Synthesis and Application of (4-Benzyl(p-Tolylthio)amino)benzenesulfonamides

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology, specifically relating to the synthesis and application of (4-benzyl(p-tolylthio)amino)benzenesulfonamide compounds. The (4-benzyl(p-tolylthio)amino)benzenesulfonamide compounds described herein utilize relatively inexpensive, common raw materials such as N-chlorosuccinimide, p-tolylthiophenol, dichloromethane, and triethylamine during the synthesis process. A stable intermediate, 1-(p-tolylthio)pyrrolidine-2,5-dione, is synthesized, and the target product is obtained in a high overall yield. The entire synthetic process is economical, safe, and simple. The two synthesized new (4-benzyl(p-tolylthio)amino)benzenesulfonamide compounds exhibit significant anti-Streptococcus pneumoniae activity.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to the synthesis and application of (4-benzyl(p-tolylthio)amino)benzenesulfonamide compounds. Background Art

[0002] In the medical and health field, antibacterial drugs play an important role in the prevention and treatment of bacterial infections. However, with the increasing bacterial resistance, the development of new antibacterial drugs has become an urgent need. As an important organic synthesis intermediate, benzenesulfonamide compounds are widely used in the development of antibacterial drugs. Benzenesulfonamide compounds have the following antibacterial characteristics: a broad antibacterial spectrum, benzenesulfonamide compounds have antibacterial activity against a variety of bacteria, such as Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, etc.; good antibacterial effect, benzenesulfonamide compounds can effectively inhibit the growth and reproduction of bacteria and have good antibacterial effect; low drug resistance, compared with traditional antibacterial drugs, benzenesulfonamide compounds have lower bacterial resistance and can effectively avoid the development of drug resistance; small side effects, benzenesulfonamide compounds have low toxicity and small side effects after use, and are suitable for long-term use.

[0003] The current synthesis method for sulfonamide compounds primarily involves the following steps: an aromatic amine reacts with p-methoxybenzenesulfonyl chloride in a dichloromethane solvent to produce the intermediate N-benzyl-4-methoxybenzenesulfonamide. This intermediate then reacts with p-toluenethiophenol under base-catalyzed conditions to yield the target compound, N-benzyl-4-(p-tolylthio)aminobenzenesulfonamide. Finally, the target compound undergoes post-processing steps such as desalination and crystallization to yield the final product. Despite their widespread applications and advantages in antibacterial applications, benzenesulfonamide compounds still suffer from several drawbacks: The current synthesis methods for benzenesulfonamides are complex, requiring the use of multiple organic solvents and raw materials, resulting in high synthesis costs. Furthermore, some intermediates and target compounds exhibit poor stability and are susceptible to deterioration or decomposition, further increasing production costs. Summary of the Invention

[0004] To address the above technical problems, the present invention provides the synthesis and application of (4-benzyl(p-tolylthio)amino)benzenesulfonamide compounds. The synthesis process is simple and the intermediates are stable. Furthermore, the resulting products exhibit strong antibacterial activity.

[0005] The (4-benzyl(p-tolylthio)amino)benzenesulfonamide compound of the present invention has the following specific structure:

[0006] .

[0007] The preparation method of the (4-benzyl(p-tolylthio)amino)benzenesulfonamide compound of the present invention comprises the following specific steps:

[0008] (1) Under nitrogen, 0.5-1.5 mmol N-chlorosuccinimide, 1 mmol p-toluenethiophenol and dichloromethane were added to the reaction vessel in sequence, and the mixture was vigorously reacted at -10-10°C for 0.5-2 h. Then, 0.5-1.5 mmol triethylamine was added and stirred until the mixture returned to room temperature. The mixture was stirred overnight. After the reaction was completed, the mixture was quenched with saturated aqueous ammonium chloride solution and separated by column chromatography to obtain 1-(p-tolylthio)pyrrolidine-2,5-dione.

[0009] (2) In the air, 0.5-1 mmol of 1-(p-tolylthio)pyrrolidine-2,5-dione, 1 mmol of sulfonamide and dimethyl sulfoxide were added to the reaction vessel in sequence, and the mixture was vigorously reacted at 100°C for 4-24 h. After the reaction was completed, the mixture was cooled to room temperature and separated by column chromatography to obtain 4-((p-tolylthio)amino)benzenesulfonamide; 1 mmol of 4-((p-tolylthio)amino)benzenesulfonamide and 0.5-1.5 mmol of tetrahydrofuran were added to the reaction vessel under nitrogen, 4-6 mmol of NaH was added thereto, and the mixture was reacted at -10-10°C for 0.5-1.5 h. Then, 0.5-1.5 mmol of benzyl bromide was added thereto, and the mixture was slowly returned to room temperature and vigorously stirred for 4-24 h. h. After the reaction is completed, the target product (4-benzyl (p-tolylthio) amino) benzenesulfonamide compound is obtained by column chromatography separation; the (4-benzyl (p-tolylthio) amino) benzenesulfonamide compound is specifically ((4-benzyl (p-tolylthio) amino) benzenesulfonamide or N-benzyl-(4-benzyl (p-tolylthio) amino) benzenesulfonamide.

[0010] The preparation method of the (4-benzyl(p-tolylthio)amino)benzenesulfonamide compound of the present invention comprises the following specific steps:

[0011] (1) Under nitrogen, 1 mmol N-chlorosuccinimide, 1 mmol p-toluenethiophenol, and dichloromethane were added sequentially to a 25 mL Schlenk reaction tube. The mixture was vigorously reacted at 0 °C for 1 h. Then, 1 mmol triethylamine was added and the mixture was stirred until it returned to room temperature. The mixture was stirred overnight. After the reaction was completed, the mixture was quenched with saturated aqueous ammonium chloride solution and separated by column chromatography to obtain 1-(p-tolylthio)pyrrolidine-2,5-dione.

[0012] (2) In a 25 mL Schlenk reaction tube, 1 mmol of 1-(p-tolylthio)pyrrolidine-2,5-dione, 1 mmol of sulfonamide, and dimethyl sulfoxide were added in sequence under air, and the mixture was vigorously reacted at 100°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature and separated by column chromatography to obtain 4-((p-tolylthio)amino)benzenesulfonamide. In a 25 mL Schlenk reaction tube, 1 mmol of 4-((p-tolylthio)amino)benzenesulfonamide and tetrahydrofuran were added under nitrogen, and 5 mmol of NaH was added thereto. The mixture was reacted at 0°C for 1 h, and then 1 mmol of benzyl bromide was added thereto. The mixture was slowly returned to room temperature and vigorously stirred for 12 h. h. After the reaction is completed, the target product (4-benzyl (p-tolylthio) amino) benzenesulfonamide compound is obtained by column chromatography separation; the (4-benzyl (p-tolylthio) amino) benzenesulfonamide compound is specifically (4-benzyl (p-tolylthio) amino) benzenesulfonamide or N-benzyl-(4-benzyl (p-tolylthio) amino) benzenesulfonamide.

[0013] The (4-benzyl(p-tolylthio)amino)benzenesulfonamide compounds of the present invention are used for preparing anti-Staphylococcus aureus drugs.

[0014] The intermediate in the synthesis process of the (4-benzyl(p-tolylthio)amino)benzenesulfonamide compound of the present invention has the following specific structure:

[0015] .

[0016] Compared to existing technologies, the (4-benzyl(p-tolylthio)amino)benzenesulfonamide compounds described in this invention utilize relatively inexpensive, common raw materials such as N-chlorosuccinimide, p-tolylthiophenol, dichloromethane, and triethylamine during their synthesis. This results in a stable intermediate, 1-(p-tolylthio)pyrrolidine-2,5-dione, and a high overall yield of the target product. The entire synthetic process is economical, safe, and simple. The two synthesized new (4-benzyl(p-tolylthio)amino)benzenesulfonamide compounds exhibit significant anti-Staphylococcus aureus activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 : Hydrogen spectrum of the intermediate 1-(p-tolylthio)pyrrolidine-2,5-dione. Figure 2 : Carbon spectrum of intermediate 1-(p-tolylthio)pyrrolidine-2,5-dione. Figure 3 : A is the structural formula of (4-benzyl(p-tolylthio)amino)benzenesulfonamide; B is the structural formula of N-benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide. Figure 4 : Hydrogen spectrum of N-benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide. Figure 5: Carbon spectrum of N-benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide. Figure 6 :Schematic diagram of the synthesis of (4-benzyl(p-tolylthio)amino)benzenesulfonamide compounds. DETAILED DESCRIPTION

[0018] The synthesis and application of the (4-benzyl(p-tolylthio)amino)benzenesulfonamide compounds of the present invention are further described below with reference to specific examples, but the scope of protection of the present invention is not limited thereto. Example

[0019] Under nitrogen, 1 mmol of N-chlorosuccinimide, 1 mmol of p-toluenethiophenol, and dichloromethane were added sequentially to a 25 mL Schlenk reaction tube. The mixture was vigorously reacted at 0°C for 1 h. 1 mmol of triethylamine was then added and stirred until the mixture returned to room temperature. Stirring was continued overnight. After the reaction was completed, the mixture was quenched with saturated aqueous ammonium chloride solution and separated by column chromatography to obtain 1-(p-tolylthio)pyrrolidine-2,5-dione as a white solid in 83% yield. 1 H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 8.2,1.7 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 2.76 (d, J = 0.9 Hz, 2H), 2.31 (s,3H); 13 C NMR (101 MHz, CDCl3) δ 178.0, 176.6, 140.8, 133.6, 130.2, 29.5, 28.5,21.3. HRMS (ESI) calcd for C 11 H 11 O2NS, [M+H] + : 222.0589; found: 222.0599.

[0020] To a 25 mL Schlenk reaction tube, 1 mmol of 1-(p-tolylthio)pyrrolidine-2,5-dione, 1 mmol of sulfonamide, and dimethyl sulfoxide were added sequentially under air and reacted vigorously at 100 °C for 12 h. After cooling to room temperature, the mixture was separated by column chromatography to obtain 4-((p-tolylthio)amino)benzenesulfonamide in a 92% yield. To a 25 mL Schlenk reaction tube, 1 mmol of 4-((p-tolylthio)amino)benzenesulfonamide and tetrahydrofuran were added under nitrogen, followed by 5 mmol of NaH and reaction at 0 °C for 1 h. Finally, 1 mmol of benzyl bromide was added, the mixture was slowly returned to room temperature, and vigorous stirring was continued for 12 h. After completion of the reaction, the target products, (4-benzyl(p-tolylthio)amino)benzenesulfonamide and N-benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide, were obtained.

[0021] Among them, (4-benzyl (p-tolylthio) amino) benzenesulfonamide is a white solid with a yield of 56%. Its structural formula is shown in the attached figure. Figure 3 A, H and C spectra data are shown in the attached figure. Mp: 138–140 °C; 1 H NMR (400 MHz, DMSO- d 6) δ 7.70 (d, J = 9.0 Hz, 1H), 7.37–7.26 (m, 7H), 7.21–7.18 (m, 4H), 7.12 (d, J =8.2 Hz, 2H), 5.10 (s, 2H), 2.27 (s, 3H); 13 C NMR (101 MHz, DMSO- d 6) δ 151.4,137.4, 136.1, 134.8, 134.7, 130.1, 128.7, 127.3, 126.5, 123.7, 114.9, 59.6,20.6; HRMS (ESI) calcd for C 20 H 20 O2N2S2, [M+H] + : 385.1044; found: 385.1025.

[0022] Among them, N-benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide is a white solid with a yield of 22%. Its structural formula is shown in the attached figure. Figure 3 B, the H and C spectra data are shown in the accompanying figure. Mp: 153–155 °C; 1H NMR (400 MHz, DMSO- d 6) δ 7.94 (t, J = 6.3 Hz, 1H), 7.67–7.59 (m, 2H), 7.36 (dd, J = 7.9,6.6 Hz, 2H), 7.32–7.16 (m, 12H), 7.15–7.09 (m, 2H), 5.08 (s, 2H), 3.95 (d, J = 6.3 Hz, 2H), 2.28 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 151.9, 137.8, 137.3,136.1, 134.6, 131.1, 130.1, 128.7, 128.1, 127.5, 127.3, 127.0, 126.5, 123.7,115.0, 59.5, 46.1, 20.6. HRMS (ESI) calcd for C 27 H 27 O2N2S2, [M+H] + : 475.1514;found: 475.1528. Example

[0023] Under nitrogen, 1.5 mmol N-chlorosuccinimide, 1 mmol p-toluenethiophenol, and dichloromethane were added sequentially to a 25 mL Schlenk reaction tube. The mixture was vigorously reacted at -5°C for 1.5 h. Then, 1.5 mmol of triethylamine was added and the mixture was stirred until it returned to room temperature. Stirring was continued overnight. After the reaction was completed, the mixture was quenched with saturated aqueous ammonium chloride solution and separated by column chromatography to obtain a white solid, which was identified as 1-(p-tolylthio)pyrrolidine-2,5-dione by liquid chromatography-mass spectrometry.

[0024] To a 25 mL Schlenk reaction tube under air, 1 mmol of 1-(p-tolylthio)pyrrolidine-2,5-dione, 1.5 mmol of sulfonamide, and dimethyl sulfoxide were added sequentially. The mixture was reacted vigorously at 100 °C for 4 h. After cooling to room temperature, the mixture was separated by column chromatography to obtain 4-((p-tolylthio)amino)benzenesulfonamide. To a 25 mL Schlenk reaction tube under nitrogen, 1 mmol of 4-((p-tolylthio)amino)benzenesulfonamide and tetrahydrofuran were added. 6 mmol of NaH was added and the mixture was reacted at 5 °C for 1 h. Then, 1.5 mmol of benzyl bromide was added. The mixture was slowly returned to room temperature and vigorously stirred for 8 h. After the reaction, the mixture was separated by column chromatography to obtain two compounds. Liquid chromatography analysis confirmed them to be the target products (4-benzyl(p-tolylthio)amino)benzenesulfonamide and N-benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide.

[0025] Weigh six portions of 1-(p-tolylthio)pyrrolidine-2,5-dione, seal three portions in transparent bottles and place them at 30°C for 48 h, and seal the other three portions in a refrigerator at 4°C for 48 h. Prepare a test solution with a concentration of 0.5 μg / mL in methanol and perform liquid chromatography-mass spectrometry (HPLC-QTOF-MS) on the solution. e ) detection. The RSD for both was 0.76%. These results indicate that 1-(p-tolylthio)pyrrolidine-2,5-dione has good stability.

[0026] Take frozen Staphylococcus aureus and passage it twice after thawing. When the OD value of the diluted bacterial solution is 0.6, the default concentration is 1×10 8 CFU / mL, and then diluted to a concentration of 2×10 5Weigh (4-benzyl(p-tolylthio)amino)benzenesulfonamide and N-benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide and dissolve in culture medium. Then, prepare gradient solutions with concentrations of 0 µg / mL (blank), 2 µg / mL, 8 µg / mL, 32 µg / mL, 128 µg / mL, 512 µg / mL, and 2048 µg / mL. Transfer 100 µL of each gradient solution to a 96-well plate and add 100 µL of the bacterial suspension to each well, resulting in final concentrations of 0 µg / mL, 1 µg / mL, 4 µg / mL, 16 µg / mL, 64 µg / mL, 256 µg / mL, and 1024 µg / mL, respectively. To eliminate background color, measure the OD value (initial OD value) after preparation. Then, cover with a breathable membrane and incubate in a 37°C incubator for 14 hours before measuring the OD value (final OD value). Each gradient concentration of (4-benzyl(p-tolylthio)amino)benzenesulfonamide and N-benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide should be replicated in triplicate in triplicate. Inhibition rate = (final OD value of sample - initial OD value of sample) / (final OD value of blank - initial OD value of blank). Results are shown in Table 1.

[0027] Table 1 Inhibition rates of the two new compounds at different concentrations against Staphylococcus aureus

[0028] sample Concentration (µg / mL) Antibacterial rate (100%) (4-Benzyl(p-tolylthio)amino)benzenesulfonamide 1 0 (4-Benzyl(p-tolylthio)amino)benzenesulfonamide 4 0 (4-Benzyl(p-tolylthio)amino)benzenesulfonamide 16 0 (4-Benzyl(p-tolylthio)amino)benzenesulfonamide 64 13.5 ± 3.4 (4-Benzyl(p-tolylthio)amino)benzenesulfonamide 256 46.7 ±7.6 (4-Benzyl(p-tolylthio)amino)benzenesulfonamide 1024 100 N-Benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide 1 0 N-Benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide 4 7.2 ±4.6 N-Benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide 16 65.9 ±11.3 N-Benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide 64 100 N-Benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide 256 100 N-Benzyl-(4-benzyl(p-tolylthio)amino)benzenesulfonamide 1024 100 .

Claims

1. A (4-benzyl(p-tolylthio)amino)benzenesulfonamide compound, characterized in that The specific structure is as follows: 。 2. The method for preparing the (4-benzyl(p-tolylthio)amino)benzenesulfonamide compound according to claim 1, wherein The specific steps are as follows: (1) Under nitrogen, 0.5-1.5 mmol N-chlorosuccinimide, 1 mmol p-toluenethiophenol and dichloromethane were added to the reaction vessel in sequence, and the mixture was vigorously reacted at -10-10°C for 0.5-2 h. Then, 0.5-1.5 mmol triethylamine was added and stirred until the mixture returned to room temperature. The mixture was stirred overnight. After the reaction was completed, the mixture was quenched with saturated aqueous ammonium chloride solution and separated by column chromatography to obtain 1-(p-tolylthio)pyrrolidine-2,5-dione. (2) In the air, 0.5-1 mmol of 1-(p-tolylthio)pyrrolidine-2,5-dione, 1 mmol of sulfonamide and dimethyl sulfoxide were added to the reaction vessel in sequence, and the mixture was vigorously reacted at 100°C for 4-24 h. After the reaction was completed, the mixture was cooled to room temperature and separated by column chromatography to obtain 4-((p-tolylthio)amino)benzenesulfonamide; 1 mmol of 4-((p-tolylthio)amino)benzenesulfonamide and 0.5-1.5 mmol of tetrahydrofuran were added to the reaction vessel under nitrogen, 4-6 mmol of NaH was added thereto, and the mixture was reacted at -10-10°C for 0.5-1.5 h. Then, 0.5-1.5 mmol of benzyl bromide was added thereto, and the mixture was slowly returned to room temperature and vigorously stirred for 4-24 h. h. After the reaction is completed, the target product (4-benzyl (p-tolylthio) amino) benzenesulfonamide compound is obtained by column chromatography separation; the (4-benzyl (p-tolylthio) amino) benzenesulfonamide compound is specifically (4-benzyl (p-tolylthio) amino) benzenesulfonamide or N-benzyl-(4-benzyl (p-tolylthio) amino) benzenesulfonamide.

3. The method for preparing the (4-benzyl(p-tolylthio)amino)benzenesulfonamide compound according to claim 1, wherein The specific steps are as follows: (1) Under nitrogen, 1 mmol N-chlorosuccinimide, 1 mmol p-toluenethiophenol, and dichloromethane were added sequentially to a 25 mL Schlenk reaction tube. The mixture was vigorously reacted at 0 °C for 1 h. Then, 1 mmol triethylamine was added and the mixture was stirred until it returned to room temperature. The mixture was stirred overnight. After the reaction was completed, the mixture was quenched with saturated aqueous ammonium chloride solution and separated by column chromatography to obtain 1-(p-tolylthio)pyrrolidine-2,5-dione. (2) In a 25 mL Schlenk reaction tube, 1 mmol of 1-(p-tolylthio)pyrrolidine-2,5-dione, 1 mmol of sulfonamide, and dimethyl sulfoxide were added in sequence under air, and the mixture was vigorously reacted at 100°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature and separated by column chromatography to obtain 4-((p-tolylthio)amino)benzenesulfonamide. In a 25 mL Schlenk reaction tube, 1 mmol of 4-((p-tolylthio)amino)benzenesulfonamide and tetrahydrofuran were added under nitrogen, and 5 mmol of NaH was added thereto. The mixture was reacted at 0°C for 1 h, and then 1 mmol of benzyl bromide was added thereto. The mixture was slowly returned to room temperature and vigorously stirred for 12 h. h. After the reaction is completed, the target product (4-benzyl (p-tolylthio) amino) benzenesulfonamide compound is obtained by column chromatography separation; the (4-benzyl (p-tolylthio) amino) benzenesulfonamide compound is specifically (4-benzyl (p-tolylthio) amino) benzenesulfonamide or N-benzyl-(4-benzyl (p-tolylthio) amino) benzenesulfonamide.

4. The use of the (4-benzyl(p-tolylthio)amino)benzenesulfonamide compound according to claim 1, wherein Used for the preparation of anti-Staphylococcus aureus drugs.

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