A substituted carbazole compound, its preparation method and application

Abstract

This application relates to a substituted carbazole compound, its preparation method, and its application, belonging to the field of chemical synthesis technology. The preparation method of the substituted carbazole compound of this application includes the following steps: dissolving 3-bromo-9-hydro-carbazole and arylboronic acid in a solvent, conducting a Suzuki coupling reaction under the presence of a palladium catalyst and an alkaline reagent, and obtaining the substituted carbazole compound after concentration to remove the solvent, washing, drying, and purification. This application provides a simple and mild synthetic method for the naturally active products 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole and 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole, which can only be extracted from the secondary metabolites of the natural mangrove endophyte *Alternaria longipes* strain, and whose sources are limited. Furthermore, this method uses widely available and inexpensive raw materials, which is beneficial for the large-scale industrial production of the naturally active products 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole and 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole.

Description

Technical Field

[0001] This application relates to the field of chemical synthesis technology, and in particular to a substituted carbazole compound, its preparation method, and its application. Background Technology

[0002] 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole and 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole are representative carbazole skeleton compounds extracted from the secondary metabolites of the natural mangrove endophyte *Alternaria longipes* strain. 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole exhibits significant anti-dengue virus activity. Currently, there is no specific treatment for dengue virus; therefore, compounds of 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole and 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole have the potential to become lead compounds for drug discovery, potentially leading to the development of effective new natural drugs.

[0003] ;

[0004] However, currently 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole and 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole can only be extracted from the fermentation broth of natural mangrove endophytic fungus (Alternaria longipes strain), and the source is very limited, which has always been a major obstacle for scientists to conduct research. Summary of the Invention

[0005] In view of this, this application provides a substituted carbazole compound, its preparation method and application, which can effectively overcome the shortcomings of existing 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole and 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole, which can only be extracted from the fermentation broth of natural mangrove endophytic fungus (Alternaria longipes strain), resulting in a very limited source.

[0006] The first aspect of this application provides a method for preparing substituted carbazole compounds, comprising the following steps:

[0007] 3-Bromo-9-hydro-carbazole was dissolved in a solvent with 2,5-dimethoxyphenylboronic acid or 2,6-dimethoxyphenylboronic acid, and a Suzuki coupling reaction was carried out in the presence of a palladium catalyst and a basic reagent. After concentration to remove the solvent, washing, drying and purification, substituted carbazole compounds were obtained.

[0008] Specifically, the synthetic route for substituted carbazole compounds is as follows:

[0009] .

[0010] Preferably, the specific conditions for the Suzuki coupling reaction are: the Suzuki coupling reaction is carried out under inert gas protection, the temperature of the Suzuki coupling reaction is 80~100℃, and the time of the Suzuki coupling reaction is 5h. More preferably, the temperature of the Suzuki coupling reaction is 90℃.

[0011] Preferably, the palladium catalyst is selected from at least one of tricyclohexylphosphine tetrafluoroborate, tetra(triphenylphosphine)palladium, palladium acetate, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, tris(dibenzylacetone)palladium, palladium chloride, bis(dibenzylacetone)palladium, bis(acetonitrile)palladium dichloride, bis(triphenylphosphine)palladium dichloride, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride dichloromethane complex, bis(benzonitrile)palladium dichloride, 1,4-bis(diphenylphosphine)butane palladium chloride, bis(acetonitrile)palladium dichloride, and allyl palladium chloride dimer. More preferably, the palladium catalyst is tetratriphenylphosphine palladium.

[0012] Preferably, the alkaline reagent is selected from at least one of potassium phosphonate, potassium carbonate, sodium carbonate, and cesium carbonate. More preferably, the alkaline reagent is sodium carbonate.

[0013] Preferably, the solvent is selected from at least one of water, ethanol, toluene, xylene, 1,4-dioxane, tetrahydrofuran, tetrahydropyran, pyridine, piperidine, phenol, chlorobenzene, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide. More preferably, the solvent is a mixed solution of water, ethanol, and toluene.

[0014] Preferably, the specific process of concentration and solvent removal is as follows: after the reaction is completed, the reaction mixture is cooled to room temperature and extracted with ethyl acetate; the organic layer is collected, and then the organic layer is washed with saturated sodium chloride solution, the solvent is removed by rotary evaporation under reduced pressure, and purified by rapid chromatography to obtain a white solid product.

[0015] Preferably, the washing and drying process is as follows: the white solid product is repeatedly extracted three times with ethyl acetate, the organic phase is collected, the organic phase is washed with saturated sodium chloride solution, and concentrated and dried by rotary evaporation under reduced pressure.

[0016] Preferably, the purification process involves chromatography using a 200-300 mesh silica gel column.

[0017] A second aspect of this application also provides a substituted carbazole compound, wherein the substituted carbazole compound prepared by the above method includes 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole and 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole.

[0018] A third aspect of this application also provides the use of the aforementioned substituted carbazole compound in dengue virus drugs.

[0019] Compared with the prior art, this application has the following advantages:

[0020] This application provides a method for synthesizing the natural active products 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole (i.e., compound A) and 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole (i.e., compound B). This method offers a simple and mild synthetic approach for these naturally active products, which are limited in origin and can only be extracted from the secondary metabolites of the natural mangrove endophyte *Alternaria longipes* strain. Furthermore, the method utilizes widely available and inexpensive raw materials, facilitating large-scale industrial production of these products and laying a solid foundation for related activity studies. Attached Figure Description

[0021] To more clearly illustrate the technical solutions in this application or the prior art, the drawings used in the description of this application or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0022] Figure 1 The hydrogen spectrum of 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole;

[0023] Figure 2 The carbon spectrum of 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole;

[0024] Figure 3 The hydrogen spectrum of 3-(2,6-dimethoxyphenyl)-9-hydrocarbazole;

[0025] Figure 4 The carbon spectrum of 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of this application clearer, the technical solutions of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0027] Unless otherwise specified, the experimental methods used in the embodiments of this application are all conventional methods.

[0028] In the following examples, unless otherwise specified, all raw materials can be obtained by commercial purchase or conventional methods.

[0029] Example 1: Synthesis of 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole

[0030] ;

[0031] S1. Compound 1 was reacted with 2,5-dimethoxyphenylboronic acid reagent to give compound 2. Compound 1 (0.10 g (1.0 mmol) of 3-bromo-9-hydro-carbazole, 0.088 g (1.2 mmol) of arylboronic acid, 0.129 g (3.0 mmol) of sodium carbonate, and 0.023 g (0.05 mmol) of tetraphenylphosphine palladium was placed in a 10 mL flask and dissolved in a solvent of water:ethanol:toluene = 1:1:2 mL. The mixture was heated at 90 °C for 5 hours. The reaction was monitored by thin-layer chromatography (TLC, PE / EA = 10:1). After the reaction was complete, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL × 3). The organic layer was collected, washed with saturated sodium chloride solution, and the solvent was removed by rotary evaporation under reduced pressure. The organic layer was then purified by rapid chromatography (petroleum ether / ethyl acetate = 40:1 to 5:1) to give a white solid compound (yield 85%).

[0032] Following the above method, 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole was prepared using different reaction systems, and the results are shown in Table 1.

[0033] Pd(OAc)2: Palladium acetate; PdCl2(dppf): [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride;

[0034] Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium dichloride; Pd2(dba)3: tris(dibenzylpyridinium acetone)palladium dichloride;

[0035] Pd(PPh3)4: Tetra(triphenylphosphine)palladium;

[0036] Table 1. Preparation of 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole under different conditions

[0037]

[0038] As shown in Table 1, the above conditions can all yield the product 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole. Table 1 also shows that tetra-triphenylphosphine palladium has a higher yield than other palladium catalysts. However, the yield decreases when the amount of tetra-triphenylphosphine palladium added decreases. At 80℃, the byproducts increase significantly, and the yield is significantly lower than at 90℃. The 1H and 1C spectra of 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole are shown below. Figure 1 and Figure 2 As shown.

[0039] 1 H NMR (400 MHz, Chloroform-d) δ 8.25 (s, 1H), 8.12 (d, J = 7.8 Hz,2H), 7.64 (dd, J = 8.4, 1.7 Hz, 1H), 7.50-7.41 (m, 3H), 7.06 (d, J = 3.1 Hz,1H), 6.99 (d, J = 8.9 Hz, 1H), 6.89 (dd, J = 8.9, 3.1 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H).

[0040] 13 CNMR (101 MHz, Chloroform-d) δ 153.87, 150.99, 139.86, 138.73,132.65, 129.81, 127.67, 125.84, 123.57, 123.36, 121.20, 120.40, 119.48,117.18, 112.88, 112.56, 110.63, 110.05, 56.51, 55.86.

[0041] Example 2: Synthesis of 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole

[0042] ;

[0043] S2. Compound 1 was reacted with 2,6-dimethoxyphenylboronic acid reagent via a substitution reaction to give compound 3; compound 1 (3-bromo-9-hydro-carbazole 0.10) was then reacted with the 2,6-dimethoxyphenylboronic acid reagent to give compound 3. 0.088 g (1.2 mmol) of arylboronic acid, 0.129 g (3.0 mmol) of sodium carbonate, and 0.023 g (0.05 mmol) of tetrakis(triphenylphosphine)palladium were placed in a 10 mL flask and dissolved in a solvent of water:ethanol:toluene = 1:1:2 mL. The mixture was heated at 90 °C for 5 hours. The reaction was monitored by thin-layer chromatography (TLC, PE / EA = 10:1). After the reaction was complete, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL × 3). The organic layer was collected, washed with saturated sodium chloride solution, and the solvent was removed by rotary evaporation under reduced pressure. The organic layer was then purified by rapid chromatography (using a 200–300 mesh silica gel column) (petroleum ether / ethyl acetate = 40:1 to 5:1) to give a white solid compound 3 (yield 86%).

[0044] Following the method described above, 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole was prepared under different conditions, and the results are shown in Table 2.

[0045] Pd(PPh3)4: Tetra(triphenylphosphine)palladium;

[0046] Table 2. Preparation of 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole under different conditions

[0047]

[0048] As shown in Table 2, the product 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole can be prepared under all the above conditions. However, when toluene / ethanol / water is used as the solvent, sodium carbonate is used as the basic reagent, resulting in the highest yield. The proton and carbon spectra of 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole are shown below. Figure 3 and Figure 4 As shown.

[0049] 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.38 (d, J = 9.1 Hz, 1H), 7.31(t, J = 8.4 Hz, 1H), 7.20 (ddd, J = 8.0, 6.6, 1.6 Hz, 1H), 6.71 (d, J = 8.4Hz, 2H), 3.75 (s, 6H).

[0050] 13 CNMR (101 MHz, Chloroform-d) δ 158.06, 139.79, 138.57, 128.89,128.30, 125.54, 125.05, 123.74, 123.25, 122.66, 120.41, 120.36, 119.24,110.48, 109.91, 104.40, 56.03.

[0051] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A method for preparing a substituted carbazole compound, characterized in that, Includes the following steps: 3-Bromo-9-hydro-carbazole was dissolved in a solvent with 2,5-dimethoxyphenylboronic acid or 2,6-dimethoxyphenylboronic acid, and a Suzuki coupling reaction was carried out in the presence of a palladium catalyst and a basic reagent. After concentration to remove the solvent, washing, drying and purification, substituted carbazole compounds were obtained.

2. The method for preparing substituted carbazole compounds according to claim 1, characterized in that, The specific conditions for the Suzuki coupling reaction are as follows: the Suzuki coupling reaction is carried out under inert gas protection, the temperature of the Suzuki coupling reaction is 80~100℃, and the time of the Suzuki coupling reaction is 5h.

3. The method for preparing substituted carbazole compounds according to claim 1, characterized in that, The palladium catalyst is selected from at least one of tricyclohexylphosphine tetrafluoroborate, tetra(triphenylphosphine)palladium, palladium acetate, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, tris(dibenzylacetone)palladium, palladium chloride, bis(dibenzylacetone)palladium, bis(acetonitrile)palladium dichloride, bis(triphenylphosphine)palladium dichloride, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride dichloride dichloromethane complex, bis(benzonitrile)palladium dichloride, 1,4-bis(diphenylphosphine)butane palladium chloride, bis(acetonitrile)palladium dichloride, and allyl palladium chloride dimer.

4. The method for preparing substituted carbazole compounds according to claim 1, characterized in that, The alkaline reagent is selected from at least one of potassium phosphonate, potassium carbonate, sodium carbonate, and cesium carbonate.

5. The method for preparing substituted carbazole compounds according to claim 1, characterized in that, The solvent is selected from at least one of water, ethanol, toluene, xylene, 1,4-dioxane, tetrahydrofuran, tetrahydropyran, pyridine, piperidine, phenol, chlorobenzene, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide.

6. The method for preparing substituted carbazole compounds according to claim 1, characterized in that, The specific process of concentration and solvent removal is as follows: after the reaction is completed, the reaction mixture is cooled to room temperature and extracted with ethyl acetate; the organic layer is collected, and then the organic layer is washed with saturated sodium chloride solution, the solvent is removed by rotary evaporation under reduced pressure, and purified by rapid chromatography to obtain a white solid product.

7. The method for preparing substituted carbazole compounds according to claim 6, characterized in that, The specific washing and drying process is as follows: the white solid product is repeatedly extracted three times with ethyl acetate, the organic phase is collected, the organic phase is washed with saturated sodium chloride solution, and concentrated and dried by rotary evaporation under reduced pressure.

8. The method for preparing substituted carbazole compounds according to claim 6, characterized in that, The specific purification process is as follows: chromatography using a 200-300 mesh silica gel column.

9. A substituted carbazole compound, characterized in that, The substituted carbazole compound prepared by the method according to any one of claims 1 to 8, wherein the substituted carbazole compound includes 3-(2,5-dimethoxyphenyl)-9-hydro-carbazole and 3-(2,6-dimethoxyphenyl)-9-hydro-carbazole.

10. The use of the substituted carbazole compound of claim 9 in dengue virus drugs.

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