WO2021022469A1 - 连续化合成-纯化一体装置及含有其的连续化反应系统 - Google Patents

连续化合成-纯化一体装置及含有其的连续化反应系统 Download PDF

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WO2021022469A1
WO2021022469A1 PCT/CN2019/099380 CN2019099380W WO2021022469A1 WO 2021022469 A1 WO2021022469 A1 WO 2021022469A1 CN 2019099380 W CN2019099380 W CN 2019099380W WO 2021022469 A1 WO2021022469 A1 WO 2021022469A1
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continuous
reaction
purification
section
temperature
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PCT/CN2019/099380
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English (en)
French (fr)
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洪浩
洪亮
陶建
陈富荣
王波辉
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吉林凯莱英医药化学有限公司
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Priority to PCT/CN2019/099380 priority Critical patent/WO2021022469A1/zh
Publication of WO2021022469A1 publication Critical patent/WO2021022469A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
    • C07B41/02—Formation or introduction of functional groups containing oxygen of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B63/00—Purification; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
    • C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
    • C07C37/74—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by distillation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
    • C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
    • C07C37/74—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by distillation
    • C07C37/78—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by distillation by azeotropic distillation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/08—Dihydroxy benzenes; Alkylated derivatives thereof

Definitions

  • the present invention relates to the field of medicine and chemical industry, in particular to a continuous synthesis-purification integrated device and a continuous reaction system containing the same.
  • the main purpose of the present invention is to provide a continuous synthesis-purification integrated device and a continuous reaction system containing the same, so as to solve the problem that the existing synthesis device needs to be additionally equipped with a purification device and further has a complicated reaction route.
  • a continuous synthesis-purification integrated device includes a reaction section, a purification section and a temperature control unit, and the reaction section is provided with a feed port , The first gas phase communication port and the first liquid phase communication port; the purification section is provided with a replenishment port, a second gas phase communication port and a product outlet, the second gas phase communication port is connected to the first liquid phase communication port, and the purification section
  • the gas-phase materials are discharged through the first gas-phase communication port, and the liquid supplement added through the liquid supplement port includes the impurity removing agent;
  • the temperature control unit is used to control the temperature of the continuous synthesis-purification integrated device.
  • the continuous synthesis-purification integrated device further includes a condensation reflux section, the condensation reflux section is provided with a tail gas outlet and a gas phase inlet, and the gas phase inlet is in communication with the first gas phase communication port.
  • the continuous synthesis-purification integrated device further includes: a first temperature measurement device, a second temperature measurement device, and a third temperature measurement device.
  • the first temperature measuring device is used to detect the temperature of the condensing reflux section;
  • the second temperature measuring device is used to detect the temperature of the reaction section;
  • the third temperature measuring device is used to detect the temperature of the purification section.
  • the temperature control unit includes a first temperature control device, and the first temperature control device is used to control the temperature of the condensation reflux section.
  • the temperature control unit further includes: a second temperature control device and a third temperature control device, the second temperature control device is used to control the temperature of the reaction section; and the third temperature control device is used to control the temperature of the purification section.
  • the continuous reaction system includes: a pre-mixing unit, the pre-mixing unit is provided with a raw material inlet and a pre-reaction product outlet; the above-mentioned continuous synthesis-purification integrated device, continuous The chemical synthesis-purification integrated device is provided with a feed port, and the feed port and the pre-reaction product outlet are connected through a pre-reaction product delivery pipeline.
  • the continuous synthesis-purification integrated device is also provided with a tail gas outlet
  • the continuous reaction system further includes a tail gas receiving device, the tail gas receiving device is provided with a tail gas inlet, and the tail gas inlet and the tail gas outlet are connected through a tail gas delivery pipeline.
  • the continuous reaction system further includes a pressure control device, which is arranged on the tail gas delivery pipeline.
  • the continuous reaction system further includes: a replenishment supply device and a first delivery pump, the replenishment supply device is provided with a replenishment supply port, and the replenishment supply port is connected to the replenishment port of the continuous synthesis-purification integrated device through a replenishment delivery pipeline; And the first delivery pump is arranged on the fluid supplement delivery pipeline.
  • the pre-mixing unit includes: a raw material storage device, a pre-mixing device, and a second delivery pump.
  • the raw material storage device is provided with a raw material supply port
  • the pre-mixing device is provided with a raw material inlet and a pre-reaction product outlet
  • the raw material supply port and the raw material inlet are connected through a raw material liquid delivery pipeline
  • the pre-reaction product outlet is connected to the continuous synthesis-purification integrated device.
  • the material port is connected; and the second delivery pump is arranged on the raw material liquid delivery pipeline.
  • the continuous reaction system further includes a product receiving device, and the inlet end of the product receiving device is in communication with the product outlet of the continuous synthesis-purification integrated device.
  • the pre-mixing device is a continuous reaction coil or a continuous columnar reactor.
  • the continuous synthesis-purification integrated device adopts precise multi-stage temperature control to ensure that as the reaction continues, the reaction process can be discharged in time according to the difference in boiling points of products, raw materials, and by-products and impurities generated by the reaction By-products and impurities generated in the process, the conversion rate of reaction raw materials and the yield of products are improved, and the separation and purification of products can be realized simultaneously.
  • the above-mentioned continuous synthesis-purification integrated device can not only meet the temperature requirements in the reaction process, but also ensure the timely discharge of the low-boiling by-products generated in the reaction.
  • the continuous synthesis-purification integrated device Compared with a traditional reaction device that requires an additional separation and purification device, the continuous synthesis-purification integrated device provided in this application makes the reaction process simpler, the reaction conditions are more stable, and the safety of the reaction device is greatly improved. On this basis, the use of the above-mentioned continuous synthesis-purification integrated device can not only improve the conversion rate of raw materials and the yield of the product, but also improve the purity of the product, shorten the reaction route, and reduce the number of equipment, reaction time, floor space, and labor intensity. And energy consumption.
  • Figure 1 shows a schematic structural diagram of a continuous synthesis-purification integrated device provided by a typical embodiment of the present invention.
  • Fig. 2 shows a schematic structural diagram of a continuous reaction system including a continuous synthesis-purification integrated device provided by a typical embodiment.
  • Continuous synthesis-purification integrated device 110, condensation reflux section; 111, tail gas outlet; 112, gas phase inlet; 120, reaction section; 121, feed port; 122, first gas phase communication port; 123, first liquid Phase communication port; 130, purification section; 131, replenishment port; 132, product outlet; 133, second gas phase communication port; 140, temperature control unit; 141, first temperature control device; 142, second temperature control device; 143 , The third temperature control device; 144, the temperature control medium supply device; 150, the first temperature measurement device; 160, the second temperature measurement device; 170, the third temperature measurement device, 180, the filler;
  • Pre-mixing unit 210, raw material storage device; 220, pre-mixing device; 230, second delivery pump; 201, pre-reaction product delivery pipeline; 202, raw material liquid delivery pipeline;
  • Fluid supplement supply device 400.
  • First delivery pump 401.
  • the existing synthesis device needs to be additionally equipped with a purification device to purify the product, which in turn has the problems of low product conversion rate and complex reaction route.
  • the present application provides a continuous synthesis-purification integrated device 100. As shown in FIG.
  • the continuous synthesis-purification integrated device 100 includes: a reaction section 120, a purification section 130, and a temperature control unit 140
  • the reaction section 120 is provided with a feed port 121, a first gas phase communication port 122, and a first liquid phase communication port 123;
  • the purification section 130 is provided with a replenishment port 131, a second gas phase communication port 133 and a product outlet 132, and the second gas phase is connected
  • the port 133 is connected to the first liquid phase communication port 123, and the gas-phase material in the purification section 130 enters the condensing reflux section 110 through the reaction section 120, and the fluid supplement added through the fluid supplement port 131 includes an impurity removing agent;
  • the temperature control unit 140 is used for The temperature of the continuous synthesis-purification integrated device 100 is controlled.
  • the above-mentioned continuous synthesis-purification integrated device 100 includes a reaction section 120 and a purification section 130 at the same time.
  • the reaction raw materials undergo chemical reactions in the reaction section 120 and are simultaneously transformed into a main product system and a by-product system with different boiling points.
  • the temperature control unit 140 can accurately control the temperature of each part of the continuous synthesis-purification integrated device 100.
  • the boiling point temperature of the by-product system is lower, and the boiling point temperature of the main product system is higher. Therefore, the low-boiling by-products are discharged through the first gas phase communication port 122, and the main product system is under gravity. Enter the purification section 130 under the action.
  • the impurities in the main product system and the impurity removal agent added from the liquid supplement port 131 form a low-boiling azeotrope, and are discharged through the first gas phase outlet of the reaction section 120.
  • the continuous synthesis-purification integrated device 100 adopts accurate multi-stage temperature control to ensure that as the reaction continues, according to the product, raw material, and the boiling point difference of the by-products and impurities generated by the reaction, the by-products and the by-products generated during the reaction can be discharged in time. Impurities, increase the conversion rate of reaction raw materials and the yield of products, and realize the separation and purification of products simultaneously.
  • the above-mentioned continuous synthesis-purification integrated device 100 can not only meet the temperature requirements in the reaction process, but also ensure the timely discharge of the low-boiling by-products generated in the reaction.
  • the continuous synthesis-purification integrated device 100 Compared with a traditional reaction device that requires an additional separation and purification device, the continuous synthesis-purification integrated device 100 provided in the present application makes the reaction process simpler, the reaction conditions are more stable, and the safety of the reaction device is greatly improved. On this basis, the use of the above-mentioned continuous synthesis-purification integrated device 100 can not only improve the conversion rate of raw materials and the yield of the product, but also improve the purity of the product, shorten the reaction route, and reduce the number of equipment, reaction time, floor space, and labor. Strength and energy consumption, etc.
  • the continuous synthesis-purification integrated device 100 further includes a condensation reflux section 110, the condensation reflux section 110 is provided with a tail gas outlet 111 and a gas phase inlet 112, and the gas phase inlet 112 is in communication with the first gas phase communication port 122.
  • the reaction continues, relatively low-boiling by-products continue to be produced, and the low-boiling by-products and part of the solvent will evaporate into gas, and volatilize up the reaction section 120 into the condensation reflux section 110.
  • the temperature of the condensing reflux section 110 is between the low-boiling by-products and the boiling point of the evaporated solvent to ensure that most of the solvent can be condensed and refluxed into the reaction section 120 to prevent the solvent from evaporating too much and affecting the continued reaction of the reaction system.
  • by-products with low boiling points can continue to volatilize and be discharged from the tail gas outlet 111.
  • the temperature control method of the condensing reflux section 110 can be accurately controlled by changing the length of the condensing reflux section 110 or by the first temperature control device 141.
  • the continuous synthesis-purification integrated device 100 further includes: a first temperature measuring device 150, a second temperature measuring device 160, and The third temperature measurement device 170, the first temperature measurement device 150 is used to detect the temperature of the condensing reflux section 110, the second temperature measurement device 160 is used to detect the temperature of the reaction section 120, and the third temperature measurement device 170 is used to detect the purification section 130 temperature.
  • the above-mentioned temperature control unit 140 is used to control the temperature of the condensing reflux section 110, the reaction section 120 and the purification section 130 in the continuous synthesis-purification integrated device 100.
  • the aforementioned temperature control unit 140 includes a first temperature control device 141, wherein the first temperature control device 141 is used to control the temperature of the condensing reflux section 110.
  • the above-mentioned temperature control unit 140 further includes a second temperature control device 142 and a third temperature control device 143, the second temperature control device 142 is used to control the temperature of the reaction section 120, and the third temperature control device The device 143 is used to control the temperature of the purification section 130.
  • the above-mentioned reaction section 120 and purification section 130 are filled with filler 180.
  • the packing 180 in the reaction section 120 and the purification section 130 can greatly increase the residence time of the reaction material system in the reaction section 120 and the purification section 130, increase the heat transfer effect inside the reaction section 120, and make the reaction of the reaction materials more thorough. This is beneficial to further increase the selectivity and conversion rate of the reaction.
  • the material of the filler 180 can be glass, stainless steel, polytetrafluoroethylene, etc., and the shape of the filler 180 can be spherical, columnar, spring, or wire mesh filler 180.
  • the material of the above-mentioned continuous synthesis-purification integrated device 100 can be glass, stainless steel, etc., and enamel, tetrafluoride spraying, etc. can be selected according to the corrosiveness of the reaction system.
  • reaction section 120, purification section 130, and condensing reflux section 110 in the above-mentioned continuous synthesis-purification integrated device 100 can be connected in sections, such as flanges, quick openings and threads, or they can be made integrally.
  • the continuous reaction system includes: a pre-mixing unit 200 and the above-mentioned continuous synthesis-purification integrated device 100, the pre-mixing unit 200 is provided with The raw material inlet and the pre-reaction product outlet, the continuous synthesis-purification integrated device 100 is provided with a feed port 121, and the feed port 121 and the pre-reaction product outlet are connected through a pre-reaction product delivery pipeline 201.
  • the above-mentioned continuous reaction system includes a pre-mixing unit 200 and a continuous synthesis-purification integrated device 100.
  • the reaction raw materials are first mixed in the pre-mixing unit 200 to fully mix the reaction raw materials, which is beneficial to improve the full reaction degree of the reaction raw materials in the continuous synthesis-purification integrated device 100.
  • the continuous synthesis-purification integrated device 100 adopts accurate multi-stage temperature control to ensure that as the reaction continues, the by-products generated during the reaction can be discharged in time according to the difference in boiling points of products, raw materials, and by-products and impurities generated by the reaction And impurities, increase the conversion rate of the raw materials and the yield of the product, and realize the separation and purification of the product simultaneously.
  • the above-mentioned continuous synthesis-purification integrated device 100 can not only meet the temperature requirements in the reaction process, but also ensure the timely discharge of the low-boiling by-products generated in the reaction.
  • the continuous reaction system provided in this application makes the reaction process simpler, the reaction conditions are more stable, and the safety of the reaction device is greatly improved.
  • the continuous reaction system can reduce the number of reaction steps and the number of operations, so that the number of equipment, reaction time, floor space, labor intensity and energy consumption are significantly reduced.
  • the temperature control unit 140 in the integrated continuous synthesis-purification device 100 is used to control the temperature of the condensing reflux section 110, the reaction section 120 and the purification section 130 in the integrated continuous synthesis-purification device 100.
  • the aforementioned temperature control unit 140 includes a first temperature control device 141, wherein the first temperature control device 141 is used to control the temperature of the condensing reflux section 110.
  • the temperature control unit 140 further includes a second temperature control device 142, a third temperature control device 143, and a temperature control medium supply device 144.
  • the second temperature control device 142 is provided with a first temperature control device 142.
  • the temperature control medium storage cavity includes a first temperature control medium inlet and a first temperature control medium outlet respectively connected to the first temperature control medium storage cavity; and the third temperature control device 143 is provided with a second temperature control medium reservoir.
  • the cavity includes a second temperature control medium inlet and a second temperature control medium outlet respectively connected to the second temperature control medium storage cavity, the second temperature control medium outlet communicates with the first temperature control medium inlet, and a temperature control medium supply device 144 is provided with a temperature control medium supply port and a temperature control medium recovery port, the temperature control medium supply port is connected with the second temperature control medium inlet, and the temperature control medium recovery port is connected with the first temperature control medium outlet.
  • the aforementioned continuous synthesis-purification integrated device 100 is further provided with a tail gas outlet 111, and the aforementioned continuous reaction system further includes a tail gas receiving device 300.
  • 300 is provided with a tail gas inlet, and the tail gas inlet and the tail gas outlet 111 are connected through a tail gas delivery pipeline 301.
  • the aforementioned tail gas recovery device is a condensation device. In the tail gas recovery process, the tail gas is collected by condensation in the tail gas recovery device.
  • the above-mentioned continuous reaction system further includes a pressure control device 310 which is arranged on the tail gas delivery pipeline 301.
  • the pressure control device 310 can adjust the reaction pressure in the reaction section 120 to make it proceed toward a reaction that can increase the product conversion rate.
  • the continuous reaction system further includes a replenishment supply device 400 and a first delivery pump 410.
  • the replenishment supply device 400 is provided with a replenishment supply port, and the replenishment supply port is connected to the replenishment port 131 through a replenishment delivery pipe 401. through.
  • the supplemental liquid is continuously delivered to the purification section 130, where the supplemental liquid includes an impurity remover, a solvent, etc., which is beneficial to improve the continuity of the entire continuous reaction device.
  • the continuous reaction system further includes a raw material storage device 210, a pre-mixing device 220, and a second delivery pump 230.
  • the raw material storage device 210 is provided with a raw material supply port, and the raw material supply port is communicated with the raw material inlet through a raw material liquid delivery pipeline 202.
  • the pre-mixing device 220 is provided with the raw material inlet and the pre-reaction product outlet, the raw material supply port is connected with the raw material inlet through the raw material liquid conveying pipe 202, the pre-reaction product outlet is connected to the feed port 121, and the second delivery pump 230 is arranged on the raw material On the liquid delivery pipeline 202.
  • the aforementioned pre-mixing device 220 can be a mixing device commonly used in the art.
  • the aforementioned pre-mixing device 220 is a continuous synthesis coil or a continuous cylindrical reactor. Using the above two devices as the pre-mixing device 220 can make the reaction raw materials undergo a preliminary reaction, thereby increasing the reaction rate in the reaction section 120.
  • the continuous reaction system further includes a product receiving device 500, and the inlet end of the product receiving device 500 is in communication with the product outlet 132 of the continuous synthesis-purification integrated device 100.
  • the continuous reaction system shown in Figure 2 is used to synthesize.
  • the temperature of each section of the reaction device is precisely controlled to 70°C through the jacket.
  • the reaction raw materials (27.0g of O-methoxymethylphenol and 23.0g of 38% hydrochloric acid) total 50g and
  • the 5V organic solvent methanol mixture is pumped into the pre-mixing device by the feed pump at a rate of 4.5 mL/min, and enters the continuous synthesis-purification integrated device (reaction section 120), and the organic solvent methanol passes through the feed pump in the middle replenishment section It is injected into the reaction device at 1.5 mL/min, and the synthesis reaction, separation of by-products and simultaneous purification of the product are completed in the above-mentioned reaction device. After 40 minutes, a sample is taken at the product outlet 132 to check the conversion rate of the raw material and the yield and purity of the product.
  • the reaction results are significantly better than batch reactions.
  • Example 1 The difference from Example 1 is that it does not go through the pre-mixing device, but directly enters the continuous synthesis-purification integrated device.
  • reaction materials 8g of O-methoxymethylphenol and 6.9g of 38% hydrochloric acid
  • organic solvent methanol 5V organic solvent methanol 5V
  • Table 1 shows the conversion rate of the raw materials and the yield and purity data of the products in Comparative Example 1, Examples 1 to 2.
  • the continuous synthesis-purification integrated device adopts precise multi-stage temperature control to ensure that as the reaction continues, according to the product, raw material and reaction
  • the difference in boiling point between the generated by-products and impurities can promptly discharge the by-products and impurities generated in the reaction process, improve the conversion rate of reaction raw materials and the yield of products, and realize the separation and purification of products simultaneously.
  • the above-mentioned continuous synthesis-purification integrated device can not only meet the temperature requirements in the reaction process, but also ensure the timely discharge of the low-boiling by-products generated in the reaction.
  • the continuous synthesis-purification integrated device Compared with a traditional reaction device that requires an additional separation and purification device, the continuous synthesis-purification integrated device provided in this application makes the reaction process simpler, the reaction conditions are more stable, and the safety of the reaction device is greatly improved. On this basis, the use of the above-mentioned continuous synthesis-purification integrated device can not only improve the conversion rate of raw materials and the yield of the product, but also improve the purity of the product, shorten the reaction route, and reduce the number of equipment, reaction time, floor space, and labor intensity. And energy consumption.

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Abstract

本发明提供了一种连续化合成-纯化一体装置及含有其的连续化反应系统。连续化合成-纯化一体装置包括：反应段、纯化段和控温单元，反应段设置有进料口、第一气相连通口和第一液相连通口；纯化段设置有补液口、第二气相连通口和产品出口，第二气相连通口与第一液相连通口相连通，且纯化段中的气相物料经第一气相连通口排出，经补液口加入的补液包括除杂剂；控温单元用于控制连续化合成-纯化一体装置的温度。采用上述连续化合成-纯化一体装置不仅能够提高原料转化率及产品的收率，还能够提高产品纯度，并缩短反应路线，降低设备数量、反应时间、占地面积、劳动强度和能耗等。

Description

连续化合成-纯化一体装置及含有其的连续化反应系统 技术领域
本发明涉及医药化工领域，具体而言，涉及一种连续化合成-纯化一体装置及含有其的连续化反应系统。
背景技术
目前世界上已经研究并开发出了许多适用于医药化工行业的反应器，包括盘管式反应器及釜式反应器等。但上述反应器对于可逆反应的反应效果并不明显，且无法实现分离纯化一体，需要在反应器后单独设置分离纯化的装置，导致工艺流程变复杂。许多先进的反应技术无法达到理想的产品转化率、产品收率和纯度，从而无法将反应技术应用到实际生产中。而高选择性同步纯化一体连续化合成装置，可以促进反应向产物方向进行，简化反应流程，加快反应速率，缩短反应时间，提高原料转化率及产品的收率，节省能耗。因此分析研究这种能够提高反应过程中原料转化率和产品收率的反应器是当前针对医药化工行业反应过程中亟待解决的难题。
目前在医药化工行业中可逆反应的应用越来越多，提高反应器的多功能性和选择性是当前设计反应器的主要需求，常规使用的反应器大部分只具备单一反应的功能，无法满足选择性需求和同步分离纯化一体。即当前医药化工的研发及生产过程中使用的普通反应装置不能实现随着反应的进行不断的排出反应中生成的副产物及同步纯化产品的目的，使得反应的原料转化率及产物的收率和纯度降低，无法满足研发及生产的要求。这不仅影响了反应的顺利进行，又增加了反应过程中的危险性。而在反应器之后单独设置分离纯化的装置，使得工艺流程变复杂，设备成本大大增加。另外，在有强腐蚀性反应体系时，使用现在常用的反应装置对材料耐腐蚀的要求较高，这也使得设备费用提高。
发明内容
本发明的主要目的在于提供一种连续化合成-纯化一体装置及含有其的连续化反应系统，以解决现有的合成装置存在需要额外设置纯化装置，进而存在反应路线复杂的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种连续化合成-纯化一体装置，连续化合成-纯化一体装置包括：反应段、纯化段和控温单元，反应段设置有进料口、第一气相连通口和第一液相连通口；纯化段设置有补液口、第二气相连通口和产品出口，第二气相连通口与第一液相连通口相连通，且纯化段中的气相物料经第一气相连通口排出，经补液口加入的补液包括除杂剂；控温单元用于控制连续化合成-纯化一体装置的温度。
进一步地，连续化合成-纯化一体装置还包括冷凝回流段，冷凝回流段设置有尾气出口和气相入口，气相入口与第一气相连通口连通。
进一步地，连续化合成-纯化一体装置还包括：第一测温装置、第二测温装置和第三测温装置。第一测温装置用于检测冷凝回流段的温度；第二测温装置用于检测反应段的温度；第三测温装置用于检测纯化段的温度。
进一步地，控温单元包括第一控温装置，第一控温装置用于控制冷凝回流段的温度。
进一步地，控温单元还包括：第二控温装置和第三控温装置，第二控温装置用于控制反应段的温度；及第三控温装置用于控制纯化段的温度。
本申请的另一方面还提供了一种连续化反应系统，该连续化反应系统包括：预混合单元，预混合单元设置有原料入口和预反应产物出口；上述连续化合成-纯化一体装置，连续化合成-纯化一体装置设置有进料口，进料口与预反应产物出口通过预反应产物输送管路连通。
进一步地，连续化合成-纯化一体装置还设置有尾气出口，连续化反应系统还包括尾气接收装置，尾气接收装置设置有尾气入口，尾气入口与尾气出口通过尾气输送管路连通。
进一步地，连续化反应系统还包括控压装置，控压装置设置在尾气输送管路上。
进一步地，连续化反应系统还包括：补液供应装置和第一输送泵，补液供应装置设置有补液供应口，补液供应口与连续化合成-纯化一体装置的补液口通过补液输送管路相连通；及第一输送泵设置在补液输送管路上。
进一步地，预混合单元包括：原料储存装置、预混合装置和第二输送泵。原料储存装置设置有原料供应口，预混合装置设置有原料入口和预反应产物出口，原料供应口与原料入口通过原料液输送管路连通，预反应产物出口与连续化合成-纯化一体装置的进料口连通；及第二输送泵设置在原料液输送管路上。
进一步地，连续化反应系统还包括产品接收装置，产品接收装置的入口端与连续化合成-纯化一体装置的产品出口连通。
进一步地，预混合装置为连续反应盘管或连续化柱状反应器。
应用本发明的技术方案，对连续化合成-纯化一体装置采用精确的多段温度控制，保证随着反应不断进行，根据产品、原料以及反应生成副产物和杂质的沸点差异，可以及时的排出反应过程中生成的副产物和杂质，提高反应原料转化率及产物的收率，以及同步实现产品的分离纯化。上述连续化合成-纯化一体装置既能满足反应过程中的温度要求，又能保证反应中生成的低沸点副产物的及时排出。相比于传统反应装置需要额外设置分离纯化的装置，本申请提供的连续化合成-纯化一体装置使反应流程更简单，反应条件更稳定，大大提高了反应装置使用的安全性。在此基础上，采用上述连续化合成-纯化一体装置不仅能够提高原料转化率及产品的收率，还能够提高产品纯度，并缩短反应路线，降低设备数量、反应时间、占地面积、劳动强度和能耗等。
附图说明
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：
图1示出了根据本发明的一种典型的实施方式体提供的连续化合成-纯化一体装置的结构示意图；以及
图2示出了一种典型的实施方式体提供的含有连续化合成-纯化一体装置的连续化反应系统的结构示意图。
其中，上述附图包括以下附图标记：
100、连续化合成-纯化一体装置；110、冷凝回流段；111、尾气出口；112、气相入口；120、反应段；121、进料口；122、第一气相连通口；123、第一液相连通口；130、纯化段；131、补液口；132、产品出口；133、第二气相连通口；140、控温单元；141、第一控温装置；142、第二控温装置；143、第三控温装置；144、控温介质供应装置；150、第一测温装置；160、第二测温装置；170、第三测温装置；180、填料；
200、预混合单元；210、原料储存装置；220、预混合装置；230、第二输送泵；201、预反应产物输送管路；202、原料液输送管路；
300、尾气接收装置；310、控压装置；301、尾气输送管路
400、补液供应装置；410、第一输送泵；401、补液输送管路
500、产品接收装置。
具体实施方式
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。下面将结合实施例来详细说明本发明。
正如背景技术所描述的，现有的合成装置需要额外设置纯化装置采用对产物进行纯化，进而存在产品转化率低、反应路线复杂的问题。为了解决上述技术问题，本申请提供了一种连续化合成-纯化一体装置100，如图1所示，该连续化合成-纯化一体装置100包括：反应段120、纯化段130和控温单元140，反应段120设置有进料口121、第一气相连通口122和第一液相连通口123；纯化段130设置有补液口131、第二气相连通口133和产品出口132，第二气相连通口133与第一液相连通口123相连通，且纯化段130中的气相物料经反应段120进入冷凝回流段110中，经补液口131加入的补液包括除杂剂；控温单元140用于控制连续化合成-纯化一体装置100的温度。
上述连续化合成-纯化一体装置100同时包含反应段120和纯化段130，反应原料在反应段120中进行化学反应，同时转化成不同沸点的主产物体系和副产物体系。通过控温单元140能够精准控制连续化合成-纯化一体装置100中各部分的温度。相比于反应段120的反应温度，副产物体系的沸点温度较低，主产物体系的沸点温度较高，因而低沸点的副产物经第一气相 连通口122排出，主产物体系在自身重力的作用下进入纯化段130。然后主产物体系中的杂质与从补液口131加入的除杂剂形成低沸点的共沸物，并经过反应段120的第一气相出口排出。
对连续化合成-纯化一体装置100采用精确的多段温度控制，保证随着反应不断进行，根据产品、原料以及反应生成副产物和杂质的沸点差异，可以及时的排出反应过程中生成的副产物和杂质，提高反应原料转化率及产物的收率，以及同步实现产品的分离纯化。上述连续化合成-纯化一体装置100既能满足反应过程中的温度要求，又能保证反应中生成的低沸点副产物的及时排出。相比于传统反应装置需要额外设置分离纯化的装置，本申请提供的连续化合成-纯化一体装置100使反应流程更简单，反应条件更稳定，大大提高了反应装置使用的安全性。在此基础上，采用上述连续化合成-纯化一体装置100不仅能够提高原料转化率及产品的收率，还能够提高产品纯度，并缩短反应路线，降低设备数量、反应时间、占地面积、劳动强度和能耗等。
在一种优选的实施例中，连续化合成-纯化一体装置100还包括冷凝回流段110，冷凝回流段110设置有尾气出口111和气相入口112，气相入口112与第一气相连通口122连通。
随着反应的不断进行，持续有相对低沸点的副产物产生，低沸点的副产物和部分溶剂会蒸发成气体，并沿反应段120向上挥发进入冷凝回流段110。使冷凝回流段110的温度介于低沸点副产物和蒸发出溶剂的沸点之间，保证溶剂能够大部分冷凝回流到反应段120内，以防溶剂蒸发出过多而影响反应体系的继续反应。同时低沸点的副产物可以继续挥发并从尾气出口111排出。由于副产物被不断蒸发出反应体系，反应可以继续向产物方向进行，使原料转化率更高，反应更彻底。优选地，冷凝回流段110的控温方式可以通过改变冷凝回流段110的长度或通过第一控温装置141对冷凝回流段110进行精确控温。
为了更准确地监测连续化合成-纯化一体装置100的温度，在一种优选的实施例中，连续化合成-纯化一体装置100还包括：第一测温装置150、第二测温装置160和第三测温装置170，第一测温装置150用于检测冷凝回流段110的温度，第二测温装置160用于检测反应段120的温度，第三测温装置170用于检测纯化段130的温度。
上述控温单元140用于控制连续化合成-纯化一体装置100中冷凝回流段110、反应段120和纯化段130的温度。在一种优选的实施例中，上述控温单元140包括第一控温装置141，其中第一控温装置141用于控制冷凝回流段110的温度。在另一种优选的实施例中，上述控温单元140还包括第二控温装置142和第三控温装置143，第二控温装置142用于控制反应段120的温度，第三控温装置143用于控制纯化段130的温度。
优选地，上述反应段120和纯化段130中填充有填料180。反应段120和纯化段130中设置填料180能够大大增加反应物料体系在反应段120和纯化段130内的停留时间，增加了反应段120内部的传热效果，也使得反应物料反应进行更彻底，从而有利于进一步提高反应的选择性和转化率。更优选地，填料180的材质可选用玻璃、不锈钢、聚四氟乙烯等，填料180的形状可选用球形、柱状、弹簧状、丝网填料180等。
上述连续化合成-纯化一体装置100的材质可选用玻璃、不锈钢等，可根据反应体系腐蚀性选用搪瓷、喷涂四氟等。
上述连续化合成-纯化一体装置100中的反应段120、纯化段130和冷凝回流段110可以分段连接，如法兰、快开和螺纹，也可以整体制作。
本申请的另一方面还提供了一种连续化反应系统，如图2所示，该连续化反应系统包括：预混合单元200和上述连续化合成-纯化一体装置100，预混合单元200设置有原料入口和预反应产物出口，连续化合成-纯化一体装置100设置有进料口121，进料口121与预反应产物出口通过预反应产物输送管路201连通。
上述该连续化反应系统包括预混合单元200和连续化合成-纯化一体装置100。先将反应原料在预混合单元200中进行混合，使反应原料充分混合，有利于提高连续化合成-纯化一体装置100中反应原料的充分反应程度。对连续化合成-纯化一体装置100采用精确的多段温度控制，保证随着反应不断进行，跟据产品、原料以及反应生成副产物和杂质的沸点差异，可以及时的排出反应过程中生成的副产物和杂质，提高反应的原料转化率及产物的收率，以及同步实现产品的分离纯化。上述连续化合成-纯化一体装置100既能满足反应过程中的温度要求，又能保证反应中生成的低沸点副产物的及时排出。相比于传统反应装置需要额外设置分离纯化的装置，本申请提供的连续化反应系统使反应流程更简单，反应条件更稳定，大大提高了反应装置使用的安全性。同时该连续化反应系统可以减少反应步骤和操作次数，使得设备数量、反应时间、占地面积、劳动强度和能耗明显降低。
上述连续化合成-纯化一体装置100中的控温单元140用于控制连续化合成-纯化一体装置100中冷凝回流段110、反应段120和纯化段130的温度。在一种优选的实施例中，上述控温单元140包括第一控温装置141，其中第一控温装置141用于控制冷凝回流段110的温度。在另一种优选的实施例中，上述控温单元140还包括第二控温装置142、第三控温装置143和控温介质供应装置144，第二控温装置142的内部设置有第一控温介质储腔，包括分别与第一控温介质储腔相连通的第一控温介质入口和第一控温介质出口；及第三控温装置143的内部设置有第二控温介质储腔，包括分别与第二控温介质储腔相连通的第二控温介质入口和第二控温介质出口，第二控温介质出口与第一控温介质入口相连通，控温介质供应装置144设置有控温介质供应口和和控温介质回收口，控温介质供应口与第二控温介质入口相连通，控温介质回收口与第一控温介质出口相连通。
为了提高连续化反应系统的环保性，在一种优选的实施例中，上述连续化合成-纯化一体装置100还设置有尾气出口111，上述连续化反应系统还包括尾气接收装置300，尾气接收装置300设置有尾气入口，尾气入口与尾气出口111通过尾气输送管路301连通。优选地，上述尾气回收装置为冷凝装置。尾气回收过程中，尾气在尾气回收装置中因被冷凝而收集。
在一种优选的实施例中，上述连续化反应系统还包括控压装置310，该控压装置310设置在尾气输送管路301上。控压装置310能够调节反应段120中的反应压力，使其向能够提高产品转化率的反应进行。
补液中的除杂剂用于与从反应段120排出的产物体系中的杂质形成低沸点共沸物。在一种优选的实施例中，连续化反应系统还包括补液供应装置400和第一输送泵410，补液供应装置400设置有补液供应口，补液供应口与补液口131通过补液输送管路401相连通。在第一输送泵410的作用下，补液连续地输送至纯化段130，其中补液包括除杂剂、溶剂等，这有利于提高整个连续化反应装置的连续性。
为了进一步提高预混合单元200的自动化程度，在一种优选的实施例中，连续化反应系统还包括原料储存装置210、预混合装置220和第二输送泵230。原料储存装置210设置有原料供应口，原料供应口与原料入口通过原料液输送管路202连通。预混合装置220设置有所述原料入口和预反应产物出口，原料供应口与原料入口通过原料液输送管路202连通，预反应产物出口与进料口121连通，第二输送泵230设置在原料液输送管路202上。
上述预混合装置220可以选用本领域常用的混合装置。优选地，上述预混合装置220为连续化合成盘管或连续化柱状反应器。采用上述两种装置作为预混合装置220，能够使反应原料进行初步反应，从而提高其在反应段120中的反应速率。
为了便于产品的收集，优选地，连续化反应系统还包括产品接收装置500，产品接收装置500的入口端与连续化合成-纯化一体装置100的产品出口132连通。
以下结合具体实施例对本申请作进一步详细描述，这些实施例不能理解为限制本申请所要求保护的范围。
实施例1
采用图2所示的连续化反应系统合成，通过夹套精确控制反应装置各段的温度至70℃，将反应原料(O-甲氧甲基苯酚27.0g和38％盐酸23.0g)共50g和5V的有机溶剂甲醇混合液由进料泵按照4.5mL/min的速度打入预混合装置，并进入连续化合成-纯化一体装置(反应段120)内，有机溶剂甲醇通过加料泵在中间补液段按照1.5mL/min打入反应装置内，在上述反应装置内完成合成反应、副产物的分离及产品的同步纯化，40min后在产品出口132取样检测原料的转化率及产品的收率和纯度，反应结果明显优于批次反应。
实施例2
与实施例1的区别为：不经过预混合装置，直接进入连续化合成-纯化一体装置。
在产品出口132取样检测原料的转化率及产品的收率和纯度，反应结果明显优于批次反应。
对比例1(批次操作)
将反应原料(O-甲氧甲基苯酚8.1g和38％盐酸6.9g)混合液共15g，有机溶剂甲醇5V，加入到三口烧瓶中混合，三口瓶上设冷凝管，对三口烧瓶进行外浴加热至70℃，开始反应，分别在反应时间为15min和60min后取样检测原料的转化率及产品的收率和纯度。
对比例1、实施例1至2中原料的转化率及产品的收率和纯度数据见表1。
表1
Figure PCTCN2019099380-appb-000001
由表1中数据可知，相比于批次反应装置，在同等条件下，采用本申请提供的连续化反应系统能够大大提高产品的收率和纯度。
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：对连续化合成-纯化一体装置采用精确的多段温度控制，保证随着反应不断进行，根据产品、原料以及反应生成副产物和杂质的沸点差异，可以及时的排出反应过程中生成的副产物和杂质，提高反应原料转化率及产物的收率，以及同步实现产品的分离纯化。上述连续化合成-纯化一体装置既能满足反应过程中的温度要求，又能保证反应中生成的低沸点副产物的及时排出。相比于传统反应装置需要额外设置分离纯化的装置，本申请提供的连续化合成-纯化一体装置使反应流程更简单，反应条件更稳定，大大提高了反应装置使用的安全性。在此基础上，采用上述连续化合成-纯化一体装置不仅能够提高原料转化率及产品的收率，还能够提高产品纯度，并缩短反应路线，降低设备数量、反应时间、占地面积、劳动强度和能耗等。
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 (12)

  1. 一种连续化合成-纯化一体装置，其特征在于，所述连续化合成-纯化一体装置包括：
    反应段(120)，所述反应段(120)设置有进料口(121)、第一气相连通口(122)和第一液相连通口(123)；
    纯化段(130)，所述纯化段(130)设置有补液口(131)、产品出口(132)和第二气相连通口(133)，所述第二气相连通口(133)与所述第一液相连通口(123)相连通，且所述纯化段(130)中的气相物料经所述第一气相连通口(122)排出，经所述补液口(131)加入的补液包括除杂剂；
    控温单元(140)，所述控温单元(140)用于控制所述连续化合成-纯化一体装置的温度。
  2. 根据权利要求1所述的连续化合成-纯化一体装置，其特征在于，所述连续化合成-纯化一体装置还包括冷凝回流段(110)，所述冷凝回流段(110)设置有尾气出口(111)和气相入口(112)，所述气相入口(112)与所述第一气相连通口(122)连通。
  3. 根据权利要求2所述的连续化合成-纯化一体装置，其特征在于，所述连续化合成-纯化一体装置还包括：
    第一测温装置(150)，所述第一测温装置(150)用于检测所述冷凝回流段(110)的温度；
    第二测温装置(160)，所述第二测温装置(160)用于检测所述反应段(120)的温度；
    第三测温装置(170)，所述第三测温装置(170)用于检测所述纯化段(130)的温度。
  4. 根据权利要求2或3所述的连续化合成-纯化一体装置，其特征在于，所述控温单元(140)包括第一控温装置(141)，所述第一控温装置(141)用于控制所述冷凝回流段(110)的温度。
  5. 根据权利要求4所述的连续化合成-纯化一体装置，其特征在于，所述控温单元(140)还包括：
    第二控温装置(142)，所述第二控温装置(142)用于控制所述反应段(120)的温度；及
    第三控温装置(143)，所述第三控温装置(143)用于控制所述纯化段(130)的温度。
  6. 一种连续化反应系统，其特征在于，所述连续化反应系统包括：
    预混合单元(200)，所述预混合单元(200)设置有原料入口和预反应产物出口；
    权利要求1至5中任一项所述的连续化合成-纯化一体装置(100)，所述连续化合成-纯化一体装置(100)设置有所述进料口(121)，所述进料口(121)与所述预反应产物出口通过预反应产物输送管路(201)连通。
  7. 根据权利要求6所述的连续化反应系统，其特征在于，所述连续化合成-纯化一体装置(100)还设置有尾气出口(111)，所述连续化反应系统还包括尾气接收装置(300)，所述尾气接收装置(300)设置有尾气入口，所述尾气入口与所述尾气出口(111)通过尾气输送管路(301)连通。
  8. 根据权利要求7所述的连续化反应系统，其特征在于，所述连续化反应系统还包括控压装置(310)，所述控压装置(310)设置在所述尾气输送管路(301)上。
  9. 根据权利要求6至8中任一项所述的连续化反应系统，其特征在于，所述连续化反应系统还包括：
    补液供应装置(400)，所述补液供应装置(400)设置有补液供应口，所述补液供应口与所述连续化合成-纯化一体装置(100)的补液口(131)通过补液输送管路(401)相连通；及
    第一输送泵(410)，所述第一输送泵(410)设置在所述补液输送管路(401)上。
  10. 根据权利要求6至8中任一项所述的连续化反应系统，其特征在于，所述预混合单元(200)包括：
    原料储存装置(210)，所述原料储存装置(210)设置有原料供应口，
    预混合装置(220)，所述预混合装置(220)设置有所述原料入口和所述预反应产物出口，所述原料供应口与所述原料入口通过原料液输送管路(202)连通，所述预反应产物出口与所述连续化合成-纯化一体装置(100)的进料口(121)连通；及
    第二输送泵(230)，所述第二输送泵(230)设置在所述原料液输送管路(202)上。
  11. 根据权利要求9或10所述的连续化反应系统，其特征在于，所述连续化反应系统还包括产品接收装置(500)，所述产品接收装置(500)的入口端与所述连续化合成-纯化一体装置(100)的产品出口(132)连通。
  12. 根据权利要求10所述的连续化反应系统，其特征在于，所述预混合装置(220)为连续反应盘管或连续化柱状反应器。
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EP0332452A1 (en) * 1988-03-11 1989-09-13 Takeda Chemical Industries, Ltd. Automated synthesizing apparatus
CN203061178U (zh) * 2012-12-19 2013-07-17 王陆瑶 一种提高产物收率的反应装置
CN208511890U (zh) * 2018-06-15 2019-02-19 南通汇潜新材料科技有限公司 一种连续脱除流体物质中低沸物的装置
CN208771389U (zh) * 2018-06-15 2019-04-23 辽宁凯莱英医药化学有限公司 连续反应装置及系统
CN110372462A (zh) * 2019-08-06 2019-10-25 吉林凯莱英医药化学有限公司 连续化合成-纯化一体装置及含有其的连续化反应系统

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0332452A1 (en) * 1988-03-11 1989-09-13 Takeda Chemical Industries, Ltd. Automated synthesizing apparatus
CN203061178U (zh) * 2012-12-19 2013-07-17 王陆瑶 一种提高产物收率的反应装置
CN208511890U (zh) * 2018-06-15 2019-02-19 南通汇潜新材料科技有限公司 一种连续脱除流体物质中低沸物的装置
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