A method for continuously preparing imidacloprid intermediate 3-methyl-2-(4-morpholinyl)cyclobutyl acid methyl ester

Abstract

The application relates to a method for continuously preparing imidacloprid intermediate 3-methyl-2-(4-morpholinyl)cyclobutyl acid methyl ester, and the specific steps are as follows: raw material morpholinyl propylene and methyl acrylate are respectively introduced into a preheater, then the preheated raw materials are pumped into a micro-channel reactor for reaction, after the reaction is completed, the materials are discharged from the micro-channel reactor outlet into a reaction kettle, reaction is carried out, then the cyclization liquid obtained in the reaction kettle is subjected to light removal in a light removal tower, 3-methyl-2-(4-morpholinyl)cyclobutyl acid methyl ester after light removal is collected from the tower kettle of the light removal tower, the 3-methyl-2-(4-morpholinyl)cyclobutyl acid methyl ester is introduced into a pentyl ester synthesis process, and the recovered methyl acrylate collected from the top of the light removal tower is reused in the reaction kettle to participate in the ripening reaction. The application has the advantages of high product purity, low raw material unit consumption, good safety, low labor cost and the like.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for the continuous preparation of methyl 3-methyl-2-(4-morpholino)cyclobutyrate, an intermediate of imidacloprid. Background Technology

[0002] Imidacloprid (chemical name: 1-(6-chloropyridin-3-pyridinylmethyl)-N-nitroimidazolidine-2-ylamine) is the most widely used neonicotinoid insecticide globally. It possesses excellent insecticidal activity and low mammalian toxicity, and its rapid development is due to its high efficiency, broad spectrum, and good environmental compatibility. It can be used on crops such as rice, wheat, corn, and fruit trees. Currently, the main production processes for imidacloprid in China include the benzylamine-n-propanal method, the cyclopentadiene-acrylaldehyde method, and the morpholine-n-propanal method.

[0003] The benzylamine-propanal method involves synthesizing N-benzyl-N-propenylacetamide from benzylamine with propanal and acetic anhydride, respectively. The N-benzyl-N-propenylacetamide is then further chlorinated and cyclized to obtain 2-chloro-5-methylpyridine (CMP). Subsequent methyl chlorination of the side chain yields 2-chloro-5-chloromethylpyridine (CCMP). This method has several drawbacks. The byproduct, benzyl chloride, has a similar boiling point to the product 2-chloro-5-methylpyridine, making separation difficult. Furthermore, the large quantity of benzyl chloride requires ammonolysis to synthesize benzylamine, a complex and costly process. The chlorination of phosphorus oxychloride generates large amounts of phosphorus-containing wastewater, which is difficult to treat. Currently, domestic manufacturers using this route to produce imidacloprid are operating at half capacity.

[0004] Cyclopentadiene-Acrolein Method: This method is characterized by readily available raw materials and low technical barriers, and is currently the most widely used method for producing imidacloprid in China, accounting for over 70% of imidacloprid production methods. First, dimerized cyclopentadiene is depolymerized to form cyclopentadiene, which then undergoes an addition reaction with acrolein, followed by a secondary addition reaction with acrylonitrile to generate [2,2,1]cycloheptane-α-aldehyde-β-propionitrile-5-ene. This intermediate is then pyrolyzed under high temperature and high vacuum to generate 4-aldehyde-pentenyl nitrile. Due to the high vacuum, the low-boiling-point cyclopentadiene is difficult to recover. The 4-aldehyde-pentenyl nitrile is then chlorinated to generate 2-chloro-3-chloromethyl-4-cyanobutyraldehyde, which cyclizes under the action of phosphorus oxychloride to form CCMP. The main disadvantages of this method are: the low boiling point of cyclopentadiene makes it difficult to recover; acrolein and acrylonitrile are listed in the "List of Highly Toxic Chemicals," posing significant safety and environmental risks; the use of phosphorus oxychloride as a chlorinating agent results in the generation of phosphate waste, which is difficult to treat, leading to a large amount of hazardous waste.

[0005] Morpholine-n-propionaldehyde method: Yangnong Group is the only company in the world using this process to produce 2-chloro-5-methylpyridine and 2-chloro-5-chloromethylpyridine. Morpholine and n-propionaldehyde are added under alkaline conditions to obtain morpholinylpropene (abbreviated as enamine), which then undergoes a secondary addition reaction with methyl acrylate to obtain methyl 3-methyl-4-morpholinylcyclobutanecarboxylate (abbreviated as methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate). This methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate is then subjected to pressurized catalytic ammonolysis to synthesize 5-methyl-3,4-dihydropyridin-2(1H)-one (abbreviated as pyridinone). Pyridinone is then added to chlorine and dehydrochlorinated to aromatize and obtain 2-chloro-5-methylpyridine, which is further chlorinated to generate 2-chloro-5-chloromethylpyridine. The unique byproduct of this process, 2,3-dichloro-5-methylpyridine, can be used to produce 2,3-dichloro-5-trifluoromethylpyridine, which is a major raw material for the production of important pesticide varieties such as chlorpyrifos, fluazinam, and glyphosate, greatly improving the comprehensive utilization level of the production process.

[0006] In the 1990s, Yangnong Group established a 200-ton / year imidacloprid-propionaldehyde production facility. Through continuous technological upgrades, product yield and quality have been significantly improved. However, the synthesis of the important intermediate methyl 3-methyl-2-(4-morpholino)cyclobutyrate still faces the following problems: using a batch reactor, the reaction temperature is 110℃, and the residence time is 6-8 hours.

[0007] 1) Existing batch reactors require high labor costs and have low unit capacity due to limitations in reactor size.

[0008] 2) The synthesis of methyl 3-methyl-2-(4-morpholino)cyclobutyrate is a strongly exothermic reaction, with a heat of reaction reaching 195 kJ / mol. Both methyl 3-methyl-2-(4-morpholino)cyclobutyrate and the impurity morpholinoacrylate generated during the synthesis process are heat-sensitive substances. Measurements show that the maximum thermal decomposition rate of methyl 3-methyl-2-(4-morpholino)cyclobutyrate is reached in 8 hours at temperatures TD8 (139℃) and TD24 (126℃). These characteristics pose significant safety risks to the existing batch-process synthesis of methyl 3-methyl-2-(4-morpholino)cyclobutyrate.

[0009] 3) Methyl acrylate, one of the reactants, readily polymerizes at high temperatures, which not only increases raw material costs but also reduces the yield of methyl 4-formylvalerate in the subsequent synthesis. Methyl acrylate polymerizes during both the synthesis process and the subsequent purification and removal of light components.

[0010] The existing batch-type synthesis process for methyl 3-methyl-2-(4-morpholino)cyclobutyrate has the following problems:

[0011] 1) Existing batch reactors require high labor costs and have low unit capacity due to limitations in reactor size.

[0012] 2) The synthesis of methyl 3-methyl-2-(4-morpholino)cyclobutyrate is a strongly exothermic reaction, with a heat of reaction reaching 195 kJ / mol. Both methyl 3-methyl-2-(4-morpholino)cyclobutyrate and the impurity morpholinoacrylate generated during the synthesis process are heat-sensitive substances. Measurements show that the maximum thermal decomposition rate of methyl 3-methyl-2-(4-morpholino)cyclobutyrate is reached in 8 hours at temperatures TD8 (139℃) and TD24 (126℃). These characteristics pose significant safety risks to the existing batch-process synthesis of methyl 3-methyl-2-(4-morpholino)cyclobutyrate.

[0013] 3) Methyl acrylate, one of the reactants, readily polymerizes at high temperatures, which not only increases raw material costs but also reduces the yield of methyl 4-formylvalerate in the subsequent synthesis. Methyl acrylate polymerizes during both the synthesis process and the subsequent purification and removal of light components. Summary of the Invention

[0014] The present invention aims to provide a continuous preparation method for methyl 3-methyl-2-(4-morpholino)cyclobutyrate, an intermediate in the propionaldehyde-morpholino imidacloprid process, which can solve the above-mentioned problems existing in the current synthesis process of methyl 3-methyl-2-(4-morpholino)cyclobutyrate.

[0015] The specific technical solution of the present invention is as follows:

[0016] A method for the continuous preparation of methyl 3-methyl-2-(4-morpholino)cyclobutyrate, an intermediate of imidacloprid, comprising the following:

[0017] The preparation is carried out using the system, which includes equipment such as a preheater, a microchannel reactor, a reaction vessel, and a light-weight removal tower;

[0018] The specific steps are as follows: Morpholinylpropylene and methyl acrylate are fed into a preheater, and then the preheated raw materials are pumped into a microchannel reactor for reaction; the material is discharged from the outlet of the microchannel reactor and enters the reaction vessel for further reaction; the reaction liquid flows out of the reaction vessel and enters a heat exchanger, and flows out from the outlet of the heat exchanger and enters a light removal tower for light removal to obtain methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate.

[0019] Furthermore, the preheating temperature of both the raw materials morpholinopropylene and methyl acrylate reached 80°C.

[0020] Furthermore, the molar ratio of the raw material morpholinopropylene to methyl acrylate is 1:1.05 to 1.6.

[0021] Furthermore, the reaction temperature in the microchannel reactor is 80–120°C, the reaction pressure is 0.2 MPa–1.5 MPa, and the reaction time is 60–480 s.

[0022] Furthermore, the reaction temperature in the reactor is 75–110°C, and the reaction time is 1–3 hours.

[0023] Furthermore, the morpholinopropylene stream has a flow rate of 18.8 ml / min to 188 ml / min, and the methyl acrylate stream has a flow rate of 12.8 ml / min to 177.3 ml / min.

[0024] Furthermore, the pressure of the light-removal tower is 20 mmHg to 80 mmHg, the methyl acrylate content at the bottom of the tower is <1.0%, the methyl 3-methyl-2-(4-morpholino)cyclobutyrate content is >85%, and the methyl acrylate content at the top of the tower is >90%.

[0025] Furthermore, the raw material morpholinopropyl content requirements are: morpholinopropyl > 90%, morpholine < 3%.

[0026] Furthermore, the recovered methyl acrylate collected from the top of the light-light-removal tower is reused in the reactor to participate in the reaction.

[0027] Furthermore, the temperature drop when the reaction liquid enters the light-weight removal tower is less than 60°C.

[0028] The beneficial effects of this invention are: (1) high product purity and low raw material consumption. In the early stage of the reaction with the greatest exothermic reaction, a microchannel reactor is used for the reaction, and the heat exchange effect is far superior to that of a batch reactor, avoiding the problems of untimely heat transfer leading to excessive impurities and methyl ester polymerization that may occur in a batch reactor.

[0029] (2) High safety. In a batch reactor, if the refrigerant fails to transfer heat due to unforeseen circumstances such as water outage, power outage, or leakage, the material inside the reactor will continue to react and release heat, causing an abnormal rise in temperature. This can lead to the massive decomposition and exothermic explosion of three heat-sensitive substances: methyl 3-methyl-2-(4-morpholino)cyclobutyrate, methyl ester, and morpholinoacrylate. In contrast, in this invention, the large exothermic phase of the reaction takes place in a microchannel reactor with a low liquid holdup, eliminating safety hazards. The material already has a high conversion rate when it enters the reactor, resulting in low potential heat release.

[0030] (3) Low labor costs. Traditional batch reactors require manual feeding, discharging, and removal of light components, which are disadvantageous due to their complex operation and high personnel requirements. This invention involves a continuous reaction process in a steady state, thus requiring fewer personnel and less stringent operational requirements. Attached Figure Description

[0031] Figure 1This is a process flow diagram of a method for the continuous preparation of methyl 3-methyl-2-(4-morpholino)cyclobutyrate, an intermediate of imidacloprid, according to the present invention. Detailed Implementation

[0032] The technical solutions in the specification will be further explained and illustrated in conjunction with the embodiments and accompanying drawings.

[0033] A method for the continuous preparation of methyl 3-methyl-2-(4-morpholino)cyclobutyrate, an intermediate of imidacloprid, comprising the following:

[0034] The preparation is carried out using the system, which includes equipment such as a preheater, a microchannel reactor, a reaction vessel, and a light-weight removal tower;

[0035] The specific steps are as follows: Morpholinylpropylene and methyl acrylate are fed into a preheater, and then the preheated raw materials are pumped into a microchannel reactor for reaction; the material is discharged from the outlet of the microchannel reactor and enters the reaction vessel for further reaction; the reaction liquid flows out of the reaction vessel and enters a heat exchanger, and flows out from the outlet of the heat exchanger and enters a light removal tower for light removal to obtain methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate.

[0036] Furthermore, the preheating temperature of both raw materials, morpholinopropylene and methyl acrylate, reached 80°C.

[0037] Furthermore, the molar ratio of the raw material morpholinopropylene to methyl acrylate is 1:1.05 to 1.6.

[0038] Furthermore, the reaction temperature in the microchannel reactor is 80–120°C, the reaction pressure is 0.2 MPa–1.5 MPa, and the reaction time is 60–480 s.

[0039] Furthermore, the reaction temperature in the reactor is 75–110°C, and the reaction time is 1–3 hours.

[0040] Furthermore, the morpholinopropylene stream has a flow rate of 18.8 ml / min to 188 ml / min, and the methyl acrylate stream has a flow rate of 12.8 ml / min to 177.3 ml / min.

[0041] Furthermore, the pressure of the light-removal tower is 20 mmHg to 80 mmHg, the methyl acrylate content at the bottom of the tower is <1.0%, the methyl 3-methyl-2-(4-morpholino)cyclobutyrate content is >85%, and the methyl acrylate content at the top of the tower is >90%.

[0042] Furthermore, the raw material morpholinopropyl content requirements are: morpholinopropyl > 90%, morpholine < 3%.

[0043] Furthermore, the recovered methyl acrylate collected from the top of the light-light-removal tower is reused in the reactor to participate in the reaction.

[0044] Furthermore, the temperature drop when the reaction liquid enters the light-weight removal tower is less than 60°C.

[0045] The specific implementation method is as follows:

[0046] Implementation Method 1

[0047] Morpholinylpropene and methyl acrylate were preheated to 80°C in a preheater and then 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 regulating the feed flow rate. The microchannel reactor output was fed into a reaction vessel and reacted at 100°C for 1.5 h. The reaction solution was then fed into a light ester removal column at a pressure of 40 mmHg for light ester removal. The top of the column continuously collected recovered methyl acrylate, which was reused in the reaction vessel. The bottom of the column collected methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate. Online GC analysis of the collected materials showed that the methyl acrylate content in the top material was 90.63%, the methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate content in the bottom material was 85.53%, and the methyl acrylate content was 0.25%. The enamine conversion rate was 96.68%, and the selectivity was 87.38%.

[0048] Implementation Method 2

[0049] Morpholinylpropylene and methyl acrylate were preheated to 80°C in a preheater and then pumped into a microchannel reactor at a molar ratio of 1:1.5. The feed flow rates were 35.3 ml / min and 36.1 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 regulating the feed flow rate. The micro-reactor output was fed into a reaction vessel and reacted at 100°C for 1.5 h. The reaction solution was then fed into a light ester removal column at a pressure of 40 mmHg for light ester removal. The top of the column continuously collected recovered methyl acrylate, which was reused in the reaction vessel. The bottom of the column collected methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate. Online GC analysis of the collected materials showed that the methyl acrylate content in the top material was 95.12%, the methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate content in the bottom material was 93.38%, and the methyl acrylate content was 0.36%. (476 ml) The enamine conversion rate was 98.12%, and the selectivity was 90.88%.

[0050] Implementation Method 3

[0051] Morpholinylpropene and methyl acrylate were preheated to 80°C in a preheater and then pumped into a microchannel reactor at a molar ratio of 1:1.5, with feed flow rates of 43.9 ml / min and 43.3 ml / min, respectively. The reaction temperature was 100°C, and the reaction pressure was 0.6 MPa. The residence time was adjusted to 320 s by regulating the feed flow rate. The micro-reactor output was fed into a reaction vessel and reacted at 100°C for 1.5 h. The reaction solution was then fed into a light ester removal column at a pressure of 40 mmHg for light ester removal. The top of the column continuously collected recovered methyl acrylate, which was reused in the reaction vessel. The bottom of the column collected methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate. Online GC analysis of the collected materials showed that the methyl acrylate content in the top material was 96.02%, the methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate content in the bottom material was 91.88%, and the methyl acrylate content was 0.41%. The enamine conversion rate was 97.32%, and the selectivity was 89.22%.

[0052] Implementation Method 4

[0053] Morpholinylpropene and methyl acrylate were preheated to 80°C in a preheater and then pumped into a microchannel reactor at a molar ratio of 1:1.2, with feed flow rates of 56.2 ml / min and 45.7 ml / min, respectively. The reaction temperature was 100°C, and the reaction pressure was 0.6 MPa. The residence time was adjusted to 280 s by regulating the feed flow rate. The micro-reactor output was fed into a reaction vessel and reacted at 100°C for 1.0 h. The reaction solution was then fed into a light ester removal column at a pressure of 40 mmHg for light ester removal. The top of the column continuously collected recovered methyl acrylate, which was reused in the reaction vessel. The bottom of the column collected methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate. Online GC analysis of the collected materials showed that the methyl acrylate content in the top material was 92.32%, the methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate content in the bottom material was 88.39%, and the methyl acrylate content was 0.48%. The enamine conversion rate was 96.48%, and the selectivity was 90.11%.

[0054] Example 5

[0055] Morpholinylpropene and methyl acrylate were preheated to 80°C in a preheater and then pumped into a microchannel reactor at a molar ratio of 1:1.3. The feed flow rates were 52.5 ml / min and 42.7 ml / min, respectively. The reaction temperature was 90°C and the reaction pressure was 0.5 MPa. The residence time was adjusted to 300 s by regulating the feed flow rate. The micro-reactor output was fed into a reaction vessel and reacted at 100°C for 2.5 h. The reaction solution was then fed into a light ester removal column at a pressure of 40 mmHg for light ester removal. The top of the column continuously collected recovered methyl acrylate, which was reused in the reaction vessel. The bottom of the column collected methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate. Online GC analysis of the collected materials showed that the methyl acrylate content in the top material was 91.34%, the methyl 3-methyl-2-(4-morpholinyl)cyclobutyrate content in the bottom material was 90.11%, and the methyl acrylate content was 0.47%. The enamine conversion rate was 95.19%, and the selectivity was 91.83%.

[0056] Comparative Example 1

[0057] A batch reactor synthesis process was employed: morpholinopropylene and methyl acrylate were added to a reactor. The reactor was heated to 80°C using a stirring jacket. The heat transfer medium in the reactor jacket was then switched to a cooling medium to balance the heat of reaction, controlling the reaction temperature at approximately 110°C. During the later stages of the reaction, the heat transfer medium was switched back to maintain the reactor temperature at the technical control point. After 6 hours of reaction, the temperature was lowered to 50°C, and the material was pumped to the bottom of an intermittent light ester removal tower for light ester removal. The operating pressure was 30 mmHg, and the final bottom temperature was 100°C. The recovered methyl acrylate from the top of the tower contained 85.53% methyl acrylate, while the bottom residue contained 82.16% methyl 3-methyl-2-(4-morpholino)cyclobutyrate and 1.01% methyl acrylate. The enamine conversion rate was 93.17%, and the selectivity was 84.69%.

[0058] In summary, the present invention has the following technical effects: (1) High product purity and low raw material consumption. In the early stage of the reaction with the greatest exothermic reaction, a microchannel reactor is used for the reaction, and the heat exchange effect is far superior to that of a batch reactor, avoiding the problems of untimely heat transfer leading to excessive impurities and methyl ester polymerization that may occur in a batch reactor.

[0059] (2) High safety. In a batch reactor, if the refrigerant fails to transfer heat due to unforeseen circumstances such as water outage, power outage, or leakage, the material inside the reactor will continue to react and release heat, causing an abnormal rise in temperature. This can lead to the massive decomposition and exothermic explosion of three heat-sensitive substances: methyl 3-methyl-2-(4-morpholino)cyclobutyrate, methyl ester, and morpholinoacrylate. In contrast, in this invention, the large exothermic phase of the reaction takes place in a microchannel reactor with a low liquid holdup, eliminating safety hazards. The material already has a high conversion rate when it enters the reactor, resulting in low potential heat release.

[0060] (3) Low labor costs. Traditional batch reactors require manual feeding, discharging, and removal of light components, which are disadvantageous due to their complex operation and high personnel requirements. This invention involves a continuous reaction process in a steady state, thus requiring fewer personnel and less stringent operational requirements.

[0061] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for the continuous preparation of methyl 3-methyl-2-(4-morpholino)cyclobutyrate, an intermediate of imidacloprid, characterized in that, The specific steps are as follows: The raw materials morpholinylpropene and methyl acrylate are preheated to 80°C in a preheater. Then, the preheated raw materials morpholinylpropene and methyl acrylate are pumped into a microchannel reactor at a molar ratio of 1:1.05-1.6 for reaction. The raw material morpholinylpropene content is required to be: morpholinylpropene > 90%, morpholine < 3%. The reaction temperature is 80-120°C, the reaction pressure is 0.2 MPa-1.5 MPa, and the reaction time is 60-480 s. The material is discharged from the outlet of the microchannel reactor and enters the reaction vessel for further reaction; the reaction temperature is 75-110℃ and the reaction time is 1h-3h. The reaction solution flows out of the reactor and sequentially enters a heat exchanger and a light ester removal tower to finally obtain methyl 3-methyl-2-(4-morpholino)cyclobutyrate. The temperature of the reaction solution entering the light ester removal tower is less than 60°C, the pressure of the light ester removal tower is 20 mmHg to 80 mmHg, the methyl acrylate content at the bottom of the tower is <1.0%, the methyl acrylate content at the top of the tower is >85%, and the methyl acrylate content at the top of the tower is >90%.

2. The method for continuous preparation of imidacloprid intermediate methyl 3-methyl-2-(4-morpholino)cyclobutyrate according to claim 1, characterized in that, The morpholinopropylene stream has a flow rate of 18.8 ml / min to 188 ml / min, and the methyl acrylate stream has a flow rate of 12.8 ml / min to 177.3 ml / min.

3. The method for continuous preparation of imidacloprid intermediate methyl 3-methyl-2-(4-morpholino)cyclobutyrate according to claim 1, characterized in that, The recovered methyl acrylate collected from the top of the light-light removal tower is reused in the reactor to participate in the aging reaction.

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