Method for preparing 1, 3-dithio indolizine compound without catalyst and application of 1, 3-dithio indolizine compound

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a method for preparing a 1, 3-dithio indolizine compound without a catalyst and application of the 1, 3-dithio indolizine compound. In an organic solvent, substituted 2-methylpyridine, alpha-bromoketone and N-thiosuccinimide are used as raw materials, and a reflux stirring reaction is performed to obtain the 1, 3-dithio indolizine compound. The method does not need to use a metal catalyst and a chemical oxidant, is mild in reaction condition, conforms to the green chemistry principle, and has the characteristics of simplicity and convenience in operation, high yield, good functional group compatibility and the like. Meanwhile, a cell experiment result shows that the 1, 3-dithio indolizine compound provided by the invention has relatively good inhibitory activity on standard strains, sensitive strains and drug-resistant strains of mycobacterium tuberculosis, so that a drug lead compound and a drug candidate are provided for development of a novel anti-tuberculosis drug, and the 1, 3-dithio indolizine compound has a broad application prospect. The important significance is realized on the prevention and / or treatment of tuberculosis.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic chemistry technology, specifically relating to a method and application for the preparation of 1,3-dithioindoleazine compounds without a catalyst. Background Technology

[0002] Indoleazine is a nitrogen-containing heterocyclic compound formed by the fusion of a six-membered ring and a five-membered ring. It is widely found in natural products, fluorescent materials, and numerous biologically active molecules, including anticancer drugs, antituberculosis drugs, antimalarial drugs, apoptosis inducers, and antifungal drugs. This compound has attracted widespread attention due to its anti-inflammatory, antibacterial, and antioxidant activities.

[0003] Organosulfur compounds have attracted much attention in synthetic chemistry due to their multifunctionality. They are not only key intermediates in the construction of complex molecules, but also widely used as highly efficient catalysts. When sulfur atoms combine with heterocyclic systems, they often endow molecules with rich biological activities. Among them, sulfur-modified indoleazines are a class of bioactive molecules with significant potential. Therefore, the study of skeletal construction and functional group modification of thioether-functionalized indoleazine compounds is not only of great value in synthetic methodology, but also provides new chemical spaces for drug discovery and development, possessing profound scientific significance and application prospects.

[0004] Over the past few decades, the synthesis of 1,3-dithioindoleazine compounds has primarily relied on introducing sulfur-containing groups onto a pre-constructed indoleazine skeleton. Common strategies include thioetherification via transition metal-catalyzed cross-coupling reactions, or electrophilic sulfidation modification of the indoleazine structure by activating the thioreagent with an oxidant. However, these methods largely depend on expensive noble metal catalysts or environmentally harmful oxidants, thus limiting their sustainability and economic viability. Summary of the Invention

[0005] This invention provides a method and application for the direct synthesis of 1,3-dithioindoleazine compounds from 2-methylpyridine, α-bromoketone, and N-thiosuccinimide under catalyst-free conditions. One objective of this invention is to provide a class of 1,3-dithioindoleazine compounds; another objective is to provide a method for preparing and purifying the above-mentioned 1,3-dithioindoleazine compounds; and a third objective is to apply the above-mentioned 1,3-dithioindoleazine compounds to the preparation of drugs for the prevention and / or treatment of tuberculosis.

[0006] The above-mentioned objective of the present invention is achieved through the following technical solution:

[0007] In an organic solvent, using 2-methylpyridine (as shown in formula (I), α-bromoketone (as shown in formula (II), and N-thiosuccinimide (as shown in formula (III)) as starting materials, a reflux reaction is carried out under certain temperature conditions to obtain the 1,3-dithioindoleazine compound shown in formula (IV). The reaction equation is shown below:

[0008] ,

[0009] Among them, substituent R 1 Hydrogen atom, halogen, C1-C 10 Alkyl, alkoxy, R 2 It is a phenyl, naphthyl, or phenyl group substituted with one or more substituents, wherein the substituents are alkoxy, alkyl, or halogen, R 3 For C1-C 10 Alkyl, 3-6 carbocyclic alkyl, naphthyl, furanyl, phenyl, phenyl with one substituent, wherein the substituent is halogen, alkyl, alkoxy, or cyano.

[0010] The molar ratio of 2-methylpyridine with the structure shown in formula (I), α-bromoketone with the structure shown in formula (II), and N-thiosuccinimide with the structure shown in formula (III) is 1:1:2-1:1:3, preferably 1:1:3.

[0011] The organic solvent is one or more of 1,2-dichloroethane, 1,4-dioxane, toluene, DMF, and DMSO, preferably 1,2-dichloroethane.

[0012] The reflux reaction is carried out at 90℃ for 4-10 hours.

[0013] After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent with a volume ratio of petroleum ether to ethyl acetate of (30-10):1. The eluent was collected, and the solvent was evaporated by rotary evaporation to obtain the 1,3-dithioindoleazine compound shown in formula (Ⅳ).

[0014] The 1,3-dithioindoleazine compounds and their pharmaceutically acceptable salts, solvates, or hydrates described in this invention all possess anti-tuberculosis activity. These compounds exhibit significant bactericidal / bacteriostatic activity against standard strains, susceptible strains, and resistant strains of Mycobacterium tuberculosis.

[0015] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and one or more pharmaceutically acceptable carriers or diluents; said active ingredient is selected from any one or more of the aforementioned 1,3-dithioindoleazine compounds, their pharmaceutically acceptable salts, solvates or hydrates.

[0016] The beneficial effects of this invention are as follows:

[0017] (1) The reaction is mild and can be carried out without harsh conditions, and it shows good tolerance to a variety of functional groups.

[0018] (2) The reaction system does not require catalysts and strong oxidants, which fundamentally avoids product pollution caused by metal residues and reduces the generation of harmful reaction wastes, which meets the requirements of green chemistry and sustainable development.

[0019] (3) In vitro experimental results show that the 1,3-dithioindolezine compound provided by the present invention has significant inhibitory activity against the standard strain, sensitive strain and drug-resistant strain of Mycobacterium tuberculosis. Its MIC value is low, showing good anti-tuberculosis activity and development potential. Detailed Implementation

[0020] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0021] This invention provides the following technical solution: In an organic solvent, using 2-methylpyridine as shown in formula (I), α-bromoketone as shown in formula (II), and N-thiosuccinimide as shown in formula (III) as raw materials, a reflux reaction is carried out under certain temperature conditions to obtain a 1,3-dithioindoleazine compound as shown in formula (IV). The reaction equation is shown below:

[0022] ,

[0023] Among them, substituent R 1 Hydrogen atom, halogen, C1-C 10 Alkyl, alkoxy, R 2 It is a phenyl, naphthyl, or phenyl group substituted with one or more substituents, wherein the substituents are alkoxy, alkyl, or halogen, R 3 For C1-C 10 Alkyl, 3-6 carbocyclic alkyl, naphthyl, furanyl, phenyl, phenyl with one substituent, wherein the substituent is halogen, alkyl, alkoxy, or cyano.

[0024] Example 1

[0025] The reaction equation is shown below:

[0026]

[0027] 2,3-Dimethylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 1-p-toluenethiopyrrolidone-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by rotary evaporation to remove the solvent. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 25 / 1) to give the target compound 1a in 90% yield. 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.0 Hz, 1H),7.36–7.24 (m, 5H), 7.06–6.99 (m, 4H), 6.87–6.84 (m, 2H), 6.76(d, J = 8.0 Hz,2H), 6.72 (d, J = 6.8 Hz, 1H), 6.67–6.58 (m, 1H), 2.71 (s, 3H), 2.27 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 142.8, 139.2, 138.2, 135.3, 133.9, 133.4, 133.1,130.6, 130.1, 130.0, 129.6, 127.4, 127.4, 125.3, 124.8, 123.1, 123.0, 112.2,108.5, 98.1, 20.9, 20.8, 19.7.

[0028] Example 2

[0029] 2,3-Dimethylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 1-p-toluenethiopyrrolidone-2,5-dione (0.6 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 25 / 1) to give the target compound 1a in 65% yield.

[0030] Example 3

[0031] 2,3-Dimethylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 1-p-toluenethiopyrrolidone-2,5-dione (0.9 mmol), and 1,4-dioxane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 25 / 1) to give the target compound 1a in 81% yield.

[0032] Example 4

[0033] 2,3-Dimethylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 1-p-toluenethiopyrrolidone-2,5-dione (0.9 mmol), and DMF (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (200-300 mesh silica gel, eluent: petroleum ether / ethyl acetate = 25 / 1) to give the target compound 1a in 75% yield.

[0034] Example 5

[0035] The reaction equation is shown below:

[0036]

[0037] 0.3 mmol of 5-ethyl-2-methylpyridine, 0.3 mmol of 2-bromoacetophenone, 0.9 mmol of 1-p-toluenethiopyrrolidone-2,5-dione, and 2 mL of 1,2-dichloroethane were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 30 / 1) to give the target compound 1b in 89% yield. 1H NMR (400 MHz, CDCl3) δ 8.23 ​​(s, 1H), 7.57 (d,J = 9.0 Hz, 1H), 7.36–7.25 (m, 5H), 7.13–7.08 (m, 3H), 7.01 (d, J = 8.0 Hz,2H), 6.83–6.73 (m, 4H), 2.55 (q, J = 8.1, 7.4 Hz, 2H), 2.21 (s, 3H), 2.17 (s,3H), 1.13 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 140.5, 137.6, 135.9,135.4, 134.2, 133.1, 132.4, 130.2, 130.1, 129.8, 129.1, 127.8, 127.5, 125.1,125.1, 124.8, 121.1, 117.0, 107.4, 96.3, 25.1, 20.4, 20.3, 14.9.

[0038] Example 6

[0039] The reaction equation is shown below:

[0040]

[0041] 0.3 mmol of 5-methoxy-2-methylpyridine, 0.3 mmol of 2-bromoacetophenone, 0.9 mmol of 1-p-toluenethiopyrrolidone-2,5-dione, and 2 mL of 1,2-dichloroethane were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 25 / 1) to give the target compound 1c in 85% yield. 1 H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.59 (d,J = 9.0 Hz, 1H), 7.34–7.26 (m, 5H), 7.15–7.06 (m, 3H), 7.01 (d,J = 8.0 Hz,2H), 6.82–6.73 (m, 4H), 3.81 (s, 2H), 2.21 (s, 3H), 2.16 (s, 3H); 13C NMR (100MHz, CDCl3) δ 140.6, 137.6, 135.7, 135.3, 134.3, 133.2, 132.5, 130.3, 130.1,129.7, 129.1, 127.6, 127.4, 125.1, 125.1, 124.6, 121.1, 117.1, 107.4, 96.3,55.3 20.5, 20.4.

[0042] Example 7

[0043] The reaction equation is shown below:

[0044]

[0045] 2-Methylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 1-p-toluenethiopyrrolidone-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 20 / 1) to give the target compound 1d, with a yield of 82%. 1 H NMR (CDCl3, 400 MHz) δ 8.49 (d, J = 7.0 Hz, 1H); 7.85 (d, J = 9.0 Hz, 1H); 7.53–7.42 (m, 2H); 7.40–7.25 (m, 3H); 7.12–6.94 (m, 5H); 6.87 (d, J = 8.2 Hz, 2H); 6.74 (d, J = 8.2 Hz, 2H); 6.69 (td, J = 7.0,1.0 Hz, 1H); 2.34–2.29 (m, 6H); 13 C NMR (100 MHz, CDCl3) δ 141.4, 139.3,136.4, 135.6, 134.4, 133.2, 133.0, 130.6, 130.3, 130.1, 127.5, 127.8, 125.6,125.2, 124.5, 122.4, 118.2, 112.1, 107.8, 97.5, 20.7, 20.5.

[0046] Example 8

[0047] The reaction equation is shown below:

[0048]

[0049] 2-Methylpyridine (0.3 mmol), 2-bromo-4'-methylacetophenone (0.3 mmol), 1-p-toluenethiopyrrolidone-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by rotary evaporation to remove the solvent. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 25 / 1) to give the target compound 1e in 78% yield. 1 H NMR (CDCl3, 400 MHz) δ 8.31 (d, J = 7.0 Hz,1H); 7.68 (d, J = 8.9 Hz, 1H); 7.29 (d, J = 8.0 Hz, 2H); 7.25–6.97 (m, 12H); 6.89 (d, J = 7.4 Hz, 2H); 6.73 (td, J = 6.8, 1.0 Hz, 1H); 2.30 (s, 3H); 13 CNMR (100 MHz, CDCl3) δ 141.6, 140.2, 139.5, 137.2, 136.9, 130.4, 130.1,129.4, 128.6, 128.4, 125.4, 125.2, 125.1, 124.7, 124.4, 122.0, 117.8, 112.5,107.3, 97.1, 21.5.

[0050] Example 9

[0051] The reaction equation is shown below:

[0052]

[0053] 2-Methylpyridine (0.3 mmol), 2-bromo-4'-methoxyacetophenone (0.3 mmol), 1-p-tolylthiopyrrolidone-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (200-300 mesh silica gel, eluent: petroleum ether / ethyl acetate = 15 / 1) to give the target compound 1f in 75% yield.1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.0Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.42–7.36 (m, 2H), 7.07–6.97 (m, 5H), 6.93–6.84 (m, 4H), 6.80 (d, J = 8.0 Hz, 2H), 6.75–6.65 (m, 1H), 3.79 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 159.1, 141.2, 139.3,136.7, 135.4, 134.3, 133.0, 131.5, 130.1, 129.6, 125.8, 125.4, 125.3, 124.4,122.0, 117.7, 113.2, 112.6, 107.7, 97.6, 55.3, 20.9, 20.8.

[0054] Example 10

[0055] The reaction equation is shown below:

[0056]

[0057] 2-Methylpyridine (0.3 mmol), 2-bromo-4'-fluoroacetophenone (0.3 mmol), 1-p-toluenethiopyrrolidone-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by rotary evaporator to remove the solvent, and the residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15 / 1) to give 1 g of the target compound, with a yield of 88%. 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.0 Hz,1H), 7.71 (d, J = 8.0 Hz, 1H), 7.45–7.37 (m, 2H), 7.06 – 6.93 (m, 7H), 6.85(d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 6.76–6.71 (m, 1H), 2.29 (s,3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ162.4 (d, J = 246.8 Hz), 140.4,139.2, 136.4, 135.6, 134.4, 132.9, 132.2 (d, J = 8.1 Hz), 130.1, 129.6, 129.3 (d, J = 3.3 Hz), 125.5, 125.3, 124.5, 122.4, 117.9, 114.8 (d, J = 21.3 Hz), 112.8, 108.1, 97.6, 20.9, 20.8.

[0058] Example 11

[0059] The reaction equation is shown below:

[0060]

[0061] 2-Methylpyridine (0.3 mmol), 2,4'-dibromoacetophenone (0.3 mmol), 1-p-toluenethiopyrrolidone-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15 / 1) to obtain the target compound in 1 h, with a yield of 86%. 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.46–7.39 (m, 2H), 7.34–7.29(m, 2H), 7.06–6.97 (m,5H), 6.90 (d, J = 8.0 Hz, 2H), 6.81–6.73 (m, 3H), 2.25 (s, 3H), 2.23 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 140.1, 139.4, 136.2, 135.7, 134.5, 132.5, 132.2,132.0, 130.9, 130.2, 129.6, 125.4, 125.2, 124.5, 122.2, 121.7, 117.9, 112.8,108.1, 97.7, 20.9, 20.7.

[0062] Example 12

[0063] The reaction equation is shown below:

[0064]

[0065] 2-Methylpyridine (0.3 mmol), 2-naphthylbromomethyl ketone (0.3 mmol), 1-p-toluenethiopyrrolidone-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 12 / 1) to give the target compound 1i in 73% yield. 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 7.0 Hz, 1H), 7.85 (s, 1H), 7.80 –7.74 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.2Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.49–7.38 (m, 2H), 7.07–6.98 (m, 5H), 6.95–6.91 (m, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.76–6.70 (m, 1H), 2.25 (s, 3H),2.24 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 141.3, 139.4, 136.5, 135.5, 134.6,133.0, 132.9, 132.7, 130.8, 130.1, 129.8, 129.5, 128.5, 128.3, 127.6, 127.1,125.9, 125.7, 125.6, 125.5, 124.5, 122.1, 117.9, 112.7, 108.5, 98.3, 20.9,20.7.

[0066] Example 13

[0067] The reaction equation is shown below:

[0068]

[0069] 2-Methylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 1-(4-methoxyphenylthio)-pyrrolline-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 20 / 1) to give the target compound 1j in 87% yield. 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 7.0 Hz,1H), 7.72 (d, J = 8.0 Hz, 1H), 7.49–7.43 (m, 2H), 7.40–7.33 (m, 3H), 7.07–6.9(m, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.77–6.71(m,5H), 3.75 (s, 3H), 3.73 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 158.1, 157.5,141.1, 138.9, 133.4, 130.7, 127.8, 127.7, 127.4, 127.1, 126.8, 124.4, 121.8,117.9, 114.8, 114.5, 112.5, 108.8, 99.1, 55.3, 55.2

[0070] Example 14

[0071] The reaction equation is shown below:

[0072]

[0073] 2-Methylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 1-(4-chlorophenylthio)-pyrrololin-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 12 / 1) to give the target compound 1K in 91% yield. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 7.0 Hz, 1H),7.65 (d, J = 8.0 Hz, 1H), 7.43–7.33 (m, 5H), 7.24–7.13 (m, 4H), 7.10–7.04 (m,1H), 6.89 (d, J = 8.5 Hz, 2H), 6.83–6.75 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ141.8, 139.5, 138.6, 135.1, 132.7, 131.6, 130.5, 130.3, 129.3, 128.9, 127.8,127.7, 126.6, 126.5, 124.3, 122.6, 117.0, 113.1, 107.4, 97.4.

[0074] Example 15

[0075] The reaction equation is shown below:

[0076]

[0077] 2-Methylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 1-(4-trifluoromethylphenylthio)-pyrrolline-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 10 / 1) to give 1 L of the target compound, with a yield of 93%. 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 7.0 Hz,1H), 7.69 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.0 Hz,2H), 7.40–7.33 (m, 5H), 7.16–7.11 (m, 1H), 7.06 (d, J = 8.2 Hz, 2H), 6.97 (d,J = 8.2 Hz, 2H), 6.85–6.80 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 145.2, 142.3,141.7, 139.5, 132.6, 130.2, 128.1, 128.0, 127.8, 126.9, 126.6 (q, J =276.6Hz), 126.6, 126.3 (q, J = 4.0 Hz), 125.6 (q, J = 4.0 Hz), 124.9(d, J =10.6 Hz), 124.5, 124.2(q, J = 272.6Hz), 123.1, 117.8, 113.4, 106.5, 96.3.

[0078] Example 16

[0079] The reaction equation is shown below:

[0080]

[0081] 2-Methylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 2-naphthylmercaptopyrrolidone-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 15 / 1) to give the target compound 1 M in 75% yield. 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 7.0 Hz, 1H), 7.82-7.65 (m, 5H), 7.62 –7.55 (m, 2H), 7.53–7.47 (m, 2H), 7.44–7.35 (m, 5H), 7.32–7.23 (m, 5H), 7.13 (dd, J = 8.6, 2.0 Hz, 1H), 7.09–6.98 (m, 1H), 6.72 (t, J =6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 141.9, 139.6, 137.8, 134.1, 133.8,133.7, 133.1, 131.5, 131.1, 130.4, 129.1, 128.3, 127.8, 127.7, 127.7, 127.6,127.0, 126.8, 126.6, 126.4, 125.5, 125.0, 124.6, 124.3, 123.7, 123.1, 122.7,122.4, 117.9, 112.8, 107.7, 97.3.

[0082] Example 17

[0083] The reaction equation is shown below:

[0084]

[0085] 2-Methylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 1-n-butylthiopyrrolidone-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 30 / 1) to give the target compound 1n in 80% yield. 1 H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 7.0, 1.0 Hz, 1H),7.73–7.70 (m, 1H), 7.62–7.55 (m, 2H), 7.47–7.41 (m, 2H), 7.39–7.32 (m, 1H), 6.96–6.91 (m, 1H), 6.75–6.70 (m, 1H), 2.45 (t, J = 7.0 Hz, 2H), 2.39 (t, J =7.0 Hz, 2H), 1.30–1.19 (m, 8H), 0.72 (t, J = 7.2, 2.7 Hz, 3H), 0.70 (t, J =7.2, 2.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 139.9, 137.8, 134.5, 131.1,127.7, 126.9, 124.1, 120.2, 117.9, 111.6, 111.3, 101.2, 36.8, 35.3, 31.4,31.2, 21.5, 21.4, 13.6, 13.5.

[0086] Example 18

[0087] The reaction equation is shown below:

[0088]

[0089] 2-Methylpyridine (0.3 mmol), 2-bromoacetophenone (0.3 mmol), 2-thiophenethio-pyrrolline-2,5-dione (0.9 mmol), and 1,2-dichloroethane (2 mL) were added to a 25 mL reaction flask equipped with a magnetic stirrer. After addition, the reaction mixture was refluxed at 90 °C for 10 hours. After the reaction was complete, the organic phase was purified by removing the solvent using a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel mesh 200-300 mesh, eluent: petroleum ether / ethyl acetate = 25 / 1) to give the target compound 1o in 83% yield. 1 H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.60–7.52 (m, 2H), 7.47–7.40 (m, 3H), 7.13 (d, J = 4.0Hz, 1H), 7.09–7.04 (m, 2H), 6.90–6.82 (m, 2H), 6.79–6.72 (m, 3H); 13 C NMR (100MHz, CDCl3) δ 139.9, 138.8, 138.1, 134.8, 133.3, 131.1, 129.4, 128.5, 127.8,127.6, 127.4, 127.4, 127.1, 126.6, 124.3, 122.0, 117.8, 112.6, 110.3, 101.5.

[0090] Example 19: In vitro antituberculosis activity and MIC determination of the compound.

[0091] The in vitro antibacterial activity of the target compound 1a-1o against standard strains of Mycobacterium tuberculosis, susceptible strains of Mycobacterium tuberculosis, and drug-resistant strains of Mycobacterium tuberculosis was determined using the micro-dilution method. The specific procedures are as follows:

[0092] Standard strains of Mycobacterium tuberculosis (H37Rv), clinical isolates of susceptible Mycobacterium tuberculosis (STB-MTB), and clinical isolates of drug-resistant Mycobacterium tuberculosis (MDR-MTB) were selected and cultured for 2-3 weeks to prepare bacterial suspensions. These suspensions were inoculated into 7H9 medium containing 0.05% Tween 80 and 10% ADC. 200 μL of the diluted bacterial suspension was added to each well of a 96-well plate, followed by serially diluted compound 1a-1o. After static incubation for 10 days, the results were observed. The minimum inhibitory concentration (MIC) at which bacterial growth was completely inhibited in the wells was defined as the minimum inhibitory concentration. A negative control group (7H9 medium containing the same DMSO content) and a positive control group (isoniacinamide (INH) at the same concentration gradient as the compound) were also set up. Specific experimental results are shown in the table below.

[0093] compound MIC value of H37Rv (μg / mL) MIC value of STB-MTB (μg / mL) MIC value of MDR-MTB (μg / mL) INH 0.039 0.061 >50 1a 0.045 0.053 0.067 1b 0.037 0.055 0.059 1c 0.033 0.048 0.047 1d 0.037 0.062 0.081 1e 0.040 0.059 0.090 1f 0.027 0.037 0.073 1g 0.031 0.046 0.064 1h 0.041 0.064 0.082 1i 0.034 0.036 0.051 1j 0.024 0.047 0.043 1k 0.042 0.071 0.074 1l 0.025 0.031 0.038 1m 0.043 0.044 0.069 1n 0.038 0.038 0.053 1o 0.021 0.029 0.032

[0094] Note: H37Rv: Standard strain; STB-MTB: Sensitive strain; MDR-MTB: Drug-resistant strain, resistant to isoniazid and rifampin.

[0095] The test results showed that most of the compounds of this invention exhibited significant antibacterial activity in the in vitro inhibition experiment of Mycobacterium tuberculosis, effectively inhibiting bacterial growth. Furthermore, most compounds showed superior activity against clinically resistant strains compared to the control drug isoniazid. In particular, compound 1o achieved MIC values ​​of 0.021 μg / mL, 0.029 μg / mL, and 0.032 μg / mL against H37Rv, STB-MTB, and MDR-MTB strains, respectively, demonstrating excellent potential against drug-resistant Mycobacterium tuberculosis.

[0096] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A catalyst-free method for preparing 1,3-dithioindoleazine compounds, characterized in that: The method is as follows: using 2-methylpyridine (as shown in formula (I), α-bromoketone (as shown in formula (II), and N-thiosuccinimide (as shown in formula (III)) as raw materials in an organic solvent, a reflux reaction is carried out to obtain a 1,3-dithioindoleazine compound (as shown in formula (IV), and the reaction equation is as follows: ， Among them, substituent R 1 Hydrogen atom, halogen, C1-C 10 Alkyl, alkoxy; R 2 The phenyl group is phenyl, naphthyl, or a phenyl group substituted with one or more substituents, wherein the substituents are alkoxy, alkyl, or halogen; R 3 For C1-C 10 Alkyl, 3-6 carbocyclic alkyl, naphthyl, furanyl, phenyl, phenyl with one substituent, wherein the substituent is halogen, alkyl, alkoxy, or cyano.

2. The method for preparing 1,3-dithioindoleazine compounds without a catalyst according to claim 1, characterized in that, The molar ratio of 2-methylpyridine with structure (I), α-bromoketone with structure (II), and N-thiosuccinimide with structure (III) is 1:1:2-3.

3. The method for preparing 1,3-dithioindoleazine compounds without a catalyst according to claim 2, characterized in that, The molar ratio of 2-methylpyridine (I), α-bromoketone (II), and N-thiosuccinimide (III) is 1:1:

3.

4. The method for preparing 1,3-dithioindoleazine compounds without a catalyst according to claim 1, characterized in that, The organic solvent is selected from one of 1,2-dichloroethane, 1,4-dioxane, toluene, N,N-dimethylformamide, or dimethyl sulfoxide.

5. The method for preparing 1,3-dithioindoleazine compounds without a catalyst according to claim 1, characterized in that, The reflux reaction temperature is 90℃, and the reaction time is 4-10 hours.

6. The method for preparing 1,3-dithioindoleazine compounds without a catalyst according to claim 1, characterized in that, After stirring and reaction, the mixture was concentrated under reduced pressure and separated by column chromatography. A mixture of petroleum ether and ethyl acetate was used as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate was 30–10:

1.

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a 1,3-dithioindoleazine compound prepared according to the method of claim 1, a medically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

8. The use of a pharmaceutical composition according to claim 7, characterized in that, The pharmaceutical composition is used to prepare a medicine for the prevention and / or treatment of tuberculosis.

9. The application of the pharmaceutical composition according to claim 8, characterized in that, The Mycobacterium tuberculosis includes standard strains of Mycobacterium tuberculosis, susceptible strains of Mycobacterium tuberculosis, or drug-resistant strains of Mycobacterium tuberculosis.

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