Method for continuously preparing 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester

Abstract

The present invention provides a method for preparing 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl esters in a continuous manner, comprising: (E)-1-N-morpholinyl propene and methyl acrylate are respectively continuously vaporized, (E)-1-N-morpholinyl propene vaporized gas and methyl acrylate vaporized gas are mixed and continuously passed into a tubular reactor for reaction; The obtained reaction mixture is continuously discharged from the reactor, and continuous cooling quenching and continuous evaporation separation are performed to obtain 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl esters. The preparation method uses a tubular reactor to react, and the reaction time is short, which effectively improves the reaction rate and reaction conversion rate. The continuous vaporization, reaction, cooling and separation process allow the reaction to proceed uninterruptedly, improve production efficiency, and reduce production costs. The continuous cooling and separation process reduces the residence time of materials at high temperatures, improves production safety, and can also make the preparation capacity no longer subject to the size of the reactor.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate. Background Art

[0002] The morpholine-propionaldehyde process for producing 2-chloro-5-methylpyridine was first used industrially in Jiangsu Yangnong Chemical Group Co., Ltd. in 2000 with an annual capacity of 700 tons. The company later expanded its production capacity to 2,000 tons per year. The process mainly includes: using morpholine and propionaldehyde as raw materials to prepare (E)-1-N-morpholinyl propene through a microchannel reactor, and continuously preparing the intermediate 3-methyl-4-morpholinyl cyclobutanecarboxylic acid methyl ester by reacting (E)-1-N-morpholinyl propene with excess methyl acrylate. The intermediate 3-methyl-4-morpholinyl cyclobutanecarboxylic acid methyl ester is then aminolyzed with ammonia water in the presence of a corresponding catalyst to obtain 5-methyl-3,4-dihydropyridine-2(1H)-one (referred to as pyridone), and the pyridone is then chlorinated and phosgenated to finally obtain the product 2-chloro-5-methylpyridine. Among them, methyl 3-methyl-4-morpholinylcyclobutanecarboxylate is an important intermediate for the production of 2-chloro-5-methylpyridine. The preparation of methyl 3-methyl-4-morpholinylcyclobutanecarboxylate is usually prepared by reacting (E)-1-N-morpholinyl propene with methyl acrylate. The synthesis reaction rate of this reaction is mainly controlled by thermodynamics and interphase mass transfer. When the reaction is carried out in the liquid phase, material transfer and dispersion need to occur at the liquid phase interface before the reaction can occur. This feature greatly increases the reaction resistance.

[0003] Patent CN116987049A discloses a method for preparing imidacloprid intermediate 3-methyl-2-(4-morpholinyl) cyclobutyric acid methyl ester in a continuous manner, wherein the preparation method comprises the following steps: first, raw material morpholinyl propylene and methyl acrylate are respectively introduced into a preheater, and then the preheated raw material pump is sent into a microchannel reactor for reaction, and then the reacted mixed material is discharged from the microchannel reactor outlet into a reactor for further reaction. Then, the cyclized liquid obtained by the reaction in the reactor enters a light removal tower for light removal, and 3-methyl-2 (4-morpholinyl) cyclobutyric acid methyl ester after light removal is extracted from the tower kettle of the light removal tower. Although the method uses a microchannel reactor for partial reaction, it is still necessary to further prepare cyclobutane in a liquid phase reaction; and there is also insufficient raw material conversion in the reaction synthesis liquid, and a kettle reactor is still required to be used for aging materials, and the reaction time is relatively long, and a microchannel reactor is used in series with a kettle, and the equipment investment is large, and the light removal residence time is long, the temperature is high, and there are problems such as potential safety hazards.

[0004] In order to further improve the reaction rate and conversion rate in the production and preparation process of 2-chloro-5-methylpyridine intermediate 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, improve production safety and efficiency, and reduce investment costs, it is urgent to develop a more preferred method for producing 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester. Summary of the invention

[0005] The main purpose of the present invention is to provide a method for continuously preparing 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, so as to solve the problems of low reaction rate, low conversion rate and low product selectivity, insufficient overall production efficiency and safety, and high production investment cost in the process of producing 2-chloro-5-methylpyridine intermediate 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester in the prior art.

[0006] In order to solve the above problems, the present invention provides a method for continuously preparing 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, which comprises the following steps: (E)-1-N-morpholinyl propene and methyl acrylate are continuously vaporized respectively to obtain (E)-1-N-morpholinyl propene vaporized gas and methyl acrylate vaporized gas; (E)-1-N-morpholinyl propene vaporized gas and methyl acrylate vaporized gas are mixed, and then continuously introduced into a reactor for reaction to obtain a reaction mixture; wherein the reactor is a tubular reactor; the reaction mixture is continuously discharged from the reactor, and then continuously cooled and quenched, and then continuously evaporated and separated to obtain 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester.

[0007] Furthermore, the tubular reactor includes a first reaction section, a second reaction section and a third reaction section connected in sequence, and the reaction temperature of the first reaction section is not lower than the reaction temperature of the second reaction section, and the reaction temperature of the second reaction section is not lower than the reaction temperature of the third reaction section; preferably, the reaction temperature of the first reaction section is 160-180°C, the reaction temperature of the second reaction section is 140-160°C, and the reaction temperature of the third reaction section is 120-140°C; preferably, the vaporization temperature is the same as the temperature of the first reaction section.

[0008] Furthermore, when the inner diameters of the tubular reactors are the same, the length ratio of the first reaction section, the second reaction section and the third reaction section is (5-20):(35-50):(30-60); preferably, the length ratio of the first reaction section, the second reaction section and the third reaction section is (5-10):(35-40):(50-60); further preferably, the length ratio of the first reaction section, the second reaction section and the third reaction section is 5:35:60.

[0009] Furthermore, the aspect ratio of the tubular reactor is (200-1200):1; preferably, the aspect ratio of the tubular reactor is (500-850):1.

[0010] Furthermore, the tubular reactor is an empty tube reactor; preferably, the empty tube reactor is a coil reactor.

[0011] Further, the molar ratio of (E)-1-N-morpholinylpropene to methyl acrylate is 1:(1.05-1.8); preferably, the molar ratio of (E)-1-N-morpholinylpropene to methyl acrylate is 1:(1.2-1.5).

[0012] Further, the reaction time of the mixture of (E)-1-N-morpholinylpropene and methyl acrylate in the tubular reactor is 15 to 360 seconds; preferably, the reaction time of (E)-1-N-morpholinylpropene and methyl acrylate in the tubular reactor is 25 to 80 seconds.

[0013] Furthermore, the evaporative separation is carried out in a thin film evaporator; preferably, the evaporation pressure in the thin film evaporator is 405-650 mmHg; preferably, the heat medium temperature in the thin film evaporator is 50-80°C; preferably, the residence time of the reaction mixture in the thin film evaporator is 15-45s; preferably, the cooling quenching temperature is ≤80°C.

[0014] Further, (E)-1-N-morpholinylpropene and methyl acrylate are vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, respectively.

[0015] Further, the (E)-1-N-morpholinylpropene vaporized gas and the methyl acrylate vaporized gas are mixed in a mixer; preferably, the mixer is a static mixer; preferably, cooling is performed in a condenser.

[0016] The present invention proposes a method for preparing 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester in a continuous manner, wherein the preparation method first continuously vaporizes reaction raw materials (E)-1-N-morpholinyl propylene and methyl acrylate respectively, and then the obtained (E)-1-N-morpholinyl propylene vaporized gas and methyl acrylate vaporized gas are mixed, and continuously passed into a tubular reactor for reaction, after the reaction is completed, and then through continuous cooling quenching and separation by evaporation, 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester is obtained. The production and preparation method adopts a tubular reactor to react, and the reaction can be completed in a very short time, effectively improving reaction rate, reaction conversion rate and reaction selectivity. In addition, the continuous vaporization process, reaction process, cooling process and separation process can make the reaction uninterrupted, improve production efficiency, reduce production cost, and the continuous cooling process and separation process simultaneously greatly reduce the residence time of materials at high temperature, improve production safety, and can also make the preparation capacity no longer subject to the size of the reactor. The above preparation process has strong operability, small equipment investment, high safety factor, high product yield, and is suitable for industrial-scale production. DETAILED DESCRIPTION

[0017] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below in conjunction with the embodiments.

[0018] As described in the background technology section, the prior art uses a traditional kettle reactor method or a microchannel reactor method in the process of preparing 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and both have the problem that the production capacity is restricted by the reactor capacity, and when the reaction is carried out in the liquid phase, it is necessary to react after the material transfer and dispersion occurs at the liquid phase interface, which greatly increases the reaction resistance, prolongs the time required for the reaction, and reduces the raw material conversion rate and selectivity. In addition, the existing preparation method also has the problems of long high temperature residence time, large safety hazards and large initial equipment investment, and the non-automatic continuous production process will further increase the cost of manual use.

[0019] In order to solve the above problems, the present invention provides a method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate. The preparation method comprises the following steps: (E)-1-N-morpholinyl propene and methyl acrylate are respectively and continuously vaporized to obtain (E)-1-N-morpholinyl propene vaporized gas and methyl acrylate vaporized gas; (E)-1-N-morpholinyl propene vaporized gas and methyl acrylate vaporized gas are mixed, and then continuously introduced into a reactor for reaction to obtain a reaction mixture; wherein the reactor is a tubular reactor; the reaction mixture is continuously discharged from the reactor, and then continuously cooled and quenched, and then separated by evaporation to obtain methyl 3-methyl-4-morpholinylcyclobutanecarboxylate.

[0020] In the above-mentioned preparation method, the reaction raw materials (E) -1-N-morpholinyl propylene and methyl acrylate are first continuously vaporized respectively, and then the obtained (E) -1-N-morpholinyl propylene vaporized gas and methyl acrylate vaporized gas are mixed, and continuously passed into a tubular reactor for reaction. The reaction is also carried out continuously, and the reaction product is discharged while feeding. As the reaction product is continuously discharged, the application continues to separate the reaction mixture through continuous cooling quenching and evaporation to obtain 3-methyl-4-morpholinyl cyclobutane carboxylic acid methyl ester. On the one hand, the above-mentioned preparation method uses a tubular reactor to make the residence time of the reaction material controllable, and the heat and mass transfer are more uniform and efficient. The whole reaction system is closer to the idealized plug flow reaction, which improves the selectivity and purity of the target product, and then also improves the reaction rate and reaction conversion rate. In addition, since the reaction is carried out in a continuously flowing tube, a large amount of materials are avoided to stay for a long time at high temperature, and the risk of safety accidents such as combustion and explosion is also reduced while reducing side reactions. The design of the tubular reactor can also better control the reaction heat and reduce the possibility of thermal runaway. On the other hand, continuous vaporization process, reaction process, cooling process and separation process can make the reaction proceed uninterruptedly, can improve production efficiency, and reduce production cost. The reaction solution after the reaction is subjected to continuous cooling process and separation process, and the residence time of the material at high temperature is further reduced, the side reaction caused by the thermal instability of 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester is reduced, and the selectivity of the reaction to the target product is improved. Wherein, the reaction equation involved in the present invention is:

[0021]

[0022] In summary, the efficient mass transfer and heat transfer characteristics of the tubular reactor and the above-mentioned continuous operation mode not only improve the reaction conversion rate and selectivity, improve the reaction efficiency, but also reduce production costs and reduce safety hazards. Compared with the traditional kettle reactor with limitations in cost, production capacity, etc., the preparation method of the present invention is very suitable for industrial continuous production processes.

[0023] In a preferred embodiment, the tubular reactor includes a first reaction section, a second reaction section and a third reaction section connected in sequence, and the reaction temperature of the first reaction section is not lower than the reaction temperature of the second reaction section, and the reaction temperature of the second reaction section is not lower than the reaction temperature of the third reaction section. Preferably, the reaction temperature of the first reaction section is higher than the reaction temperature of the second reaction section, and the reaction temperature of the second reaction section is higher than the reaction temperature of the third reaction section. In a specific reaction, after the vaporized gas of (E)-1-N-morpholinyl propene and the vaporized gas of methyl acrylate are mixed and passed into the reactor, the reaction raw materials are first reacted by about 60-70% in the first reaction section, and the concentration of the reaction product 3-methyl-4-morpholinyl cyclobutane carboxylic acid methyl ester in the tubular reactor is gradually accumulated in this reaction stage, thereby increasing the pressure of the system; then entering the second reaction section with a relatively low temperature, the pressure in the system can be fully buffered. At the same time, the unreacted reaction mixture can be further reacted in the second reaction section, and can continue to react for about 15-20%. Similarly, the reaction temperature of the third reaction section is lower than that of the second reaction section, which can further buffer the reaction pressure in the system, and a small amount of unreacted reaction raw materials will continue to react in the third reaction section until the reaction is complete. The above-mentioned reaction raw materials (E)-1-N-morpholinyl propene and methyl acrylate are reacted through the first reaction section, the second reaction section and the third reaction section connected in sequence, and the setting mode of reducing the reaction temperature gradient of each reaction section can make the reaction more thorough, while further reducing the occurrence of side reactions, improving the selectivity and yield of the target product, and making the reaction system safer. Preferably, the reaction temperature of the first reaction section is 160-180°C, the reaction temperature of the second reaction section is 140-160°C, and the reaction temperature of the third reaction section is 120-140°C. The reaction temperatures of the first reaction section, the second reaction section and the third reaction section are set in the above manner to further improve the reaction conversion rate. Preferably, the vaporization temperature is the same as the temperature of the first reaction stage; making the vaporization temperature the same as the temperature of the first reaction stage enables the (E)-1-N-morpholinylpropene vaporized gas and the methyl acrylate vaporized gas to react after being mixed and introduced into the reactor, so that the reaction in the first reaction stage can be carried out more efficiently.

[0024] In a preferred embodiment, when the inner diameters of the tubular reactors are the same, the length ratio of the first reaction section, the second reaction section, and the third reaction section is (5-20): (35-50): (30-60); preferably, the length ratio of the first reaction section, the second reaction section, and the third reaction section is (5-10): (35-40): (50-60). Controlling the length ratio of the first reaction section, the second reaction section, and the third reaction section within the above range can enable each reaction section to fully react, avoid local overheating, and further improve the reaction conversion rate. Further preferably, the length ratio of the first reaction section, the second reaction section, and the third reaction section is 5:35:60. Setting the length of each reaction section according to the above ratio will result in better reaction effects.

[0025] In a preferred embodiment, the aspect ratio of the tubular reactor is (200-1200):1; the aspect ratio will affect the residence time and heat transfer efficiency of the reaction raw materials (E)-1-N-morpholinyl propene and methyl acrylate in the reactor. Controlling the aspect ratio of the tubular reactor within the above range can further improve the uniformity and conversion rate of the reaction. Preferably, the aspect ratio of the tubular reactor is (500-850):1. Controlling the aspect ratio of the tubular reactor within the above range will have a better reaction effect.

[0026] In a preferred embodiment, the tubular reactor is an empty tube reactor; preferably, the empty tube reactor is a coil reactor. The tubular reactor has the characteristics of good heat and mass transfer performance and can effectively control the reaction temperature. The coil reactor has the advantages of compact structure and smaller footprint, and is suitable for chemical reactions that require high-efficiency heat transfer, especially in continuous production, which can improve the stability and safety of the reaction.

[0027] In a preferred embodiment, the molar ratio of (E)-1-N-morpholinyl propene to methyl acrylate is 1:(1.05-1.8); controlling the molar ratio of (E)-1-N-morpholinyl propene to methyl acrylate within the above range can make the (E)-1-N-morpholinyl propene react more thoroughly, and the low-boiling methyl acrylate can also be easier to separate later. Preferably, the molar ratio of (E)-1-N-morpholinyl propene to methyl acrylate is 1:(1.2-1.5), and controlling the reaction raw materials within the above preferred ratio range will have a better reaction effect.

[0028] In a preferred embodiment, the reaction time of the mixture of (E)-1-N-morpholinyl propene and methyl acrylate in the tubular reactor is 15 to 360 seconds; controlling the reaction time of the reaction raw materials in the tubular reactor within the above range can effectively avoid the overreaction of the reaction raw materials and the occurrence of side reactions, and can also effectively avoid side reactions caused by the decomposition of the generated products, further improve the selectivity of the reaction for the target product, and improve the yield of the product. Preferably, the reaction time of (E)-1-N-morpholinyl propene and methyl acrylate in the tubular reactor is 25 to 80 seconds. Controlling the reaction time of the reaction raw materials in the tubular reactor within the above preferred range can make the reaction proceed better.

[0029] In a preferred embodiment, the evaporation separation is carried out in a thin film evaporator; preferably, the evaporation pressure in the thin film evaporator is 405-650 mmHg; preferably, the heat medium temperature in the thin film evaporator is 50-80°C; preferably, the residence time of the reaction mixture in the thin film evaporator is 15-45s. Using a thin film evaporator for continuous distillation purification can greatly reduce the residence time of the reaction mixture at high temperature, thereby more effectively avoiding the side reactions caused by product decomposition at high temperature, and at the same time can also improve the evaporation efficiency and further improve the reaction conversion rate. Preferably, the temperature of cooling quenching is ≤80°C.

[0030] In a preferred embodiment, (E)-1-N-morpholinyl propene and methyl acrylate are vaporized in a vaporizer to obtain (E)-1-N-morpholinyl propene vaporized gas and methyl acrylate vaporized gas. As described above, the reaction of (E)-1-N-morpholinyl propene and methyl acrylate to generate 3-methyl-4-morpholinyl cyclobutanecarboxylic acid methyl ester is controlled by thermodynamics and interphase mass transfer. In liquid phase reaction, it is necessary to transfer and disperse the liquid phase interface before the reaction can be achieved, which greatly increases the reaction resistance. However, the reaction can be carried out faster and better after (E)-1-N-morpholinyl propene and methyl acrylate are vaporized in a vaporizer to generate vaporized gas.

[0031] In a preferred embodiment, (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas are mixed in a mixer; preferably, the mixer is a static mixer. After (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas are fully mixed in the static mixer, the mixed stream is fully mixed at a high flow rate and then enters the reactor, which can further improve the conversion rate of the reaction. Preferably, cooling is performed in a condenser.

[0032] The present application is further described in detail below in conjunction with specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed in the present application.

[0033] It should be further explained that the specifications of the coil reactor used in the embodiment of the present invention are: material S31603, length 700 cm, inner diameter 1.0 cm. In the embodiment of the present invention, the length ratio of the first reaction section, the second reaction section and the third reaction section is 5:35:60.

[0034] Example 1

[0035] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 175° C.; (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 1.3 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 1.6 L / min for mixing (at this time, (E)-1-N-morpholinylpropene and The molar ratio of methyl acrylate is 1:1.23), and the obtained mixed vaporized gas is continuously introduced into the coil reactor, and sequentially passes through the first reaction section with a reaction temperature of 175°C, the second reaction section with a reaction temperature of 155°C, and the third reaction section with a reaction temperature of 130°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section and the third reaction section are 35cm, 245cm and 420cm respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 46s. The reaction mixture flowing out of the outlet of the coil reactor is introduced into a condenser and quenched to 60°C, and then continuously introduced into a thin film evaporator, and stays at a pressure of 450mmHg and a temperature of 65°C for 20s, and the heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0036] Example 2

[0037] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 180° C. (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 1.3 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 1.6 L / min for mixing (at this time, (E)-1-N-morpholinylpropene and The molar ratio of methyl acrylate is 1:1.23), and the obtained mixed vaporized gas is continuously introduced into the coil reactor, and sequentially passes through the first reaction section with a reaction temperature of 180°C, the second reaction section with a reaction temperature of 160°C, and the third reaction section with a reaction temperature of 140°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section, and the third reaction section are 70cm, 280cm, and 350cm, respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 46s. The reaction mixture flowing out of the outlet of the coil reactor is introduced into a condenser and quenched to 80°C, and then continuously introduced into a thin film evaporator, and stays at a pressure of 405mmHg and a temperature of 80°C for 15s, and the heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0038] Example 3

[0039] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 160° C.; (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 1.3 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 1.6 L / min for mixing (at this time, (E)-1-N-morpholinylpropene and The molar ratio of methyl acrylate is 1:1.23), and the obtained mixed vaporized gas is continuously introduced into the coil reactor, and sequentially passes through the first reaction section with a reaction temperature of 160°C, the second reaction section with a reaction temperature of 140°C, and the third reaction section with a reaction temperature of 120°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section, and the third reaction section are 70cm, 245cm, and 385cm, respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 46s. The reaction mixture flowing out of the outlet of the coil reactor is introduced into a condenser and quenched to 60°C, and then continuously introduced into a thin film evaporator, and stays at a pressure of 650mmHg and a temperature of 50°C for 45s, and the heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0040] Example 4

[0041] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 175° C.; (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 1.23 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 1.66 L / min for mixing (at this time, (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas are continuously introduced into a static mixer at a flow rate of 1.66 L / min for mixing). The molar ratio of methyl acrylate to methyl acrylate is 1:1.35), and the obtained mixed vaporized gas is continuously introduced into the coil reactor, and sequentially passes through the first reaction section with a reaction temperature of 175°C, the second reaction section with a reaction temperature of 155°C, and the third reaction section with a reaction temperature of 130°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section, and the third reaction section are 35cm, 245cm, and 420cm, respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 46s. The reaction mixture flowing out of the outlet of the coil reactor is introduced into a condenser and quenched to 60°C, and then continuously introduced into a thin film evaporator, and stays at a pressure of 450mmHg and a temperature of 65°C for 20s. The heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0042] Example 5

[0043] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 175° C.; (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 1.16 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 1.74 L / min for mixing (at this time, (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas are continuously introduced into a static mixer at a flow rate of 1.74 L / min). The molar ratio of methyl acrylate to methyl acrylate is 1:1.5), and the obtained mixed vaporized gas is continuously passed into the coil reactor, and sequentially passes through the first reaction section with a reaction temperature of 175°C, the second reaction section with a reaction temperature of 155°C, and the third reaction section with a reaction temperature of 130°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section and the third reaction section are 35cm, 245cm and 420cm respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 46s. The reaction mixture flowing out of the outlet of the coil reactor is passed into a condenser and quenched to 60°C, and then continuously passed into a thin film evaporator, and stays at a pressure of 450mmHg and a temperature of 65°C for 20s. The heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0044] Example 6

[0045] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 175° C.; (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 1.41 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 1.49 L / min for mixing (at this time, (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas are continuously introduced into a static mixer at a flow rate of 1.41 L / min). The molar ratio of methyl acrylate to methyl acrylate is 1:1.05), and the obtained mixed vaporized gas is continuously introduced into the coil reactor, and successively passes through the first reaction section with a reaction temperature of 175°C, the second reaction section with a reaction temperature of 155°C, and the third reaction section with a reaction temperature of 130°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section and the third reaction section are 35cm, 245cm and 420cm respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 46s. The reaction mixture flowing out of the outlet of the coil reactor is introduced into a condenser and quenched to 60°C, and then continuously introduced into a thin film evaporator, and stays at a pressure of 450mmHg and a temperature of 65°C for 20s. The heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0046] Example 7

[0047] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 175° C.; (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 1.03 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 1.87 L / min for mixing (at this time, (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas are continuously introduced into a static mixer at a flow rate of 1.87 L / min). The molar ratio of methyl acrylate to methyl acrylate is 1:1.8), and the obtained mixed vaporized gas is continuously passed into the coil reactor, and sequentially passes through the first reaction section with a reaction temperature of 175°C, the second reaction section with a reaction temperature of 155°C, and the third reaction section with a reaction temperature of 130°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section and the third reaction section are 35cm, 245cm and 420cm respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 46s. The reaction mixture flowing out of the outlet of the coil reactor is passed into a condenser and quenched to 60°C, and then continuously passed into a thin film evaporator, and stays at a pressure of 450mmHg and a temperature of 65°C for 20s. The heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0048] Example 8

[0049] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 175° C.; (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 2.39 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 2.94 L / min for mixing (at this time, (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas are continuously introduced into a static mixer at a flow rate of 2.94 L / min for mixing). The molar ratio of methyl acrylate to methyl acrylate is 1:1.23), and the obtained mixed vaporized gas is continuously introduced into the coil reactor, and sequentially passes through the first reaction section with a reaction temperature of 175°C, the second reaction section with a reaction temperature of 155°C, and the third reaction section with a reaction temperature of 130°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section and the third reaction section are 35cm, 245cm and 420cm respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 25s. The reaction mixture flowing out of the coil reactor outlet is introduced into a condenser and quenched to 60°C, and then continuously introduced into a thin film evaporator, and stays at a pressure of 450mmHg and a temperature of 65°C for 20s. The heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0050] Example 9

[0051] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 175° C. (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 0.75 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 0.92 L / min to mix (at this time, (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 0.92 L / min to mix (at this time, (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 0.75 L / min). The molar ratio of methyl acrylate to methyl acrylate is 1:1.23), and the obtained mixed vaporized gas is continuously passed into the coil reactor, and successively passes through the first reaction section with a reaction temperature of 175°C, the second reaction section with a reaction temperature of 155°C, and the third reaction section with a reaction temperature of 130°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section and the third reaction section are 35cm, 245cm and 420cm respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 80s. The reaction mixture flowing out of the coil reactor outlet is passed into a condenser and quenched to 60°C, and then continuously passed into a thin film evaporator, and stays at a pressure of 450mmHg and a temperature of 65°C for 20s. The heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0052] Example 10

[0053] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 175° C. (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 4.0 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 4.9 L / min for mixing (at this time, (E)-1-N-morpholinylpropene and The molar ratio of methyl acrylate is 1:1.23), and the obtained mixed vaporized gas is continuously introduced into the coil reactor, and successively passes through the first reaction section with a reaction temperature of 175°C, the second reaction section with a reaction temperature of 155°C, and the third reaction section with a reaction temperature of 130°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section and the third reaction section are 35cm, 245cm and 420cm respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 15s. The reaction mixture flowing out of the outlet of the coil reactor is introduced into a condenser and quenched to 60°C, and then continuously introduced into a thin film evaporator, and stays at a pressure of 450mmHg and a temperature of 65°C for 20s, and the heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0054] Embodiment 11

[0055] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 175° C. (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 0.17 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 0.20 L / min for mixing (at this time, (E)-1-N-morpholinylpropene and The molar ratio of methyl acrylate is 1:1.23), and the obtained mixed vaporized gas is continuously introduced into the coil reactor, and successively passes through the first reaction section with a reaction temperature of 175°C, the second reaction section with a reaction temperature of 155°C, and the third reaction section with a reaction temperature of 130°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section and the third reaction section are 35cm, 245cm and 420cm respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 360s. The reaction mixture flowing out of the coil reactor outlet is introduced into a condenser and quenched to 60°C, and then continuously introduced into a thin film evaporator, and stays at a pressure of 450mmHg and a temperature of 65°C for 20s, and the heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0056] Example 12

[0057] (E)-1-N-morpholinylpropene and methyl acrylate are respectively vaporized in a vaporizer to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas, wherein the vaporization temperature is 140° C. (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 0.08 L / min, and methyl acrylate vaporized gas is continuously introduced into a static mixer at a flow rate of 0.18 L / min for mixing (at this time, (E)-1-N-morpholinylpropene vaporized gas is continuously introduced into a static mixer at a flow rate of 0.18 L / min for mixing). The molar ratio of methyl acrylate to methyl acrylate is 1:2.2), and the obtained mixed vaporized gas is continuously introduced into the coil reactor, and sequentially passes through the first reaction section with a reaction temperature of 140°C, the second reaction section with a reaction temperature of 120°C, and the third reaction section with a reaction temperature of 100°C to obtain a reaction mixture, wherein the lengths of the first reaction section, the second reaction section, and the third reaction section are 35 cm, 245 cm, and 420 cm, respectively, and the reaction time of the mixed vaporized gas passing through the coil reactor is 500 s. The reaction mixture flowing out of the coil reactor outlet is introduced into a condenser and quenched to 60°C, and then continuously introduced into a thin film evaporator, and stays at a pressure of 450 mmHg and a temperature of 65°C for 20 s. The heavy component collector produces 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, and the light component collector produces methyl acrylate.

[0058] Comparative Example 1

[0059] 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester was synthesized using a conventional autoclave reactor. 5.8 kg of (E)-1-N-morpholinyl propene and 4.9 kg of methyl acrylate were added into the autoclave reactor (the molar ratio of (E)-1-N-morpholinyl propene to methyl acrylate was 1.25). Stirring was started and the temperature was raised to 120° C. for heat preservation and reaction. After 6 hours, the obtained reaction solution was separated by distillation to remove the remaining methyl acrylate, thereby obtaining 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester.

[0060] Comparative Example 2

[0061] (E)-1-N-morpholinylpropene and methyl acrylate were respectively preheated to 80°C in a preheater and pumped into a microchannel reactor at a molar ratio of 1:1.05. The feed flow rates were 41.6 mL / min and 29.8 mL / min, respectively. The reaction temperature was 120°C and the reaction pressure was 1.0 MPa. The residence time was adjusted to 400 s by adjusting the feed flow rate. The micro-reaction discharge entered the reactor and reacted at 100°C for 1.5 h. After the reaction was completed, the resulting reaction solution entered a light removal tower and was removed at a pressure of 40 mmHg. Methyl acrylate was continuously recovered from the top of the tower and applied to the reactor, and 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester was recovered from the bottom of the tower.

[0062] The reaction times in Examples 1 to 12 and Comparative Examples 1 and 2 were summarized, and the prepared 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester content (product content) and reaction conversion rate were tested and calculated. The results are shown in Table 1.

[0063] The content of 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester is the content of 3-methyl-4-morpholinylcyclobutanecarboxylic acid liquid after distillation and light removal, which is obtained by testing it with a gas chromatograph, and can reflect the selectivity of the reaction for 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester. The specific test analysis parameters include: instruments: (1) Agilent gas chromatograph: with hydrogen flame ionization detector detection; (2) chromatography workstation: Agilent chemstation; (3) micro-injector: 10um; (4) chromatographic column: HP-1 30m*0.32mm*0.25um; chromatographic conditions: temperature gradient: chromatographic column temperature 80℃, hold for 2min; first-order heating rate 5℃ / min, first-order final temperature 100℃, first-order final temperature holding time 5min; second-order heating rate 30℃ / min, second-order final temperature 220℃, second-order final temperature holding time 5min. Vaporization chamber temperature: 300℃; detector temperature: 300℃; carrier gas nitrogen: 25ml / min; split ratio: 30:1; carrier gas pressure: 10.09psi; injection volume: 0.2uL; set parameters according to the above chromatographic conditions, and after the instrument is stable, perform sample analysis.

[0064] The calculation method of the reaction conversion rate is: reaction conversion rate = 1-(amount of output (E)-1-N-morpholinyl propylene / amount of input (E)-1-N-morpholinyl propylene). The reaction conversion rate can reflect the reaction conversion of the raw material (E)-1-N-morpholinyl propylene.

[0065] Table 1

[0066]

[0067]

[0068] From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects:

[0069] Embodiment 1 to embodiment 11 are the methods for continuously preparing 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester by using tubular reactor described in the present application, and the above-mentioned synthesis reaction that the parameters in the preparation process are controlled to be carried out within the preferred range. As shown in Table 1, the preparation method of the present invention can be used to complete the reaction in a shorter reaction time, and the content of 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester in the obtained reaction solution is higher, indicating that the above-mentioned preparation method has higher selectivity for 3-methyl-4-morpholinylcyclobutanecarboxylic acid methyl ester, (E)-1-N-morpholinyl propylene also has higher conversion rate, and the above-mentioned reaction can be carried out better. The parameters in the preparation process of Example 12 are not within the preferred range. Although the (E)-1-N-morpholinopropene has a higher conversion rate due to the prolonged reaction time, the content of 3-methyl-4-morpholinocyclobutanecarboxylic acid methyl ester in the reaction solution is reduced, indicating that the selectivity of the reaction for 3-methyl-4-morpholinocyclobutanecarboxylic acid methyl ester is reduced. The overall reaction effect is slightly worse than that of Examples 1 to 11, but still has a good effect.

[0070] Comparative Example 1 is a reaction using a traditional kettle reactor, which not only has a long reaction time, but also has a relatively low content of methyl 3-methyl-4-morpholinylcyclobutanecarboxylate in the reaction solution and a relatively low conversion rate of (E)-1-N-morpholinylpropene. Comparative Example 2 is a reaction for synthesizing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate using a microchannel reactor, and the content of methyl 3-methyl-4-morpholinylcyclobutanecarboxylate in the reaction solution and the conversion rate of (E)-1-N-morpholinylpropene are not as good as the overall effect of the preparation method of the present invention.

[0071] In summary, the tubular reactor proposed in the present invention can complete the reaction in a very short time, effectively improving the reaction rate, reaction selectivity and reaction conversion rate. The continuous vaporization process, reaction process, cooling process and separation process can make the reaction proceed uninterruptedly, can effectively improve production efficiency and reduce production costs. In addition, due to the simultaneous continuous cooling process and separation process, the residence time of the material at high temperature is greatly reduced, the production safety is improved, and the preparation capacity is no longer subject to the capacity of the reactor. The above-mentioned preparation process method is highly operable, has a small equipment investment, a high safety factor, and a high product yield, and is suitable for industrial-scale production.

[0072] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate, characterized in that: The method comprises the following steps: Continuously vaporizing (E)-1-N-morpholinylpropene and methyl acrylate respectively to obtain (E)-1-N-morpholinylpropene vaporized gas and methyl acrylate vaporized gas; The (E)-1-N-morpholinylpropene vaporized gas and the methyl acrylate vaporized gas are mixed and then continuously introduced into a reactor for reaction to obtain a reaction mixture; wherein the reactor is a tubular reactor; The reaction mixture is continuously discharged from the reactor, and then continuously cooled and quenched, and then continuously evaporated and separated to obtain the methyl 3-methyl-4-morpholinylcyclobutanecarboxylate.

2. The method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate according to claim 1, characterized in that: The tubular reactor comprises a first reaction section, a second reaction section and a third reaction section which are connected in sequence, and the reaction temperature of the first reaction section is not lower than the reaction temperature of the second reaction section, and the reaction temperature of the second reaction section is not lower than the reaction temperature of the third reaction section; Preferably, the reaction temperature of the first reaction stage is 160-180°C, the reaction temperature of the second reaction stage is 140-160°C, and the reaction temperature of the third reaction stage is 120-140°C; Preferably, the vaporization temperature is the same as the first reaction stage temperature.

3. The method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate according to claim 1 or 2, characterized in that: When the inner diameters of the tubular reactors are the same, the length ratio of the first reaction section, the second reaction section and the third reaction section is (5-20):(35-50):(30-60); Preferably, the length ratio of the first reaction section, the second reaction section and the third reaction section is (5-10): (35～40):(50～60)； Further preferably, the length ratio of the first reaction section, the second reaction section and the third reaction section is 5:35:

60.

4. The method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate according to any one of claims 1 to 3, characterized in that: The aspect ratio of the tubular reactor is (200-1200):1; Preferably, the aspect ratio of the tubular reactor is (500-850):

1.

5. The method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate according to any one of claims 1 to 3, characterized in that: The tubular reactor is an empty tube reactor; Preferably, the empty tube reactor is a coil reactor.

6. The method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate according to any one of claims 1 to 3, characterized in that: The molar ratio of the (E)-1-N-morpholinylpropylene to the methyl acrylate is 1:(1.05-1.8); Preferably, the molar ratio of the (E)-1-N-morpholinylpropene to the methyl acrylate is 1:(1.2-1.5).

7. The method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate according to any one of claims 1 to 3, characterized in that: The reaction time of the (E)-1-N-morpholinylpropylene and the methyl acrylate mixture in the tubular reactor is 15 to 360 seconds; Preferably, the reaction time of the (E)-1-N-morpholinylpropene and the methyl acrylate in the tubular reactor is 25 to 80 seconds.

8. The method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate according to any one of claims 1 to 3, characterized in that: The evaporative separation is carried out in a thin film evaporator; Preferably, the evaporation pressure in the thin film evaporator is 405-650 mmHg; Preferably, the temperature of the heat medium in the thin film evaporator is 50-80°C; Preferably, the residence time of the reaction mixture in the thin film evaporator is 15 to 45 seconds; Preferably, the cooling quenching temperature is ≤80°C.

9. The method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate according to any one of claims 1 to 3, characterized in that: The (E)-1-N-morpholinylpropene and the methyl acrylate are respectively vaporized in a vaporizer to obtain the (E)-1-N-morpholinylpropene vaporized gas and the methyl acrylate vaporized gas.

10. The method for continuously preparing methyl 3-methyl-4-morpholinylcyclobutanecarboxylate according to any one of claims 1 to 3, characterized in that: Mixing the (E)-1-N-morpholinylpropene vaporized gas and the methyl acrylate vaporized gas in a mixer; preferably, the mixer is a static mixer; Preferably, the cooling is performed in a condenser.

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