N-alkylation method of sulfonamide compound

Abstract

The invention discloses an N-alkylation method of a sulfonamide compound. The N-alkylation method comprises the following steps: mixing p-toluenesulfonic acid and trifluoroethanol for an in-situ reaction, and then adding an alcohol compound and a sulfonamide compound for a reaction to prepare an N-alkylated sulfonamide compound, so that N-alkylation of the sulfonamide compound is realized. According to the invention, a TsOH-TFEA cluster generated by TsOH and TFEA in situ is used as a catalyst, so that the selective N-alkylated sulfonamide compound is realized; meanwhile, the method provided by the invention has the advantages of simple reaction conditions, high yield, low raw material price, high atom economy, environment friendliness, safety in operation and the like.

Description

Technical Field

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

[0002] N-substituted sulfonamide compounds are an important class of organic synthesis intermediates with multiple biological activities and are widely used in pesticides, medicines, etc. Therefore, studying the synthesis of such compounds has important theoretical significance and practical value. For example, almotriptan, a selective 5-HT receptor agonist for the treatment of acute attacks of migraine (Mol. Diag. Ther. 2022, 16, 501-507; Expert Rev. Neurother. 2019, 19, 759-768); niraparib, a drug for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer (Targ. Oncol. 2018, 13, 533-539; Expert Rev. Anticanc. 2018, 18, 727-733), etc.

[0003] The traditional synthesis method of N-alkylsulfonamide compounds is mainly prepared by the substitution reaction of sulfonyl chloride and amine. This method has obvious shortcomings, such as the raw material sulfonyl chloride is unstable, easy to decompose, difficult to store, highly toxic, low selectivity, cumbersome operation steps, harsh conditions, etc., which greatly limits its applicability. Alcohol is a bulk chemical with stable properties, wide sources, low toxicity and easy to handle. In the cross-coupling reaction with another molecule, only water is produced as a by-product. It not only meets the requirements of green chemistry, but is also an ideal coupling reagent. The synthesis of N-alkylsulfonamides using alcohols as coupling reagents and sulfonamides is a synthetic method developed in recent years, such as: (1) transition metal-catalyzed hydrogen reduction strategy (Chem. Rev. 2018, 118, 1410-1459; Coord. Chem. Rev. 2017, 331, 1-36; Chem. Rev. 2010, 110, 681-703), which inevitably requires the use of transition metals such as palladium, ruthenium, iridium, and rhodium; (2) Lewis acid ((BiCl3, FeCl3, MoCl5, NaAuCl4, InBr3, Ca(NTf2)2, MoO2(acac)2) catalyzed nucleophilic substitution reaction (Chem. Commun. 2006, 31, 3352-3354; J. Org. Chem. 2006, 71, 8298-8301; Tetrahedron Lett.2007, 48, 7169-7172; Adv.Synth.Catal.2006, 348, 2063-2607; Eur.J.Org.Chem.2007, 2007, 2248-2253; Adv.Synth.Catal.2011, 353, 469-474; Eur. J. Org. Chem. 2009, 2009, 666-672; J. Org. Chem. 2003, 68, 9340-9347; Angew. Edron Lett. 2007, 48, 8174-8177), this type of method often uses metal Lewis acid as a catalyst, and inevitably has self-coupling byproducts; in addition, there is (3) ionic liquid (Adv. Synth. Catal. 2012, 354, 1052-1060; Green Chem. 2011, 13, 1244-1250) and the like to promote the coupling of alcohol and sulfonamide, but these methods also have the disadvantages of long reaction time and high reaction temperature. Therefore, it is an urgent problem to provide a new method for N-alkylation of sulfonamide with mild reaction conditions, simple operation, high efficiency and green environmental protection. Summary of the invention

[0004] The main purpose of the present invention is to provide a method for N-alkylation of sulfonamide compounds to overcome the deficiencies of the prior art.

[0005] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention includes:

[0006] The embodiment of the present invention provides a method for N-alkylation of sulfonamide compounds, which comprises: mixing p-toluenesulfonic acid and trifluoroethanol to react in situ, then adding an alcohol compound and a sulfonamide compound to react, to obtain an N-alkylated sulfonamide compound, thereby achieving N-alkylation of the sulfonamide compound. The method uses p-toluenesulfonic acid-trifluoroethanol cluster (TsOH-TFEA cluster) generated in situ by p-toluenesulfonic acid (TsOH) and trifluoroethanol (TFEA) as a catalyst, which can well stabilize the carbon cation formed by dehydroxylation of common aromatic alcohols, so as to help achieve nucleophilic substitution of sulfonamide.

[0007] Compared with the prior art, the present invention has the following beneficial effects:

[0008] (1) The present invention uses aromatic alcohol as raw material and TsOH-TFEA cluster generated in situ by TsOH and TFEA as catalyst to achieve selective N-alkylation of sulfonamide compounds; at the same time, the method provided by the present invention can react at room temperature, the reaction conditions are simple, the operation is safe and simple, all raw materials are cheap and easy to obtain, the reaction yield is high, the compatibility with functional groups is high, and the adaptability to substrates is wide;

[0009] (2) The method provided by the present invention realizes simple and efficient N-alkylation of sulfonamide compounds, with a yield of up to 99%. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0011] Figure 1 is the hydrogen spectra of the products obtained in Examples 1-6 and Comparative Examples 1-3;

[0012] Figure 2 is the carbon spectrum of the products obtained in Examples 1-6 and Comparative Examples 1-3;

[0013] Figure 3 is the hydrogen spectrum of the product obtained in Example 7;

[0014] Figure 4 is the carbon spectrum of the product obtained in Example 7;

[0015] Figure 5 is the hydrogen spectrum of the product obtained in Example 8;

[0016] Figure 6 is the carbon spectrum of the product obtained in Example 8;

[0017] Figure 7 is the hydrogen spectrum of the product obtained in Example 9;

[0018] Figure 8 is the carbon spectrum of the product obtained in Example 9;

[0019] Fig. 9 is the hydrogen spectrum of the product obtained in Example 10;

[0020] Fig.10 is the carbon spectrum of the product obtained in Example 10;

[0021] Fig.11 is the hydrogen spectrum of the product obtained in Example 11;

[0022] Fig.12 is the carbon spectrum of the product obtained in Example 11;

[0023] Fig.13 is the hydrogen spectrum of the product obtained in Example 12;

[0024] Fig.14 is the carbon spectrum of the product obtained in Example 12;

[0025] Fig.15 is the hydrogen spectrum of the product obtained in Example 13;

[0026] Fig.16 is the carbon spectrum of the product obtained in Example 13;

[0027] Fig.17 is the hydrogen spectrum of the product obtained in Example 14;

[0028] Fig.18 is the carbon spectrum of the product obtained in Example 14;

[0029] Fig.19 is the hydrogen spectrum of the product obtained in Example 15;

[0030] Fig. 20 is the carbon spectrum of the product obtained in Example 15;

[0031] Fig.21 is the hydrogen spectrum of the product obtained in Example 16;

[0032] Fig. 22 is the carbon spectrum of the product obtained in Example 16;

[0033] Fig.23is the hydrogen spectrum of the product obtained in Example 17;

[0034] Fig.24 is the carbon spectrum of the product obtained in Example 17;

[0035] Fig.25 is the hydrogen spectrum of the product obtained in Example 18;

[0036] Fig.26 is the carbon spectrum of the product obtained in Example 18;

[0037] Fig. 27 is the hydrogen spectrum of the product obtained in Example 19;

[0038] Fig.28 is the carbon spectrum of the product obtained in Example 19;

[0039] Fig.29 is the hydrogen spectrum of the product obtained in Example 20;

[0040] Fig.30 is the carbon spectrum of the product obtained in Example 20;

[0041] Fig.31 is the hydrogen spectrum of the product obtained in Example 21;

[0042] Fig.32 is the carbon spectrum of the product obtained in Example 21;

[0043] Fig.33 This is the 1H NMR monitoring diagram after adding TFEA to TsOH in Example 1. DETAILED DESCRIPTION

[0044] In view of the defects of the prior art, the inventors of this case have proposed the technical solution of the present invention after long-term research and extensive practice. It provides alcohol (aromatic alcohol, diaryl methanol compounds) as electrophilic reagents, sulfonamide as nucleophilic reagents, and TsOH-TFEA clusters generated in situ by TsOH and TFEA as catalysts to achieve N-alkylation of sulfonamide. This method has the advantages of simple reaction conditions, good yield, low raw material price, high atom economy, green environmental protection, safe operation, etc.

[0045] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0046] Specifically, as one aspect of the technical solution of the present invention, a method for N-alkylation of a sulfonamide compound involves: mixing p-toluenesulfonic acid and trifluoroethanol to react in situ, and then adding an alcohol compound and a sulfonamide compound to react to obtain an N-alkylated sulfonamide compound, thereby achieving N-alkylation of the sulfonamide compound.

[0047] In some preferred embodiments, the N-alkylation method specifically comprises: mixing p-toluenesulfonic acid and trifluoroethanol and reacting them in situ at room temperature for 5 to 10 minutes to obtain a p-toluenesulfonic acid-trifluoroethanol cluster;

[0048] Furthermore, an alcohol compound, a sulfonamide compound and the p-toluenesulfonic acid-trifluoroethanol cluster are mixed and stirred for reaction at 10-80° C., and then post-treated to obtain an N-alkylated sulfonamide compound.

[0049] In some preferred embodiments, the alcohol compound includes an aromatic alcohol compound; preferably, the aromatic alcohol compound includes any one or more combinations of benzhydrol, 4,4'-dimethylbenzhydrol, 4,4'-dimethoxybenzhydrol, 4,4'-difluorobenzhydrol, di(naphthalene-1-yl)methanol, 4-methylbenzhydrol, 4-bromobenzhydrol, 4-methylbenzhydrol, benzyl alcohol, 1-phenyl-1-propanol, 1-phenyl-1-butanol, and 1-(4-methylphenyl)ethanol, and is not limited thereto.

[0050] In some preferred embodiments, the sulfonamide compounds include benzenesulfonamide, 2-methylbenzenesulfonamide, 4-methylbenzenesulfonamide, 4-ethylbenzenesulfonamide, 4-hydroxybenzenesulfonamide, 4-methoxybenzenesulfonamide, 4-tert-butylbenzenesulfonamide, 4-fluorobenzenesulfonamide, 4-chlorobenzenesulfonamide, 3-bromobenzenesulfonamide, 4-trifluoromethylbenzenesulfonamide, 4-cyanobenzenesulfonamide, 4-cyanobenzenesulfonamide, 4-vinylbenzenesulfonamide, 4-acetylbenzenesulfonamide, N-methylbenzenesulfonamide, Any one or more combinations of N-methyl toluenesulfonamide, naphthalene-2-sulfonamide, 6-chloro-3-sulfapyridine, 2-thiophenesulfonamide, 5-chlorothiophene-2-sulfonamide, 5-bromothiophene-2-sulfonamide, methanesulfonamide, ethylsulfonamide, isopropylsulfonamide, tert-butylsulfonamide, n-propylsulfonamide, n-hexylsulfonamide, cyclopropanesulfonamide, ethylenesulfonamide, benzylsulfonamide, methanesulfonylmethylamine, 1,1-dioxoisothiazole, and 1,4-butanesulfonam, and are not limited thereto.

[0051] In some preferred embodiments, the molar ratio of p-toluenesulfonic acid to the alcohol compound is 0.2:1; the molar volume ratio of the alcohol compound to trifluoroethanol is 0.1-0.5 mol:1L.

[0052] In some preferred embodiments, the molar ratio of the sulfonamide compound to the alcohol compound is 1-2:1.

[0053] In some preferred embodiments, the stirring reaction time is 1 to 5 hours.

[0054] In some preferred embodiments, the stirring reaction is carried out at a stirring rate of 10 to 200 rpm.

[0055] In some preferred embodiments, the post-treatment includes: cooling, concentrating and purifying the obtained product after the stirring reaction is completed.

[0056] Furthermore, column chromatography is used for purification; wherein the column chromatography uses an eluent which is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of petroleum ether to ethyl acetate is 5 to 3:1.

[0057] In some more specific embodiments, the N-alkylation method of the sulfonamide compound of the present invention comprises: providing an alcohol compound as an electrophilic reagent, a sulfonamide compound as a nucleophilic reagent, and using a TsOH-TFEA cluster generated in situ by TsOH and TFEA as a catalyst to achieve N-alkylation of the sulfonamide compound. The specific reaction formula is shown below:

[0058]

[0059] Among them, R 1 , R 2 , R 3 , R 4 There are three situations:

[0060] (1)R 1 =Ph, R 2 =Ph, R 4 =H or Me, R 3 =Ph, 2-Me-Ph, 4-Me-Ph, 4-Et-Ph, 4-OH-Ph, 4-OMe-Ph, 4-tBu-Ph, 4-F-Ph, 4-C1-Ph, 3-Br-Ph, 4-CF3-Ph, 4-CN-Ph, 3-CN-Ph, 4-ethenyl-Ph, 4-acetyl-Ph;

[0061] (2)R 1 =Ph, R 2 =Ph, R 4 =H, R 3=5-(2-Cl-pyridyl), 2-thienyl, 2-(5-Cl-thienyl), 2-(5-Br-thienyl), 2-naphthyl, Me, Et, iPr, tBu, n-propyl, n-hexyl, cyclopropanyl, ethenyl, benzyl;

[0062] (3)R 1 , R 2 =4-Me-Ph; R 1 , R 2 =4-OMe-Ph; R 1 , R 2 =4-F-Ph; R 1 , R 2 =1-naphthyl;

[0063] R 1 =4-Me-Ph, R 2 =Ph; R 1 =4-Br-Ph, R 2 =Ph; R 1 =1-naphthyl, R 2 =Me;

[0064] R 1 =Ph, R 2 =Me; R1 = Ph, R 2 =Et; R 1 =Ph, R 2 =n-propyl; R 1 =4-Me-Ph, R 2 =Me;

[0065] R 3 =Ph, R 4 =H.

[0066] The technical solution of the present invention is further described in detail below in conjunction with several preferred embodiments and drawings. This embodiment is implemented on the premise of the technical solution of the invention, and a detailed implementation method and specific operation process are given, but the protection scope of the present invention is not limited to the following embodiments.

[0067] Unless otherwise specified, the experimental materials used in the following examples can be purchased from conventional biochemical reagent companies.

[0068] The selectivity of para-alkylation in the products of all the following examples was 100%.

[0069] Comparative Example 1

[0070] In a 25 mL reaction tube, add 17.2 mg of p-toluenesulfonic acid and 2.0 mL of water, shake at room temperature for 5 minutes, then add 0.5 mmol of benzhydrol and 1.0 mmol of benzsulfamide. Stir the reaction at 80 °C in air for 12 hours, stop heating and stirring, cool to room temperature, and distill under reduced pressure to obtain a crude product. Separate and purify by column chromatography to obtain the target product. The column chromatography eluent used is petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 8%.

[0071] The structural characterization data of the product obtained in Comparative Example 1 are as follows ( Figure 1 and Figure 2 shown):

[0072] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=7.8Hz, 2H), 7.44 (t, J=7.4Hz, 1H), 7.30 (dd, J=11.6, 4. 6Hz, 2H), 7.22-7.14 (m, 6H), 7.09 (dd, J=7.2, 3.0Hz, 4H), 5.58 (dd, J=19.0, 7.6Hz, 2H).

[0073] 13 C NMR (100MHz, CDCl3) δ140.3, 140.2, 132.3, 128.7, 128.5, 127.5, 127.3, 127.0, 61.3.

[0074] The structure of the product deduced from the above data is as follows:

[0075]

[0076] Comparative Example 2

[0077] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of acetonitrile were added, and the mixture was shaken at room temperature for 5 minutes, followed by the addition of 0.5 mmol of benzhydrol and 1.0 mmol of benzsulfamide. The mixture was stirred at 80°C in air for 12 hours, and then the heating and stirring were stopped. The mixture was cooled to room temperature and distilled under reduced pressure to obtain a crude product. The crude product was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, and the yield was 60%.

[0078] The structural characterization data of the product obtained in Comparative Example 2 are as follows ( Figure 1 and Figure 2 shown):

[0079] 1H NMR(400MHz, CDCl3)δ 7.66 (d, J=7.8Hz, 2H), 7.44 (t, J=7.4Hz, IH), 7.30 (dd, J=11.6, 4.6Hz, 2H), 7 .22-7.14 (m, 6H), 7.09 (dd, J=7.2, 3.0Hz, 4H), 5.58 (dd, J=19.0, 7.6Hz, 2H).

[0080] 13 C NMR (100MHz, CDCl3) δ140.3, 140.2, 132.3, 128.7, 128.5, 127.5, 127.3, 127.0, 61.3.

[0081] The structure of the product deduced from the above data is as follows:

[0082]

[0083] Comparative Example 3

[0084] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of p-xylene were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 1.0 mmol of benzsulfamide were added. After stirring at 80°C for 12 hours in air, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 57%.

[0085] The structural characterization data of the product obtained in Comparative Example 3 are as follows ( Figure 1 and Figure 2 shown):

[0086] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=7.8Hz, 2H), 7.44 (t, J=7.4Hz, IH), 7.30 (dd, J=11.6, 4. 6Hz, 2H), 7.22-7.14 (m, 6H), 7.09 (dd, J=7.2, 3.0Hz, 4H), 5.58 (dd, J=19.0, 7.6Hz, 2H).

[0087] 13 C NMR (100MHz, CDCl3) δ140.3, 140.2, 132.3, 128.7, 128.5, 127.5, 127.3, 127.0, 61.3.

[0088] The structure of the product deduced from the above data is as follows:

[0089]

[0090] Example 1

[0091] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 1.0 mmol of benzsulfamide were added. After stirring at 80°C for 12 hours in air, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 90%.

[0092] In this example, in order to verify the interaction between TFEA and TsOH, TFEA was added to TsOH and 1 H NMR monitoring, such as Fig.33 As shown in Figure 3, the exchange protons between TsOH and TFEA move more and more upfield with the increase of TFEA concentration. These results indicate that TsOH and TFEA can interact in any ratio to form corresponding TsOH-TFEA clusters.

[0093] The structural characterization data of the product obtained in Example 1 are as follows ( Figure 1 and Figure 2 shown):

[0094] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=7.8Hz, 2H), 7.44 (t, J=7.4Hz, 1H), 7.30 (dd, J=11.6, 4. 6Hz, 2H), 7.22-7.14 (m, 6H), 7.09 (dd, J=7.2, 3.0Hz, 4H), 5.58 (dd, J=19.0, 7.6Hz, 2H).

[0095] 13 C NMR (100MHz, CDCl3) δ140.3, 140.2, 132.3, 128.7, 128.5, 127.5, 127.3, 127.0, 61.3.

[0096] The structure of the product deduced from the above data is as follows:

[0097]

[0098] Example 2

[0099] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of benzsulfamide were added. After stirring at 80°C for 12 hours under air, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 93%.

[0100] The structural characterization data of the product obtained in Example 2 are as follows ( Figure 1 and Figure 2 shown):

[0101] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=7.8Hz, 2H), 7.44 (t, J=7.4Hz, 1H), 7.30 (dd, J=11.6, 4. 6Hz, 2H), 7.22-7.14 (m, 6H), 7.09 (dd, J=7.2, 3.0Hz, 4H), 5.58 (dd, J=19.0, 7.6Hz, 2H).

[0102] 13 C NMR (100MHz, CDCl3) δ140.3, 140.2, 132.3, 128.7, 128.5, 127.5, 127.3, 127.0, 61.3.

[0103] The structure of the product deduced from the above data is as follows:

[0104]

[0105] Example 3

[0106] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of benzsulfamide were added. After stirring at 80°C in air for 0.5 hour, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 81%.

[0107] The structural characterization data of the product obtained in Example 3 are as follows ( Figure 1 and Figure 2 shown):

[0108] 1H NMR (400MHz, CDCl3) δ7.66 (d, J=7.8Hz, 2H), 7.44 (t, J=7.4Hz, 1H), 7.30 (dd, J=11.6, 4. 6Hz, 2H), 7.22-7.14 (m, 6H), 7.09 (dd, J=7.2, 3.0Hz, 4H), 5.58 (dd, J=19.0, 7.6Hz, 2H).

[0109] 13 C NMR (100MHz, CDCl3) δ140.3, 140.2, 132.3, 128.7, 128.5, 127.5, 127.3, 127.0, 61.3.

[0110] The structure of the product deduced from the above data is as follows:

[0111]

[0112] Example 4

[0113] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of benzsulfamide were added. After stirring at 80°C for 1 hour under air, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 84%.

[0114] The structural characterization data of the product obtained in Example 4 are as follows ( Figure 1 and Figure 2 shown):

[0115] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=7.8Hz, 2H), 7.44 (t, J=7.4Hz, 1H), 7.30 (dd, J=11.6, 4. 6Hz, 2H), 7.22-7.14 (m, 6H), 7.09 (dd, J=7.2, 3.0Hz, 4H), 5.58 (dd, J=19.0, 7.6Hz, 2H).

[0116] 13 C NMR (100MHz, CDCl3) δ 140.3, 140.2, 132.3, 128.7, 128.5, 127.5, 127.3, 127.0, 61.3.

[0117] The structure of the product deduced from the above data is as follows:

[0118]

[0119] Example 5

[0120] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added, and the mixture was shaken at room temperature for 5 minutes, followed by the addition of 0.5 mmol of benzhydrol and 0.7 mmol of benzsulfamide. The mixture was stirred at 80°C in air for 2 hours, and then the heating and stirring were stopped. The mixture was cooled to room temperature and distilled under reduced pressure to obtain a crude product. The crude product was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, and the yield was 90%.

[0121] The structural characterization data of the product obtained in Example 5 are as follows ( Figure 1 and Figure 2 shown):

[0122] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=7.8Hz, 2H), 7.44 (t, J=7.4Hz, 1H), 7.30 (dd, J=11.6, 4. 6Hz, 2H), 7.22-7.14 (m, 6H), 7.09 (dd, J=7.2, 3.0Hz, 4H), 5.58 (dd, J=19.0, 7.6Hz, 2H).

[0123] 13 C NMR (100MHz, CDCl3) δ 140.3, 140.2, 132.3, 128.7, 128.5, 127.5, 127.3, 127.0, 61.3.

[0124] The structure of the product deduced from the above data is as follows:

[0125]

[0126] Example 6

[0127] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of benzsulfamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 92%.

[0128] The structural characterization data of the product obtained in Example 6 are as follows ( Figure 1 and Figure 2 shown):

[0129] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=7.8Hz, 2H), 7.44 (t, J=7.4Hz, 1H), 7.30 (dd, J=11.6, 4. 6Hz, 2H), 7.22-7.14 (m, 6H), 7.09 (dd, J=7.2, 3.0Hz, 4H), 5.58 (dd, J=19.0, 7.6Hz, 2H).

[0130] 13 C NMR (100MHz, CDCl3) δ 140.3, 140.2, 132.3, 128.7, 128.5, 127.5, 127.3, 127.0, 61.3.

[0131] The structure of the product deduced from the above data is as follows:

[0132]

[0133] Example 7

[0134] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of p-toluenesulfonamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 92%.

[0135] The structural characterization data of the product obtained in Example 7 are as follows ( Figure 3 and Figure 4 shown):

[0136] 1 H NMR (400MHz, CDCl3) δ7.55-7.52 (m, 2H), 7.18-7.14 (m, 6H), 7.11-7.06 (m, 6H), 5.69 (d, J=7.7Hz, 1H), 5.56 (d, J=7.7Hz, 1H), 2.33 (s, 3H).

[0137] 13 C NMR (100MHz, CDCl3) δ143.0, 140.5, 137.3, 129.2, 128.4, 127.4, 127.3, 127.1, 61.2, 21.4.

[0138] The structure of the product deduced from the above data is as follows:

[0139]

[0140] Example 8

[0141] In a 25 mL reaction tube, add 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol. After shaking at room temperature for 5 minutes, add 0.5 mmol of benzhydrol and 0.7 mmol of p-cyanobenzenesulfonamide. After stirring at room temperature under air for 2 hours, stop heating and stirring, cool to room temperature, and distill under reduced pressure to obtain a crude product. Then, separate and purify by column chromatography to obtain the target product. The column chromatography eluent used is petroleum ether / ethyl acetate in a ratio of 3:1, with a yield of 80%.

[0142] The structural characterization data of the product obtained in Example 8 are as follows ( Figure 5 and Figure 6 shown):

[0143] 1 H NMR (400MHz, CDCl3) δ7.69-7.62 (m, 2H), 7.57-7.48 (m, 2H), 7.23-7.14 (m, 6H), 7.12-7.02 (m, 4H), 5.80 (d, J=7.9Hz, 1H), 5.67 (d, J=8.0Hz, 1H).

[0144] 13 C NMR (100MHz, CDCl3) δ144.6, 139.5, 132.3, 128.6, 127.9, 127.6, 127.3, 117.3, 115.7, 61.6.

[0145] The structure of the product deduced from the above data is as follows:

[0146]

[0147] Example 9

[0148] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of 4-vinylbenzenesulfonamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 86%.

[0149] The structural characterization data of the product obtained in Example 9 are as follows ( Figure 7 and Figure 8 shown):

[0150] 1 H NMR (400MHz, CDCl3) δ7.59 (d, J=8.4Hz, 2H), 7.34-7.25 (m, 2H), 7.17 (qd, J=4.1, 1.5Hz, 6H), 7.11-7.0 8 (m, 4H), 6.67 (dd, J=17.6, 10.9Hz, 1H), 5.80 (d, J=17.5Hz, 1H), 5.59 (s, 2H), 5.38 (d, J=10.9Hz, 1H).

[0151] 13 C NMR (100MHz, CDCl3) δ141.4, 140.4, 139.1, 135.4, 128.5, 127.5, 127.4, 127.3, 126.3, 117.1, 61.3.

[0152] The structure of the product deduced from the above data is as follows:

[0153]

[0154] Example 10

[0155] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of naphthalene-2-sulfonamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 82%.

[0156] The structural characterization data of the product obtained in Example 10 are as follows ( Fig. 9 and Fig.10 shown):

[0157] 1 H NMR (400MHz, CDCl3) δ8.21 (d, J=8.7Hz, IH), 7.88-7.73 (m, 3H), 7.68-7.52 (m, 3H), 7.11 (d, J=1.4Hz, 10H), 5.65 (s, 1H), 5.53 (d, J=7.4Hz, 1H).

[0158] 13 C NMR (100MHz, CDCl3) δ140.3, 137.1, 134.6, 131.9, 129.2, 129.1, 128.6, 128.6, 128.5, 127.7, 127.6, 127.3, 127.2, 122.2, 61.47.

[0159] The structure of the product deduced from the above data is as follows:

[0160]

[0161] Embodiment 11

[0162] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of N-methylbenzenesulfonamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 84%.

[0163] The structural characterization data of the product obtained in Example 11 are as follows ( Fig.11 and Fig.12 shown):

[0164] 1 H NMR (400MHz, CDCl3) δ7.73 (dd, J=7.8, 1.6Hz, 2H), 7.54-7.49 (m, 1H), 7.43-7.39 ( m, 2H), 7.27-7.22 (m, 6H), 7.07 (dd, J=6.8, 2.9Hz, 4H), 6.47 (s, 1H), 2.70 (s, 3H).

[0165] 13 C NMR (100MHz, CDCl3) δ139.8, 138.2, 132.3, 128.8, 128.7, 128.3, 127.6, 127.1, 64.2, 31.2.

[0166] The structure of the product deduced from the above data is as follows:

[0167]

[0168] Example 12

[0169] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added, and the mixture was shaken at room temperature for 5 minutes, followed by the addition of 0.5 mmol of benzhydrol and 0.7 mmol of 2-thiophenesulfonamide. The mixture was stirred at room temperature under air for 2 hours, and then the heating and stirring were stopped. The mixture was cooled to room temperature and distilled under reduced pressure to obtain a crude product. The crude product was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, and the yield was 96%.

[0170] The structural characterization data of the product obtained in Example 12 are as follows ( Fig.13 and Fig.14 shown):

[0171] 1 H NMR (400MHz, CDCl3) δ7.45 (dd, J=5.0, 1.4Hz, IH), 7.37 (dd, J=3.7, 1.4Hz, 1H), 7.26-7.20 (m, 6H ), 7.16-7.11 (m, 4H), 6.89 (dd, J=5.0, 3.8Hz, 1H), 5.66 (d, J=7.5Hz, 1H), 5.44 (d, J=7.5Hz, 1H).

[0172] 13 C NMR (100MHz, CDCl3) δ141.3, 140.2, 132.5, 131.9, 128.6, 127.7, 127.3, 127.1, 61.6.

[0173] The structure of the product deduced from the above data is as follows:

[0174]

[0175] Example 13

[0176] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of isopropylsulfonamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 90%.

[0177] The structural characterization data of the product obtained in Example 13 are as follows ( Fig.15 and Fig.16 shown):

[0178] 1 H NMR (400MHz, CDCl3) δ7.36-7.31 (m, 6H), 7.30-7.25 (m, 4H), 5.74 (d, J = 8.1Hz, 1H), 5.09 (d, J = 8.1Hz, 1H), 2.84 (hept, J = 6.8Hz, 1H), 1.20 (d, J = 6.8Hz, 6H).

[0179] 13C NMR (100MHz, CDCl3) δ141.3, 128.7, 127.8, 127.4, 61.2, 54.1, 16.3.

[0180] The structure of the product deduced from the above data is as follows:

[0181]

[0182] Embodiment 14

[0183] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of ciprosulfonamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 96%.

[0184] The structural characterization data of the product obtained in Example 14 are as follows ( Fig.17 and Fig.18 shown):

[0185] 1 H NMR (400MHz, CDCl3) δ7.37-7.29 (m, 8H), 7.26 (ddd, J=5.6, 3.7, 2.4Hz, 3H), 5.72 (d, J=8.1Hz, 1H), 5.49 (d, J=8.1Hz, 1H), 2.02 (tt, J=8.0, 4.8Hz, 1H), 1.02-0.93 (m, 2H), 0.63 (qd, J=5.6, 1.1Hz, 2H).

[0186] 13 C NMR (100MHz, CDCl3) δ 141.2, 128.6, 127.7, 127.4, 61.2, 31.4, 5.8.

[0187] The structure of the product deduced from the above data is as follows:

[0188]

[0189] Embodiment 15

[0190] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of ethylenesulfonamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 87%.

[0191] The structural characterization data of the product obtained in Example 15 are as follows ( Fig.19 and Fig. 20 shown):

[0192] 1 H NMR (400MHz, CDCl3) δ7.34-7.24 (m, 10H), 6.21 (dd, JJ=16.5, 9.8Hz, 1H), 6.05 (d, J=16.5Hz, 1H), 5.64 (dd, J=11.2, 8.9Hz, 2H), 5.44 (d, J=8.1Hz, 1H).

[0193] 13 C NMR (100MHz, CDCl3) δ140.7, 136.5, 128.7, 127.8, 127.1, 126.0, 61.1.

[0194] The structure of the product deduced from the above data is as follows:

[0195]

[0196] Example 16

[0197] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of methanesulfonylamine were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 89%.

[0198] The structural characterization data of the product obtained in Example 16 are as follows ( Fig.21 and Fig. 22 shown):

[0199] 1 H NMR (400MHz, CDCl3) δ7.41-7.33(m, 5H), 7.31-7.25(m, 4H), 6.40(s, 1H), 2.76(s, 3H), 2.66(s, 3H).

[0200] 13 C NMR (100MHz, CDCl3) δ137.8, 128.7, 128.6, 127.9, 64.3, 38.1, 30.6.

[0201] The structure of the product deduced from the above data is as follows:

[0202]

[0203] Embodiment 17

[0204] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of benzhydrol and 0.7 mmol of 1,1-dioxoisothiazole were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, and the yield was 85%.

[0205] The structural characterization data of the product obtained in Example 17 are as follows ( Fig.23 and Fig.24 shown):

[0206] 1 H NMR (400MHz, CDCl3) δ7.37-7.28 (m, 10H), 6-01 (s, IH), 3.12 (dt, J=12.4, 7.1Hz, 4H), 2.32-2.24 (m, 2H).

[0207] 13 CNMR (100MHz, CDCl3) δ 138.7, 128.6, 128.4, 127.7, 60.8, 47.2, 43.6, 18.9.

[0208] The structure of the product deduced from the above data is as follows:

[0209]

[0210] Embodiment 18

[0211] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added, and the mixture was shaken at room temperature for 5 minutes. Then, 0.5 mmol of 1-(2-naphthyl)ethanol and 0.7 mmol of naphthalene-2-sulfonamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, and the yield was 99%.

[0212] The structural characterization data of the product obtained in Example 18 are as follows ( Fig.25 and Fig.26 shown):

[0213] 1 H NMR(400MHz, CDCl3)δ 7.72 (dd, J=8.3, 1.4Hz, 2H), 7.50-7.44 (m, 1H), 7.37 (dd, J=10.9, 4.7Hz, 2H), 7.16 (dt, J=4.8, 2. 4Hz, 3H), 7.11-7.06 (m, 2H), 5.26 (d, J=7.2Hz, 1H), 4.49 (p, J=6.9Hz, 1H), 1.42 (d, J=6.9Hz, 3H).

[0214] 13 C NMR (100MHz, CDCl3) δ 141.8, 140.5, 132.3, 128.8, 128.5, 127.4, 127.0, 126.0, 53.7, 23.6.

[0215] The structure of the product deduced from the above data is as follows:

[0216]

[0217] Embodiment 19

[0218] In a 25 mL reaction tube, add 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol. After shaking at room temperature for 5 minutes, add 0.5 mmol of 1-phenyl-1-butanol and 0.7 mmol of naphthalene-2-sulfonamide. After stirring at room temperature under air for 2 hours, stop heating and stirring, cool to room temperature, and distill under reduced pressure to obtain a crude product. Then, separate and purify by column chromatography to obtain the target product. The column chromatography eluent used is petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 81%.

[0219] The structural characterization data of the product obtained in Example 19 are as follows ( Fig. 27 and Fig.28 shown):

[0220] 1H NMR (400MHz, CDCl3) δ7.64 (dt, J=8.4, 1.4Hz, 2H), 7.41 (dd, J=10.5, 4.4Hz, 1H), 7.32-7.26 (m, 2H), 7.15-7.08 (m, 3H), 7.0 2-6.95 (m, 2H), 5.25 (d, J=7.6Hz, 1H), 4.30 (q, J=6.2Hz, 1H), 1.73-1.58 (m, 2H), 1.34-1.22 (m, 2H), 0.82 (t, J=7.3Hz, 3H).

[0221] 13 C NMR (100MHz, CDCl3) δ 140.8, 140.6, 132.2, 128.7, 128.4, 127.4, 126.97, 126.5, 58.2, 39.8, 19.1, 13.6.

[0222] The structure of the product deduced from the above data is as follows:

[0223]

[0224] Embodiment 20

[0225] In a 25 mL reaction tube, 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added. After shaking at room temperature for 5 minutes, 0.5 mmol of 1-(4-methoxyphenyl)ethanol and 0.7 mmol of naphthalene-2-sulfonamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, with a yield of 83%.

[0226] The structural characterization data of the product obtained in Example 20 are as follows ( Fig.29 and Fig.30 shown):

[0227] 1 H NMR(400MHz, CDCl3)δ 7.73 (ddd, J=4.0, 2.1, 1.1Hz, 2H), 7.49-7.42 (m, 1H), 7.34 (dd, J=10.6, 4.8Hz, 2H), 7.19-7.12 (m, 3H), 7.11-7.00 (m, 3H), 5.49 (d, J=7.3Hz, 1H), 4.48 (p, J=7.0Hz, 1H), 1.41 (dd, J=7.0, 0.8Hz, 3H).

[0228] 13C NMR (100MHz, CDCl3) δ141.8, 140.5, 132.2, 128.7, 128.4, 127.3, 126.9, 126.0, 53.7, 23.5.

[0229] The structure of the product deduced from the above data is as follows:

[0230]

[0231] Embodiment 21

[0232] 17.2 mg of p-toluenesulfonic acid and 2.0 mL of trifluoroethanol were added to a 25 mL reaction tube. After shaking at room temperature for 5 minutes, 0.5 mmol of 4-bromobenzhydrol and 0.7 mmol of naphthalene-2-sulfonamide were added. After stirring at room temperature under air for 2 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. The crude product was distilled under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was petroleum ether / ethyl acetate in a ratio of 5:1, and the yield was 82%.

[0233] The structural characterization data of the product obtained in Example 21 are as follows ( Fig.31 and Fig.32 shown):

[0234] 1 H NMR (400MHz, CDCl3) δ7.69-7.62 (m, 2H), 7.47 (dd, J=10.7, 4.3Hz, 1H), 7.38-7.27 (m, 4H), 7.22- 7.15 (m, 3H), 7.08-7.01 (m, 2H), 7.01-6.97 (m, 2H), 5.69 (d, J = 7.6Hz, 1H), 5.54 (d, J = 7.6Hz, 1H).

[0235] 13 C NMR (100MHz, CDCl3) δ140.0, 139.7, 139.4, 132.5, 131.5, 129.0, 128.8, 128.7, 127.8, 127.2, 127.0, 121.5, 60.8.

[0236] The structure of the product deduced from the above data is as follows:

[0237]

[0238] In addition, the inventors of this case also referred to the aforementioned embodiments and conducted experiments with other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0239] It should be understood that the technical solution of the present invention is not limited to the above-mentioned specific implementation cases. Any technical deformation made according to the technical solution of the present invention without departing from the scope of protection of the purpose of the present invention and the claims shall fall within the protection scope of the present invention.

Claims

1. A method for N-alkylation of sulfonamide compounds, characterized in that: include: p-Toluenesulfonic acid and trifluoroethanol are mixed to react in situ, and then an alcohol compound and a sulfonamide compound are added to react to obtain an N-alkylated sulfonamide compound, thereby achieving N-alkylation of the sulfonamide compound.

2. The N-alkylation method according to claim 1, characterized in that Specifically include: The p-toluenesulfonic acid and trifluoroethanol are mixed and reacted in situ at room temperature for 5 to 10 minutes to obtain a p-toluenesulfonic acid-trifluoroethanol cluster; and an alcohol compound and a sulfonamide compound are mixed with the p-toluenesulfonic acid-trifluoroethanol cluster and stirred at 10 to 80° C. for reaction, followed by post-treatment to obtain an N-alkylated sulfonamide compound.

3. The N-alkylation method according to claim 1 or 2, characterized in that: The alcohol compound includes an aromatic alcohol compound; preferably, the aromatic alcohol compound includes any one or more combinations of benzhydrol, 4,4′-dimethylbenzhydrol, 4,4′-dimethoxybenzhydrol, 4,4′-difluorobenzhydrol, di(naphthalene-1-yl)methanol, 4-methylbenzhydrol, 4-bromobenzhydrol, 4-methylbenzhydrol, benzyl alcohol, 1-phenyl-1-propanol, 1-phenyl-1-butanol, and 1-(4-methylphenyl)ethanol.

4. The N-alkylation method according to claim 1 or 2, characterized in that: The sulfonamide compounds include benzenesulfonamide, 2-methylbenzenesulfonamide, 4-methylbenzenesulfonamide, 4-ethylbenzenesulfonamide, 4-hydroxybenzenesulfonamide, 4-methoxybenzenesulfonamide, 4-tert-butylbenzenesulfonamide, 4-fluorobenzenesulfonamide, 4-chlorobenzenesulfonamide, 3-bromobenzenesulfonamide, 4-trifluoromethylbenzenesulfonamide, 4-cyanobenzenesulfonamide, 4-cyanobenzenesulfonamide, 4-vinylbenzenesulfonamide, 4-acetylbenzenesulfonamide, N-methylbenzenesulfonamide, N- Any one or more combinations of methyl toluenesulfonamide, naphthalene-2-sulfonamide, 6-chloro-3-sulfapyridine, 2-thiophenesulfonamide, 5-chlorothiophene-2-sulfonamide, 5-bromothiophene-2-sulfonamide, methanesulfonamide, ethylsulfonamide, isopropylsulfonamide, tert-butylsulfonamide, n-propylsulfonamide, n-hexylsulfonamide, cyclopropanesulfonamide, ethylenesulfonamide, benzylsulfonamide, methanesulfonylmethylamide, 1,1-dioxoisothiazole, and 1,4-butanesulfonam.

5. The N-alkylation method according to claim 1 or 2, characterized in that: The molar ratio of the p-toluenesulfonic acid to the alcohol compound is 0.2:1; the molar volume ratio of the alcohol compound to trifluoroethanol is 0.1-0.5 mol:1L.

6. The N-alkylation method according to claim 1 or 2, characterized in that: The molar ratio of the sulfonamide compound to the alcohol compound is 1-2:

1.

7. The N-alkylation method according to claim 2, characterized in that: The stirring reaction time is 1 to 5 hours.

8. The N-alkylation method according to claim 2, characterized in that: The stirring reaction is carried out at a stirring rate of 10 to 200 rpm.

9. The N-alkylation method according to claim 2, characterized in that: The post-treatment includes: cooling, concentrating and purifying the obtained product after the stirring reaction is completed.

10. The N-alkylation method according to claim 9, characterized in that Specifically include: Column chromatography is used for purification; wherein the column chromatography uses an eluent which is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of petroleum ether to ethyl acetate is 5 to 3:1.

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