3-azido-n-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno) propanamide

Abstract

The invention belongs to the field of pharmacy, and particularly relates to 3-azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno) propanamide as well as a preparation method and application thereof. The compound provided by the invention is prepared by selenylation of alkene azide without metal catalysis and is red liquid, and a high-resolution mass spectrum gives a quasi-molecular ion peak [M + Na] +: 441.9944. The application relates to the application of the 3-azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenyl seleno) propanamide in the preparation of the antibacterial medicine. The invention also relates to the application of the 3-azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenyl seleno) propanamide.

Description

Technical Field

[0001] The present invention relates to the field of chemistry, and in particular to a compound 3-azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno)propionamide, a preparation method thereof, and an application thereof. Background Art

[0002] Organic azides have extensive applications in the fine chemical and pharmaceutical industries. Azide groups are not only well-suited functional groups for organic synthesis transformations, but also serve as functional groups in pharmaceuticals. Carbon-N3 bonds are an important synthetic mechanism, providing a method for introducing nitrogen atoms into various organic molecules. Therefore, how to introduce N3 into organic molecules has always been a hot topic of research for organic chemists. Consequently, there is a constant need in synthetic organic chemistry to develop sustainable and practical methods for forming carbon-N3 bonds. Furthermore, nitrogen-containing heterocycles are key skeletal structures in many pharmaceutical molecules, particularly the structurally diverse quinoline-2,4-diones, which are widely present in numerous natural products, pharmaceuticals, and agrochemicals. Although several methods for constructing quinoline-2,4-diones have been reported, metal-free, free radical cascade carbocyclization reactions are undoubtedly one of the best options for achieving atom and step economies and, therefore, accessing these complex molecules.

[0003] Organoselenium compounds are important intermediates in synthetic chemistry, serving as core structural frameworks in a significant number of biologically active drug molecules. They have a wide range of applications in organic synthesis, pharmaceuticals, and organic materials. Therefore, the development of novel, green, efficient, and practical methods for synthesizing organoselenium compounds has attracted widespread attention from chemists. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a compound 3-azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno)propionamide and a preparation method and application thereof.

[0005] The technical solution of the present invention to solve the above technical problems is as follows:

[0006] One of the purposes of the present invention is to provide a compound 3-azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno)propionamide, whose chemical structure 2 is as follows:

[0007]

[0008] The preparation method of the above compound is as follows: using N-(4-chloro-2-cyanophenyl)methacrylamide (1) as a substrate, the olefin azide-selenoylation product is efficiently obtained by the reaction of (PhSe)2 and PhI(OAc)2 pre-activated TMSN3 in DMSO through an azide-selenoylation process. After the reaction is completed by shaking for 12 hours, the mixture is quenched with H2O and extracted with CH2Cl2. The organic solvent is then concentrated in vacuo, and the residue is purified by flash column chromatography using petroleum ether and ethyl acetate (5:1) as eluent to obtain 3-azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno)propionamide (2).

[0009] Further, the reaction equation is:

[0010]

[0011] Furthermore, the compound 3-azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno)propionamide (2) is used in the preparation of antibacterial drugs.

[0012] The beneficial effects of the present invention are: disclosing a method for the selenization of olefins by metal-free catalysis, the chemical process complies with the two principles of green chemistry, environmental protection and energy-saving design, the obtained new compound has antibacterial activity and can be used in the preparation of antibacterial drugs.

[0013] 3-Azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno)propionamide (2) Structure analysis:

[0014] like Figure 1-3 As shown, the compound 2 of the present invention 1 H NMR, 13 The structure of the compound was determined by C NMR and HR-ESI-MS spectra. Specifically, the molecular formula of compound 2 is C 17 H 14 ClN5Ose, red liquid, Rf (petroleum ether:ethyl acetate=5:1): 0.48. 1 HNMR (600MHz, CDCl3): δ8.76 (s, 1H), 8.29 (d, J = 9.0Hz, 1H), 7.59-7.58 (m, 2H), 7.56-7.53 (m, 2H), 7.42-7.39(m,1H),7.32-7.29(m,2H),3.91(d,J=12.6Hz,1H),3.70(d,J=12.6Hz,1H),1.68(s,3H). 13C NMR (150MHz,CDCl3):δ170.64,139.06,137.58,134.39,131.53,130.06,129.47,129.40,125.23,122.17,115.05,103.47,58.07,51.18,22.49. HRMS (ESI) measured its [M+Na] + :441.9944,found:441.9944. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 Compound 2 1 H NMR spectrum;

[0016] Figure 2 Compound 2 13 C NMR spectrum;

[0017] Figure 3 HR-ESI-MS spectrum of compound 2. DETAILED DESCRIPTION

[0018] The present invention is further described below by way of examples so that those skilled in the art can more fully understand the present invention, but the present invention is not limited in any way.

[0019] Example 1

[0020] At room temperature, N-(4-chloro-2-cyanophenyl)methacrylamide (1) (0.3 mmol, 66 mg) was added to a reaction tube and the reaction was carried out with trimethylsilyl azide TMSN (93%, 3.0 equiv, 0.9 mmol, 127 μL) pre-activated with diphenyl diselenide (PhSe) 2 (0.3 mmol, 93.6 mg) and diethyl iodophenyl ester PhI(OAc) 2 (0.45 mmol, 145 mg) in DMSO (2 mL). The reaction tube was then stirred at room temperature for 12 hours until the starting material was completely consumed as monitored by TLC analysis. After the reaction was completed, the mixture was quenched with H 2 O (15 mL) and extracted with CH 2 Cl 2 (3×5 mL). The organic solvent was then concentrated in vacuo. The residue was purified by flash column chromatography using petroleum ether and ethyl acetate (5:1) as eluent, Rf = 0.48 to obtain 3-azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno)propionamide (2) in a yield of 56%, 70.3 mg. The reaction equation is:

[0021]

[0022] Example 2

[0023] Antibacterial activity test:

[0024] Test bacterial strains: Staphylococcus aureus (CMCC(B)26003), Bacillus subtilis (CMCC(B)63501), Pseudomonas aeruginosa (CMCC(B)10104), Proteus vulgaris (CMCC(B)49027).

[0025] Experimental methods

[0026] The microdilution method was used to evaluate the antibacterial activity of the test samples against the test bacteria. The bacteria were activated with LB medium, inoculated into LB medium and cultured to the logarithmic phase, and then diluted to 1×10 6 CFU / mL and inoculated into a sterile 96-well plate, with 100 μL per well. Compound 2 was dissolved in DMSO and serially diluted two-fold with LB culture medium to obtain compound concentrations of 1024, 512, 256, 128, 64, 32, 16, and 8 μg / mL. Chloramphenicol was used as a positive control, and LB medium containing 0.5% DMSO was used as a negative control. Each experiment was repeated three times. The 96-well plate was incubated in a 37°C constant temperature incubator for 24 hours, and the growth was observed. The minimum concentration corresponding to the well with sterile growth was the minimum inhibitory concentration (MIC) of the sample.

[0027] Based on the MIC experiment, 5 μL of the bacteria whose growth was inhibited in each well was applied to the nutrient agar medium and cultured in a constant temperature incubator at 37°C for 24 hours. Each group of experiments was repeated 3 times, and the lowest drug concentration at which the bacteria were completely killed was the minimum bactericidal concentration (MBC).

[0028] Experimental results

[0029] The MIC and MBC values of compound 2 and the positive control drug chloramphenicol against four standard bacterial strains are shown in Table 1. The results show that compound 2 has inhibitory effects on all four selected standard strains. Compound 2's inhibitory effect on Staphylococcus aureus is comparable to that of the positive control drug, with an MIC of 512 μg / mL and an MBC of 1024 μg / mL. Compound 2's antibacterial activity against Bacillus subtilis is slightly better than that of the positive control drug chloramphenicol, with an MIC of 256 μg / mL and an MBC of 512 μg / mL.

[0030] Table 1 MIC and MBC values of compound 2 against four tested bacterial strains (μg / mL)

[0031]

[0032] “-” in the table means that the corresponding MIC and MBC values were not detected within the experimental concentration range.

[0033] In summary, the present invention has discovered a method for preparing azide-substituted quinoline-2,4-diones through a free radical tandem carbocyclization reaction. The obtained compound 2 has antibacterial activity and has the potential to develop antibacterial drugs.

[0034] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the description and implementation methods. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. 3-Azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno)propionamide, characterized in that The structural formula of the compound is shown in 2:

2. Application of 3-azido-N-(4-chloro-2-cyanophenyl)-2-methyl-2-(phenylseleno)propionamide (2) in the preparation of antibacterial drugs.

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