WO2022011731A1 - 哌啶-4-甲酸乙酯的连续化合成方法及其应用 - Google Patents

哌啶-4-甲酸乙酯的连续化合成方法及其应用 Download PDF

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WO2022011731A1
WO2022011731A1 PCT/CN2020/103307 CN2020103307W WO2022011731A1 WO 2022011731 A1 WO2022011731 A1 WO 2022011731A1 CN 2020103307 W CN2020103307 W CN 2020103307W WO 2022011731 A1 WO2022011731 A1 WO 2022011731A1
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reaction
synthesis method
carboxylate
continuous synthesis
catalyst
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PCT/CN2020/103307
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French (fr)
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洪浩
洪亮
陶建
胡忠
张岩
左键
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 WO2022011731A1 publication Critical patent/WO2022011731A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4

Definitions

  • the invention relates to the technical field of synthesis of pharmaceutical chemicals, in particular to a continuous synthesis method and application of ethyl piperidine-4-carboxylate.
  • Ethyl piperidine-4-carboxylate is an important pharmaceutical and pesticide intermediate. It is widely used in sedative drugs and antiarrhythmic drugs. It is in clinical stage neuropeptide Y5 receptor inhibitor and ⁇ 4 ⁇ 1 integrin inhibitor. It is also used in medicines and other medicines. The product is also used in Cu or alloy surface treatment fluids, anti-ash materials, copolymers of ethylene and alkyl acetate.
  • the disadvantages of the batch catalytic process mainly lie in: (1) The process of directly using hydrogen as the reducing agent requires the use of a large amount of hydrogen and large pressure-resistant equipment, which is difficult to repair and replace, and has high equipment investment costs and greater safety. There are hidden dangers, so it cannot be applied on a large scale in production practice. (2) In order to avoid the use of hydrogen, hydrogenation is carried out by using amine formate or the like as a hydrogen donor and using Pd/C as a catalyst. This process prolongs the process flow, reduces the reaction yield, introduces impurities, and increases the cost of raw materials.
  • the main purpose of the present invention is to provide a continuous synthesis method of ethyl piperidine-4-carboxylate and its application, so as to solve the problem that the existing synthetic method of ethyl piperidine-4-carboxylate has high cost or low product yield And the problem of low product purity.
  • one aspect of the present invention provides a continuous synthesis method of ethyl piperidine-4-carboxylate, the continuous synthesis method comprising: dispersing a mixture of ethyl pyridine-4-carboxylate and hydrogen, A gas-liquid mixture containing small droplets of 50 nm to 5 mm is used as the reaction raw material; the reaction raw material is continuously fed into a fixed bed reactor for catalytic hydrogenation, and piperidine-4-ethyl carboxylate is continuously discharged.
  • gas-liquid ratio in the dispersion process is 1:(1-100).
  • the particle size of the small droplets in the reaction raw material is 100-5000 ⁇ 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 reaction temperature is 80-160° C.
  • the reaction pressure is 4.0-5.0 MPa
  • the volume space velocity is 0.2-1.0 h ⁇ 1
  • the bed pressure drop of the fixed-bed reactor is less than 0.2 MPa/m.
  • the method adopted in the above-mentioned dispersion process is selected from atomization method, jet method, Venturi method or collision convection method;
  • the fixed bed reactor is selected from axial adiabatic fixed reaction bed, radial adiabatic fixed reaction bed or column and tube. Fixed bed.
  • the continuous synthesis method also includes: dispersing ethyl pyridine-4-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 synthesis method in the synthesis of sedative drugs or antiarrhythmic drugs.
  • the present application uses ethyl pyridine-4-carboxylate and hydrogen to form a gas-liquid mixture containing 50nm-5mm droplets through a dispersion process, and uses this as a reaction raw material 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, which is beneficial to improve the sufficient reaction degree of the reaction raw materials, shorten the reaction time, and improve. Yield and purity of ethyl piperidine-4-carboxylate.
  • the above-mentioned continuous synthesis method has less reaction raw materials per unit time, and the adopted reaction device occupies a small area, and has great advantages in heat exchange and improvement of equipment pressure.
  • the modularization of the reaction device can be successfully realized; this can greatly save the equipment investment cost, reduce the land occupation, and greatly reduce the safety risk caused by the large-scale use of hydrogen.
  • the above continuous synthesis method has the advantages of low cost, high yield and high purity of ethyl piperidine-4-carboxylate.
  • the existing synthesis methods of ethyl piperidine-4-carboxylate have problems of potential safety hazards, high cost or low product yield and low purity.
  • the present application provides a continuous synthesis method of ethyl piperidine-4-carboxylate, the continuous synthesis method comprises: dispersing a mixture of ethyl pyridine-4-carboxylate and hydrogen to form The gas-liquid mixture containing 50nm-5mm 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 piperidine-4-ethyl carboxylate is continuously discharged.
  • ethyl pyridine-4-carboxylate and hydrogen are dispersed to form a gas-liquid mixture containing small droplets of 50 nm to 5 mm, and this is used as a reaction raw material 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, which is beneficial to improve the sufficient reaction degree of the reaction raw materials, shorten the reaction time, and improve. Yield and purity of ethyl piperidine-4-carboxylate.
  • the above-mentioned continuous synthesis method has less reaction raw materials per unit time, and the adopted reaction device occupies a small area, and has great advantages in heat exchange and improvement of equipment pressure.
  • the modularization of the reaction device can be successfully realized; this can greatly save the equipment investment cost, reduce the land occupation, and greatly reduce the safety risk caused by the large-scale use of hydrogen.
  • the above continuous synthesis method has the advantages of low cost, high yield and high purity of ethyl piperidine-4-carboxylate.
  • the gas-liquid ratio in the dispersion process is 1:(1 ⁇ 100).
  • the particle size of the small droplets in the reaction raw material is 100-5000 ⁇ 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.
  • the fixed bed reactor is loaded with particulate catalyst.
  • the particle size of the catalyst is 0.1-5 mm.
  • the reaction temperature is 80-160°C
  • the reaction pressure is 4.0-5MPa
  • the volumetric space velocity is 0.2-1.0h -1
  • the bed pressure drop of the fixed-bed reactor is less than 0.01MPa/m.
  • limiting the reaction temperature, reaction pressure, space velocity and bed pressure drop in the catalytic hydrogenation process within the above ranges is beneficial to further improve the yield and purity of ethyl piperidine-4-carboxylate.
  • 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 ).
  • the methods used in the above dispersion process include but are 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 improving 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 synthesis method further comprises: dispersing ethyl pyridine-4-carboxylate with hydrogen and an organic solvent. Adding an organic solvent to the reaction raw materials is conducive to making the catalytic hydrogenation reaction in a more stable environment, and further improving the sufficient reaction degree of the reaction raw materials, thereby improving the safety of the reaction and the yield of ethyl piperidine-4-carboxylate. Rate.
  • 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 a continuous synthesis method of ethyl piperidine-4-carboxylate in the synthesis of sedative drugs or antiarrhythmic drugs.
  • the continuous synthesis method of ethyl piperidine-4-carboxylate provided by the present application has the advantages of low cost, high yield and high purity of ethyl piperidine-4-carboxylate. Therefore, 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.
  • the collision convection method was used to disperse ethyl pyridine-4-carboxylate and hydrogen at a gas-liquid ratio of 1:100 to form small droplets with a particle size of 50nm-5mm, which were used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle 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 a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor to carry out catalytic hydrogenation reaction to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.31h -1 , the reaction pressure is 4.0-4.2MPa, and the reaction temperature is 160 °C, pressure drop is less than 100.Pa/m, stable operation for 50 hours.
  • the conversion rate was 100% and the product purity was 90%.
  • the catalyst utilization (w/w) was 35.89.
  • the collision convection method was used to disperse ethyl pyridine-4-carboxylate and hydrogen at a gas-liquid ratio of 1:100 to form small droplets with a particle size of 50nm-5mm, which were used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle 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 a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor to carry out catalytic hydrogenation reaction to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.32h -1 , the reaction pressure is 4.0-4.2MPa, and the reaction temperature is 80 °C °C, the pressure drop is 100Pa/m, and the stable operation is 50 hours.
  • the conversion rate was 87% and the product purity was 75%.
  • the catalyst utilization (w/w) was 26.01.
  • the collision convection method was used to disperse ethyl pyridine-4-carboxylate and hydrogen at a gas-liquid ratio of 1:100 to form small droplets with a particle size of 50nm-5mm, which were used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle 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 a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor to carry out catalytic hydrogenation reaction to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.32h -1 , the reaction pressure is 4.0-4.2MPa, and the reaction temperature is 100 °C, the pressure drop is 100Pa/m, and the stable operation is 50 hours.
  • the conversion rate was 93% and the product purity was 80%.
  • the catalyst utilization (w/w) was 29.67.
  • the collision convection method was used to disperse ethyl pyridine-4-carboxylate and hydrogen at a gas-liquid ratio of 1:100 to form small droplets with a particle size of 50nm-5mm, which were used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle 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 a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor for catalytic hydrogenation to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.32h -1 , the reaction pressure is 4.0-4.2MPa, and the reaction temperature is 120 °C, the pressure drop is 100Pa/m, and the stable operation is 50 hours.
  • the conversion rate was 98.1%, and the product purity was 92.5%.
  • the catalyst utilization (w/w) was 36.15.
  • the collision convection method was used to disperse ethyl pyridine-4-carboxylate and hydrogen at a gas-liquid ratio of 1:100 to form small droplets with a particle size of 50nm-5mm, which were used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle 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 a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor for catalytic hydrogenation to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.5h -1 , the reaction pressure is 4.0-4.1MPa, and the reaction temperature is 120 °C, the pressure drop is 100Pa/m, the conversion rate is 75% after stable operation for 50 hours, and the product purity is 84.2%.
  • the catalyst utilization (w/w) was 31.9.
  • the collision convection method was used to disperse ethyl pyridine-4-carboxylate and hydrogen at a gas-liquid ratio of 1:100 to form small droplets with a particle size of 50nm-5mm, which were used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle 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 a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor for catalytic hydrogenation to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.8h -1 , the reaction pressure is 4.0-4.1MPa, and the reaction temperature is 120 °C, the pressure drop is 100Pa/m, and the stable operation is 50 hours.
  • the conversion rate was 55.2%, and the product purity was 52.5%.
  • the catalyst utilization (w/w) was 28.89.
  • the collision convection method was used to disperse ethyl pyridine-4-carboxylate and hydrogen at a gas-liquid ratio of 1:100 to form small droplets with a particle size of 50nm-5mm, which were used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle catalyst packing mass is 28.56g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 3mm, as a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor for catalytic hydrogenation to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.32h -1 , the reaction pressure is 4.0-4.1MPa, and the reaction temperature is 120 °C, the pressure drop is 100Pa/m, and the stable operation is 50 hours.
  • the conversion rate was 75%, and the product purity was 73.3%.
  • the catalyst utilization (w/w) was 28.33.
  • the collision convection method was used to disperse ethyl pyridine-4-carboxylate and hydrogen at a gas-liquid ratio of 1:100 to form small droplets with a particle size of 50nm-5mm, which were used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle catalyst packing mass is 16.1g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 5mm, as a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor for catalytic hydrogenation to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.32h -1 , the reaction pressure is 4.0-4.1MPa, and the reaction temperature is 120 °C, the pressure drop is 100Pa/m, and the stable operation is 50 hours.
  • the conversion rate was 69%, and the product purity was 66.1%.
  • the catalyst utilization (w/w) was 32.
  • the collision convection method was used to disperse ethyl pyridine-4-carboxylate and hydrogen at a gas-liquid ratio of 1:100 to form small droplets with a particle size of 50nm-5mm, which were used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle catalyst packing mass is 35g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 0.1mm, as a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor to carry out catalytic hydrogenation reaction to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.32h -1 , the reaction pressure is 4.0-4.1MPa, and the reaction temperature is 120 °C, the pressure drop is 100Pa/m, and the stable operation is 50 hours.
  • the conversion rate is 98.1%, the product purity is 91.5%, and the catalyst utilization rate (the catalyst utilization rate mentioned here and below is defined as how many products are produced corresponds to 1 g of catalyst; w/w) is 28.99, but there is a problem of high pressure drop .
  • Dispersion process Disperse ethyl pyridine-4-carboxylate and hydrogen by collision convection method with a gas-liquid ratio of 1:200 to form small droplets with a particle size of 80-120 ⁇ m, which are used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (5mm), the middle catalyst packing mass is 15.91g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor for catalytic hydrogenation to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.32h -1 , the reaction pressure is 4.0-4.1MPa, and the reaction temperature is 120 °C, stable operation for 50 hours.
  • the conversion was 75%, the product purity was 78%, and the catalyst utilization (referred to here and below as catalyst utilization is defined as how much product is produced for 1 g of catalyst; w/w) was 23.33.
  • Dispersion process Disperse ethyl pyridine-4-carboxylate and hydrogen by collisional convection with a gas-liquid ratio of 1:80 to form small droplets with a particle size of 50nm-5mm, which are used as reaction raw materials.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (5mm), the middle catalyst packing mass is 16.11g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 1mm, as a fixed bed reactor.
  • the above-mentioned reaction raw materials are continuously fed into the above-mentioned fixed-bed reactor for catalytic hydrogenation to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 0.32h -1 , the reaction pressure is 2-2.5MPa, and the reaction temperature is 120 °C, stable operation for 50 hours.
  • the conversion rate was 35.4%, the product purity was 41.2%, and the catalyst utilization rate was 5.72.
  • Example 1 The difference from Example 1 is that the reaction device used in the catalytic hydrogenation reaction is a moving bed reactor.
  • the conversion rate was 100%, the product purity was 82.5%, and the catalyst utilization rate (the catalyst utilization rate referred to here and below is defined as how much product is produced corresponds to 1 g of catalyst; w/w) was 39.0.
  • Example 2 The difference from Example 1 is that the particle size of the small droplets in the reaction raw material is 30 nm.
  • the conversion rate is 100%, the product purity is 82%, the catalyst utilization rate (the catalyst utilization rate mentioned here and below is defined as how many products are produced corresponds to 1 g of catalyst; w/w) is 5.2, and the equipment cost is high.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle catalyst packing mass is 24.33g, the packing height is 300mm, the packing diameter is 19.2mm, and the catalyst particle size is 7mm, as a fixed bed reactor.
  • the conversion was 65%, the product purity was 66.5%, and the catalyst utilization (referred to here and below as catalyst utilization is defined as how much product is produced for 1 g of catalyst; w/w) was 20.1.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle 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 a fixed bed reactor.
  • Hydrogen and ethyl pyridine-4-carboxylate are continuously fed into the above-mentioned fixed-bed reactor at a volume ratio of 1:100 to carry out catalytic hydrogenation to obtain ethyl piperidine-4-carboxylate, wherein the volume space velocity is 1h -1 ,
  • the gas-liquid mixture is not subjected to forced mass transfer. It operates stably for 50 hours at 4.0 ⁇ 4.2MPa and 120°C.
  • the conversion rate was 44%, and the product purity was 43.5%.
  • the catalyst utilization (w/w) was 23.89.
  • the reaction column was packed with 5% Ru/C catalyst. Both ends are alumina microspheres (1mm), the middle 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 a fixed bed reactor.
  • Hydrogen and ethyl pyridine-4-carboxylate are continuously fed into the above-mentioned fixed-bed reactor at a volume ratio of 1:100 to carry out catalytic hydrogenation to obtain ethyl piperidine-4-carboxylate, wherein the space velocity is 0.32h -1 ,
  • the gas-liquid mixture is not subjected to forced mass transfer. Stable operation at 4.0-4.5MPa and 120°C for 50 hours.
  • the conversion rate was 65%, and the product purity was 63.5%.
  • the catalyst utilization (w/w) was 16.4.

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  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明提供了一种哌啶-4-甲酸乙酯的连续化合成方法及其应用。该连续化合成方法包括：将吡啶-4-甲酸乙酯与氢气的混合物进行分散，以形成粒径为50nm～5mm的小液滴，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，并连续地排出哌啶-4-甲酸乙酯。上述强制分散过程能够使反应原料在催化氢化反应过程进行高性能传质，进而能够提高反应原料的充分反应程度，缩短反应时间，提高哌啶-4-甲酸乙酯的收率和纯度。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，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，能极大地节省设备投资成本，大大降低由大量使用氢气带来的安全风险。

Description

哌啶-4-甲酸乙酯的连续化合成方法及其应用 技术领域
本发明涉及医药化学品合成技术领域，具体而言，涉及一种哌啶-4-甲酸乙酯的连续化合成方法及其应用。
背景技术
哌啶-4-甲酸乙酯是一种重要的医药农药中间体，在镇静类药物和抗心律失常类药物中大量使用，在处于临床阶段的神经肽Y5受体抑制剂和α4β1型整合素抑制剂等药物中也有使用。该产品还应用于Cu或合金表面处理液、抗灰材料、乙稀和醋酸烷基酯的共聚物中。
现有针对哌啶-4-甲酸乙酯的合成方法有很多，其中较简单的方式为在高压反应釜中，以异烟酸乙酯(吡啶-4-甲酸乙酯)为原料进行催化还原反应，主要方法为：(1)Pd/C为催化剂，H 2压力20Kg/cm 2，收率99％；(2)乙醇中使用NaBH 4-RhCl 3为还原剂直接还原，收率为94％，纯度为93.5％；(3)Raney Ni为催化剂，H 2压力125Kg/cm 2，收率88％，纯度为87％。
但是批次催化工艺的缺点主要在于：(1)直接以氢气为还原剂的工艺需要使用大量氢气和较大的耐压设备，检修及替换较为困难，设备投资成本高，并存有较大的安全隐患，所以在生产实践中不能大规模应用。(2)为了避免氢气使用，以甲酸胺等为氢给予体，通过Pd/C为催化剂进行加氢。该工艺会延长工艺流程，降低反应收率，引入杂质，并增加原料成本。
鉴于上述问题的存在，有必要提供一种新型吡啶-4-甲酸乙酯连续催化氢化工艺。
发明内容
本发明的主要目的在于提供一种哌啶-4-甲酸乙酯的连续化合成方法及其应用，以解决现有的哌啶-4-甲酸乙酯的合成方法存在成本高或者产物收率低和产品纯度不高的问题。
为了实现上述目的，本发明的一个方面提供了一种哌啶-4-甲酸乙酯的连续化合成方法，该连续化合成方法包括：将吡啶-4-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，并连续地排出哌啶-4-甲酸乙酯。
进一步地，分散过程的气液比为1:(1～100)。
进一步地，反应原料中小液滴的粒径为100～5000μm。
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。
进一步地，催化剂的粒径为0.1～5mm。
进一步地，催化氢化反应中，反应温度为80～160℃，反应压力为4.0～5.0MPa，体积空速为0.2～1.0h -1，固定床反应器的床层压降小于0.2MPa/m。
进一步地，上述分散过程采用的方法选自雾化法、射流法、文丘里法或碰撞对流法；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。
进一步地，连续化合成方法还包括：将吡啶-4-甲酸乙酯与氢气及有机溶剂进行分散过程。
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。
本申请的另一方面还提供了一种上述连续化合成方法在镇静类药物或抗心律失常类药物的合成中的应用。
应用本发明的技术方案，本申请将吡啶-4-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进行高性能传质，这有利于提高反应原料的充分反应程度，缩短反应时间，并提高哌啶-4-甲酸乙酯的收率和纯度。此外，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，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。在此基础上，上述连续化合成方法具有成本低、哌啶-4-甲酸乙酯收率高和纯度高等优点。
具体实施方式
正如背景技术部分所描述的，现有的哌啶-4-甲酸乙酯的合成方法存在安全隐患、成本高或者产物收率低和纯度不高的问题。为了解决上述技术问题，本申请提供了一种哌啶-4-甲酸乙酯的连续化合成方法，该连续化合成方法包括：将吡啶-4-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，并连续地排出哌啶-4-甲酸乙酯。
本申请将吡啶-4-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进行高性能传质，这有利于提高反应原料的充分反应程度，缩短反应时间，并提高哌啶-4-甲酸乙酯的收率和纯度。此外，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，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。在此基础上，上述连续化合成方法具有成本低、哌啶-4-甲酸乙酯收率高和纯度高等优点。
将反应原料中小液滴的粒径限定在50nm～5mm范围内有利于提高反应原料的传质过程。为了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的反应程度和哌啶-4-甲酸乙酯的产率和纯度，优选地，分散过程的气液比为1:(1～100)。
在一种优选的实施例中，反应原料中小液滴的粒径为100～5000μm。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。
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。
催化氢化过程中，在固定床反应器上负载有颗粒状的催化剂。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。
在一种优选的实施例中，催化氢化反应中，反应温度为80～160℃，反应压力为4.0～5MPa，体积空速为0.2～1.0h -1，固定床反应器的床层压降小于0.01MPa/m。相比于其它范围，将催化氢化反应过程的反应温度、反应压力、空速及床层压降限定在上述范围内有利于进一步提高哌啶-4-甲酸乙酯的收率和纯度。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。
在一种优选的实施例中，上述分散过程采用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。
在一种优选的实施例中，连续化合成方法还包括：将吡啶-4-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哌啶-4-甲酸乙酯的收率。
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。
本申请的另一方面还提供了一种哌啶-4-甲酸乙酯的连续化合成方法在镇静类药物或抗心律失常类药物的合成中的应用。
由于本申请提供的哌啶-4-甲酸乙酯的连续化合成方法具有成本低、哌啶-4-甲酸乙酯收率高和纯度高等优点。因而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及药效。
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。
实施例1
分散过程：采用碰撞对流法，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成粒径为50nm～5mm的小液滴，作为反应原料。
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，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.31h -1，反应压力为4.0～4.2MPa，反应温度为160℃，压降小于100.Pa/m，稳定运行50小时。转化率为100％，产品纯度为90％。催化剂利用率(w/w)为35.89。
实施例2
分散过程：采用碰撞对流法，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成粒径为50nm～5mm的小液滴，作为反应原料。
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，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.32h -1，反应压力为4.0～4.2MPa，反应温度为80℃，压降为100Pa/m，稳定运行50小时。转化率为87％，产品纯度为75％。催化剂利用率(w/w)为26.01。
实施例3
分散过程：采用碰撞对流法，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成粒径为50nm～5mm的小液滴，作为反应原料。
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，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.32h -1，反应压力为4.0～4.2MPa，反应温度为100℃，压降为100Pa/m，稳定运行50小时。转化率为93％，产品纯度为80％。催化剂利用率(w/w)为29.67。
实施例4
分散过程：采用碰撞对流法，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成粒径为50nm～5mm的小液滴，作为反应原料。
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，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.32h -1，反应压力为4.0～4.2MPa，反应温度为120℃，压降为100Pa/m，稳定运行50小时。转化率为98.1％，产品纯度为92.5％。催化剂利用率(w/w)为36.15。
实施例5
分散过程：采用碰撞对流法，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成粒径为50nm～5mm的小液滴，作为反应原料。
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，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.5h -1，反应压力为4.0-4.1MPa，反应温度为120℃，压降为100Pa/m，稳定运行50小时转化率为75％，产品纯度为84.2％。催化剂利用率(w/w)为31.9。
实施例6
分散过程：采用碰撞对流法，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成粒径为50nm～5mm的小液滴，作为反应原料。
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，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.8h -1，反应压力为4.0～4.1MPa，反应温度为120℃，压降为100Pa/m，稳定运行50小时。转化率为55.2％，产品纯度为52.5％。催化剂利用率(w/w)为28.89。
实施例7
分散过程：采用碰撞对流法，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成粒径为50nm～5mm的小液滴，作为反应原料。
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28.56g，填装高度300mm，填装直径19.2mm，催化剂粒径3mm，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.32h -1，反应压力为4.0～4.1MPa，反应温度为120℃，压降为100Pa/m，稳定运行50小时。转化率为75％，产品纯度为73.3％。催化剂利用率(w/w)为28.33。
实施例8
分散过程：采用碰撞对流法，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成粒径为50nm～5mm的小液滴，作为反应原料。
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16.1g，填装高度300mm，填装直径19.2mm，催化剂粒径5mm，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.32h -1，反应压力为4.0～4.1MPa，反应温度为120℃，压降为100Pa/m，稳定运行50小时。转化率为69％，产品纯度为66.1％。催化剂利用率(w/w)为32。
实施例9
分散过程：采用碰撞对流法，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:100，形成粒径为50nm～5mm的小液滴，作为反应原料。
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35g，填装高度300mm，填装直径19.2mm，催化剂粒径0.1mm，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.32h -1，反应压力为4.0～4.1MPa，反应温度为120℃，压降为100Pa/m，稳定运行50小时。转化率为98.1％，产品纯度为91.5％，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28.99，但是存在压降较高的问题。
实施例10
分散过程：以碰撞对流法，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:200，形成粒径为80～120μm的小液滴，作为反应原料。
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(5mm)，中间催化剂填装质量15.91g，填装高度300mm，填装直径19.2mm，催化剂粒径1mm，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.32h -1，反应压力为4.0～4.1MPa，反应温度为120℃，稳定运行50小时。转化率为75％，产品纯度为78％，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23.33。
实施例11
分散过程：以碰撞对流方式，将吡啶-4-甲酸乙酯与氢气进行分散，气液比为1:80，形成粒径50nm～5mm的小液滴，作为反应原料。
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(5mm)，中间催化剂填装质量16.11g，填装高度300mm，填装直径19.2mm，催化剂粒径1mm，作为固定床反应器。
将上述反应原料连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为0.32h -1，反应压力为2-2.5MPa，反应温度为120℃，稳定运行50小时。转化率为35.4％，产品纯度为41.2％，催化剂利用率为5.72。
对比例1
批次反应：高压加氢釜中，利用5％Ru/C为催化剂，催化剂粒径0.1mm，在2.0-2.5MPa，140℃下，反应48h。转化率为100％，产品纯度为80％，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4.166。
对比例2
与实施例1的区别为：催化氢化反应采用的反应装置为移动床反应器。
转化率为100％，产品纯度为82.5％，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39.0。
对比例3
与实施例1的区别为：反应原料中小液滴的粒径为30nm。
转化率为100％，产品纯度为82％，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5.2，设备成本较高。
对比例4
与实施例1的区别为：
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24.33g，填装高度300mm，填装直径19.2mm，催化剂粒径7mm，作为固定床反应器。
转化率为65％，产品纯度为66.5％，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20.1。
对比例5
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，作为固定床反应器。
将氢气与吡啶-4-甲酸乙酯按1:100体积比，连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，体积空速为1h -1，气液混合物未经过强制传质过程。在4.0～4.2MPa，120℃稳定运行50小时。转化率为44％，产品纯度为43.5％。催化剂利用率(w/w)为23.89。
对比例6
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，作为固定床反应器。
将氢气与吡啶-4-甲酸乙酯按1:100体积比，连续通入上述固定床反应器进行催化氢化反应，得到哌啶-4-甲酸乙酯，其中，空速为0.32h -1，气液混合物未经过强制传质过程。在4.0-4.5MPa，120℃稳定运行50小时。转化率为65％，产品纯度为63.5％。催化剂利用率(w/w)为16.4。
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：
比较实施例1至11及对比例1至6可知，采用本申请提供的连续化合成方法有利于提高哌啶-4-甲酸乙酯的产率和纯度。
比较实施例1至4可知，将催化氢化反应过程的反应温度限定在本申请优选的范围内有利于提高哌啶-4-甲酸乙酯的产率和纯度。
比较实施例8至11可知，将催化氢化反应过程使用的催化剂的粒径及催化氢化反应的反应条件限定在本申请优选的范围内有利于提高哌啶-4-甲酸乙酯的产率和纯度。
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。

Claims (10)

  1. 一种哌啶-4-甲酸乙酯的连续化合成方法，其特征在于，所述连续化合成方法包括：
    将吡啶-4-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，并连续地排出所述哌啶-4-甲酸乙酯。
  2. 根据权利要求1所述的连续化合成方法，其特征在于，所述分散过程的气液比为1:(1～100)。
  3. 根据权利要求1所述的连续化合成方法，其特征在于，所述反应原料中小液滴的粒径为100～5000μm。
  4. 根据权利要求2所述的连续化合成方法，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。
  5. 根据权利要求4所述的连续化合成方法，其特征在于，所述催化剂的粒径为0.1～5mm。
  6. 根据权利要求1所述的连续化合成方法，其特征在于，所述催化氢化反应中，反应温度为80～160℃，反应压力为4.0～5.0MPa，体积空速为0.2～1.0h -1，所述固定床反应器的床层压降小于0.2MPa/m。
  7. 根据权利要求6所述的连续化合成方法，其特征在于，所述分散过程采用的方法选自雾化法、射流法、文丘里法或碰撞对流法；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。
  8. 根据权利要求2所述的连续化合成方法，其特征在于，所述连续化合成方法还包括：将所述吡啶-4-甲酸乙酯与所述氢气及有机溶剂进行所述分散过程。
  9. 根据权利要求8所述的连续化合成方法，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。
  10. 一种权利要求1至9中任一项所述的连续化合成方法在镇静类药物或抗心律失常类药物的合成中的应用。
PCT/CN2020/103307 2020-07-15 2020-07-21 哌啶-4-甲酸乙酯的连续化合成方法及其应用 WO2022011731A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1104754A1 (en) * 1998-08-11 2001-06-06 Daiichi Pharmaceutical Co., Ltd. Novel sulfonyl derivatives
JP2001294572A (ja) * 2000-02-09 2001-10-23 Dai Ichi Seiyaku Co Ltd 新規スルホニル誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1104754A1 (en) * 1998-08-11 2001-06-06 Daiichi Pharmaceutical Co., Ltd. Novel sulfonyl derivatives
JP2001294572A (ja) * 2000-02-09 2001-10-23 Dai Ichi Seiyaku Co Ltd 新規スルホニル誘導体

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI YONGJIN, REN GUO-FEN,WANG XIAO-ZHONG,CHEN YING-QI: "Synthesis of Ethyl 4-Piperidingcarboxylate", CHINESE JOURNAL OF SYNTHETIC CHEMISTRY, CHENGDU YUJI HUAXUESUO, CN, vol. 15, no. 4, 31 December 2007 (2007-12-31), CN , pages 513 - 515, XP055886969, ISSN: 1005-1511, DOI: 10.15952/j.cnki.cjsc.2007.04.035 *
YAO, JINGFANG ET AL.: "Research Status and Application of Gas-Liquid Jet Reactors", PROCEEDINGS OF THE 9TH CHINESE ACADEMIC CONFERENCE ON FLAVOURS AND FRAGRANCES, 22 October 2013 (2013-10-22), CN, pages 17 - 22, XP009533565 *

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