1,2,3-triazole sulfonamide derivatives, processes for their preparation and use

Abstract

The application discloses a 1, 2, 3-triazole sulfamide derivative, a preparation method and application thereof. The compound has a general formula (A). The synthesis method is as follows: sulfamide is used as a starting material, diazotization, azidation, and then coupling with ethyl acetoacetate to complete the docking of the triazole ring and the sulfamide, and an amide bond is introduced into the structure, and then a series of novel 1, 2, 3-triazole sulfamide derivatives are synthesized. The compounds have excellent bacteriostatic, insecticidal and fungicidal functions on escherichia coli, pseudomonas aeruginosa, salmonella typhi, staphylococcus aureus, bacillus subtilis, and fungi such as candida albicans and aspergillus niger, pests and plant pathogenic bacteria in forestry and other fields.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic compound synthesis and pesticides, and particularly relates to a 1, 2, 3-triazole sulfamide derivative, a preparation method and application thereof. BACKGROUND

[0002] In this era of continuous biological variation, the increasing drug resistance of various microorganisms constantly prompts people to design and develop new drugs. Compounds containing nitrogen and nitrogen-containing heterocyclic rings with pyrazole rings, isoxazole rings and other nitrogen-containing groups in the molecular structure generally have various biological activities such as antibacterial and anticancer drugs. Therefore, the modification, synthesis and activity research of nitrogen heterocyclic rings or nitrogen-containing side chains of the compounds have become an important field.

[0003] In recent years, the research on developing new antibacterial agents by connecting two different active fragments has gradually attracted the attention of researchers. The drugs synthesized by this method have two independent structural parts in the molecule, which can realize the combination with two or more biological targets and the synchronous accumulation at the target. This dual or multi-acting drug can greatly overcome the current drug resistance of microorganisms or reduce the possibility of emergence of new drug-resistant strains.

[0004] The currently used antibacterial drugs such as indole, pyrazine amide, isoniazid, fluconazole and the like have a nitrogen-containing heterocyclic system, that is, indole, pyrazine, pyridine, triazole and fused compounds thereof, which have attracted the attention of researchers due to their significant biological activity. In the nitrogen-containing heterocyclic ring, 1, 2, 3-triazole has good solubility and affinity with biological targets due to some unique structural characteristics such as hydrogen bonding, dipole-dipole interaction, and π-π stacking, and has a wide range of pharmacological effects, and is a part of the structure of antibacterial, antituberculosis drugs, neuraminidase inhibitors, anticancer compounds, antiviral drugs, analgesic anti-inflammatory compounds, antidiabetic drugs, herbicides and plant growth regulators. Sulfa compounds have multiple effects such as antimicrobial, antitumor, anti-inflammatory, hypoglycemic, antipsychotic, anticancer and the like. Since the first sulfa drug, sulfonamidochin, was used, more and more researchers have been committed to the development and screening of sulfa drugs. Sulfa antibacterial drugs are widely used, such as sulfamethoxazole (SMZ), sulfamethylisoxazole (SIZ), sulfonamidochin (SG), sulfamethoxine (SM2), sulfadiazine (SD), sulfamethoxydiazine (SMP). The antibacterial mechanism is to competitively inhibit the synthesis and metabolism of PABA used by bacteria to inhibit bacterial growth. Sulfa compounds and 1, 2, 3-triazole have wide biological activity, and the present application synthesizes 1, 2, 3-triazole sulfamide by taking sulfa as a starting material, and then introduces the common antibacterial active group amide bond, and further synthesizes a series of 1, 2, 3-triazole benzene sulfamide compounds. Such compounds show excellent bacteriostatic, insecticidal and fungicidal functions on Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Staphylococcus aureus, Bacillus subtilis, and fungi such as Candida albicans, Aspergillus niger, pests and plant pathogens in forestry and other fields. SUMMARY

[0005] In view of the above problems, the purpose of the present application is to provide a 1, 2, 3-triazole benzene sulfamide derivative and a preparation method and application thereof, and the compound has excellent bacteriostatic and insecticidal activity and can be used as an insecticide for the prevention and treatment of agricultural diseases. In order to achieve the above purpose, the present application provides the following synthesis route of 1, 2, 3-triazole benzene sulfamide.

[0006]

[0007]

[0008] Further, the synthesis method of each step in the above synthesis route is as follows:

[0009] 1) The sulfamide reacts with nitrous acid in hydrochloric acid solution to generate a diazonium salt, which further reacts with sodium azide to generate azidosulfamide (compound

[0010] 2) Sulfonamide (0.69 g, 4 mmol) was dissolved in a 250 mL round-bottom flask containing 2 mol / L hydrochloric acid and stirred at 0 °C until completely dissolved. Sodium nitrite (0.35 g, 5 mmol) was dissolved in cold water and slowly added to the reaction mixture through a constant-pressure funnel. After complete addition, sodium azide (0.325 g, 5 mmol) dissolved in a very small amount of water was added to the reaction system. The reaction system was stirred at room temperature, the residue was collected by filtration, washed with deionized water, and dried to obtain product 2, with a yield of 92.0%.

[0011] 2) The azidosulfonamide is coupled with ethyl acetoacetate to generate 1,2,3-triazolesulfonamide (compound 3). Specifically, ethyl acetoacetate (0.27 g, 2.00 mmol) and piperidine (25 μL) are added to a 150 mL round-bottom flask containing an appropriate amount of DMSO. The mixture is heated and stirred in a silicone oil bath at 70 °C for five minutes, and then compound 2 (0.40 g, 2.00 mmol) is added. After addition, the reaction mixture is heated to 95 °C.

[0012] The reaction was stirred for 4-6 hours. After the reaction was complete, the mixture was cooled and poured into cold water, then filtered to give compound 3 in 79.4% yield.

[0013] 3) 1,2,3-Triazole sulfonamides can be directly transesterified with amine compounds or reacted with amine compounds after hydrolysis and acylation. Specifically, compound 3 is hydrolyzed under alkaline conditions and acidified with hydrochloric acid to obtain a white solid 4. A 150 mL three-necked round-bottom flask, one end of which is sealed with a rubber stopper, is heated with a high-temperature spray gun for 5 minutes to remove residual water. Then, oxygen is removed from the flask using a vacuum pump and a nitrogen balloon equipped with a three-way valve, and nitrogen protection is applied. Compound 4 (0.29 g, 1 mmol) is dissolved in thionyl chloride and added to the round-bottom flask through a syringe. Excess thionyl chloride is added, and the mixture is heated under reflux for 12 hours. After the reaction is complete, excess thionyl chloride is removed by vacuum distillation. Dichloromethane is added several times, and rotary evaporation is repeated until the oily liquid is completely converted into a yellow solid, compound 5.

[0014] 4) Under alkaline conditions such as triethylamine, compound 5 reacts with amine compounds to give 1,2,3-triazole sulfonamide derivatives (compound 6). Detailed Implementation

[0015] The present invention will be further described in detail below with reference to specific embodiments in order to better understand the content of the present invention, but the present invention is not limited to the following embodiments.

[0016] Example 1: Synthesis of compound 6a

[0017] Take aniline (0.047 g, 0.5 mmol), triethylamine (0.31 g, 3.0 mmol) in a 150 mL round-bottom flask, add appropriate amount of dioxane, then add compound 5 (0.1 g, 0.33 mmol), heat the system to reflux for 1 h, after the reaction is completed, dilute the mixture with water, filter out the solid precipitate, and wash with 0.5 mol / L hydrochloric acid, sodium carbonate solution and saturated brine three times to obtain black-brown solid product 6a with a yield of 76.0%.

[0018] 1 H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.09-8.05 (m, 2H), 7.94-7.89 (m, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.60 (s, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.11 (t, J = 7.4 Hz, 1H), 2.63 (s, 3H).

[0019] Example 2: Synthesis of compound 6b

[0020] Take o-methylaniline (0.054 g, 0.5 mmol), triethylamine (0.31 g, 3.00 mmol) in a 150 mL round-bottom flask, add appropriate amount of dioxane, then add compound 5 (0.1 g, 0.33 mmol), heat the system to reflux for 1 h, after the reaction is completed, dilute the mixture with water, filter out the solid precipitate, and wash with 0.5 mol / L hydrochloric acid, sodium carbonate solution and saturated brine three times to obtain brown solid product 6b with a yield of 77.4%.

[0021] 1 H NMR (500 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.17-8.01 (m, 2H), 7.95-7.85 (m, 2H), 7.60 (s, 2H), 7.51 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 2.61 (s, 3H), 2.29 (s, 3H).

[0022] Example 3: Synthesis of compound 6c

[0023] Take compound 3 (0.1 g, 0.33 mmol), excess ethylenediamine into a 150 mL round-bottom flask containing appropriate amount of methanol, react at 65°C for 5 h, after the reaction is completed, rotary evaporate the methanol and excess ethylenediamine, obtain brown-yellow solid, recrystallize with ethanol to obtain product 6c with a yield of 92.4%.

[0024] 1 H NMR (500 MHz, DMSO-d6) δ 8.55 (t, J = 5.9 Hz, 1H), 8.05 (d, J = 8.3 Hz, 2H), 7.87 (d, J = 8.3 Hz, 2H), 3.27 (d, J = 6.3 Hz, 2H), 2.69 (t, J = 6.6 Hz, 2H), 2.57 (s, 3H), 2.53 (s, 2H).

[0025] Example 4: Synthesis of compound 6d

[0026] Take 2,4-dimethylaniline (0.042g, 0.34mmol), triethylamine 4 drops, appropriate amount of dichloromethane into a 150mL round bottom flask, after stirring and mixing, slowly add compound 5 (0.05g, 0.17mmol), heat reflux, thin layer chromatography track reaction complete, respectively, with 0.5mol / L hydrochloric acid, sodium carbonate solution and saturated brine wash reaction system three times, dry organic phase with anhydrous sodium sulfate 3h, then remove the solvent by rotary evaporation, get light yellow powder solid product 6d, yield 52.7%.

[0027] 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.08 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.61 (s, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 8.1, 2.0 Hz, 1H), 2.61 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H).

[0028] Example 5: Synthesis of compound 6e

[0029] Take 3,5-dimethylaniline (0.061g, 0.2mmol), triethylamine 4 drops, appropriate amount of dichloromethane into a 150mL round bottom flask, after stirring and mixing, slowly add compound 5 (0.05g, 0.17mmol), heat reflux, thin layer chromatography track reaction complete, respectively, with 0.5mol / L hydrochloric acid solution, sodium carbonate solution and saturated brine wash reaction system three times, dry organic phase with anhydrous sodium sulfate 3h, then remove the solvent by rotary evaporation, get yellow brown powder solid 6e, yield 58.4%.

[0030] 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.14 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.67 (s, 2H), 7.55 (s, 2H), 6.82 (s, 1H), 2.69 (s, 3H), 2.33 (s, 6H).

[0031] Example 6: Synthesis of compound 6f

[0032] Into a 150 mL round bottom flask, 2,6-dimethylaniline (0.061 g, 0.2 mmol), triethylamine 4 drops, appropriate amount of dichloromethane were added, after stirring and mixing, compound 5 (0.05 g, 0.17 mmol) was added slowly, heated to reflux, thin layer chromatography to track the completion of the reaction, the reaction system was washed with 0.5 mol / L hydrochloric acid solution, sodium carbonate solution and saturated brine respectively for three times, the organic phase was dried with anhydrous sodium sulfate for 3 h, then dichloromethane was removed by rotary evaporation, a dark yellow powder solid product 6f was obtained, the yield was 64.5%.

[0033] 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.14 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.67 (s, 2H), 7.55 (s, 2H), 6.82 (s, 1H), 2.69 (s, 3H), 2.33 (s, 6H).

[0034] Example 7: Synthesis of compound 6g

[0035] Into a 150 mL round bottom flask, 2,6-dimethylaniline (0.061 g, 0.2 mmol), triethylamine 4 drops, appropriate amount of dichloromethane were added, after stirring and mixing, compound 5 (0.05 g, 0.17 mmol) was added slowly, heated to reflux, thin layer chromatography to track the completion of the reaction, the reaction system was washed with 0.5 mol / L hydrochloric acid solution, sodium carbonate solution and saturated brine respectively for three times, the organic phase was dried with anhydrous sodium sulfate for 3 h, then dichloromethane was removed by rotary evaporation, a dark yellow powder solid product 6f was obtained, the yield was 64.5%.

[0036] 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.14 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.67 (s, 2H), 7.55 (s, 2H), 6.82 (s, 1H), 2.69 (s, 3H), 2.33 (s, 6H).

[0037] Example 8: Synthesis of compound 6h

[0038] To a 150 mL round bottom flask, p-chloroaniline (0.044 g, 0.34 mmol), triethylamine 4 drops, and appropriate amount of dichloromethane were added. After stirring the mixture, compound 5 (0.5 g, 0.17 mmol) was added slowly. The reaction was heated to reflux and followed by thin layer chromatography until the reaction was completed. The reaction system was washed with 0.5 mol / L hydrochloric acid solution, sodium carbonate solution and saturated brine solution, respectively. The organic phase was dried over anhydrous sodium sulfate for 3 h. Then dichloromethane was removed by rotary evaporation to obtain brown-yellow powder solid product 6h with a yield of 48.0%.

[0039] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.18 - 8.12 (m, 2H), 8.00 - 7.95 (m, 4H), 7.68 (s, 2H), 7.47 (d, J = 8.7 Hz, 2H), 2.69 (s, 3H).

[0040] Example 9: Synthesis of compound 6i

[0041] To a 150 mL round bottom flask, p-chloroaniline (0.044 g, 0.34 mmol), triethylamine 4 drops, and appropriate amount of dichloromethane were added. After stirring the mixture, compound 5 (0.5 g, 0.17 mmol) was added slowly. The reaction was heated to reflux and followed by thin layer chromatography until the reaction was completed. The reaction system was washed with 0.5 mol / L hydrochloric acid solution, sodium carbonate solution and saturated brine solution, respectively. The organic phase was dried over anhydrous sodium sulfate for 3 h. Then dichloromethane was removed by rotary evaporation to obtain brown-yellow powder solid product 6h with a yield of 48.0%.

[0042] 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.18 - 8.12 (m, 2H), 8.00 - 7.95 (m, 4H), 7.68 (s, 2H), 7.47 (d, J = 8.7 Hz, 2H), 2.69 (s, 3H).

[0043] Example 10: Synthesis of compound 6j

[0044] To a 150 mL round bottom flask, p-chloroaniline (0.044 g, 0.34 mmol), triethylamine 4 drops, and appropriate amount of dichloromethane were added. After stirring the mixture, compound 5 (0.5 g, 0.17 mmol) was added slowly. The reaction was heated to reflux and followed by thin layer chromatography until the reaction was completed. The reaction system was washed with 0.5 mol / L hydrochloric acid solution, sodium carbonate solution and saturated brine solution, respectively. The organic phase was dried over anhydrous sodium sulfate for 3 h. Then dichloromethane was removed by rotary evaporation to obtain brown-yellow powder solid product 6h with a yield of 48.0%.

[0045] 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.23 (dd, J = 8.5, 3.1 Hz, 1H), 8.07 (q, J = 9.0 Hz, 4H), 7.99 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.63 (s, 2H), 2.63 (s, 3H), 2.40 (s, 3H).

[0046] Example 11: Synthesis of compound 6k

[0047] To 4-amino pyrimidine (0.048 g, 0.2 mmol) taken in 150 mL round bottom flask with suitable amount of toluene, 8 drops of triethylamine was added, stirred for five minutes at room temperature, compound 5 (0.5 g, 0.17 mmol) was added, the reaction was heated to 120 °C and refluxed and the reaction was followed by thin layer chromatography, after completion of the reaction, the precipitate was filtered off, washed with 0.5 mol of hydrochloric acid, saturated brine three times and dried in an oven to get brown yellow product 6k with 68.2% yield.

[0048] 1 H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.80 (d, J = 4.9 Hz, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.28 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 2.62 (s, 3H).

[0049] Example 12: Evaluation of antibacterial effect

[0050] The in vitro antibacterial activity of the synthesized compounds was determined by the punch method. Sulfamethoxazole (SMZ) was used as a positive control for gram-negative and gram-positive bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Staphylococcus aureus, Bacillus subtilis); fluconazole (FLUCZ) as a positive control for fungi (Candida albicans, Aspergillus niger). The synthesized compounds and the two positive drugs were dissolved in DMSO, respectively, and prepared into 512 μg / mL, then diluted with DMSO into 256 μg / mL, 128 μg / mL, 64 μg / mL, 32 μg / mL, 16 μg / mL, 8 μg / mL, 4 μg / mL, 2 μg / mL, 1 μg / mL, respectively, and the diameters of the inhibition zones of the drugs at the above ten concentrations were determined. The concentration of 1 x 10 6The pathogenic bacteria (determined by McFarland turbidity method) were tested at 106CFU / mL. The solid medium was TSB prepared and sterilized, and a solid culture with a height of about 5 mm was injected on the surface of each culture dish. After solidification, 100 μL of sterile liquid was sprayed on the surface of the solid medium with a pipette gun. The Oxford cup was clamped on the solid medium with sterilized tweezers to punch a hole. About 50 μL of various drug solutions were sucked into the hole with a pipette gun. The culture dish was placed in a constant temperature incubator for 18-25 h, and the temperature was adjusted according to the optimum temperature of each strain. After the culture was completed, the culture dish was taken out, and the size of the inhibition zone was measured with a vernier caliper. The inhibition results of 1, 2, 3-triazole benzene sulfonyl derivatives are shown in Table 1. The 1, 2, 3-triazole benzene sulfonyl derivatives of the present application have good antibacterial effect on various strains.

[0051] Table 1 Minimum inhibitory concentration of compounds 6a-6k, SMZ, FLUCZ.

[0052]

Claims

1. A 1,2,3-triazole sulfamide derivative characterized in that, Structures are shown in 6a-6k below; 。 2. Use of the 1,2,3-triazole sulfamides according to claim 1 for the preparation of an antibacterial agent.

3. Use according to claim 2, characterized in that, The antibacterial agent is used to inhibit or kill plant pathogenic bacteria.

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