Method for continuously preparing fluralana by ionic liquid method
The continuous preparation of frerana in the micro reactor by the ionic liquid method is solved, and the problems of environmental pollution and low production efficiency in traditional methods are achieved, efficient and safe frerana synthesis is improved, and product quality and yield are improved.
Patent Information
- Application Number
- CN202411726069.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-28
- Publication Date
- 2025-02-28
AI Technical Summary
The existing frerana synthesis method uses traditional organic solvents, resulting in environmental pollution, solvent residue, low production efficiency, complex operation and high energy consumption, making it difficult to achieve large-scale production.
Frerana was continuously prepared by ionic liquid method, and aldol condensation, dehydration, amide condensation and cyclization reaction were carried out through a micro reactor, and crystallization was concentrated and crystallized by benign organic solvents to obtain high-purity Frerana.
The reaction efficiency and selectivity are improved, the reaction conditions are optimized, and the efficient and safe continuous production is achieved, energy consumption and production costs are reduced, and product quality and yield are improved.
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Figure CN119528839A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for continuously preparing flurana using an ionic liquid method. Background Art
[0002] As a new type of isoxazoline insecticide and acaricide, flurellan is highly effective, low toxic, and has a long-lasting effect. It is widely used in agriculture and animal husbandry, and can effectively control a variety of pests and mites, which is of great significance to protecting the health of crops and livestock. At the same time, in the field of medicine, flurellan also shows certain medicinal potential, but its specific medicinal mechanism and application are still in the research and exploration stage.
[0003] At present, the common method for synthesizing flurellana mainly uses traditional organic solvents as reaction media and synthesizes through multi-step intermittent reactions. However, such prior art has many defects. The use of traditional organic solvents is not only unfriendly to the environment, but also may cause solvent residues, affecting product quality and safety. Multi-step intermittent reactions result in low production efficiency, complicated operations, and difficulty in achieving automated and continuous production. In addition, the reaction conditions are harsh, the energy consumption is high, and the separation and purification process after the reaction is complicated, which is not conducive to large-scale production. Summary of the invention
[0004] The purpose of the present invention is to solve the shortcomings of the prior art and provide a method for continuously preparing flurellan using an ionic liquid method.
[0005] The technical solution adopted in the present invention is:
[0006] A method for continuously preparing flurana using an ionic liquid method comprises the following steps:
[0007] A. Aldol condensation reaction: 4-acetyl-2-methylbenzoic acid reacts with 3,5-dichloro-2,2,2-trifluoroacetophenone in an ionic liquid to produce an ionic liquid solution of intermediate I;
[0008] B. Dehydration reaction: a dehydrating agent is added to the ionic liquid solution of the intermediate I, and the product flows out continuously. After washing and drying, an ionic liquid solution of the intermediate II is obtained;
[0009] C. Amide condensation reaction: adding a condensing agent to the ionic liquid solution of the intermediate II, introducing an ionic liquid solution containing 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride after TLC detection shows that the intermediate II is completely converted into an active intermediate, and after the reaction is completed, the product flows out continuously, and the ionic liquid solution of the intermediate III is obtained after washing;
[0010] D. Cyclization reaction: adding tetrabutylammonium bromide to the ionic liquid solution of the intermediate III through a micro-reaction pipeline, and then slowly dripping a sodium hydroxide aqueous solution containing hydroxylamine hydrochloride, and performing liquid phase detection. After the reaction is completed, an ionic liquid solution containing fluoranil is obtained;
[0011] E. Concentration and crystallization: repeatedly washing the ionic liquid solution containing fluororana with a benign organic solvent until the content of fluororana in the ionic liquid solution is less than 0.001 g / L to obtain an organic solution containing fluororana, and passing it into a micro-crystallizer after concentration; mixing and crystallizing with a poor solvent in the crystallization system, filtering by suction, washing the filter cake with a small amount of cold detergent, and vacuum drying to obtain fluororana.
[0012] Preferably, the ionic liquid includes but is not limited to 1-butyl-3-methylimidazolium bistrifluoromethanesulfonyl imide, 1-octyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, and 1-ethyl-3-methylimidazolium acetate.
[0013] Preferably, in step A, the pH of the reaction system is controlled at 8-9, and the reaction temperature is controlled at 40-70°C.
[0014] Preferably, in step B, the dehydrating agent includes but is not limited to concentrated sulfuric acid, phosphorus pentoxide, p-toluenesulfonic acid, phosphoric acid, and acetic anhydride; the amount of the dehydrating agent is 2 to 8 equivalents of intermediate I, and the reaction temperature is 25 to 55°C.
[0015] Preferably, in step C, the amide condensation reaction is carried out under anhydrous conditions, the pH of the reaction system is controlled at 7 to 8, and the reaction temperature is -15 to 25°C.
[0016] Preferably, the amount of the condensing agent is 1.05-1.30 equivalents of intermediate II;
[0017] Preferably, in step C, the condensing agent includes any one of DPPA (diphenylphosphoryl azide), CDI (N,N'-carbonyldiimidazole), DCC (N,N'-dicyclohexylcarbodiimide), and PyBop (benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate).
[0018] Preferably, in step D, the equivalent ratio of intermediate III: hydroxylamine hydrochloride: sodium hydroxide is 1:2:4, 1:3:6, 1:4:8 or 1:6:12. The reaction temperature is -10-30°C.
[0019] Preferably, in step E, the good organic solvent / poor solvent crystallization system comprises one of ethyl acetate / n-hexane, dichloromethane / n-hexane, tetrahydrofuran / n-hexane, ethyl acetate / n-heptane, dichloromethane / n-heptane, tetrahydrofuran / n-heptane, acetic acid / water, methanol / water, ethanol / water or isopropanol / water.
[0020] The beneficial effects obtained by the present invention are:
[0021] 1. With the help of microreactors, more precise reaction control is achieved, improving reaction efficiency and selectivity.
[0022] 2. Optimize the reaction conditions of each step to make the reaction more controllable and efficient, and significantly improve product quality and yield.
[0023] 3. Continuous production throughout the entire process significantly improves production efficiency and reduces the uncertainty caused by manual operation and intermittent reactions.
[0024] 4. The reaction conditions are mild and controllable, which reduces energy consumption and improves the safety of the reaction and the stability of product quality.
[0025] 5. Ionic liquids can be recycled, further reducing production costs and reducing environmental impact. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 is the liquid phase spectrum of the intermediate I of Example 1;
[0027] Figure 2 is the liquid phase spectrum of intermediate II of Example 1;
[0028] Figure 3 is the liquid phase spectrum of intermediate III of Example 1;
[0029] Figure 4 This is the liquid phase spectrum of the flurellana product of Example 1. DETAILED DESCRIPTION
[0030] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.
[0031] In a microreactor, various ionic liquids are used as solvents to sequentially perform aldol condensation, dehydration, amide condensation, and cyclization reactions to generate a crude product, which is then extracted with a benign solvent, dried, concentrated, and crystallized with a poor solvent in a microcrystallizer, then washed with cold washing, and finally filtered and dried to obtain the flurellana product. Each reaction unit uses specific ionic liquids and reagents, and the conditions are controlled to improve the yield and purity, with a total yield of over 85%.
[0032] Embodiment 1:
[0033] Step 1: Preparation of Intermediate I
[0034] A continuous flow device including a microreactor and a microcrystallizer was built, covering an aldol condensation microreactor, a dehydration reaction unit, an amide condensation reaction unit, a cyclization reaction unit and a subsequent processing unit. In the aldol condensation microreactor, 1000 mL of 1-ethyl-3-methylimidazolium acetate ionic liquid was added, 150.01 g (0.842 mol) of 4-acetyl-2-methylbenzoic acid and 214.03 g (0.885 mol) of 3,5-dichloro-2,2,2-trifluoroacetophenone were continuously introduced into the microreactor, and the pH of the reaction system was adjusted to 9 with an appropriate alkaline solution (such as sodium carbonate solution), and the temperature was controlled at 50° C. Liquid phase detection was performed. After 6 hours of reaction, the reaction was completed (the raw material was less than 0.5%), and the reaction liquid was continuously discharged. After corresponding washing and drying treatment, 1100 mL of ionic liquid solution containing 344.16 g of intermediate I (0.819 mol) was obtained, with a purity of 99.37% and a yield of 97.16%. After sampling, the ionic liquid solution was introduced into the dehydration reaction unit.
[0035] from Figure 1 It is known that the peak time of intermediate I in the liquid phase spectrum of intermediate I is 14.467min.
[0036] Step 2: Preparation of Intermediate II:
[0037] In the dehydration reaction unit, concentrated sulfuric acid was added as a dehydration agent to 1000 mL of an ionic liquid solution containing 320.56 g (0.763 mol) of intermediate I. The amount of concentrated sulfuric acid used was 3 equivalents of intermediate I. The temperature was controlled at 30°C. After the dehydration reaction was completed after 5 hours of reaction, the product flowed out continuously. After corresponding washing and drying treatments, 1200 mL of an ionic liquid solution of 304.27 g (0.757 mol) of intermediate II was obtained with a purity of 98.94% and a yield of 99.17%. After sampling, the ionic liquid solution was introduced into the amide condensation reaction unit.
[0038] Figure 2 Liquid phase spectrum of intermediate II: Isomer 1 has a peak time of 16.320 min and an area percentage of 98.70%; Isomer 2 has a peak time of 16.633 min and an area percentage of 0.24%.
[0039] Step 3: Preparation of intermediate III:
[0040] In the amide condensation reaction unit, 1.05 equivalents of condensation agent diphenylphosphoryl azide were added to the ionic liquid solution (1000 mL) containing 285.14 g (0.709 mol) of intermediate II, and after complete conversion into the active intermediate, 200 mL of ionic liquid solution containing 149.93 g (0.780 mol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride was introduced, the reaction temperature was 15 ° C, the liquid phase was monitored, and the reaction time was 3 hours. After the reaction was completed, the product flowed out continuously, and after washing, 1500 mL of ionic liquid solution of 370.14 g of intermediate III was obtained, with a purity of 98.56% and a yield of 96.41%. After sampling, 1300 mL of ionic liquid solution containing 351.22 g of intermediate III (0.650 mol) was introduced into the cyclization reaction unit.
[0041] Figure 3 Liquid phase spectrum of intermediate III: Isomer 1 has a peak time of 15.325 min, and an area percentage of 95.26%; Isomer 2 has a peak time of 15.617 min, and an area percentage of 3.30%.
[0042] Step 4: Preparation of Flurellana:
[0043] In the cyclization reaction unit, 0.05 equivalent of tetrabutylammonium bromide was added to 1300 mL of ionic liquid solution containing 351.22 g of intermediate III (0.650 mol) through a micro-reaction pipeline, and 500 mL of sodium hydroxide aqueous solution of hydroxylamine hydrochloride was slowly dripped in, the equivalent ratio of intermediate III: hydroxylamine hydrochloride: sodium hydroxide was 1:4:8, the reaction temperature was 5 ° C, liquid phase detection was performed, and after the reaction was completed for 3 hours, the ionic liquid was repeatedly washed with ethyl acetate until the fluorine in the ionic liquid was completely eliminated. The content of flurana was less than 0.001 g / L. After drying, 1800 mL of ethyl acetate solution containing 355.28 g (0.640 moL) of flurana was concentrated to 500 mL and then passed into a micro-crystallizer. It was mixed with n-heptane at a volume ratio of 1:5 for crystallization. After washing with a small amount of cold ethanol, it was vacuum dried at 60°C for 8 h to obtain 343.62 g (0.619 moL) of flurana with a purity of 99.92%, a yield of 95.19%, and a total yield of 88.42%.
[0044] Figure 4 Liquid phase spectrum of flurellana product: main peak elution time is 16.935min.
[0045] The preparation route is as follows:
[0046]
[0047] Example 2
[0048] Step 1: Preparation of Intermediate I
[0049] A continuous flow device including a microreactor and a microcrystallizer was built, covering an aldol condensation microreactor, a dehydration reaction unit, an amide condensation reaction unit, a cyclization reaction unit and a subsequent processing unit. In the aldol condensation microreactor, 1000 mL of 1-butyl-3-methylimidazole bistrifluoromethanesulfonyl imide salt ionic liquid was added, 160.06 g (0.898 mol) of 4-acetyl-2-methylbenzoic acid and 228.37 g (0.944 mol) of 3,5-dichloro-2,2,2-trifluoroacetophenone were continuously introduced into the microreactor, and the pH of the reaction system was adjusted to 8.5 with appropriate sodium carbonate, and the temperature was controlled at 45° C. Liquid phase detection was performed. After 6 hours of reaction, the reaction was completed (the raw material was less than 0.5%), and the reaction liquid flowed out continuously. After corresponding washing and drying treatment, 1250 mL of ionic liquid solution containing 372.05 g of intermediate I (0.886 mol) was obtained, with a purity of 99.17% and a yield of 98.64%. After sampling, the ionic liquid solution was introduced into the dehydration reaction unit.
[0050] Step 2: Preparation of Intermediate II:
[0051] In the dehydration reaction unit, phosphorus pentoxide as a dehydrating agent was added to 1100 mL of an ionic liquid solution containing 330.38 g (0.787 mol) of intermediate I in an amount of 4 equivalents of intermediate I, the temperature was controlled at 35° C., and the reaction was carried out for 4 hours. After the dehydration reaction was completed, the product flowed out continuously, and after corresponding washing and drying treatments, 1300 mL of an ionic liquid solution of 313.59 g (0.780 mol) of intermediate II was obtained, with a purity of 98.50% and a yield of 99.17%. After sampling, the ionic liquid solution was introduced into the amide condensation reaction unit.
[0052] Step 3: Preparation of intermediate III:
[0053] In the amide condensation reaction unit, 1.05 equivalents of benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate as a condensing agent were added to an ionic liquid solution (1200 mL) containing 289.47 g (0.720 moL) of intermediate II, and after complete conversion into an active intermediate, 350 mL of ionic liquid solution containing 152.10 g (0.792 moL) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride was introduced, the reaction temperature was 5°C, and liquid phase monitoring was performed. After the reaction was completed, the product flowed out continuously, and after washing, 1550 mL of ionic liquid solution of 79.32 g (0.701 moL) of intermediate III was obtained, with a purity of 99.45% and a yield of 97.32%. After sampling, 1450 mL of ionic liquid solution containing 354..83 g of intermediate III (0.656 moL) was introduced into the cyclization reaction unit.
[0054] Step 4: Preparation of Flurellana:
[0055] In the cyclization reaction unit, 0.03 equivalents of tetrabutylammonium bromide were added to 1450 mL of an ionic liquid solution containing 354.83 g of intermediate III (0.656 mol) through a micro-reaction pipeline, and 450 mL of a sodium hydroxide aqueous solution of hydroxylamine hydrochloride was slowly dripped in, the equivalent ratio of intermediate III: hydroxylamine hydrochloride: sodium hydroxide was 1:6:12, the reaction temperature was 10 ° C, and liquid phase detection was performed. After the reaction was completed for 4 hours, the ionic liquid was repeatedly washed with ethanol until the ionic liquid was The content of flurellana is less than 0.001g / L. After drying, 1500mL of ethanol solution containing 355.28g (0.640moL) of flurellana is concentrated to 500mL and then passed into a micro-crystallizer. It is mixed with purified water in a volume ratio of 1:2 for crystallization. After washing with a small amount of cold ethanol, it is vacuum dried at 60°C for 6h to obtain 346.06g (0.623moL) of flurellana, 99.92%, the yield is 95.04%, and the total yield is 90.48%.
[0056] Example 3
[0057] Step 1: Preparation of Intermediate I
[0058] A continuous flow device including a microreactor and a microcrystallizer was built, covering an aldol condensation microreactor, a dehydration reaction unit, an amide condensation reaction unit, a cyclization reaction unit and a subsequent processing unit. In the aldol condensation microreactor, 1200mL of 1-octyl-3-methylimidazolium tetrafluoroborate ionic liquid was added, 180.11g (1.012moL) of 4-acetyl-2-methylbenzoic acid and 256.97g (1.062moL) of 3,5-dichloro-2,2,2-trifluoroacetophenone were continuously introduced into the microreactor, and the pH of the reaction system was adjusted to 8 with an appropriate sodium carbonate solution, and the temperature was controlled at 50°C. Liquid phase detection was performed, and the reaction was completed after 6 hours of reaction (the raw material was less than 0.5%), and the reaction liquid was continuously discharged. After corresponding washing and drying treatment, 1350mL of an ionic liquid solution containing 412.17g of intermediate I (0.9813moL) was obtained, with a purity of 99.42% and a yield of 96.97%. After sampling, the ionic liquid solution was introduced into a dehydration reaction unit.
[0059] Step 2: Preparation of Intermediate II:
[0060] In the dehydration reaction unit, acetic anhydride as a dehydrating agent was added to 1250 mL of an ionic liquid solution containing 381.64 g (0.909 mol) of intermediate I, and the amount thereof was 2.5 equivalents of intermediate I. The temperature was controlled at 30° C. and the reaction was carried out for 4.5 hours. After the dehydration reaction was completed, the product flowed out continuously. After the corresponding washing and drying treatment, 1300 mL of an ionic liquid solution of 364.07 g (0.906 mol) of intermediate II was obtained, with a purity of 99.02% and a yield of 99.67%. After sampling, the ionic liquid solution was introduced into the amide condensation reaction unit.
[0061] Step 3: Preparation of intermediate III:
[0062] In the amide condensation reaction unit, 1.05 equivalents of condensation agent N,N'-dicyclohexylcarboximide were added to the ionic liquid solution (1200 mL) containing 336.06g (0.836moL) of intermediate II, and after complete conversion into the active intermediate, 300mL of ionic liquid solution containing 176.59g (0.920moL) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride was introduced, the reaction temperature was 15°C, liquid phase monitoring, and the reaction time was 3h. After the reaction was completed, the product flowed out continuously, and after washing, 1500mL of ionic liquid solution of 437.39g intermediate III (0.810moL) was obtained, with a purity of 99.32% and a yield of 96.88%. After sampling, 1400mL of ionic liquid solution containing 408.27g intermediate III (0.756moL) was introduced into the cyclization reaction unit.
[0063] Step 4: Preparation of Flurellana:
[0064] In the cyclization reaction unit, 0.02 equivalents of tetrabutylammonium bromide were added to 1400 mL of an ionic liquid solution containing 408.27 g of intermediate III (0.756 mol) through a micro-reaction pipeline, and 600 mL of a sodium hydroxide aqueous solution of hydroxylamine hydrochloride was slowly dripped in, the equivalent ratio of intermediate III: hydroxylamine hydrochloride: sodium hydroxide was 1:2:4, the reaction temperature was -5 °C, and liquid phase detection was performed. After the reaction was completed for 3 h, the ionic liquid was repeatedly washed with ethyl acetate until the fluorine in the ionic liquid was completely eliminated. The content of flurana is less than 0.001g / L. After drying, 1500mL of dichloromethane solution containing 402.11g (0.724moL) of flurana is concentrated to 500mL and then passed into a micro-crystallizer. It is mixed with n-heptane at a volume ratio of 1:4 for crystallization. After washing with a small amount of cold ethanol, it is vacuum dried at 60°C for 10h to obtain 393.48g (0.709moL) of flurana with a purity of 99.94%, a yield of 93.77%, and a total yield of 87.80%.
[0065] Comparative Example 1
[0066] Preparation of Flurellana by a batch process:
[0067] Step 1: Preparation of Intermediate I
[0068] In a reactor, add 1000mL of 1-ethyl-3-methylimidazolium acetate ionic liquid, then add 150.05g (0.842moL) of 4-acetyl-2-methylbenzoic acid and 214.01g (0.885moL) of 3,5-dichloro-2,2,2-trifluoroacetophenone, use an appropriate alkaline solution (such as sodium carbonate solution) to adjust the pH of the reaction system to 9, control the temperature to 50°C, stop the reaction after 8 hours (the raw material is less than 0.5%), separate, wash and dry. The amount of intermediate I obtained is: 299.41g, the yield is 84.44%, and the purity is 96.77%.
[0069] Step 2: Preparation of Intermediate II
[0070] In a reaction kettle, a dehydrating agent, acetic anhydride, was added to the ionic liquid solution containing intermediate I in an amount of 3 equivalents of intermediate I. The temperature was controlled at 30° C. and the reaction was carried out for 7 hours to obtain 297.86 g of intermediate II with a yield of 87.99% and a purity of 96.88%.
[0071] Step 3: Preparation of Intermediate III
[0072] In a reaction kettle, 1.05 equivalents of a condensing agent was added to the ionic liquid solution containing the intermediate II, and after the intermediate II was completely converted into an active intermediate, an ionic liquid solution containing 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride was introduced, and the reaction temperature was 20°C for 5 hours to obtain 372.87 g of the intermediate III with a yield of 82.00% and a purity of 97.44%.
[0073] Step 4: Preparation of Flurella
[0074] In a reaction kettle, corresponding reagents were added to the ionic liquid solution containing the intermediate III, and the reaction conditions were controlled to carry out the reaction, thereby obtaining 373.80 g of flurellane with a yield of 79.99%, a purity of 99.82%, and a total yield of 48.73%.
[0075] Comparative Example 2
[0076] Synthesis of Fluorana by a continuous flow method using conventional organic solvents:
[0077] Step 1: Preparation of Intermediate I
[0078] In a continuous flow device, a conventional organic solvent (such as dichloromethane) is used as a reaction medium, 150.01 g (0.842 mol) of 4-acetyl-2-methylbenzoic acid and 214.03 g (0.885 mol) of 3,5-dichloro-2,2,2-trifluoroacetophenone are continuously introduced into the reaction system, an appropriate alkaline solution (such as sodium carbonate solution) is used to adjust the pH of the reaction system to 9, the temperature is controlled at 55°C, and the reaction is carried out for 7 hours to generate intermediate I. 319.14 g of intermediate I is obtained, the yield is 90.19%, and the purity is about 96.04%
[0079] The subsequent preparation steps of intermediate II, intermediate III and flurellana are also carried out in a continuous flow device, and the corresponding reaction conditions and time are controlled respectively.
[0080] Step 2: Preparation of Intermediate II
[0081] 281.48 g of intermediate II was obtained with a yield of 92.15% and a purity of 96.44%.
[0082] Step 3: Preparation of Intermediate III
[0083] 355.95 g of intermediate III was obtained with a yield of 94.13% and a purity of 98.41%.
[0084] Step 4: Preparation of Flurellana
[0085] 327.16 g of fluororana was obtained, with a yield of 89.42%, a purity of 99.86%, and a total yield of 69.96%.
[0086] Compared with the intermittent preparation method of ionic liquids of the present invention, the continuous flow method using traditional organic solvents improves efficiency to a certain extent, but the yield and purity are still far behind those of the present invention, and traditional organic solvents have problems such as environmental unfriendliness and solvent residue.
[0087] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A method for continuously preparing flurana using an ionic liquid method, characterized in that : Includes the following steps: A. Aldol condensation reaction: 4-acetyl-2-methylbenzoic acid reacts with 3,5-dichloro-2,2,2-trifluoroacetophenone in an ionic liquid to produce an ionic liquid solution of intermediate I; B. Dehydration reaction: a dehydrating agent is added to the ionic liquid solution of the intermediate I, and the product flows out continuously. After washing and drying, an ionic liquid solution of the intermediate II is obtained; C. Amide condensation reaction: adding a condensing agent to the ionic liquid solution of the intermediate II, introducing an ionic liquid solution containing 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride after TLC detection shows that the intermediate II is completely converted into an active intermediate, and after the reaction is completed, the product flows out continuously, and the ionic liquid solution of the intermediate III is obtained after washing; D. Cyclization reaction: adding tetrabutylammonium bromide to the ionic liquid solution of the intermediate III through a micro-reaction pipeline, and then slowly dripping a sodium hydroxide aqueous solution containing hydroxylamine hydrochloride, and performing liquid phase detection. After the reaction is completed, an ionic liquid solution containing fluoranil is obtained; E. Concentration and crystallization: repeatedly washing the ionic liquid solution containing fluorolelanine with a benign organic solvent until the content of fluorolelanine in the ionic liquid solution is less than 0.001 g / L, to obtain an organic solution containing fluorolelanine, and then concentrating the organic solution and passing it into a micro-crystallizer; The mixture is mixed with a poor solvent in the crystallization system to form a crystal, and then filtered. After the filter cake is washed with a small amount of cold detergent, it is vacuum dried to obtain flurellan.
2. The method for continuously preparing flurana using an ionic liquid method according to claim 1, characterized in that The ionic liquids include but are not limited to 1-butyl-3-methylimidazolium bistrifluoromethanesulfonyl imide salt, 1-octyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, and 1-ethyl-3-methylimidazolium acetate.
3. The method for continuously preparing flurana using an ionic liquid method according to claim 1, characterized in that In step A, the pH of the reaction system is controlled at 8-9 and the reaction temperature is controlled at 40-70°C.
4. The method for continuously preparing flurana using an ionic liquid method according to claim 1, characterized in that In step B, the dehydrating agent includes but is not limited to concentrated sulfuric acid, phosphorus pentoxide, p-toluenesulfonic acid, phosphoric acid, and acetic anhydride; the amount of the dehydrating agent is 2 to 8 equivalents of intermediate I, and the reaction temperature is 25 to 55°C.
5. The method for continuously preparing flurana using an ionic liquid method according to claim 1, characterized in that In step C, the amide condensation reaction is carried out under anhydrous conditions, the pH of the reaction system is controlled at 7 to 8, the reaction temperature is -15 to 25°C, and the amount of the condensing agent is 1.05 to 1.30 equivalents of the intermediate II.
6. The method for continuously preparing flurana using an ionic liquid method according to claim 1, characterized in that : In the step C, the condensing agent includes any one of DPPA (diphenylphosphoryl azide), CDI (N,N'-carbonyldiimidazole), DCC (N,N'-dicyclohexylcarbodiimide), and PyBop (benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate).
7. The method for continuously preparing flurana using an ionic liquid method according to claim 5, characterized in that :; The equivalent ratio of the intermediate III: hydroxylamine hydrochloride: sodium hydroxide is 1:2:4, 1:3:6, 1:4:8 or 1:6:
12.
8. The method for continuously preparing flurana using an ionic liquid method according to claim 1, characterized in that : In the step D, the reaction temperature is -10-30°C.
9. The method for continuously preparing flurana using an ionic liquid method according to claim 1, characterized in that : In the step E, the volume ratio of the ethyl acetate solution containing flurana to the crystallization system is 1:
5.
10. The method for continuously preparing flurana using an ionic liquid method according to claim 1, characterized in that : The good organic solvent / poor solvent crystallization system is one of ethyl acetate / n-hexane, dichloromethane / n-hexane, tetrahydrofuran / n-hexane, ethyl acetate / n-heptane, dichloromethane / n-heptane, tetrahydrofuran / n-heptane, acetic acid / water, methanol / water, ethanol / water or isopropanol / water.