A microreaction system and method for continuously synthesizing an enoxacin intermediate, 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one

Abstract

The application discloses a micro-reaction system and method for continuously synthesizing a herbicide clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-ketone. The system is formed by sequentially connecting a feeding pump, a micro-channel mixer, a micro-channel reactor and a quenching system in series. The synthesis method is as follows: after micro-mixing dimethyl malonate and a methanol solution of sodium methoxide, the mixture is introduced into the micro-channel reactor to react, obtaining a sodium salt solution of dimethyl malonate; after micro-mixing the sodium salt solution and 6-ethylthio-3-en-2-heptanone (referred to as heptenone), the mixture is introduced into the micro-channel reactor to perform a cyclization reaction; the cyclization product is subjected to a reduced-pressure desolventization to remove the solvent methanol; then, sodium hydroxide is added to perform a hydrolysis reaction; then, hydrochloric acid is added to perform a decarboxylation reaction; then, toluene is added for extraction; and after the reduced-pressure desolventization, the target product is obtained. The system and method can realize low-energy-consumption, safe and continuous production of the clethodim intermediate, the conversion rate of the heptenone is as high as 99%, and the product purity and yield are higher than 95% and 92%, respectively.

Description

Technical Field

[0001] This invention belongs to the field of chemical product synthesis technology, specifically relating to a microreactor system and method for the continuous synthesis of the herbicide clethodim intermediate 5-[2-(ethio)propyl]-3-hydroxy-2-cyclohexene-1-one. Background Technology

[0002] 5-[2-(ethio)propyl]-3-hydroxy-2-cyclohexen-1-one is an important intermediate of cyclohexenone herbicides. These herbicides have the advantages of good herbicidal activity, high selectivity and easy excretion. They are mainly used to control annual and perennial grass weeds and free-growing cereal crops in broadleaf fields, and have broad market prospects.

[0003] Its chemical structural formula is as follows:

[0004] Currently, the industrial preparation of clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one is carried out using a batch reactor. Toluene is used as the solvent. When the temperature is raised to 35 °C, dimethyl malonate is added dropwise, with the addition rate controlled and the temperature controlled at 38-40 °C for 4 h. After the addition is completed, the temperature is maintained at 38-42 °C for one hour. Then, the temperature is controlled below 40 °C, and heptenone is added dropwise to the reactor, with the addition rate strictly controlled and the temperature controlled at 43-47 °C for 1.5-2 h. After the addition is completed, the temperature is maintained at this temperature and stirred for 3 h. Toluene is removed by desolvation under reduced pressure. The cyclized product is dissolved in water, sodium hydroxide solution is added, and the reaction is refluxed at 70 °C for 5 h. Then, the pH is adjusted to 4 with hydrochloric acid, and the reaction is carried out at 55 °C for 4 h. After the reaction is completed, toluene is extracted, and desolvation under reduced pressure is carried out to obtain the target product clethodim intermediate. Traditional batch reactors have several problems: First, due to the large volume of the reactor, mechanical stirring is ineffective, easily leading to uneven distribution of reactant concentrations and the generation of localized hot spots, which can cause safety accidents. Second, the long batch reaction time not only results in high energy consumption but also poor product stability; the longer reaction time also leads to more significant decomposition of clethodim intermediates. Currently, the yield of clethodim intermediates in industrial production is between 80% and 85%.

[0005] The master's thesis of Nanjing University of Science and Technology, "Synthesis and Process Optimization of Clethodim" (2013), studied this cyclization reaction. Methanol was used as solvent, and the reaction was carried out under reflux at 65 °C for 16 h. The yield was about 81%, and it was even more difficult to guarantee the yield when scaled up.

[0006] With the development of modern chemical technology, miniaturization of reaction processes has become an important trend. Compared with conventional reaction devices, microchemical technology can achieve rapid mixing, enhance mass and heat transfer performance, and improve process safety. Therefore, using microreactors is an effective way to produce clethodim intermediates, which is conducive to achieving green, safe, and efficient production of clethodim. Summary of the Invention

[0007] To address the problems of long reaction time, low yield, and low content of clethodim intermediates in existing synthesis techniques for clethodim, this invention proposes a microreaction system and method for the continuous synthesis of clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one. This method offers rapid reaction, high yield of the prepared clethodim intermediate, and safe process. Furthermore, it simplifies post-processing, allows for solvent recyclability, minimizes environmental pollution, and is suitable for continuous large-scale production.

[0008] The technical solution of this invention is as follows: This invention provides a microreaction system for the continuous synthesis of the clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one. The microreaction system includes two microchannel mixers and two microchannel reactors. The microchannel mixers include a low-flow-rate micromixer and a high-flow-rate micromixer. The low-flow-rate micromixer has a Z-shaped or serrated single-channel structure with a two-inlet-one-outlet mixing design and a liquid holdup of 0.2-20 mL / min. The high-flow-rate micromixer has a three-inlet-one-outlet mixing design and a liquid holdup of 50-200 mL / min. The microchannel reactor consists of multiple reaction coils connected in series. The reaction coils include two types: a first microchannel reaction coil and a second microchannel reaction coil. The first microchannel reaction coil has an inner diameter of 0.8 mm, a 3 mL liquid holdup, and a 10-turn coil structure. The second microchannel reaction coil has an inner diameter of 0.8 mm, a 12 mL liquid holdup, and a 40-turn coil structure. The microchannel reactor is equipped with a reaction heat exchange system; the reactants in the microchannel reactor are preheated before entering the mixing process; the reaction coils in the microchannel reactor are equipped with a heating system; and the reactants in the microchannel reactor are quenched before discharge. The heating system has a temperature range of -20 to 200 ℃, good heat transfer performance, and stable temperature control.

[0009] The Z-shaped or sawtooth channel has an angle of 90° to 160°; the hydraulic diameter of a single pipe in the microchannel mixer is 0.1 to 4 mm and the length is 0.2 to 90 cm; when the reactants flow in the channel with an angle of 90° to 160°, the flow direction is constantly changed or turbulence occurs to achieve mixing and reaction.

[0010] The microchannel reactor further includes multiple microchannel reaction coils connected in series to form a larger internal effective volume, which facilitates the control of the residence time required for the reaction. This allows the material to be retained in the microchannel reaction coils for 1 to 10 hours, thereby maximizing the conversion of raw materials.

[0011] The method includes the following steps: (1) Dimethyl malonate and sodium methoxide methanol solution are respectively fed to a small flow micro mixer for mixing, and then enter the first microchannel reaction coil for salt formation reaction to obtain sodium salt solution of dimethyl malonate. (2) The above sodium salt solution and heptenone are respectively transported to a high-flow micro mixer for mixing, and then enter the second microchannel reaction coil for cyclization reaction. The temperature is controlled by the heat exchange system. The cyclization product comes out from the outlet and the reaction is monitored. After the conversion rate of heptenone reaches 99%, it is collected and the solvent methanol is removed by desolventizing under reduced pressure.

[0012] (3) The above cyclized product was dissolved in water and entered into a product collector. Sodium hydroxide solution was added for hydrolysis reaction, followed by hydrochloric acid for decarboxylation reaction. After detection and analysis, toluene was added for extraction, and the target product 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexene-1-one was obtained after desolvation under reduced pressure.

[0013] The specific chemical reaction formula is as follows:

[0014] Preferably, in step (1), the concentration of the sodium methoxide methanol solution is controlled at 10% to 50%, more preferably, the concentration of the sodium methoxide methanol solution is controlled at 20% to 40%.

[0015] Preferably, in step (1), the flow ratio of dimethyl malonate and the methanol solution of sodium methoxide is controlled to be delivered to the low-flow micro-mixer, so that the molar ratio of dimethyl malonate to the methanol solution of sodium methoxide is in the range of (1.0~1.3):1. More preferably, the molar ratio of dimethyl malonate to the methanol solution of sodium methoxide is in the range of (1.0~1.2):1.

[0016] Preferably, in step (1), the content of the generated sodium salt is controlled within the range of 20~40 g / L, more preferably, the content of the generated sodium salt is controlled within the range of 25~35 g / L, and the generated sodium salt needs to be prevented from crystallizing during the reaction process.

[0017] Preferably, in step (1), the temperature inside the first microchannel reaction coil is controlled within the range of 15~30℃; more preferably, the temperature inside the first microchannel reaction coil is controlled within the range of 15~25℃. The residence time of the mixed reactants inside the first microchannel reaction coil is 0.1~15 minutes; more preferably, the residence time of the mixed reactants inside the first microchannel reaction coil is 0.1~10 minutes. Preferably, the back pressure during the reaction is 0.1~0.5 MPa; more preferably, the back pressure during the reaction is 0.1~0.2 MPa.

[0018] Preferably, in step (2), the flow ratio of sodium salt and heptenone delivered to the high-flow-rate micro-mixer is controlled such that the molar ratio of sodium salt to heptenone is in the range of (1.00~1.20):1. More preferably, the molar ratio of sodium salt to heptenone is controlled in the range of (1.00~1.15):1.

[0019] Preferably, in step (2), the temperature inside the second microchannel reaction coil is controlled within the range of 50~85 ℃, more preferably, the temperature inside the second microchannel reaction coil is controlled within the range of 60~80 ℃. The residence time of the mixed reactants inside the second microchannel reaction coil is 0.1~20 minutes, more preferably, the residence time of the mixed reactants inside the second microchannel reaction coil is 0.1~10 minutes. The back pressure during the reaction is 0.1~4.0 MPa, more preferably, the back pressure during the reaction is 1.0~3.5 MPa.

[0020] Preferably, in step (3), the molar ratio of the sodium hydroxide solution to the moderating product is within the range of (1.0~4.0:1.0), more preferably, the molar ratio of the sodium hydroxide solution to the moderating product is within the range of (1.0~3.0:1.0). The temperature of the hydrolysis reaction is 40~70℃, more preferably, the temperature of the hydrolysis reaction is 50~70℃.

[0021] Preferably, in step (3), the pH of the decarboxylation reaction is 3.0~7.0, more preferably, the pH of the decarboxylation reaction is 3.0~5.0. The temperature of the decarboxylation reaction is 40~70℃, more preferably, the temperature of the decarboxylation reaction is 50~70℃.

[0022] The technical solution of the present invention has the following beneficial effects: 1. This invention uses a microchannel reactor as its core technology. Due to its high mass transfer rate, the reaction time required for the conversion of more than 99% of the raw material heptenone is reduced by one order of magnitude compared with the traditional process. In this invention, the special coil structure of the microchannel reactor further enhances the mixing, mass transfer and heat transfer between reactants. The large-volume microchannel reactor connected in series can effectively control the residence time required for the reaction, providing an optimal reaction platform for raw material mixing, reaction and suppression of side reactions.

[0023] 2. This invention uses methanol instead of toluene as the solvent in traditional methods. Combined with the microchannel reactor used, it significantly improves the reaction rate and the selectivity of the target product, achieving efficient, safe and continuous preparation.

[0024] 3. The system and method provided by this invention are significant in terms of continuous and safe production and engineering, realizing continuous production, rapid and efficient conversion and high selectivity of clethodim intermediates, with a total yield of about 92% and a clethodim intermediate content of about 95%, which has high economic, environmental and social benefits.

[0025] 4. The continuous production intermediate of clethodim provided by this invention has a purity of about 96% and a yield of about 93% after subsequent hydrolysis and decarboxylation treatment, which are improvements compared with the original batch process. Attached Figure Description

[0026] Figure 1 This is a system flow diagram of the continuous synthesis of the clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one according to the present invention; Figure 2 This invention relates to a low-flow-rate micro-mixer, with a flow rate of 0.2-20 ml / min and a two-inlet, one-outlet mixing design. Figure 3 This is a simplified design diagram of the internal mixing principle of the high-flow-rate micro-mixer of the present invention, with a flow rate of 50-200 mL / min and a three-inlet-one-outlet design. Detailed Implementation

[0027] The present invention will be further described and illustrated below with reference to embodiments thereof.

[0028] The raw materials used in this invention, including heptenone, dimethyl malonate, and sodium methoxide, were all purchased from the market and will not be described in detail here.

[0029] like Figure 1 The diagram shown is a system flow chart for the continuous synthesis of clethodim intermediates used in an embodiment of the present invention; the system includes a microchannel mixer and a microchannel reactor connected in series, and the microchannel reactor is equipped with a heat exchange device.

[0030] The microchannel mixer has a Z-shaped or serrated single-channel structure; the microchannel reaction coil has an inner diameter of 0.8 mm and a liquid holding capacity of 12 mL.

[0031] The microchannel reactor's microchannel reaction coil is made of 316L stainless steel.

[0032] Example 1

[0033] Using heptenone (purity: 63 wt.%) and the sodium salt formed by dimethyl malonate and sodium methoxide as raw materials, and methanol as solvent, the methanol solutions of dimethyl malonate and sodium methoxide were first pumped into a low-flow-rate micromixer at a rate of 0.5 mL / min, and then entered the first microchannel reaction coil (volume 3 mL, inner diameter 0.8 mm). The generated sodium salt solution flowed out from the outlet of the first microchannel reaction coil. The back pressure during the reaction was 0.2 MPa, and the temperature inside the first microchannel reaction coil was controlled at 25 °C. After 180 seconds of reaction, the sodium salt after hydrolysis of the compound flowed out from the outlet of the first microchannel reaction coil. Heptenone and the above sodium salt solution were pumped into a high-flow-rate micromixer at rates of 1.50 mL / min and 3.38 mL / min, respectively, to achieve a molar ratio of 1.1:1. The mixture was then fed into a second microchannel reaction coil (12 mL volume, 0.8 mm inner diameter) for cyclization reaction. The total feeding time was 30 min until the state stabilized (i.e., the temperature, pressure, and other conditions remained stable, as the state was unstable from the beginning of feeding and required 30 minutes of continuous feeding to stabilize). The back pressure during the reaction was 3.0 MPa, and the temperature inside the second microchannel reaction coil was controlled at 75°C. After 150 seconds of reaction, the hydrolyzed sodium salt flowed out from the outlet of the second microchannel reaction coil. The cyclized product was collected in a three-necked flask, dissolved in 30 g of water, and then 4.64 g (116 mmol) of sodium hydroxide was added. The temperature was raised to 65°C, and the reaction was carried out for 1 h. Then, 4.35 g (116 mmol) of hydrochloric acid was added, and the reaction was maintained at 65°C for another 1 h. After the reaction was completed, the product was extracted with toluene, filtered under reduced pressure, and analyzed by liquid chromatography using a C18 column. Analysis showed that the heptenone reaction was complete, with a conversion rate of 99%.

[0034] The yield was 92%.

[0035] Implementation Case 2-4 The same system for synthesizing clethodim intermediates as in Example 1 was used, with the molar ratios of sodium salt and heptenone in the feed controlled to be 1.0, 1.1, and 1.2, respectively. The product results are shown in Table 1.

[0036] Table 1. Effect of the molar ratio of sodium salt and heptenone on the reaction

[0037] The data in the table above shows that appropriately increasing the molar ratio of sodium salt to heptenone, i.e., appropriately increasing the amount of sodium salt, can improve the purity of heptenone and the yield of the product. Increasing the amount of sodium salt is beneficial to the reaction.

[0038] Implementation Cases 5-8 The same continuous synthesis system for clethodim intermediates as in Example 1 was used, with temperatures controlled at 65 °C, 70 °C, 75 °C, and 80 °C. The product results are shown in Table 1.

[0039] Table 2. Effect of different temperatures on the reaction

[0040] The data in the table above shows that appropriately increasing the reaction temperature accelerates the mixing and mass transfer rates between materials, increases the reaction rate, and improves the purity and product yield of heptenone. Therefore, the reaction temperature is beneficial to the reaction process.

[0041] Examples 9-14 The same continuous synthesis system for clethodim intermediates as in Example 1 was used, with the sodium salt flow rate controlled at 1.5 mL / min, 3.0 mL / min, 3.5 mL / min, 4.0 mL / min, 3.25 mL / min, and 3.38 mL / min. The product results are shown in Table 3. Table 3. Effect of sodium salt flow rate on the reaction

[0042] The data in the table above shows that appropriately increasing the sodium salt flow rate is more beneficial to the reaction.

[0043] Examples 15-20 Using the same continuous synthesis system for clethodim intermediates as in Example 1, the flow rate of heptenone was controlled at 1.50 mL / min, the sodium salt flow rate at 3.38 mL / min, and the residence time at 147 seconds; the flow rate of heptenone was 2.25 mL / min, the sodium salt flow rate at 5.07 mL / min, and the residence time at 98 seconds. The product results are shown in Table 4. Table 4. Effect of residence time on the reaction

[0044] As can be seen from the data in the table above, adjusting the feed flow rate can control the residence time of the material in the reactor. The longer the residence time, the longer the reaction time of the material, which is beneficial to the mass and heat transfer of the reaction, and is also beneficial to the purity of heptenone and the yield of the product.

[0045] Examples 21-23 The same continuous synthesis system for clethodim intermediates as in Example 1 was used, with back pressure valve pressures controlled at 1.0 bar, 3.0 bar, and 5.0 bar. Product results are shown in Table 5. Table 5. Effect of back pressure valve pressure on the reaction

[0046] As can be seen from the data in the table above, properly adjusting the pressure of the back pressure valve is beneficial to the mass and heat transfer of the reaction, which is good for both the purity of heptenone and the yield of the product.

[0047] Comparative Example 1 Currently, the production company uses a batch reactor process with toluene as the reaction solvent.

[0048] Take a 250 mL three-necked flask, add 100 mL of toluene, 10.44 g (58 mmol) of sodium methoxide, and 7.66 g (58 mmol) of dimethyl malonate to the mixed solution. After stirring thoroughly, add 10 g (58 mmol) of heptenone. Heat to 65 °C. Take samples during the reaction to analyze the progress of the reaction. After the reaction is complete, filter under reduced pressure to remove the solvent. Dissolve in 50 g of water and add 4.64 g (116 mmol) of sodium hydroxide. Heat to 65 °C and react for 1 h. Add 4.35 g (116 mmol) of hydrochloric acid and keep at 65 °C for 1 h. After the reaction is complete, extract with toluene and filter under reduced pressure to remove the solvent.

[0049] The product results are shown in Table 6. Table 6. Reaction results at different reaction times in the reactor.

[0050] As shown in the table above, under the reaction conditions used in industry, the purity of the raw material heptenone and the yield of the product are both low after 60 minutes of reaction. Due to the shortcomings of batch reaction in terms of mass and heat transfer, the conversion rate of the raw material heptenone is slow, the reaction time is long, and the possibility of side reactions and energy consumption are increased.

Claims

1. A microreaction system for the continuous synthesis of clethodim intermediate 5-[2-(ethio)propyl]-3-hydroxy-2-cyclohexen-1-one, characterized in that, The microreactor system includes two microchannel mixers and two microchannel reactors. The microchannel mixers include a low-flow-rate micromixer and a high-flow-rate micromixer. The low-flow-rate micromixer has a Z-shaped or serrated single-channel structure, a two-inlet-one-outlet mixing design, and a liquid holdup of 0.2-20 mL / min. The high-flow-rate micromixer has a three-inlet-one-outlet mixing design and a liquid holdup of 50-200 mL / min. The microchannel reactor consists of multiple reaction coils connected in series. The reaction coils include two types: a first microchannel reaction coil and a second microchannel reaction coil. The first microchannel reaction coil has an inner diameter of 0.8 mm, a 3 mL liquid holdup, and a coil structure with 10 turns. The second microchannel reaction coil has an inner diameter of 0.8 mm, a 12 mL liquid holdup, and a coil structure with 40 turns. The microchannel reactor is equipped with a heat exchange system; the reactants in the microchannel reactor are preheated before entering the mixing process; the reaction coils of the microchannel reactor are equipped with a heating system; the temperature range of the heating system is -20~200℃; the reactants in the microchannel reactor are quenched before being discharged. The angle of the Z-shaped or sawtooth-shaped single-channel structure is 90°~160°; the hydraulic diameter of the single pipe of the microchannel mixer is 0.1~4 mm and the length is 0.2~90 cm; The method for continuous synthesis of clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one using the aforementioned microreaction system comprises the following steps: (1) Dimethyl malonate and sodium methoxide methanol solution are respectively fed to a small flow micro mixer for mixing, and then enter the first microchannel reaction coil for salt formation reaction to obtain sodium salt solution of dimethyl malonate. (2) The above sodium salt solution and heptenone are respectively transported to a high-flow micro mixer for mixing, and then enter the second microchannel reaction coil for cyclization reaction. The system temperature is controlled by the heat exchange system. The cyclization product comes out from the outlet and the reaction is monitored. After the conversion rate of heptenone reaches 99%, it is collected and the solvent methanol is removed by desolventizing under reduced pressure. (3) The above cyclized product was dissolved in water, and sodium hydroxide solution was added for hydrolysis. Then hydrochloric acid was added for decarboxylation. After monitoring and analysis, toluene was added for extraction, and the product was desolvated under reduced pressure to obtain the target product 5-[2-(ethio)propyl]-3-hydroxy-2-cyclohexene-1-one.

2. The microreaction system for the continuous synthesis of the clethodim intermediate 5-[2-(ethio)propyl]-3-hydroxy-2-cyclohexen-1-one according to claim 1, characterized in that, In step (1): The concentration of the sodium methoxide methanol solution is controlled at 10%~50%; Control the flow ratio of dimethyl malonate and sodium methoxide methanol solution to be delivered to the low-flow micro-mixer so that the molar ratio of dimethyl malonate to sodium methoxide methanol solution is in the range of (1.0~1.3):1, and control the content of sodium salt generated in the range of 20~40 g / L. During the reaction, it is necessary to prevent the sodium salt generated from crystallizing. The temperature inside the first microchannel reaction coil is controlled within the range of 15~30℃; the residence time of the mixed reactants inside the first microchannel reaction coil is 0.1~15 minutes; and the back pressure during the reaction is 0.1~0.5 MPa.

3. The microreaction system for the continuous synthesis of the clethodim intermediate 5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one according to claim 1, characterized in that, In step (2): The flow rate ratio of sodium salt to heptenone in the high-flow-rate micro-mixer is controlled so that the molar ratio of sodium salt to heptenone is in the range of (1.00~1.20):1; The temperature inside the second microchannel reaction coil is controlled within the range of 50~85 ℃; the residence time of the mixed reactants inside the second microchannel reaction coil is 0.1~20 minutes; and the back pressure during the reaction is 0.1~4.0 MPa.

4. The microreaction system for the continuous synthesis of the clethodim intermediate 5-[2-(ethio)propyl]-3-hydroxy-2-cyclohexen-1-one according to claim 1, characterized in that, In step (3): The molar ratio of sodium hydroxide to the cyclization product is controlled within the range of (1.0~4.0):1.0; the temperature of the hydrolysis reaction is 40~70℃; The pH of the decarboxylation reaction is 3.0~7.0, and the temperature of the decarboxylation reaction is 40~70℃.

Images