Synthesis method of N-trifluoromethyl sulfonamide compounds

Abstract

The present invention discloses a method for synthesizing N-trifluoromethylsulfonamide compounds. The method uses aromatic isothiocyanates as starting materials and utilizes a series of reagents, including silver fluoride, triethylsilane, p-toluene thionyl chloride, m-chloroperbenzoic acid, and potassium fluoride, to synthesize N-trifluoromethylsulfonamide compounds through a multi-step reaction. The present invention introduces a trifluoromethyl group into the sulfonamide structure, while maintaining mild reaction conditions and utilizing a wide range of raw material sources.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for synthesizing N-trifluoromethylsulfonamide compounds. Background Art

[0002] The trifluoromethyl group (-CF3) is a highly oxidizing, electron-withdrawing, and highly Hansch-indexed organic fluorine building block. Its introduction into drug molecules can significantly alter their physical and chemical properties, including increasing their lipophilicity, Caco-2 permeability, metabolic stability, and bioavailability. In recent years, trifluoromethyl-containing drugs have seen rapid development, with significant effects in anti-tumor, anti-inflammatory, and anti-psychotic activities (as shown below). Their potential therapeutic benefits are also garnering increasing attention.

[0003]

[0004] Sulfonamide antibacterial and anti-inflammatory drugs are a class of drugs with the structure of p-aminobenzenesulfonamide. They are chemotherapeutic agents used to prevent and treat bacterial infections. They have a broad antimicrobial spectrum, inhibiting most Gram-positive and Gram-negative bacteria. In 1932, Domagk discovered that Prontosil could treat staphylococcal sepsis, sparking research on sulfonamides. Sulfamethoxazole, a sulfonamide introduced in 1962, has a half-life of 11 hours and strong antibacterial activity. Combining it with the potentiator trimethoprim-sulfamethoxazole significantly enhances its antibacterial efficacy, increasing it several to dozens of times. It is clinically used to treat tonsillitis, acute bronchitis, lung infections, urinary tract infections, suppurative skin infections, bacillary dysentery, and typhoid fever. Sulfonamides also play a significant role in livestock farming (e.g., pigs, chickens, and fish).

[0005] At present, the application of trifluoromethyl in drugs is mostly reflected in the construction of C-CF3 bonds on benzene rings, while the introduction of CF3 groups on other heteroatoms is relatively rare. Reports mainly show the construction of CF3 bonds on atoms such as O and S, which greatly limits the application of CF3 groups in drugs.

[0006] Reference 1 (Scattolin T., Bouayad-Gervais S., Schoenebeck F. Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas [J]. Nature, 2019, 573 (7772): 102-107.) proposed a method for the direct synthesis of N-trifluoromethylamide. Using isothiocyanate as the reaction substrate, silver fluoride and triphosgene were used to synthesize a series of N-trifluoromethylacyl fluoride compounds, and then a series of compounds containing N-trifluoromethylamide were obtained using Grignard reagents. This has gradually aroused people's interest in the construction of N-CF3 bonds on amides and their derivatives or similar structures.

[0007]

[0008] Reference 2 (Liu J., Parker M., Wang S., et al. Synthesis of N-trifluoromethylamides from carboxylic acids [J]. Chem, 2021, 7: 2245–2255.) proposes a simpler method for the direct synthesis of N-trifluoromethylamide. Isothiocyanate is used as the reaction substrate and carboxylic acid halide (or carboxylate derivative) is used as the carbonyl source. N-trifluoromethylamide is synthesized in the next step under the action of silver fluoride and pyridine (or 2,4,6-pyridine). The reaction is simple and widely applicable, further enriching the method of synthesizing the N-CF3 bond in the amide structure.

[0009]

[0010] Experimental results show that N-trifluoromethylated amides are more stable than amides themselves or N-methylamides. As a structural analog of amides, N-trifluoromethylsulfonamides may also possess high stability. However, reports on the synthesis of related N-trifluoromethylsulfonamides are relatively rare. Summary of the Invention

[0011] The present invention aims to provide a method for synthesizing N-trifluoromethylsulfonamide compounds. The method uses aromatic isothiocyanates as starting materials and utilizes a series of reagents, including silver fluoride (AgF), triethylsilane (Et3SiH), p-toluene thionyl chloride, meta-chloroperbenzoic acid (mCPBA), and potassium fluoride (KF), to synthesize N-trifluoromethylsulfonamide compounds through a multi-step reaction.

[0012] The technical solutions for achieving the purpose of the present invention are as follows:

[0013] The synthesis method of N-trifluoromethyl sulfonamide compounds, the synthesis route is as follows:

[0014]

[0015] The steps include:

[0016] Step 1, preparation of N-trifluoromethyl aromatic compounds:

[0017] Under the protection of inert gas, an aromatic isothiocyanate and triethylsilane are dissolved in anhydrous acetonitrile to obtain a mixed solution A, and then under the protection of inert gas, the mixed solution A is slowly added to silver fluoride, and the reaction is carried out at 45-55°C for 4-6 hours. After the reaction is completed, the reaction is filtered, and the filtrate is distilled under reduced pressure, and anhydrous ether is added for washing, and the washing liquid is distilled under reduced pressure to obtain an N-trifluoromethyl aromatic compound;

[0018] Step 2, preparation of N-trifluoromethylsulfonamide compounds:

[0019] Under the protection of inert gas, an N-trifluoromethyl aromatic compound is dissolved in anhydrous acetonitrile to obtain solution B; under the protection of inert gas, p-toluene thionyl chloride is dissolved in anhydrous acetonitrile to obtain solution C; under the protection of inert gas, triethylamine is dissolved in anhydrous acetonitrile to obtain solution D; m-chloroperbenzoic acid and potassium fluoride are dissolved in an acetonitrile aqueous solution to obtain solution E; under the protection of inert gas, solution B, solution C and solution D are sequentially added to a reactor at 20-30° C., reacting for 3-4 hours. After the reaction is completed, the reaction solution is filtered to obtain a filtrate, which is concentrated. Then, solution E is added to the concentrated solution at -5-5° C., reacting for 2-3 hours. After the reaction is completed, the reaction solution is distilled under reduced pressure, and the crude product is separated using a silica gel column to obtain the final product, N-trifluoromethyl sulfonamide compound.

[0020] Preferably, in step 1, the aromatic isothiocyanate is selected from isothiocyanatobenzene, 2-isothiocyanato-1,3-xylene, 1-chloro-4-isothiocyanatobenzene, 1-bromo-4-isothiocyanatobenzene or 1-isothiocyanato-3,5-dimethoxybenzene.

[0021] Preferably, in step 1, the inert gas is nitrogen or argon.

[0022] Preferably, in step 1, the washing times with anhydrous ether are two or more times.

[0023] Preferably, in step 1, the molar ratio of the aromatic isothiocyanate to triethylsilane is 1:1.5, the molar ratio of the aromatic isothiocyanate to silver fluoride is 1:5, and the concentration of the aromatic isothiocyanate in the mixed solution A is 0.2 mol / L.

[0024] Preferably, in step 2, the molar ratio of the N-trifluoromethyl aromatic compound to p-toluene thionyl chloride is 1:1, the molar ratio of the N-trifluoromethyl aromatic compound to triethylamine is 1:1, the molar ratio of the N-trifluoromethyl aromatic compound to m-chloroperbenzoic acid is 1:4, the molar ratio of the N-trifluoromethyl aromatic compound to potassium fluoride is 1:4, the acetonitrile aqueous solution is acetonitrile containing 15% water, and the concentration of the N-trifluoromethyl aromatic compound in the acetonitrile solution of the N-trifluoromethyl aromatic compound is 0.2 mol / L.

[0025] Compared with the prior art, the present invention has the following advantages:

[0026] (1) The method for in-situ generation of hydrogen fluoride used in the present invention has a high yield and is simple and convenient to post-process.

[0027] (2) Compared with the direct use of hydrogen fluoride gas or hydrogen fluoride reagent, the method of the present invention has fewer by-products and the conditions are milder and safer. DETAILED DESCRIPTION

[0028] The present invention will be further described below with reference to specific embodiments, but is not limited thereto.

[0029] The synthesis method of the N-trifluoromethyl sulfonamide compounds of the present invention has the following synthesis mechanism:

[0030]

[0031] Example 1

[0032] (1) Preparation of the initial product N-(trifluoromethyl)aniline

[0033] Under nitrogen or argon protection, dissolve 10 mL of isothiocyanatobenzene (2 mmol, 270 mg) and triethylsilane (3 mmol, 349 mg) in anhydrous acetonitrile to obtain a mixed solution A. Then, under inert gas protection, slowly add the mixed solution A to silver fluoride (10 mmol, 1269 mg), and react at 45-55°C for 4-6 hours. After completion of the reaction, filter, distill the filtrate under reduced pressure, add anhydrous ether to wash twice, and distill the washing liquid under reduced pressure to obtain N-(trifluoromethyl)aniline.

[0034] (2) Preparation of the final product 4-methyl-N-phenyl-N-(trifluoromethyl)benzenesulfonamide

[0035] Under inert gas, N-(trifluoromethyl)aniline (2 mmol, 322 mg) was dissolved in 3 mL of anhydrous acetonitrile to obtain Solution B. Under inert gas, p-toluene thionyl chloride (2 mmol, 316 mg) was dissolved in 3 mL of anhydrous acetonitrile to obtain Solution C. Under inert gas, triethylamine (2 mmol, 202 mg) was dissolved in 4 mL of anhydrous acetonitrile to obtain Solution D. m-Chloroperbenzoic acid (8 mmol, 1380 mg) and potassium fluoride (8 mmol, 464 mg) were dissolved in 5 mL of acetonitrile-water solution to obtain Solution E. Under inert gas, Solution B, Solution C, and Solution D were added sequentially to a reactor at 20-30°C and allowed to react for 3-4 hours. The reaction solution was then filtered to obtain a filtrate, which was then concentrated. Solution E was then added to the concentrate at -5-5°C and allowed to react for 2-3 hours. After the reaction is completed, the reaction solution is distilled under reduced pressure, and the crude product is separated using a silica gel column to obtain the final product 4-methyl-N-phenyl-N-(trifluoromethyl)benzenesulfonamide.

[0036] The structural formula of 4-methyl-N-phenyl-N-(trifluoromethyl)benzenesulfonamide synthesized in this example is:

[0037] White solid, melting point: 72-73 ° C, yield: 78%. Eluent: V 乙酸乙酯 :V 石油醚 =2:98.

[0038] 1 H NMR (500MHz, CDCl3) δ7.56(d,J=8.0Hz,2H),7.48(t,J=7.2Hz,1H),7.35(t,J=7.6Hz,2H),7.37(d,J=8.0Hz,2H),7.15(d,J=7.8Hz,2H),2.49(s,3H). 13 C NMR (126MHz, CDCl3) δ148.4, 134.5, 136.6, 132.6, 132.3, 130.8, 131.5, 130.4, 121.1 (q, J = 264.2Hz), 20.7. HRMS (EI): m / z calcd for C 14 H 12 F3NO2S:315.0535M + Found 315.0542.

[0039] Example 2

[0040] (1) Preparation of the initial product 2,6-dimethyl-N-(trifluoromethyl)aniline

[0041] Under nitrogen or argon protection, 2-isothiocyanato-1,3-dimethylbenzene (2 mmol, 326 mg) and triethylsilane (3 mmol, 349 mg) were dissolved in 10 mL of anhydrous acetonitrile to obtain a mixed solution A. Then, under inert gas protection, the mixed solution A was slowly added to silver fluoride (10 mmol, 1269 mg). The mixture was reacted at 45-55°C for 4-6 hours. After the reaction was completed, the mixture was filtered, and the filtrate was distilled under reduced pressure. Anhydrous ether was added for washing twice, and the washing liquid was distilled under reduced pressure to obtain 2,6-dimethyl-N-(trifluoromethyl)aniline.

[0042] (2) Preparation of the final product N-(2,6-dimethylphenyl)-4-methyl-N-(trifluoromethyl)benzenesulfonamide

[0043] Under nitrogen or argon, 2,6-dimethyl-N-(trifluoromethyl)aniline (2 mmol, 378 mg) was dissolved in 3 mL of anhydrous acetonitrile to obtain Solution B. Under inert gas, p-toluene thionyl chloride (2 mmol, 316 mg) was dissolved in 3 mL of anhydrous acetonitrile to obtain Solution C. Under inert gas, triethylamine (2 mmol, 202 mg) was dissolved in 4 mL of anhydrous acetonitrile to obtain Solution D. m-Chloroperbenzoic acid (8 mmol, 1380 mg) and potassium fluoride (8 mmol, 464 mg) were dissolved in 5 mL of aqueous acetonitrile to obtain Solution E. Under nitrogen or argon, Solution B, Solution C, and Solution D were added sequentially to a reactor at 20-30°C and allowed to react for 3-4 hours. The reaction solution was then filtered to obtain a filtrate, which was then concentrated. Solution E was then added to the concentrate at -5-5°C and allowed to react for an additional 2-3 hours. After the reaction is completed, the reaction solution is distilled under reduced pressure, and the crude product is separated using a silica gel column to obtain the final product N-(2,6-dimethylphenyl)-4-methyl-N-(trifluoromethyl)benzenesulfonamide.

[0044] The structural formula of N-(2,6-dimethylphenyl)-4-methyl-N-(trifluoromethyl)benz-enesulfonamide synthesized in this example is:

[0045] Colorless oil, yield 40%. Eluent: V 乙酸乙酯 :V 石油醚 =2:98.

[0046] 1H NMR (500MHz, CDCl3) δ7.74(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),7.24(t,J=7.5Hz,1H),7.05(d,J=7.5Hz,2H),2.48(s,3H),2.07(s,6H). 13 C NMR (126MHz, CDCl3) δ 145.8, 140.7, 136.6, 131.6, 129.8, 129.7, 129.5, 128.3, 120.7 (q, J = 263.8Hz), 21.5, 18.3. HRMS (EI): m / z calcd for C 16 H 16 F3NO2S:343.0848M + Found 343.0856.

[0047] Example 3

[0048] (1) Preparation of the initial product 4-chloro-N-(trifluoromethyl)aniline

[0049] Under nitrogen or argon protection, 1-chloro-4-isothiocyanatobenzene (2mmol, 338mg) and triethylsilane (3mmol, 349mg) were dissolved in 10mL of anhydrous acetonitrile to obtain a mixed solution A. Then, under inert gas protection, the mixed solution A was slowly added to silver fluoride (10mmol, 1269mg), and the mixture was reacted at 45-55°C for 4-6h. After completion of the reaction, the mixture was filtered, and the filtrate was distilled under reduced pressure, washed twice with anhydrous ether, and the washing liquid was distilled under reduced pressure to obtain 4-chloro-N-(trifluoromethyl)aniline.

[0050] (2) Preparation of the final product N-(4-chlorophenyl)-4-methyl-N-(trifluoromethyl)benzenesulfonamide

[0051] Under nitrogen or argon, 4-chloro-N-(trifluoromethyl)aniline (2 mmol, 390 mg) was dissolved in 3 mL of anhydrous acetonitrile to obtain Solution B. Under inert gas, p-toluene thionyl chloride (2 mmol, 316 mg) was dissolved in 3 mL of anhydrous acetonitrile to obtain Solution C. Under inert gas, triethylamine (2 mmol, 202 mg) was dissolved in 4 mL of anhydrous acetonitrile to obtain Solution D. m-Chloroperbenzoic acid (8 mmol, 1380 mg) and potassium fluoride (8 mmol, 464 mg) were dissolved in 5 mL of acetonitrile-water solution to obtain Solution E. Under nitrogen or argon, Solution B, Solution C, and Solution D were added sequentially to a reactor at 20-30°C and allowed to react for 3-4 hours. The reaction solution was then filtered to obtain a filtrate, which was then concentrated. Solution E was then added to the concentrate at -5-5°C and allowed to react for 2-3 hours. After the reaction is completed, the reaction solution is distilled under reduced pressure, and the crude product is separated using a silica gel column to obtain the final product N-(4-chlorophenyl)-4-methyl-N-(trifluoromethyl)benzenesulfonamide.

[0052] The structural formula of N-(4-chlorophenyl)-4-methyl-N-(trifluoromethyl)benz-enesulfonamide synthesized in this example is:

[0053] White solid, melting point: 72-74 ° C, yield: 54%. Eluent: V 乙酸乙酯 :V 石油醚 =2:98.

[0054] 1 H NMR (500MHz, CDCl3) δ7.68 (d, J = 8.1Hz, 2H), 7.36 (dd, J = 16.0, 8.3Hz, 4H), 7.13 (d, J = 8.4Hz, 2H), 2.48 (s, 3H). 13 C NMR (126MHz, CDCl3) δ145.6, 136.3, 135.5, 132.3, 131.89, 129.6, 129.3, 128.3, 119.8 (q, J = 264.6Hz), 21.7. HRMS (EI): m / z calcd forC 14 H 11 ClF3NO2S:349.0146M + Found 349.0162.

[0055] Example 4

[0056] (1) Preparation of the initial product 4-bromo-N-(trifluoromethyl)aniline

[0057] Under nitrogen or argon protection, 1-bromo-4-isothiocyanatobenzene (2mmol, 426mg) and triethylsilane (3mmol, 349mg) were dissolved in 10mL of anhydrous acetonitrile to obtain a mixed solution A. Then, under inert gas protection, the mixed solution A was slowly added to silver fluoride (10mmol, 1269mg), and the mixture was reacted at 45-55°C for 4-6h. After completion of the reaction, the mixture was filtered, and the filtrate was distilled under reduced pressure, washed twice with anhydrous ether, and the washing liquid was distilled under reduced pressure to obtain 4-bromo-N-(trifluoromethyl)aniline.

[0058] (2) Preparation of the final product N-(4-bromophenyl)-4-methyl-N-(trifluoromethyl)benzenesulfonamide

[0059] Under nitrogen or argon, 4-bromo-N-(trifluoromethyl)aniline (2 mmol, 479 mg) was dissolved in 3 mL of anhydrous acetonitrile to obtain Solution B. Under inert gas, p-toluene thionyl chloride (2 mmol, 316 mg) was dissolved in 3 mL of anhydrous acetonitrile to obtain Solution C. Under inert gas, triethylamine (2 mmol, 202 mg) was dissolved in 4 mL of anhydrous acetonitrile to obtain Solution D. m-Chloroperbenzoic acid (8 mmol, 1380 mg) and potassium fluoride (8 mmol, 464 mg) were dissolved in 5 mL of acetonitrile-water solution to obtain Solution E. Under nitrogen or argon, Solution B, Solution C, and Solution D were added sequentially to a reactor at 20-30°C and allowed to react for 3-4 hours. The reaction solution was then filtered to obtain a filtrate, which was then concentrated. Solution E was then added to the concentrate at -5-5°C and allowed to react for 2-3 hours. After the reaction is completed, the reaction solution is distilled under reduced pressure, and the crude product is separated using a silica gel column to obtain the final product N-(4-bromophenyl)-4-methyl-N-(trifluoromethyl)benzenesulfonamide.

[0060] The structural formula of N-(4-bromophenyl)-4-methyl-N-(trifluoromethyl)benz-enesulfonamide synthesized in this example is:

[0061] White solid, melting point: 81-82 ° C, yield: 63%. Eluent: V 乙酸乙酯 :V 石油醚 =2:98.

[0062] 1H NMR (500MHz, CDCl3) δ7.68 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 2.43 (s, 3H). 13 C NMR (126MHz, CDCl3) δ145.2, 135.8, 132.3, 132.4, 132.4, 129.7, 128.8, 124.3, 119.6 (q, J = 264.6Hz), 21.8. HRMS (EI): m / zcalcd for C 14 H 11 BrF3NO2S:392.9640M + Found 392.9659.

[0063] Example 5

[0064] (1) Preparation of the final product 3,5-dimethoxy-N-(trifluoromethyl)aniline

[0065] Under nitrogen or argon protection, 1-isothiocyanato-3,5-dimethoxybenzene (2mmol, 390mg) and triethylsilane (3mmol, 349mg) were dissolved in 10mL of anhydrous acetonitrile to obtain a mixed solution A. Then, under inert gas protection, the mixed solution A was slowly added to silver fluoride (10mmol, 1269mg), and the mixture was reacted at 45-55°C for 4-6h. After completion of the reaction, the mixture was filtered, and the filtrate was distilled under reduced pressure, washed twice with anhydrous ether, and the washing liquid was distilled under reduced pressure to obtain 3,5-dimethoxy-N-(trifluoromethyl)aniline.

[0066] (2) Preparation of intermediate product N-(3,5-dimethoxyphenyl)-4-methyl-N-(trifluoromethyl)benzenesulfonamide

[0067] Under nitrogen or argon, 3,5-dimethoxy-N-(trifluoromethyl)aniline (2 mmol, 442 mg) was dissolved in 3 mL of anhydrous acetonitrile to obtain Solution B. Under inert gas, p-toluene thionyl chloride (2 mmol, 316 mg) was dissolved in 3 mL of anhydrous acetonitrile to obtain Solution C. Under inert gas, triethylamine (2 mmol, 202 mg) was dissolved in 4 mL of anhydrous acetonitrile to obtain Solution D. m-Chloroperbenzoic acid (8 mmol, 1380 mg) and potassium fluoride (8 mmol, 464 mg) were dissolved in 5 mL of aqueous acetonitrile to obtain Solution E. Under nitrogen or argon, Solution B, Solution C, and Solution D were added sequentially to a reactor at 20-30°C and allowed to react for 3-4 hours. The reaction solution was then filtered to obtain a filtrate, which was then concentrated. Solution E was then added to the concentrate at -5-5°C and allowed to react for 2-3 hours. After the reaction is completed, the reaction solution is distilled under reduced pressure, and the crude product is separated using a silica gel column to obtain the final product N-(3,5-dimethoxyphenyl)-4-methyl-N-(trifluoromethyl)benzenesulfonamide.

[0068] The structural formula of N-(3,5-dimethoxyphenyl)-4-methyl-N-(trifluoromethyl)benzenesulfonamide synthesized in this example is:

[0069] White solid, melting point: 111-112 ° C, yield: 75%. Eluent: V 乙酸乙酯 :V 石油醚 =4:96.

[0070] 1 H NMR (500MHz, CDCl3) δ7.74(d,J=7.9Hz,2H),7.35(d,J=7.9Hz,2H),6.57(s,1H),6.33(s,2H),3.76(s,6H),2.47(s,3H). 13 C NMR (126MHz, CDCl3) δ 160.8, 145.3, 135.8, 135.2, 129.6, 128.4, 120.2 (q, J = 264.6Hz), 108.5, 102.6, 55.7, 21.3. HRMS (EI): m / zcalcdfor C 16 H 16 F3NO4S:375.0747M + Found 375.0746.

[0071] Comparative Example 1

[0072] This comparative example is basically the same as Example 1, except that triethylsilane and silver fluoride are replaced by hydrogen fluoride and pyridine reagents. The reaction has similar effects, but the amount of by-products produced increases and the difficulty of substrate separation is increased.

Claims

1. A method for synthesizing N-trifluoromethylsulfonamide compounds, characterized in that: The steps include: Step 1, preparation of N-trifluoromethyl aromatic compounds: Under the protection of inert gas, an aromatic isothiocyanate and triethylsilane are dissolved in anhydrous acetonitrile to obtain a mixed solution A, and then the mixed solution A is slowly added to silver fluoride under the protection of inert gas, and the reaction is carried out at 45-55°C for 4-6 hours. After the reaction is completed, the mixture is filtered, and the filtrate is distilled under reduced pressure, washed with anhydrous ether, and the washing solution is distilled under reduced pressure to obtain an N-trifluoromethyl aromatic compound; Step 2, preparation of N-trifluoromethylsulfonamide compounds: Under the protection of inert gas, an N-trifluoromethyl aromatic compound is dissolved in anhydrous acetonitrile to obtain solution B. Under the protection of inert gas, p-methylphenylsulfonyl chloride is dissolved in anhydrous acetonitrile to obtain solution C. Under the protection of inert gas, triethylamine is dissolved in anhydrous acetonitrile to obtain solution D. Meta-chloroperbenzoic acid and potassium fluoride are dissolved in an acetonitrile aqueous solution to obtain solution E. Under the protection of inert gas, solution B, solution C and solution D are sequentially added to a reactor at 20-30°C, and the reaction is carried out for 3-4 hours. After the reaction is completed, the reaction solution is filtered to obtain a filtrate, which is concentrated. Then, solution E is added to the concentrated solution at -5-5°C, and the reaction is carried out for 2-3 hours. After the reaction is completed, the reaction solution is distilled under reduced pressure, and the crude product is separated using a silica gel column to obtain the final product, N-trifluoromethylsulfonamide compound.

2. The synthesis method according to claim 1, wherein In step 1, the aromatic isothiocyanate is selected from isothiocyanatobenzene, 2-isothiocyanato-1,3-xylene, 1-chloro-4-isothiocyanatobenzene, 1-bromo-4-isothiocyanatobenzene or 1-isothiocyanato-3,5-dimethoxybenzene.

3. The synthesis method according to claim 1, wherein In step 1, the inert gas is nitrogen or argon.

4. The synthesis method according to claim 1, characterized in that In step 1, the washing times with anhydrous ether are more than two times.

5. The synthesis method according to claim 1, characterized in that In step 1, the molar ratio of the aromatic isothiocyanate to triethylsilane is 1:1.5, and the molar ratio of the aromatic isothiocyanate to silver fluoride is 1:

5.

6. The synthesis method according to claim 1, wherein In step 1, the concentration of the aromatic isothiocyanate in the mixed solution A is 0.2 mol / L.

7. The synthesis method according to claim 1, characterized in that In step 2, the molar ratio of the N-trifluoromethyl aromatic compound to p-methylphenylsulfonyl chloride is 1:1, the molar ratio of the N-trifluoromethyl aromatic compound to triethylamine is 1:1, the molar ratio of the N-trifluoromethyl aromatic compound to m-chloroperbenzoic acid is 1:4, and the molar ratio of the N-trifluoromethyl aromatic compound to potassium fluoride is 1:

4.

8. The synthesis method according to claim 1, characterized in that In step 2, the acetonitrile aqueous solution is acetonitrile containing 15% water.

9. The synthesis method according to claim 1, wherein In step 2, the concentration of the N-trifluoromethyl aromatic compound in the acetonitrile solution is 0.2 mol / L.

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