly save the investment cost of equipment, reduce the occupation of land, and greatly reduce the safety risk caused by the large-scale use of hydrogen.
  • Staged temperature control of the fixed-bed reactor can effectively remove the heat accumulation in the fixed-bed reactor, and effectively control the reaction state in the reactor, which greatly increases the reaction efficiency, reduces the risk of impurity generation, and improves the target product. yield.
  • the more temperature-controlled regions are, the more conducive to improving the yield of the target product, but the more temperature-controlled regions tend to increase the operating intensity of the continuous hydrogenation process.
  • Those skilled in the art can select the number of temperature-controlled regions as required. .
  • the fixed bed reactor is divided into a first temperature control section and a second temperature control section, and the temperature of the first temperature control section is 80-320°C, and the reaction pressure is 0.1 ⁇ 10MPa, volume space velocity of 0.1 ⁇ 3h -1; temperature of the second stage temperature is 70 ⁇ 310 °C, reaction pressure 0.1 ⁇ 10MPa, volume space velocity of 0.1 ⁇ 3h -1.
  • the reaction pressure and volumetric space velocity of each temperature control section are limited within the above-mentioned ranges at the same time, which can further improve the yield of the target product without increasing the operating intensity. and purity.
  • the volumetric space velocity (TOF) (h ⁇ 1 ) is the ratio of the volumetric flow rate of the reactants (L/h) to the volume of the catalyst (m 3 ). More preferably, along the flow direction of the material, the fixed bed reactor is divided into a first temperature control section and a second temperature control section, and the temperature of the first temperature control section is 100-150°C, and the reaction pressure is 2.5-6.5MPa , the volume space velocity is 0.1 ⁇ 0.8h -1 ; the temperature of the second temperature control section is 90 ⁇ 140°C, the reaction pressure is 2.5 ⁇ 6.5MPa, and the volume space velocity is 0.1 ⁇ 0.8h -1 .
  • the above-mentioned fixed bed reactor is a vertical reactor, and the first temperature control section is located above the second temperature control section.
  • the gas-liquid ratio in the dispersion process is 1:(1-100).
  • the gas-liquid ratio in the dispersion process includes but is not limited to the above range, and limiting it within the above range is conducive to further reducing the particle size in the reaction raw material, and improving the mass transfer degree of the reaction raw material in the catalytic hydrogenation process, thereby further improving the raw material. Degree of reaction and yield and purity of target product.
  • the particle size of the small droplets in the reaction raw material is 100 nm ⁇ 30 ⁇ m.
  • the particle size of the small droplets in the reaction raw material includes but is not limited to the above range, and limiting it within the above range is conducive to further improving the mass transfer efficiency of the reaction raw material, thereby further improving the yield and purity of ethyl piperidine-4-carboxylate .
  • the fixed bed reactor is loaded with a catalyst.
  • the catalyst includes, but is not limited to, one or more of the group consisting of Ru/C, Pd/C, Rh/C and Ru/Al 2 O 3 .
  • the above-mentioned catalysts have better catalytic activity, which is beneficial to further improve the reaction rate of the catalytic hydrogenation process and shorten the reaction period.
  • a particulate catalyst is supported on a fixed bed reactor.
  • the particle size of the catalyst is 0.1-5 mm.
  • the bed pressure drop of the fixed bed reactor is less than 0.01 MPa/m.
  • the bed pressure drop of the fixed bed reactor includes but is not limited to the above range, and limiting it within the above range is beneficial to further improve the selectivity of the above reaction, thereby further improving the yield of hydrogenated products.
  • the dispersing method includes but is not limited to atomization method, jet method or venturi method. Compared with other methods, the use of the above range is conducive to forming small droplets of predetermined particle size more quickly and efficiently, thereby helping to improve the mass transfer efficiency of the reaction raw materials.
  • the fixed bed reactor includes, but is not limited to, an axial adiabatic fixed reaction bed, a radial adiabatic fixed reaction bed or a tubular fixed bed.
  • the continuous hydrogenation method further comprises: dispersing ethyl pyrazine-2-carboxylate with hydrogen and an organic solvent. Adding an organic solvent to the reaction raw materials is beneficial to make the catalytic hydrogenation reaction proceed in a more stable environment, and further improve the sufficient reaction degree of the reaction raw materials, thereby helping to improve the safety of the reaction and the yield of the target product.
  • the organic solvent can be selected from those commonly used in the art.
  • the organic solvent includes, but is not limited to, one or more of the group consisting of ethanol, water, methanol and dichloromethane.
  • Another aspect of the present application also provides an application of the above-mentioned continuous hydrogenation method in the synthesis of sedative drugs or antiarrhythmic drugs.
  • the continuous hydrogenation method provided by the present application has the advantages of low cost, high yield of piperazine-4-carboxylic acid ethyl ester and high purity. Applying it in the synthesis of sedative drugs or antiarrhythmic drugs is also beneficial to reduce the synthesis cost and improve the yield, purity and efficacy of sedative drugs or antiarrhythmic drugs.
  • Hydrogen is stored in the hydrogen storage tank 10
  • ethyl pyrazine-4-carboxylate is stored in the raw material storage tank 20
  • the ethyl pyrazine-4-carboxylate and hydrogen are dispersed through the dispersing device 30 to obtain a gas-liquid mixture containing small droplets.
  • the above-mentioned gas-liquid mixture is transported to the catalytic hydrogenation device 40, and sequentially passes through the first temperature control section 41 and the second temperature control section 42 to carry out catalytic hydrogenation reaction to obtain a product system.
  • the above product system is subjected to gas-liquid separation through the gas-liquid separation device 50, and the liquid-phase product is the desired target product.
  • the target product is stored in the product receiving tank 60 .
  • Dispersion process Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50 ⁇ m, as a reaction raw material.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 160°C, the temperature of the second temperature control section 42 is 150°C, the volume space velocity is 0.25h ⁇ 1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.8%, and the product purity is 92.2%.
  • the catalyst utilization (w/w) was 31.3.
  • Dispersion process Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50 ⁇ m, as a reaction raw material.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.25h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 100%, and the product purity is 94%.
  • the catalyst utilization (w/w) was 31.9.
  • Dispersion process Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50 ⁇ m, as a reaction raw material.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.5h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 81.5%, and the product purity is 91.5%. The catalyst utilization (w/w) was 24.5.
  • Dispersion process Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50 ⁇ m, as a reaction raw material.
  • the reaction column was packed with 20% Pd(OH) 2 /C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.25h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 95.5%, and the product purity is 93.98%.
  • the catalyst utilization (w/w) was 30.03.
  • Dispersion process Disperse ethyl pyrazine-4-carboxylate and hydrogen by collisional convection (jet method) with a gas-liquid ratio of 1:100 to form a gas-liquid mixture containing small droplets with a particle size of 100nm-30 ⁇ m. as a reaction raw material.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volumetric space velocity is 0.3h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 100%, and the product purity is 95%.
  • the catalyst utilization (w/w) was 35.
  • Dispersion process Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50 ⁇ m, as a reaction raw material.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 110°C, the volume space velocity is 0.25h ⁇ 1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 100%, and the product purity is 92.5%. The catalyst utilization (w/w) was 31.4.
  • Dispersion process Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50 ⁇ m, as a reaction raw material.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volumetric space velocity is 0.25h -1 , the reaction pressure is 3.2MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 75%, and the product purity is 59.9%. The catalyst utilization (w/w) was 15.6.
  • Dispersion process Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50 ⁇ m, as a reaction raw material.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 23.56g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 3mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.25h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 80.9%, and the product purity is 77.5%. The catalyst utilization (w/w) was 21.2.
  • Dispersion process Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), and the gas-liquid ratio is 1:100. To form a gas-liquid mixture containing small droplets with a particle size of 50nm-50 ⁇ m , as the reaction raw material.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 23.56g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 5mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.25h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 76.5%, and the product purity is 91.5%. The catalyst utilization (w/w) was 23.8.
  • Dispersion process Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50 ⁇ m, as a reaction raw material.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 220°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.25h ⁇ 1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 100%, and the product purity is 53.4%.
  • the catalyst utilization (w/w) was 18.5.
  • the continuous hydrogenation method provided by the application has the advantages of safe reaction, low labor intensity, high raw material conversion rate and piperidine-4-carboxylic acid The advantages of high purity of ethyl ester.

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Abstract

Provided is a continuous hydrogenation method for ethyl pyrazine-2-carboxylate. The continuous hydrogenation method comprises: dispersing a mixture of ethyl pyrazine-2-carboxylate and hydrogen to form a gas-liquid mixture containing small liquid drops with sizes of 50 nm to 5 mm, wherein the gas-liquid mixture is used as a reaction raw material; and continuously feeding the reaction raw material into a fixed bed reactor for a catalytic hydrogenation reaction, and continuously discharging ethyl piperazine-2-carboxylate, wherein the fixed bed reactor is divided into at least two temperature control sections along the flow direction of the material, and the temperature of the latter temperature control section is lower than the temperature of the former temperature control section. According to the above forced dispersion process, the reaction raw materials can be subjected to high-performance mass transfer in the catalytic hydrogenation reaction process, the sufficient reaction degree of the reaction raw materials is improved, and the reaction time is shortened. The sectional temperature control along the flow direction of the material of the fixed bed reactor can effectively remove the heat accumulation and control the reaction state in the reactor, and can improve the yield, purity and product performance stability of the target product.

Description

吡嗪-2-甲酸乙酯的连续加氢方法及其应用Continuous hydrogenation method of pyrazine-2-carboxylate and its application 技术领域technical field
本发明涉及有机合成领域，具体而言，涉及一种吡嗪-2-甲酸乙酯的连续加氢方法及其应用。The invention relates to the field of organic synthesis, in particular to a continuous hydrogenation method of pyrazine-2-ethyl carboxylate and application thereof.
背景技术Background technique
吡嗪-2-甲酸乙酯是一种白色或淡黄色固体。现有的吡嗪-2-甲酸乙酯的加氢过程在催化氢化还原反应器中进行，整个过程为批次性反应。且上述催化氢化反应过程存在对氢气和反应装置安全性要求较高、高压釜操作劳动量大和操作要求高、催化剂需要过滤、难以控制催化剂自燃、氢化反应时间长、转化率低和不能控制还原过度及产品等问题。Pyrazine-2-carboxylic acid ethyl ester is a white or pale yellow solid. The existing hydrogenation process of pyrazine-2-carboxylate is carried out in a catalytic hydrogenation reduction reactor, and the whole process is a batch reaction. And the above-mentioned catalytic hydrogenation reaction process has high requirements on the safety of hydrogen and reaction devices, large labor and high operation requirements for autoclave operation, catalyst needs to be filtered, it is difficult to control the spontaneous combustion of the catalyst, the hydrogenation reaction time is long, the conversion rate is low, and excessive reduction cannot be controlled. and product issues.
鉴于上述问题的存在，本申请提供了一种吡嗪-2-甲酸乙酯的连续化氢化方法。In view of the existence of the above problems, the present application provides a continuous hydrogenation method of ethyl pyrazine-2-carboxylate.
发明内容SUMMARY OF THE INVENTION
本发明的主要目的在于提供一种吡嗪-2-甲酸乙酯的连续加氢方法及其应用，以解决现有的吡嗪-2-甲酸乙酯催化氢化反应过程存在对氢气和反应装置安全性要求较高、高压釜操作劳动量大和操作要求高、催化剂需要过滤、难以控制催化剂自燃、氢化反应时间长、转化率低和不能控制还原过度等问题。The main purpose of the present invention is to provide a continuous hydrogenation method of ethyl pyrazine-2-carboxylate and its application, so as to solve the problem that the existing catalytic hydrogenation reaction process of ethyl pyrazine-2-carboxylate is safe for hydrogen and reaction devices High performance requirements, high labor and high operating requirements for autoclave operation, catalyst need to be filtered, difficult to control catalyst spontaneous combustion, long hydrogenation reaction time, low conversion rate and uncontrollable excessive reduction and other problems.
为了实现上述目的，根据本发明的一个方面提供了一种吡嗪-2-甲酸乙酯的连续加氢方法，该连续加氢方法包括：将吡嗪-2-甲酸乙酯与氢气的混合物进行分散，以形成含有50nm～5mm小液滴的气液混合物作为反应原料；将反应原料连续地输入固定床反应器中进行催化氢化反应，并连续地排出哌嗪-2-甲酸乙酯，同时沿物料的流动方向，将固定床反应器分为至少两个控温段，且后一个控温段的温度低于前一个控温段的温度。In order to achieve the above object, according to one aspect of the present invention, there is provided a continuous hydrogenation method of pyrazine-2-carboxylic acid ethyl ester, the continuous hydrogenation method comprising: carrying out a mixture of pyrazine-2-carboxylic acid ethyl ester and hydrogen Disperse to form a gas-liquid mixture containing small droplets of 50 nm to 5 mm as the reaction raw material; the reaction raw material is continuously input into the fixed bed reactor for catalytic hydrogenation, and the piperazine-2-ethyl carboxylate is continuously discharged, and at the same time along the The flow direction of the material divides the fixed bed reactor into at least two temperature control sections, and the temperature of the latter temperature control section is lower than the temperature of the former temperature control section.
进一步地，沿物料的流动方向，将固定床反应器分为第一控温段和第二控温段，且第一控温段的温度为80～320℃，反应压力为0.1～10MPa，体积空速为0.1～3h -1；第二控温段的温度为70～310℃，反应压力为0.1～10MPa，体积空速为0.1～3h -1。 Further, along the flow direction of the material, the fixed-bed reactor is divided into a first temperature control section and a second temperature control section, and the temperature of the first temperature control section is 80-320 ° C, the reaction pressure is 0.1-10 MPa, and the volume The space velocity is 0.1-3h -1 ; the temperature of the second temperature control section is 70-310° C., the reaction pressure is 0.1-10MPa, and the volume space velocity is 0.1-3h -1 .
进一步地，分散过程的气液比为1:(1～100)。Further, the gas-liquid ratio in the dispersion process is 1:(1-100).
进一步地，反应原料中小液滴的粒径为100nm～30μm。Further, the particle size of the small droplets in the reaction raw material is 100 nm˜30 μm.
进一步地，催化氢化反应中，固定床反应器上负载有催化剂，且催化剂选自Ru/C、Pd/C、Rh/C和Ru/Al 2O 3组成的组中的一种或多种。 Further, in the catalytic hydrogenation reaction, the fixed bed reactor is loaded with a catalyst, and the catalyst is selected from one or more of the group consisting of Ru/C, Pd/C, Rh/C and Ru/Al 2 O 3 .
进一步地，催化剂的粒径为0.1～5mm。Further, the particle size of the catalyst is 0.1 to 5 mm.
进一步地，固定床反应器的床层压降小于0.01MPa/m。Further, the bed pressure drop of the fixed bed reactor is less than 0.01 MPa/m.
进一步地，分散过程的方法选自雾化法、射流法或文丘里法；固定床反应器选自轴向绝热式固定反应床、径向绝热式固定反应床或列管固定床。Further, the method of the dispersion process is selected from the atomization method, the jet method or the Venturi method; the fixed bed reactor is selected from the axial adiabatic fixed reaction bed, the radial adiabatic fixed reaction bed or the tubular fixed bed.
进一步地，连续加氢方法还包括：将吡嗪-2-甲酸乙酯与氢气及有机溶剂进行分散过程。Further, the continuous hydrogenation method further comprises: dispersing ethyl pyrazine-2-carboxylate with hydrogen and an organic solvent.
进一步地，有机溶剂选自乙醇、水、甲醇和二氯甲烷组成的组中的一种或多种。Further, the organic solvent is one or more selected from the group consisting of ethanol, water, methanol and dichloromethane.
本申请的另一方面还提供了一种上述连续加氢方法在镇静类药物或抗心律失常类药物的合成中的应用。Another aspect of the present application also provides an application of the above-mentioned continuous hydrogenation method in the synthesis of sedative drugs or antiarrhythmic drugs.
应用本发明的技术方案，将吡嗪-2-甲酸乙酯与氢气通过分散过程形成含有50nm～5mm小液滴的气液混合物，并以此作为反应原料进行连续催化氢化反应。相比于未进行上述强制分散步骤的催化氢化过程，上述强制分散过程能够使反应原料在催化氢化反应过程中进行高性能传质，提高反应原料的充分反应程度，并缩短反应时间。同时沿物料的流动方向，将固定床反应器分为至少两个控温段，且后一个控温段的温度低于前一个控温段的温度，通过分段控温能有效移除热量积蓄，并有效控制反应器中的反应状态，能极大地增加反应效率，降低杂质生成的风险，提高目标产品的收率、纯度和产品性能稳定性。催化氢化反应过后催化剂无需过滤，降低了催化剂自燃风险，回收的催化剂也可以回收再用。在此基础上，上述连续加氢方法具有成本低、哌啶-4-甲酸乙酯收率高和纯度高等优点。By applying the technical scheme of the present invention, pyrazine-2-ethyl carboxylate and hydrogen are dispersed to form a gas-liquid mixture containing 50nm-5mm droplets, which are used as reaction raw materials for continuous catalytic hydrogenation. Compared with the catalytic hydrogenation process without the above-mentioned forced dispersion step, the above-mentioned forced dispersion process can enable the reaction raw materials to perform high-performance mass transfer in the catalytic hydrogenation reaction process, improve the sufficient reaction degree of the reaction raw materials, and shorten the reaction time. At the same time, along the flow direction of the material, the fixed-bed reactor is divided into at least two temperature control sections, and the temperature of the latter temperature control section is lower than the temperature of the previous temperature control section, and the heat accumulation can be effectively removed through the staged temperature control. , and effectively control the reaction state in the reactor, which can greatly increase the reaction efficiency, reduce the risk of impurity generation, and improve the yield, purity and product performance stability of the target product. After the catalytic hydrogenation reaction, the catalyst does not need to be filtered, which reduces the risk of spontaneous combustion of the catalyst, and the recovered catalyst can also be recycled. On this basis, the above continuous hydrogenation method has the advantages of low cost, high yield of ethyl piperidine-4-carboxylate and high purity.
附图说明Description of drawings
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：The accompanying drawings forming a part of the present application are used to provide further understanding of the present invention, and the exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the attached image:
图1示出了根据本发明的一种典型的实施方式中采用的吡嗪-2-甲酸乙酯的连续加氢装置的结构示意图。FIG. 1 shows a schematic structural diagram of a continuous hydrogenation device for pyrazine-2-carboxylic acid ethyl ester used in a typical embodiment of the present invention.
其中，上述附图包括以下附图标记：Wherein, the above-mentioned drawings include the following reference signs:
10、氢气储罐；20、原料储罐；30、分散装置；40、催化氢化装置；41、第一控温段；42、第二控温段；50、气液分离装置；60、产品接收罐。10, hydrogen storage tank; 20, raw material storage tank; 30, dispersion device; 40, catalytic hydrogenation device; 41, first temperature control section; 42, second temperature control section; 50, gas-liquid separation device; 60, product receiving Can.
具体实施方式detailed description
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。It should be noted that the embodiments in the present application and the features of the embodiments may be combined with each other in the case of no conflict. The present invention will be described in detail below with reference to the accompanying drawings and in conjunction with the embodiments.
正如背景技术部分所描述的，现有的吡嗪-2-甲酸乙酯催化氢化反应过程存在对氢气和反应装置安全性要求较高、高压釜操作劳动量大和操作要求高、催化剂需要过滤、难以控制催化剂自燃、氢化反应时间长、转化率低和不能控制还原过度等问题。为了解决上述技术问题，本申请提供了一种吡嗪-2-甲酸乙酯的连续加氢方法，连续加氢方法包括：将吡嗪-2-甲酸乙酯与氢气的混合物进行分散，以形成含有50nm～50μm小液滴的气液混合物作为反应原料；将 反应原料连续地输入固定床反应器中进行催化氢化反应，并连续地排出哌嗪-2-甲酸乙酯，同时沿物料的流动方向，将固定床反应器分为至少两个控温段，且后一个控温段的温度低于前一个控温段的温度。As described in the background art section, the existing catalytic hydrogenation of pyrazine-2-carboxylate has high requirements on the safety of hydrogen and reaction equipment, large labor and high operating requirements for autoclave operations, catalysts need to be filtered, difficult to Control the spontaneous combustion of the catalyst, long hydrogenation reaction time, low conversion rate and inability to control excessive reduction. In order to solve the above technical problems, the present application provides a continuous hydrogenation method of pyrazine-2-ethyl carboxylate, the continuous hydrogenation method comprising: dispersing a mixture of pyrazine-2-ethyl carboxylate and hydrogen to form The gas-liquid mixture containing 50nm-50μm droplets is used as the reaction raw material; the reaction raw material is continuously input into the fixed-bed reactor for catalytic hydrogenation, and the piperazine-2-ethyl carboxylate is continuously discharged, and at the same time along the flow direction of the material , the fixed bed reactor is divided into at least two temperature control sections, and the temperature of the latter temperature control section is lower than the temperature of the former temperature control section.
将吡嗪-2-甲酸乙酯与氢气通过分散过程形成含有50nm～50μm小液滴的气液混合物，并以此作为反应原料进行连续催化氢化反应。相比于未进行上述强制分散步骤的催化氢化过程，上述强制分散过程能够使反应原料在催化氢化反应过程中进行高性能传质，提高反应原料的充分反应程度，并缩短反应时间。同时沿物料的流动方向，将固定床反应器分为至少两个控温段，且后一个控温段的温度低于前一个控温段的温度，通过分段控温能有效移除热量积蓄，并有效控制反应器中的反应状态，能极大地增加反应效率，降低杂质生成的风险，提高目标产品的收率、纯度和产品性能稳定性。催化氢化反应过后催化剂无需过滤，降低了催化剂自燃风险，回收的催化剂也可以回收再用。在此基础上，上述连续加氢方法具有成本低、哌啶-4-甲酸乙酯收率高和纯度高等优点。The ethyl pyrazine-2-carboxylate and hydrogen are dispersed to form a gas-liquid mixture containing small droplets of 50 nm to 50 μm, and the mixture is used as a reaction raw material for continuous catalytic hydrogenation reaction. Compared with the catalytic hydrogenation process without the above-mentioned forced dispersion step, the above-mentioned forced dispersion process can enable the reaction raw materials to perform high-performance mass transfer in the catalytic hydrogenation reaction process, improve the sufficient reaction degree of the reaction raw materials, and shorten the reaction time. At the same time, along the flow direction of the material, the fixed-bed reactor is divided into at least two temperature control sections, and the temperature of the latter temperature control section is lower than the temperature of the previous temperature control section, and the heat accumulation can be effectively removed through the staged temperature control. , and effectively control the reaction state in the reactor, which can greatly increase the reaction efficiency, reduce the risk of impurity generation, and improve the yield, purity and product performance stability of the target product. After the catalytic hydrogenation reaction, the catalyst does not need to be filtered, which reduces the risk of spontaneous combustion of the catalyst, and the recovered catalyst can also be recycled. On this basis, the above continuous hydrogenation method has the advantages of low cost, high yield of ethyl piperidine-4-carboxylate and high purity.
相比于批次反应，上述连续化合成法在单位时间内的反应原料量少，有效降低还原过度的风险，采用的反应装置的占地面积较小，且在换热和提高设备承压上具有较大的优势，能成功实现反应装置模块化；这能极大地节省设备投资成本，减少占地，并大大降低由大量使用氢气带来的安全风险。Compared with the batch reaction, the above-mentioned continuous synthesis method has less reaction raw materials per unit time, which effectively reduces the risk of excessive reduction. It has great advantages and can successfully realize the modularization of the reaction device; this can greatly save the investment cost of equipment, reduce the occupation of land, and greatly reduce the safety risk caused by the large-scale use of hydrogen.
将固定床反应器进行分段控温能有效移除固定床反应器中的热量积蓄，并有效控制反应器中的反应状态，极大地增加反应效率，降低杂质生成的风险，进而提高目标产品的收率。分别控温的区域越多，越有利于提高目标产品的收率，但是控温区域较多式易增加连续加氢过程的操作强度，本领域技术人员可以根据需要选择分别控温的区域的数量。在一种优选的实施例中，沿物料的流动方向，将固定床反应器分为第一控温段和第二控温段，且第一控温段的温度为80～320℃，反应压力为0.1～10MPa，体积空速为0.1～3h -1；第二控温段的温度为70～310℃，反应压力为0.1～10MPa，体积空速为0.1～3h -1。将固定床反应器分为两个控温段时，同时将各控温段的反应压力和体积空速限定在上述范围内，能够在不增加操作强度的同时，进一步地提高目标产物的收率和纯度。体积空速(TOF)(h -1)为反应物的体积流速(L/h)与催化剂的体积(m 3)之比。更优选地，沿物料的流动方向，将固定床反应器分为第一控温段和第二控温段，且第一控温段的温度为100～150℃，反应压力为2.5～6.5MPa，体积空速为0.1～0.8h -1；第二控温段的温度为90～140℃，反应压力为2.5～6.5MPa，体积空速为0.1～0.8h -1。 Staged temperature control of the fixed-bed reactor can effectively remove the heat accumulation in the fixed-bed reactor, and effectively control the reaction state in the reactor, which greatly increases the reaction efficiency, reduces the risk of impurity generation, and improves the target product. yield. The more temperature-controlled regions are, the more conducive to improving the yield of the target product, but the more temperature-controlled regions tend to increase the operating intensity of the continuous hydrogenation process. Those skilled in the art can select the number of temperature-controlled regions as required. . In a preferred embodiment, along the flow direction of the material, the fixed bed reactor is divided into a first temperature control section and a second temperature control section, and the temperature of the first temperature control section is 80-320°C, and the reaction pressure is 0.1 ~ 10MPa, volume space velocity of 0.1 ~ 3h -1; temperature of the second stage temperature is 70 ~ 310 ℃, reaction pressure 0.1 ~ 10MPa, volume space velocity of 0.1 ~ 3h -1. When the fixed-bed reactor is divided into two temperature control sections, the reaction pressure and volumetric space velocity of each temperature control section are limited within the above-mentioned ranges at the same time, which can further improve the yield of the target product without increasing the operating intensity. and purity. The volumetric space velocity (TOF) (h −1 ) is the ratio of the volumetric flow rate of the reactants (L/h) to the volume of the catalyst (m 3 ). More preferably, along the flow direction of the material, the fixed bed reactor is divided into a first temperature control section and a second temperature control section, and the temperature of the first temperature control section is 100-150°C, and the reaction pressure is 2.5-6.5MPa , the volume space velocity is 0.1～0.8h -1 ; the temperature of the second temperature control section is 90～140°C, the reaction pressure is 2.5～6.5MPa, and the volume space velocity is 0.1～0.8h -1 .
为了更进一步提高反应的充分程度，优选地，上述固定床反应器为立式反应器，第一控温段位于所述第二控温段的上方。In order to further improve the sufficiency of the reaction, preferably, the above-mentioned fixed bed reactor is a vertical reactor, and the first temperature control section is located above the second temperature control section.
将反应原料中小液滴的粒径限定在50nm～50μm范围内有利于提高反应原料的传质过程。在一种优选的实施例中，分散过程的气液比为1:(1～100)。分散过程中的气液比包括但不限于上述范围，而将其限定在上述范围内有利于进一步降低反应原料中的粒径，并提高催化氢化过程中反应原料传质程度，从而进一步提高原料的反应程度和目标产品的收率和纯度。Limiting the particle size of the small droplets in the reaction raw materials within the range of 50 nm to 50 μm is beneficial to improve the mass transfer process of the reaction raw materials. In a preferred embodiment, the gas-liquid ratio in the dispersion process is 1:(1-100). The gas-liquid ratio in the dispersion process includes but is not limited to the above range, and limiting it within the above range is conducive to further reducing the particle size in the reaction raw material, and improving the mass transfer degree of the reaction raw material in the catalytic hydrogenation process, thereby further improving the raw material. Degree of reaction and yield and purity of target product.
在另一种优选的实施例中，反应原料中小液滴的粒径为100nm～30μm。反应原料中小液滴的粒径包括但不限于上述范围，而将其限定在上述范围内有利于进一步提高反应原料的传质效率，从而进一步提高哌啶-4-甲酸乙酯的产率和纯度。In another preferred embodiment, the particle size of the small droplets in the reaction raw material is 100 nm˜30 μm. The particle size of the small droplets in the reaction raw material includes but is not limited to the above range, and limiting it within the above range is conducive to further improving the mass transfer efficiency of the reaction raw material, thereby further improving the yield and purity of ethyl piperidine-4-carboxylate .
上述催化氢化反应中，固定床反应器上负载有催化剂。优选地，催化剂包括但不限于Ru/C、Pd/C、Rh/C和Ru/Al 2O 3组成的组中的一种或多种。相比于其它催化剂，采用上述几种催化剂具有更好的催化活性，从而有利于进一步提高催化氢化过程的反应速率，缩短反应周期。 In the above catalytic hydrogenation reaction, the fixed bed reactor is loaded with a catalyst. Preferably, the catalyst includes, but is not limited to, one or more of the group consisting of Ru/C, Pd/C, Rh/C and Ru/Al 2 O 3 . Compared with other catalysts, the above-mentioned catalysts have better catalytic activity, which is beneficial to further improve the reaction rate of the catalytic hydrogenation process and shorten the reaction period.
催化氢化过程中，在固定床反应器上负载又颗粒状的催化剂。为了进一步提高反应原料与催化剂之间的传质效果，在一种优选的实施例中，催化剂的粒径为0.1～5mm。During catalytic hydrogenation, a particulate catalyst is supported on a fixed bed reactor. In order to further improve the mass transfer effect between the reaction raw materials and the catalyst, in a preferred embodiment, the particle size of the catalyst is 0.1-5 mm.
在一种优选的实施例中，固定床反应器的床层压降小于0.01MPa/m。固定床反应器的床层压降包括但不限于上述范围，而将其限定在上述范围内有利于进一步提高上述反应的选择性，从而有利于进一步提高加氢产物的收率。In a preferred embodiment, the bed pressure drop of the fixed bed reactor is less than 0.01 MPa/m. The bed pressure drop of the fixed bed reactor includes but is not limited to the above range, and limiting it within the above range is beneficial to further improve the selectivity of the above reaction, thereby further improving the yield of hydrogenated products.
在一种优选的实施例中，分散的方法包括但不限于雾化法、射流法或文丘里法。相比于其它方法，采用上述范围有利于更加快速和高效地形成预定粒径的小液滴，从而有利于提高反应原料的传质效率。优选地，固定床反应器包括但不限于轴向绝热式固定反应床、径向绝热式固定反应床或列管固定床。In a preferred embodiment, the dispersing method includes but is not limited to atomization method, jet method or venturi method. Compared with other methods, the use of the above range is conducive to forming small droplets of predetermined particle size more quickly and efficiently, thereby helping to improve the mass transfer efficiency of the reaction raw materials. Preferably, the fixed bed reactor includes, but is not limited to, an axial adiabatic fixed reaction bed, a radial adiabatic fixed reaction bed or a tubular fixed bed.
在一种优选的实施例中，连续加氢方法还包括：将吡嗪-2-甲酸乙酯与氢气及有机溶剂进行分散过程。在反应原料中加入有机溶剂有利于使催化氢化反应在更加平稳的环境中进行，并进一步提高反应原料的充分反应程度，从而有利于提高反应的安全性和目标产物的收率。In a preferred embodiment, the continuous hydrogenation method further comprises: dispersing ethyl pyrazine-2-carboxylate with hydrogen and an organic solvent. Adding an organic solvent to the reaction raw materials is beneficial to make the catalytic hydrogenation reaction proceed in a more stable environment, and further improve the sufficient reaction degree of the reaction raw materials, thereby helping to improve the safety of the reaction and the yield of the target product.
上述连续化合成反应中，有机溶剂可以选用本领域常用的种类。优选地，有机溶剂包括但不限于乙醇、水、甲醇和二氯甲烷组成的组中的一种或多种。In the above continuous synthesis reaction, the organic solvent can be selected from those commonly used in the art. Preferably, the organic solvent includes, but is not limited to, one or more of the group consisting of ethanol, water, methanol and dichloromethane.
本申请的另一方面还提供了一种上述连续加氢方法在镇静类药物或抗心律失常类药物的合成中的应用。Another aspect of the present application also provides an application of the above-mentioned continuous hydrogenation method in the synthesis of sedative drugs or antiarrhythmic drugs.
由于本申请提供的连续氢化方法具有成本低、哌嗪-4-甲酸乙酯收率高和纯度高等优点。将其应用在镇静类药物或抗心律失常类药物的合成中，同样有利于降低其合成成本，并提高镇静类药物或抗心律失常类药物的收率和纯度以及药效。Because the continuous hydrogenation method provided by the present application has the advantages of low cost, high yield of piperazine-4-carboxylic acid ethyl ester and high purity. Applying it in the synthesis of sedative drugs or antiarrhythmic drugs is also beneficial to reduce the synthesis cost and improve the yield, purity and efficacy of sedative drugs or antiarrhythmic drugs.
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面结合实施例来详细说明本发明。It should be noted that the embodiments in the present application and the features of the embodiments may be combined with each other in the case of no conflict. The present invention will be described in detail below with reference to the embodiments.
实施例采用图1所示的装置对吡嗪-4-甲酸乙酯与氢气进行催化氢化。具体过程包括：EXAMPLES The device shown in Figure 1 was used to carry out catalytic hydrogenation of ethyl pyrazine-4-carboxylate and hydrogen. The specific process includes:
氢气储存在氢气储罐10中，吡嗪-4-甲酸乙酯储存在原料储罐20中。将吡嗪-4-甲酸乙酯与氢气经分散装置30进行分散，获得含有小液滴的气液混合物。将上述气液混合物输送至催化氢化装置40中，并依次经过第一控温段41和第二控温段42进行催化氢化反应，得到产物体系。上述产物体系经过气液分离装置50进行气液分离，液相产物即为所需的目标产品。目标产品储存在产品接收罐60中。Hydrogen is stored in the hydrogen storage tank 10 , and ethyl pyrazine-4-carboxylate is stored in the raw material storage tank 20 . The ethyl pyrazine-4-carboxylate and hydrogen are dispersed through the dispersing device 30 to obtain a gas-liquid mixture containing small droplets. The above-mentioned gas-liquid mixture is transported to the catalytic hydrogenation device 40, and sequentially passes through the first temperature control section 41 and the second temperature control section 42 to carry out catalytic hydrogenation reaction to obtain a product system. The above product system is subjected to gas-liquid separation through the gas-liquid separation device 50, and the liquid-phase product is the desired target product. The target product is stored in the product receiving tank 60 .
实施例1Example 1
分散过程：以碰撞对流方式(射流法)，将吡嗪-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成含有粒径为50nm～50μm小液滴的气液混合物，作为反应原料。Dispersion process: Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50μm, as a reaction raw material.
连续反应：在反应柱中填装5％Ru/C催化剂。两端为氧化铝微球(1mm)，中间催化剂填装质量28.38g，填装高度300mm，填装直径19.2mm，催化剂粒径1mm，作为催化氢化装置40(固定床反应器)。Continuous reaction: The reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
将上述反应原料连续通入上述催化氢化装置40(固定床反应器)进行催化氢化反应，得到哌嗪-4-甲酸乙酯，其中，催化氢化装置40(固定床反应器)分两段进行控温，且沿物料流动方向，第一控温段41的温度为160℃，第二控温段42的温度为150℃，体积空速为0.25h -1，反应压力为4.5MPa，运行50h。经气液分离装置50分离后，原料的转化率为99.8％，产品纯度为92.2％。催化剂利用率(w/w)为31.3。 The above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 160°C, the temperature of the second temperature control section 42 is 150°C, the volume space velocity is 0.25h −1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 99.8%, and the product purity is 92.2%. The catalyst utilization (w/w) was 31.3.
实施例2Example 2
分散过程：以碰撞对流方式(射流法)，将吡嗪-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成含有粒径为50nm～50μm小液滴的气液混合物，作为反应原料。Dispersion process: Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50μm, as a reaction raw material.
连续反应：在反应柱中填装5％Ru/C催化剂。两端为氧化铝微球(1mm)，中间催化剂填装质量28.38g，填装高度300mm，填装直径19.2mm，催化剂粒径1mm，作为催化氢化装置40(固定床反应器)。Continuous reaction: The reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
将上述反应原料连续通入上述催化氢化装置40(固定床反应器)进行催化氢化反应，得到哌嗪-4-甲酸乙酯，其中，催化氢化装置40(固定床反应器)分两段进行控温，且沿物料流动方向，第一控温段41的温度为110℃，第二控温段42的温度为100℃，体积空速为0.25h -1，反应压力为4.5MPa，运行50h。经气液分离装置50分离后，原料的转化率为100％，产品纯度为94％。催化剂利用率(w/w)为31.9。 The above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.25h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 100%, and the product purity is 94%. The catalyst utilization (w/w) was 31.9.
实施例3Example 3
分散过程：以碰撞对流方式(射流法)，将吡嗪-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成含有粒径为50nm～50μm小液滴的气液混合物，作为反应原料。Dispersion process: Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50μm, as a reaction raw material.
连续反应：在反应柱中填装5％Ru/C催化剂。两端为氧化铝微球(1mm)，中间催化剂填装质量28.38g，填装高度300mm，填装直径19.2mm，催化剂粒径1mm，作为催化氢化装置40(固定床反应器)。Continuous reaction: The reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
将上述反应原料连续通入上述催化氢化装置40(固定床反应器)进行催化氢化反应，得到哌嗪-4-甲酸乙酯，其中，催化氢化装置40(固定床反应器)分两段进行控温，且沿物料流动方向，第一控温段41的温度为110℃，第二控温段42的温度为100℃，体积空速为0.5h -1，反应压力为4.5MPa，运行50h。经气液分离装置50分离后，原料的转化率为81.5％，产品纯度为91.5％。催化剂利用率(w/w)为24.5。 The above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.5h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 81.5%, and the product purity is 91.5%. The catalyst utilization (w/w) was 24.5.
实施例4Example 4
分散过程：以碰撞对流方式(射流法)，将吡嗪-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成含有粒径为50nm～50μm小液滴的气液混合物，作为反应原料。Dispersion process: Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50μm, as a reaction raw material.
连续反应：在反应柱中填装20％Pd(OH) 2/C催化剂。两端为氧化铝微球(1mm)，中间催化剂填装质量28.38g，填装高度300mm，填装直径19.2mm，催化剂粒径1mm，作为催化氢化装置40(固定床反应器)。 Continuous reaction: The reaction column was packed with 20% Pd(OH) 2 /C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
将上述反应原料连续通入上述催化氢化装置40(固定床反应器)进行催化氢化反应，得到哌嗪-4-甲酸乙酯，其中，催化氢化装置40(固定床反应器)分两段进行控温，且沿物料流动方向，第一控温段41的温度为110℃，第二控温段42的温度为100℃，体积空速为0.25h -1，反应压力为4.5MPa，运行50h。经气液分离装置50分离后，原料的转化率为95.5％，产品纯度为93.98％。催化剂利用率(w/w)为30.03。 The above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.25h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 95.5%, and the product purity is 93.98%. The catalyst utilization (w/w) was 30.03.
实施例5Example 5
分散过程：以碰撞对流方式(射流法)，将吡嗪-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成含有粒径为100nm～30μm小液滴的气液混合物，作为反应原料。Dispersion process: Disperse ethyl pyrazine-4-carboxylate and hydrogen by collisional convection (jet method) with a gas-liquid ratio of 1:100 to form a gas-liquid mixture containing small droplets with a particle size of 100nm-30μm. as a reaction raw material.
连续反应：在反应柱中填装5％Ru/C催化剂。两端为氧化铝微球(1mm)，中间催化剂填装质量28.38g，填装高度300mm，填装直径19.2mm，催化剂粒径1mm，作为催化氢化装置40(固定床反应器)。Continuous reaction: The reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
将上述反应原料连续通入上述催化氢化装置40(固定床反应器)进行催化氢化反应，得到哌嗪-4-甲酸乙酯，其中，催化氢化装置40(固定床反应器)分两段进行控温，且沿物料流动方向，第一控温段41的温度为110℃，第二控温段42的温度为100℃，体积空速为0.3h -1，反应压力为4.5MPa，运行50h。经气液分离装置50分离后，原料的转化率为100％，产品纯度为95％。催化剂利用率(w/w)为35。 The above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volumetric space velocity is 0.3h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 100%, and the product purity is 95%. The catalyst utilization (w/w) was 35.
实施例6Example 6
分散过程：以碰撞对流方式(射流法)，将吡嗪-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成含有粒径为50nm～50μm小液滴的气液混合物，作为反应原料。Dispersion process: Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50μm, as a reaction raw material.
连续反应：在反应柱中填装5％Ru/C催化剂。两端为氧化铝微球(1mm)，中间催化剂填装质量28.38g，填装高度300mm，填装直径19.2mm，催化剂粒径1mm，作为催化氢化装置40(固定床反应器)。Continuous reaction: The reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
将上述反应原料连续通入上述催化氢化装置40(固定床反应器)进行催化氢化反应，得到哌嗪-4-甲酸乙酯，其中，催化氢化装置40(固定床反应器)分两段进行控温，且沿物料流动方向，第一控温段41的温度为110℃，第二控温段42的温度为110℃，体积空速为0.25h -1，反应压力为4.5MPa，运行50h。经气液分离装置50分离后，原料的转化率为100％，产品纯度为92.5％。催化剂利用率(w/w)为31.4。 The above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 110°C, the volume space velocity is 0.25h −1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 100%, and the product purity is 92.5%. The catalyst utilization (w/w) was 31.4.
实施例7Example 7
分散过程：以碰撞对流方式(射流法)，将吡嗪-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成含有粒径为50nm～50μm小液滴的气液混合物，作为反应原料。Dispersion process: Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50μm, as a reaction raw material.
连续反应：在反应柱中填装5％Ru/C催化剂。两端为氧化铝微球(1mm)，中间催化剂填装质量28.38g，填装高度300mm，填装直径19.2mm，催化剂粒径1mm，作为催化氢化装置40(固定床反应器)。Continuous reaction: The reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
将上述反应原料连续通入上述催化氢化装置40(固定床反应器)进行催化氢化反应，得到哌嗪-4-甲酸乙酯，其中，催化氢化装置40(固定床反应器)分两段进行控温，且沿物料流动方向，第一控温段41的温度为110℃，第二控温段42的温度为100℃，体积空速为0.25h -1，反应压力为3.2MPa，运行50h。经气液分离装置50分离后，原料的转化率为75％，产品纯度为59.9％。催化剂利用率(w/w)为15.6。 The above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volumetric space velocity is 0.25h -1 , the reaction pressure is 3.2MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 75%, and the product purity is 59.9%. The catalyst utilization (w/w) was 15.6.
实施例8Example 8
分散过程：以碰撞对流方式(射流法)，将吡嗪-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成含有粒径为50nm～50μm小液滴的气液混合物，作为反应原料。Dispersion process: Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50μm, as a reaction raw material.
连续反应：在反应柱中填装5％Ru/C催化剂。两端为氧化铝微球(1mm)，中间催化剂填装质量23.56g，填装高度300mm，填装直径19.2mm，催化剂粒径3mm，作为催化氢化装置40(固定床反应器)。Continuous reaction: The reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 23.56g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 3mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
将上述反应原料连续通入上述催化氢化装置40(固定床反应器)进行催化氢化反应，得到哌嗪-4-甲酸乙酯，其中，催化氢化装置40(固定床反应器)分两段进行控温，且沿物料流动方向，第一控温段41的温度为110℃，第二控温段42的温度为100℃，体积空速为0.25h -1，反应压力为4.5MPa，运行50h。经气液分离装置50分离后，原料的转化率为80.9％，产品纯度为77.5％。催化剂利用率(w/w)为21.2。 The above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.25h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 80.9%, and the product purity is 77.5%. The catalyst utilization (w/w) was 21.2.
实施例9Example 9
分散过程：以碰撞对流方式(射流法)，将吡嗪-4-甲酸乙酯与氢气进行分散，气液比为1:100.，形成含有粒径为50nm～50μm小液滴的气液混合物，作为反应原料。Dispersion process: Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), and the gas-liquid ratio is 1:100. To form a gas-liquid mixture containing small droplets with a particle size of 50nm-50μm , as the reaction raw material.
连续反应：在反应柱中填装5％Ru/C催化剂。两端为氧化铝微球(1mm)，中间催化剂填装质量23.56g，填装高度300mm，填装直径19.2mm，催化剂粒径5mm，作为催化氢化装置40(固定床反应器)。Continuous reaction: The reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 23.56g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 5mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
将上述反应原料连续通入上述催化氢化装置40(固定床反应器)进行催化氢化反应，得到哌嗪-4-甲酸乙酯，其中，催化氢化装置40(固定床反应器)分两段进行控温，且沿物料流动方向，第一控温段41的温度为110℃，第二控温段42的温度为100℃，体积空速为0.25h -1，反应压力为4.5MPa，运行50h。经气液分离装置50分离后，原料的转化率为76.5％，产品纯度为91.5％。催化剂利用率(w/w)为23.8。 The above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 110°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.25h -1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 76.5%, and the product purity is 91.5%. The catalyst utilization (w/w) was 23.8.
实施例10Example 10
分散过程：以碰撞对流方式(射流法)，将吡嗪-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成含有粒径为50nm～50μm小液滴的气液混合物，作为反应原料。Dispersion process: Disperse ethyl pyrazine-4-carboxylate and hydrogen by collision convection (jet method), with a gas-liquid ratio of 1:100, to form a gas-liquid mixture containing small droplets with a particle size of 50nm-50μm, as a reaction raw material.
连续反应：在反应柱中填装5％Ru/C催化剂。两端为氧化铝微球(1mm)，中间催化剂填装质量28.38g，填装高度300mm，填装直径19.2mm，催化剂粒径1mm，作为催化氢化装置40(固定床反应器)。Continuous reaction: The reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the intermediate catalyst packing mass is 28.38g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as the catalytic hydrogenation device 40 (fixed bed reactor).
将上述反应原料连续通入上述催化氢化装置40(固定床反应器)进行催化氢化反应，得到哌嗪-4-甲酸乙酯，其中，催化氢化装置40(固定床反应器)分两段进行控温，且沿物料流动方向，第一控温段41的温度为220℃，第二控温段42的温度为100℃，体积空速为0.25h -1，反应压力为4.5MPa，运行50h。经气液分离装置50分离后，原料的转化率为100％，产品纯度为53.4％。催化剂利用率(w/w)为18.5。 The above-mentioned reaction raw materials are continuously fed into the above-mentioned catalytic hydrogenation device 40 (fixed bed reactor) to carry out catalytic hydrogenation reaction to obtain ethyl piperazine-4-carboxylate, wherein the catalytic hydrogenation device 40 (fixed bed reactor) is controlled in two stages. and along the material flow direction, the temperature of the first temperature control section 41 is 220°C, the temperature of the second temperature control section 42 is 100°C, the volume space velocity is 0.25h −1 , the reaction pressure is 4.5MPa, and the operation is 50h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 100%, and the product purity is 53.4%. The catalyst utilization (w/w) was 18.5.
对比例1Comparative Example 1
批次反应：高压加氢釜中，利用20％Pd(OH) 2/C为催化剂，催化剂粒径1mm，在1.6MPa，100-110℃下，反应48h。经气液分离装置50分离后，原料的转化率为57％，产品纯度为18％，催化剂利用率(本处及下文提及的催化剂利用率定义为生产多少产品对应1g催化剂；w/w)为2.51。 Batch reaction: In a high pressure hydrogenation kettle, 20% Pd(OH) 2 /C is used as a catalyst, the particle size of the catalyst is 1 mm, and the reaction is carried out at 1.6 MPa and 100-110° C. for 48 hours. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 57%, the product purity is 18%, and the catalyst utilization rate (the catalyst utilization rate mentioned here and below is defined as how many products are produced corresponding to 1g catalyst; w/w) is 2.51.
对比例2Comparative Example 2
批次反应：高压加氢釜中，利用10％Ru/C为催化剂，催化剂粒径1mm，在2MPa，100-110℃下，反应60h。经气液分离装置50分离后，原料的转化率为60％，产品纯度为27％，催化剂利用率(本处及下文提及的催化剂利用率定义为生产多少产品对应1g催化剂；w/w)为3.77。Batch reaction: In a high-pressure hydrogenation kettle, use 10% Ru/C as a catalyst, the catalyst particle size is 1 mm, and the reaction is carried out at 2 MPa and 100-110 ° C for 60 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 60%, the product purity is 27%, and the catalyst utilization rate (the catalyst utilization rate mentioned here and below is defined as how many products are produced corresponding to 1g catalyst; w/w) was 3.77.
对比例3Comparative Example 3
批次反应：高压加氢釜中，利用12％Ru/C为催化剂，催化剂粒径1mm，在1.8MPa，70-80℃下，反应18h。经气液分离装置50分离后，原料的转化率为14％，产品纯度为18％，催化剂利用率(本处及下文提及的催化剂利用率定义为生产多少产品对应1g催化剂；w/w)为0.95。Batch reaction: In a high-pressure hydrogenation kettle, use 12% Ru/C as a catalyst, the catalyst particle size is 1 mm, and the reaction is carried out at 1.8 MPa and 70-80 ° C for 18 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 14%, the product purity is 18%, and the catalyst utilization rate (the catalyst utilization rate mentioned here and below is defined as how many products are produced corresponding to 1g catalyst; w/w) is 0.95.
对比例4Comparative Example 4
批次反应：高压加氢釜中，利用5％Ru/C为催化剂，催化剂粒径1mm，在4.5MPa，110℃下，反应50h。经气液分离装置50分离后，原料的转化率为65％，产品纯度为57.5％，催化剂利用率(本处及下文提及的催化剂利用率定义为生产多少产品对应1g催化剂；w/w)为1.01。Batch reaction: In a high-pressure hydrogenation kettle, 5% Ru/C was used as a catalyst, the particle size of the catalyst was 1 mm, and the reaction was carried out at 4.5 MPa and 110 ° C for 50 h. After being separated by the gas-liquid separation device 50, the conversion rate of the raw material is 65%, the product purity is 57.5%, and the catalyst utilization rate (the catalyst utilization rate mentioned here and below is defined as how many products are produced corresponding to 1g catalyst; w/w) is 1.01.
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：本申请提供的连续加氢方法具有反应安全、劳动强度不高、原料转化率高和哌啶-4-甲酸乙酯纯度高等优点。From the above description, it can be seen that the above-mentioned embodiments of the present invention have achieved the following technical effects: the continuous hydrogenation method provided by the application has the advantages of safe reaction, low labor intensity, high raw material conversion rate and piperidine-4-carboxylic acid The advantages of high purity of ethyl ester.
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims (11)

  1. 一种吡嗪-2-甲酸乙酯的连续加氢方法，其特征在于，所述连续加氢方法包括：A continuous hydrogenation method of pyrazine-2-ethyl carboxylate, wherein the continuous hydrogenation method comprises:
    将所述吡嗪-2-甲酸乙酯与氢气的混合物进行分散，以形成含有50nm～5mm小液滴的气液混合物作为反应原料；Dispersing the mixture of ethyl pyrazine-2-carboxylate and hydrogen gas to form a gas-liquid mixture containing droplets of 50 nm to 5 mm as a reaction raw material;
    将所述反应原料连续地输入固定床反应器中进行催化氢化反应，并连续地排出哌嗪-2-甲酸乙酯，同时沿物料的流动方向，将所述固定床反应器分为至少两个控温段，且后一个控温段的温度低于前一个控温段的温度。The reaction raw materials are continuously input into the fixed-bed reactor for catalytic hydrogenation, and piperazine-2-ethyl carboxylate is continuously discharged, and at the same time, the fixed-bed reactor is divided into at least two along the flow direction of the material. temperature control section, and the temperature of the latter temperature control section is lower than the temperature of the previous temperature control section.
  2. 根据权利要求1所述的连续加氢方法，其特征在于，沿物料的流动方向，将所述固定床反应器分为第一控温段和第二控温段，且所述第一控温段的温度为80～320℃，反应压力为0.1～10MPa，体积空速为0.1～3h -1；所述第二控温段的温度为70～310℃，反应压力为0.1～10MPa，体积空速为0.1～3h -1。 The continuous hydrogenation method according to claim 1, wherein the fixed bed reactor is divided into a first temperature control section and a second temperature control section along the flow direction of the material, and the first temperature control section is The temperature of the section is 80～320 ℃, the reaction pressure is 0.1～10MPa, the volume space velocity is 0.1～3h −1 ; the temperature of the second temperature control section is 70～310 ℃, the reaction pressure is 0.1～10MPa, the volume empty The speed is 0.1～3h -1 .
  3. 根据权利要求2所述的连续加氢方法，其特征在于，所述分散过程的气液比为1:(1～100)。The continuous hydrogenation method according to claim 2, wherein the gas-liquid ratio in the dispersion process is 1:(1-100).
  4. 根据权利要求1所述的连续加氢方法，其特征在于，所述反应原料中小液滴的粒径为100nm～30μm。The continuous hydrogenation method according to claim 1, wherein the particle size of the small droplets in the reaction raw material is 100 nm˜30 μm.
  5. 根据权利要求2至4中任一项所述的连续加氢方法，其特征在于，所述催化氢化反应中，所述固定床反应器上负载有催化剂，且所述催化剂选自Ru/C、Pd/C、Rh/C和Ru/Al 2O 3组成的组中的一种或多种。 The continuous hydrogenation method according to any one of claims 2 to 4, characterized in that, in the catalytic hydrogenation reaction, the fixed bed reactor is loaded with a catalyst, and the catalyst is selected from Ru/C, One or more of the group consisting of Pd/C, Rh/C and Ru/Al 2 O 3 .
  6. 根据权利要求5所述的连续加氢方法，其特征在于，所述催化剂的粒径为0.1～5mm。The continuous hydrogenation method according to claim 5, wherein the particle size of the catalyst is 0.1-5 mm.
  7. 根据权利要求1至4中任一项所述的连续加氢方法，其特征在于，所述固定床反应器的床层压降小于0.01MPa/m。The continuous hydrogenation method according to any one of claims 1 to 4, wherein the bed pressure drop of the fixed bed reactor is less than 0.01 MPa/m.
  8. 根据权利要求1所述的连续加氢方法，其特征在于，所述分散的方法选自雾化法、射流法或文丘里法；所述固定床反应器选自轴向绝热式固定反应床、径向绝热式固定反应床或列管固定床。The continuous hydrogenation method according to claim 1, characterized in that, the dispersion method is selected from atomization method, jet method or Venturi method; and the fixed bed reactor is selected from axial adiabatic fixed reaction bed, Radial adiabatic fixed reaction bed or tubular fixed bed.
  9. 根据权利要求2所述的连续加氢方法，其特征在于，所述连续加氢方法还包括：将所述吡嗪-2-甲酸乙酯与所述氢气及有机溶剂进行所述分散过程。The continuous hydrogenation method according to claim 2, wherein the continuous hydrogenation method further comprises: performing the dispersion process on the ethyl pyrazine-2-carboxylate, the hydrogen and the organic solvent.
  10. 根据权利要求9所述的连续加氢方法，其特征在于，所述有机溶剂选自乙醇、水、甲醇和二氯甲烷组成的组中的一种或多种。The continuous hydrogenation method according to claim 9, wherein the organic solvent is one or more selected from the group consisting of ethanol, water, methanol and dichloromethane.
  11. 一种权利要求1至10中任一项所述的连续加氢方法在镇静类药物或抗心律失常类药物的合成中的应用。Application of the continuous hydrogenation method described in any one of claims 1 to 10 in the synthesis of sedative drugs or antiarrhythmic drugs.
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