Preparation method of sulfoxaflor

Abstract

According to the preparation method of sulfoxaflor, provided by the invention, 3-[1-(methylthio) ethyl]-6-(trifluoromethyl) pyridine is taken as a raw material, and is subjected to an S-imidization reaction in the presence of DPPH and an ionic liquid [Bmin] BF4 to prepare a sulfimide compound B; the sulfoxaflor is finally prepared through an N-cyanation reaction of the sulfoxaflor compound B and AIBN in the presence of cuprous iodide, potassium carbonate and [Bmin] BF4, the preparation method of the sulfoxaflor is short in synthesis route, the ionic liquid is creatively used as the reaction solvent, the sulfoxaflor is more environmentally friendly, the reaction can be promoted, and the preparation method of the sulfoxaflor is suitable for industrial production. The reaction time is shortened, and the target product can be prepared with high yield (the total yield of two steps is 81% or above) and high purity (99.5%).

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of sulfoxaflor. BACKGROUND

[0002] Sulfoxaflor, whose chemical structural formula is: C 10 H 10 F3N3OS, whose chemical name is: [1-[6-(trifluoromethyl)pyridin-3-yl]ethyl]methyl (oxo)-lambda-4-sulfenyl cyanamide, and whose chemical structural formula is shown in the following formula: Sulfoxaflor is a sulfonamide insecticide, which acts on a unique binding site in the cholinergic receptor to exert insecticidal function. Sulfoxaflor can be absorbed through leaves, stems and roots to enter the plant body. Sulfoxaflor is suitable for preventing and treating aphids and borer of peach trees and apple trees, and aphids and whiteflies of vegetables. Sulfoxaflor has the advantages of high efficiency, rapidness and long residual period, and can effectively prevent and treat sap-sucking pests resistant to nicotine, pyrethrin, organophosphorus and carbamate pesticides. Sulfoxaflor has the advantages of rapid effect, strong efficacy and low dosage, and has a wide prospect in the cotton and rice markets.

[0003] At present, there are many literatures reporting the synthesis of sulfoxaflor, such as: CN101641331B, WO2025017547A1, WO2017198812A2, CN105705022A, WO2013165793A1, CN101641331B, CN102264224B, CN101677570B, CN101754680B and the like. However, the above reported methods mostly have problems of long synthesis route, environmental pollution, low yield and low purity.

[0004] In summary, the preparation of sulfoxaflor in the prior art has problems of long synthesis route, environmental pollution, low yield and low selectivity, and therefore, it is urgent to provide more preparation methods of sulfoxaflor. SUMMARY

[0005] The present application aims to provide a preparation method of sulfoxaflor, which has the advantages of short synthesis route, environmental protection, high yield and high purity, so as to solve the problems of long synthesis route, environmental pollution, low yield and low purity in the prior art.

[0006] The present application is realized by the following technical scheme, and provides a preparation method of sulfoxaflor, characterized by comprising the following steps:

[0007] 1) Synthesis of compound B:

[0008] 1,1-Diphenyl-2-trinitrophenylhydrazine, 1-butyl-3-methylimidazolium tetrafluoroborate and compound A were added sequentially to a round-bottom flask. The mixture was stirred at room temperature for a period of time. The reaction mixture was then transferred to an ice-water bath and cooled to 0°C. m-chloroperbenzoic acid was slowly added while maintaining the reaction temperature at 0°C. Sodium carbonate was then added while maintaining the reaction temperature at 0-4°C. The mixture was stirred for 8-24 hours. The reaction was monitored by TLC until it was complete. After the reaction was completed, compound B was obtained through post-processing.

[0009] 2) Synthesis of compound C

[0010] Add compound B, azobisisobutyronitrile, cuprous iodide, potassium carbonate, and 1-butyl-3-methylimidazolium tetrafluoroborate, prepared in step 1), to a round-bottom flask equipped with a stir bar. Install an oxygen balloon on the reaction flask and replace the air in the flask with oxygen. Heat the reaction solution to 90°C and stir for 10-24 hours. After the reaction is complete as monitored by TLC, cool the reaction solution to room temperature and pour it into water. A white solid precipitates out. Filter to obtain crude compound C. Recrystallize the crude compound C from an ethanol solution to obtain pure compound C.

[0011] The specific synthesis route is as follows:

[0012]

[0013] Further, as a preferred embodiment of the present invention, the molar ratio of compound A to 1,1-diphenyl-2-trinitrophenylhydrazine in step 1) is 1:(1.1-1.5); preferably, the molar ratio of compound A to 1,1-diphenyl-2-trinitrophenylhydrazine in step 1) is 1:(1.1-1.2).

[0014] Further, as a preferred embodiment of the present invention, the molar ratio of compound A to m-chloroperbenzoic acid and sodium carbonate in step 1) is 1:(5-10):(10-30); preferably, the molar ratio of compound A to m-chloroperbenzoic acid and sodium carbonate in step 1) is 1:(5-6):(20-25).

[0015] Furthermore, as a preferred embodiment of the present invention, the structural formula of DPPH in step 1) is:

[0016] Furthermore, as a preferred embodiment of the present invention, the structural formula of mCPBA in step 1) is:

[0017] Furthermore, as a preferred embodiment of the present invention, the structural formula of [Bmin]BF4 in step 1) is:

[0018] Further, as a preferred technical solution of the present invention, the post-processing step in step 1) is as follows: after the reaction is complete, the reaction solution is poured into water, extracted three times with dichloromethane, dried with anhydrous sodium sulfate, filtered, evaporated to dryness, purified by silica gel column chromatography, and the eluent is ethyl acetate and petroleum ether in a volume ratio of 2:10 to obtain compound B.

[0019] Further, as a preferred embodiment of the present invention, the molar ratio of compound B, azobisisobutyronitrile, cuprous iodide, and potassium carbonate in step 2) is 1:(1.5-3):(0.1-0.5):(2-5); preferably, the molar ratio of compound B, azobisisobutyronitrile, cuprous iodide, and potassium carbonate in step 2) is 1:(1.5-2):(0.2-0.3):(2-3).

[0020] Further, as a preferred embodiment of the present invention, the recrystallization step in step 2) is as follows: crude compound C is added to an ethanol solution and heated until completely dissolved, filtered while hot, and then n-hexane is added to the filtrate, cooled to 0°C to crystallize, thereby obtaining pure compound C; the mass-volume ratio of crude compound C to ethanol and n-hexane is 1g:(10-40mL):(20mL-80mL); preferably, the recrystallization step in step 2) is as follows: crude compound C is added to an ethanol solution and heated until completely dissolved, filtered while hot, and then n-hexane is added to the filtrate, cooled to 0°C to crystallize, thereby obtaining pure compound C; the mass-volume ratio of crude compound C to ethanol and n-hexane is 1g:10mL:20mL.

[0021] Beneficial effects:

[0022] The method for preparing flonicamid provided by this invention uses 3-[1-(methylthio)ethyl]-6-(trifluoromethyl)pyridine as a raw material. In the presence of DPPH and the ionic liquid [Bmin]BF4, an S-iminolation reaction is carried out to obtain sulfonylimide compound B. Sulfonylimide compound B is then reacted with AIBN in the presence of cuprous iodide, potassium carbonate, and [Bmin]BF4, followed by an N-cyanolation reaction to finally obtain flonicamid. The method for preparing flonicamid provided by this invention not only has a short synthetic route but also creatively uses an ionic liquid as a reaction solvent, making it more environmentally friendly. Furthermore, it can promote the reaction, shorten the reaction time, and obtain the target product with high yield (over 81% overall yield of the two steps) and high purity (99.5%). Attached Figure Description

[0023] Figure 1 This is the synthetic route for flonicamid. Detailed Implementation

[0024] The present invention will be further described in detail below with reference to the embodiments, but the content of the invention is not limited to the embodiments.

[0025] Example 1

[0026] Preparation of flonicamid

[0027]

[0028] The specific synthesis steps are as follows:

[0029] 3) Synthesis of compound B:

[0030] 4.33 g of 1,1-diphenyl-2-trinitrophenylhydrazine DPPH (11 mmol), 1-butyl-3-methylimidazolium tetrafluoroborate [Bmin] BF4 (100 mL), and 2.21 g of compound A (10 mmol) were added sequentially to a 250 mL round-bottom flask. The mixture was stirred at room temperature (25 ± 2 °C) for 2 hours. The reaction mixture was then transferred to an ice-water bath and cooled to 0 °C. 8.62 g of m-chloroperbenzoic acid mCPBA (50 mmol) was slowly added, maintaining the reaction temperature at 0-5 °C. After the addition was complete, the reaction was continued... Continue stirring for 10 min, then add 21.20 g sodium carbonate (200 mmol), control the reaction temperature at 0-5℃ and continue stirring for 8 hours. Monitor the reaction by TLC until complete. After the reaction is complete, pour the reaction solution into 500 mL of water, extract with dichloromethane (500 mL × 3), dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify by silica gel column chromatography with ethyl acetate and petroleum ether in a volume ratio of 2:10 to give 2.30 g of compound B, yield 91%.

[0031] 4) Synthesis of compound C

[0032] To a 150 mL round-bottom flask equipped with a stirrer, add 0.50 g of compound B (2 mmol) prepared in step 1), 0.49 g of azobisisobutyronitrile (AIBN) (3 mmol), 0.076 g of cuprous iodide (0.4 mmol), 0.55 g of potassium carbonate (4 mmol), and 30 mL of 1-butyl-3-methylimidazolium tetrafluoroborate [Bmin]BF4. Then, attach an oxygen balloon to the reaction flask and replace the air in the flask with oxygen. Heat the reaction solution to 90 °C and stir for 10 hours. After the reaction is complete as monitored by TLC, cool the reaction solution to room temperature and pour it into 200 mL of water. A white solid precipitates out. Filter to obtain crude compound C. Add crude compound C to 5 mL of ethanol solution and heat until completely dissolved. Filter while hot, add 10 mL of n-hexane to the filtrate, and cool to 0 °C to crystallize, obtaining 0.50 g of pure compound C with a yield of 90% and a purity of 99.5%.

[0033] 1H NMR (CDCl3,400M): δ8.81(s,1H),8.13(d,1H),7.82(d,1H),4.64(q,1H),3.23(s,3H),2.14(d,3H).

[0034] Example 2

[0035] Preparation of flonicamid

[0036]

[0037] The specific synthesis steps are as follows:

[0038] 1) Synthesis of compound B:

[0039] Add 4.73 g of 1,1-diphenyl-2-trinitrophenylhydrazine DPPH (12 mmol), 1-butyl-3-methylimidazolium tetrafluoroborate [Bmin] BF4 (100 mL), and 2.22 g of compound A (10 mmol) sequentially to a 250 mL round-bottom flask. Stir the mixture at room temperature (25 ± 2 °C) for 2 hours. Then transfer the reaction mixture to an ice-water bath and cool to 0 °C. Slowly add 10.35 g of m-chloroperbenzoic acid mCPBA (60 mmol), maintaining the reaction temperature at 0-5 °C. After the addition is complete... Continue stirring for 10 min, then add 26.51 g of sodium carbonate (250 mmol), control the reaction temperature at 0-5℃ and continue stirring for 8 hours. Monitor the reaction by TLC until complete. After the reaction is complete, pour the reaction solution into 500 mL of water, extract with dichloromethane (500 mL × 3), dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify by silica gel column chromatography with ethyl acetate and petroleum ether in a volume ratio of 2:10 to give 2.32 g of compound B, yield 92%.

[0040] 2) Synthesis of compound C

[0041] To a 150 mL round-bottom flask equipped with a stirrer, add 0.51 g of compound B (2 mmol) prepared in step 1), 0.66 g of azobisisobutyronitrile (AIBN) (4 mmol), 0.095 g of cuprous iodide (0.5 mmol), 0.69 g of potassium carbonate (5 mmol), and 30 mL of 1-butyl-3-methylimidazolium tetrafluoroborate [Bmin]BF4. Then, attach an oxygen balloon to the reaction flask and replace the air in the flask with oxygen. Heat the reaction solution to 90 °C and stir for 10 hours. After the reaction is complete as monitored by TLC, cool the reaction solution to room temperature and pour it into 200 mL of water. A white solid precipitates out. Filter and dry to obtain crude compound C. Add crude compound C to 5 mL of ethanol solution and heat until completely dissolved. Filter while hot, and add 10 mL of n-hexane to the filtrate. Cool to 0 °C to crystallize and obtain 0.51 g of pure compound C, yield 92%, purity: 99.7%.

[0042] 1 H NMR (CDCl3,400M): δ8.81(s,1H),8.13(d,1H),7.82(d,1H),4.64(q,1H),3.23(s,3H),2.14(d,3H).

[0043] Comparative Example 1

[0044] Preparation of flonicamid

[0045]

[0046] The specific synthesis steps are as follows:

[0047] 1) Synthesis of compound B:

[0048] 4.33 g of 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) (11 mmol), 100 mL of methanol, and 2.21 g of compound A (10 mmol) were added sequentially to a 250 mL round-bottom flask. The mixture was stirred at room temperature (25 ± 2 °C) for 2 hours. The reaction mixture was then transferred to an ice-water bath and cooled to 0 °C. 8.62 g of m-chloroperbenzoic acid (mCPBA) (50 mmol) was slowly added while maintaining the reaction temperature at 0-5 °C. After the addition was complete, the mixture was stirred for 10 min. Then, 21.24 g of sodium carbonate (200 mmol) was added, and the reaction was stirred for another 8 hours while maintaining the reaction temperature at 0-5 °C. The reaction was monitored by TLC until complete. After the reaction was complete, the reaction mixture was poured into 150 mL of water and extracted with dichloromethane (200 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by silica gel column chromatography using ethyl acetate and petroleum ether in a volume ratio of 2:10. The result was 1.79 g of compound B, with a yield of 71%.

[0049] 2) Synthesis of compound C

[0050] To a 150 mL round-bottom flask equipped with a stirrer, add 0.51 g of compound B (2 mmol) prepared in step 1), 0.49 g of azobisisobutyronitrile (AIBN) (3 mmol), 0.076 g of cuprous iodide (0.4 mmol), 0.55 g of potassium carbonate (4 mmol), and 30 mL of acetonitrile. Then, attach an oxygen balloon to the reaction flask and replace the air in the flask with oxygen. Heat the reaction solution to 75 °C and stir for 10 hours. After the reaction is complete as monitored by TLC, cool the reaction solution to room temperature and pour it into 100 mL of water. Extract with dichloromethane (100 mL × 3). Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound C. Add crude compound C to 5 mL of ethanol solution and heat until completely dissolved. Filter while hot, add 10 mL of n-hexane to the filtrate, and cool to 0 °C to crystallize, yielding 0.43 g of pure compound C, yield 78%; purity: 98.4%.

[0051] 1 H NMR (CDCl3,400M): δ8.81(s,1H),8.13(d,1H),7.82(d,1H),4.64(q,1H),3.23(s,3H),2.14(d,3H).

[0052] It should be understood that the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims of the present invention.

Claims

1. A method for preparing flonicamid, characterized in that, Includes the following steps: 1) Synthesis of compound B: 1,1-Diphenyl-2-trinitrophenylhydrazine, 1-butyl-3-methylimidazolium tetrafluoroborate and compound A were added sequentially to a round-bottom flask. The mixture was stirred at room temperature for a period of time. The reaction mixture was then transferred to an ice-water bath and cooled to 0°C. m-chloroperbenzoic acid was slowly added while maintaining the reaction temperature at 0°C. Sodium carbonate was then added while maintaining the reaction temperature at 0-4°C. The mixture was stirred for 8-24 hours. The reaction was monitored by TLC until it was complete. After the reaction was completed, compound B was obtained through post-processing. 2) Synthesis of compound C Add compound B, azobisisobutyronitrile, cuprous iodide, potassium carbonate, and 1-butyl-3-methylimidazolium tetrafluoroborate, prepared in step 1), to a round-bottom flask equipped with a stir bar. Install an oxygen balloon on the reaction flask and replace the air in the flask with oxygen. Heat the reaction solution to 90°C and stir for 10-24 hours. After the reaction is complete as monitored by TLC, cool the reaction solution to room temperature and pour it into water. A white solid precipitates out. Filter to obtain crude compound C. Recrystallize the crude compound C from an ethanol solution to obtain pure compound C. The specific synthesis route is as follows: The structural formula of DPPH in step 1) is: The structural formula of mCPBA in step 1) is: The structural formula of [Bmin]BF4 in step 1) is:

2. The method for preparing flonicamid according to claim 1, characterized in that, In step 1), the molar ratio of compound A to 1,1-diphenyl-2-trinitrophenylhydrazine is 1:(1.1-1.5).

3. The method for preparing flonicamid according to claim 2, characterized in that, In step 1), the molar ratio of compound A to 1,1-diphenyl-2-trinitrophenylhydrazine is 1:(1.1-1.2).

4. The method for preparing flonicamid according to claim 1, characterized in that, In step 1), the molar ratio of compound A to m-chloroperbenzoic acid and sodium carbonate is 1:(5-10):(10-30).

5. The method for preparing flonicamid according to claim 4, characterized in that, In step 1), the molar ratio of compound A to m-chloroperbenzoic acid and sodium carbonate is 1:(5-6):(20-25).

6. The method for preparing flonicamid according to claim 1, characterized in that, The post-processing steps in step 1) are as follows: After the reaction is complete, the reaction solution is poured into water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by silica gel column chromatography with ethyl acetate and petroleum ether in a volume ratio of 2:10 to obtain compound B.

7. The method for preparing flonicamid according to claim 1, characterized in that, In step 2), the molar ratio of compound B, azobisisobutyronitrile, cuprous iodide, and potassium carbonate is 1:(1.5-3):(0.1-0.5):(2-5).

8. The method for preparing flonicamid according to claim 7, characterized in that, In step 2), the molar ratio of compound B, azobisisobutyronitrile, cuprous iodide, and potassium carbonate is 1:(1.5-2):(0.2-0.3):(2-3).

9. The method for preparing flonicamid according to claim 1, characterized in that, The recrystallization step in step 2) is as follows: add crude compound C to an ethanol solution and heat until completely dissolved, filter while hot, add n-hexane to the filtrate, cool to 0°C to crystallize, and obtain pure compound C; the mass-volume ratio of crude compound C to ethanol and n-hexane is 1g:(10-40mL):(20mL-80mL).

10. The method for preparing flonicamid according to claim 1, characterized in that, The recrystallization step in step 2) is as follows: add crude compound C to an ethanol solution and heat until completely dissolved, filter while hot, add n-hexane to the filtrate, cool to 0°C to crystallize, and obtain pure compound C; the mass-volume ratio of crude compound C to ethanol is 1g:10mL:20mL.

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