A tetraarylmethane compound with indole and pyrrole skeletons and a synthesis method thereof

Abstract

A tetraarylmethane compound possessing both indole and pyrrole skeletons and its synthetic method are disclosed. The chemical structural formula of the compound is shown in Formula 3. The synthetic method involves adding 2-indole-methanol and a pyrrole derivative as reactants to an organic solvent. Under the catalysis of Brønsted acid or Lewis acid and in the presence of molecular sieve additives, the reaction is stirred at room temperature. The reaction is monitored by TLC until complete, followed by filtration, concentration, and purification to obtain the final product. The tetraarylmethane compound possessing both indole and pyrrole skeletons synthesized in this invention exhibits high sensitivity and strong cytotoxic activity against HepG2 human liver cancer cells through bioactivity testing. The reaction conditions of this invention are relatively conventional, the reaction process is mild, simple, and low-cost, suitable for large-scale industrial production, thus broadening the applicability of this method. A variety of substrates are used as reactants, resulting in structurally diverse products with high yields.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a tetraarylmethane compound with both indole and pyrrole skeletons and its synthesis method. Background Technology

[0002] Indole, pyrrole, and tetraarylmethane compounds are widely found in compounds and natural products with antitumor and other pharmacological activities, and have broad application prospects in the life sciences. Introducing an indole, pyrrole, and tetraarylmethane skeleton into a single compound holds promise for obtaining compounds with good antitumor activity. Tetraarylmethane compounds possessing both indole and pyrrole skeletons are a class of compounds that have never been studied before, and their synthetic methods and cytotoxicity against HepG2 liver cancer cells have not yet been investigated. Summary of the Invention

[0003] One objective of this invention is to provide a tetraarylmethane compound that possesses both indole and pyrrole skeletons, which exhibits good sensitivity and cytotoxic activity against HepG2 human liver cancer cells.

[0004] The second objective of this invention is to provide a method for synthesizing the above-mentioned tetraarylmethane compounds that possess both indole and pyrrole skeletons. This method is mild, simple, safe and easy to operate, and has the advantages of low cost and high yield.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is: a tetraarylmethane compound possessing both indole and pyrrole skeletons, the chemical structural formula of which is shown in Formula 3:

[0006]

[0007] In Formula 3, R is selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, and halogen; R 1 and R 2 Each of the following is selected from phenyl, halogen-substituted phenyl, C1-C2 alkyl-substituted phenyl, C1-C2 alkoxy-substituted phenyl, naphthyl, and C1-C2 alkyl; R 3 It is selected from hydrogen and C1-C2 alkyl groups.

[0008] The present invention also provides a method for synthesizing the above-mentioned tetraarylmethane compounds with both indole and pyrrole skeletons. The specific steps are as follows: Compound 2-indole methanol of Formula 1 and pyrrole derivative of Formula 2 are added to an organic solvent as reaction raw materials. Under the catalysis of Brønsted acid or Lewis acid and in the presence of additives, the reaction is stirred at room temperature for 5-12 hours. The reaction is monitored by TLC until complete. The mixture is then filtered, concentrated, and purified to obtain compound of Formula 3.

[0009] The molar ratio between compound 2-indole methanol of formula 1 and the pyrrole derivative of formula 2 is 1:1.2, and the molar ratio between compound 2-indole methanol of formula 1 and the catalyst is 1:(0.05-0.2); the molar ratio between compound 2-indole methanol of formula 1 and the additive... The ratio of molecular sieves was 1.0 mmol: 1.0 g;

[0010] The structural formula of compound 2-indolemethyl is as follows: In Formula 1, R is selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, and halogen; R 1 and R 2 It is selected from one of phenyl, halogen-substituted phenyl, C1-C2 alkyl-substituted phenyl, C1-C2 alkoxy-substituted phenyl, naphthyl, and C1-C2 alkyl;

[0011] The structural formula of the pyrrole derivative of compound 2 is as follows: In Equation 2, R 3 It is selected from hydrogen and C1-C2 alkyl groups.

[0012] Preferably, the molar ratio of compound 2-indole-methanol of Formula 1 to the catalyst is 1:0.1.

[0013] Preferably, the Brønsted acid is selected from one of diphenylphosphoric acid, benzoic acid, diphenoxyphosphoric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid; the Lewis acid is copper trifluoromethanesulfonate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, and indium trifluoromethanesulfonate.

[0014] Preferably, the Lewis acid is copper trifluoromethanesulfonate.

[0015] Preferably, the organic solvent is selected from acetonitrile, acetone, ethyl acetate, 1,2-dichloroethane, toluene, and tetrahydrofuran; the volume ratio of the organic solvent to the molar amount of compound 2-indole-methanol of Formula 1 is 10 mL: 1 mmol.

[0016] Preferably, the organic solvent is 1,2-dichloroethane.

[0017] Preferably, the reaction time is 12 hours.

[0018] Preferably, the purification is performed by silica gel column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate at a volume ratio of 20:1.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] (1) The tetraarylmethane compounds with both indole and pyrrole skeletons synthesized in this invention, through bioactivity testing, show that these derivatives have high sensitivity and strong cytotoxic activity against human liver cancer cells HepG2, indicating that the tetraarylmethane compounds with both indole and pyrrole skeletons synthesized in this invention are expected to be applied in the pharmaceutical field.

[0021] (2) The reaction conditions for synthesizing tetraarylmethane compounds with both indole and pyrrole skeletons are relatively conventional. The reaction process is mild, simple, easy to operate, and low in cost, making it suitable for large-scale industrial production and broadening the scope of application of this method. The present invention uses a variety of substrates as reactants to obtain products with diverse and complex structures and high yields. Detailed Implementation

[0022] The present invention will be further described in detail below with reference to the embodiments.

[0023] In the examples below, unless otherwise stated, 2-indole-methanol, pyrrole derivatives, catalysts and other reagents are commercially available or obtained in accordance with known literature; the experimental methods are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0024] Example 1

[0025] The synthetic route for a tetraarylmethane compound of formula 3aa, which possesses both indole and pyrrole skeletons, is as follows:

[0026]

[0027] 0.1 mmol of 2-indolemethyl methanol (formula 1a) and 0.12 mmol of pyrrole derivative (formula 2a) were added to 1 mL of solvent as reactants. The reaction was carried out under the action of a 0.005-0.02 mol (5%-20 mol%) catalyst and 100 mg of [amount missing] [unclear - likely a specific chemical compound]. Under the condition of molecular sieve, the reaction was stirred at room temperature for 5-12 h. The reaction was monitored by TLC until the end. After filtration and concentration, the mixture was purified and separated by silica gel column chromatography (the eluent was a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1) to obtain a tetraarylmethane compound with both indole and pyrrole skeletons, formula 3aa. The reaction conditions and yields are shown in Table 1.

[0028] Table 1. Effects of different types of catalysts, solvents, and reaction time on reaction yield.

[0029]

[0030]

[0031] The optimal reaction conditions can be determined from the data in Table 1 as follows: the catalyst is copper trifluoromethanesulfonate, the catalyst amount is 10% mol / mL, the solvent is 1,2-dichloroethane, and the reaction time is 12 hours.

[0032] The steps for obtaining product formula 3aa under optimal reaction conditions in Example 1 are as follows:

[0033] 0.1 mmol of 2-indolemethyl methanol (formula 1a) and 0.12 mmol of pyrrole derivative (formula 2a) were added to 1 mL of solvent as reactants. The reaction was carried out under the action of a 0.01 mol (10 mol%) catalyst and 100 mg of [amount missing] [substance missing]. Under the condition of molecular sieve, the reaction was stirred at room temperature for 12 h, and the reaction was monitored by TLC until the end. After filtration and concentration, the mixture was purified and separated by silica gel column chromatography (the eluent was a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20:1) to obtain a tetraarylmethane compound with both indole and pyrrole skeletons, formula 3aa.

[0034] The structural characterization data of product formula 3aa obtained under the optimal reaction conditions in Example 1 are as follows:

[0035] white solid (71.8mg, 99% yield); mp211.3–211.7℃; IR (KBr): 3447,1594,1457,1387,1352,1122,782,764,702,617cm -1 ; 1 H NMR (400MHz, CDCl3) δ7.96 (s, 1H), 7.62 (s, 1H), 7.57 (d, J = 7.8Hz, 1H), 7.36–7.26 (m, 7H), 7.25–7.2 0(m,4H),7.20–7.15(m,1H),7.14–7.09(m,1H),6.33(s,1H),5.91(s,1H),5.88(s,1H),2.23(s,3H); 13 C NMR (100MHz, CDCl3) δ145.3,142.8,136.1,133.0,129.5,128.1,128.0,127.0 ,122.0,120.6,119.9,110.9,110.3,105.7,104.3,56.4,13.3; HRMS(ESI):m / z calcd for C 26 H 22 N2[MH] - :361.1710; found:361.1727

[0036] The synthesis methods of Examples 2-19 are the same as those of the product formula 3aa obtained under optimal reaction conditions in Example 1, except that 2-indole methanol with a different structure is used as the raw material.

[0037] The reaction synthesis route is shown below:

[0038]

[0039] The products and yields are shown in Table 2 below:

[0040] Table 2. Reactants, products, and yields of Examples 1-19

[0041]

[0042] Examples 20-23

[0043] The synthesis methods of Examples 20-23 are the same as those of the product formula 3aa obtained under optimal reaction conditions in Example 1, except that pyrrole derivatives with different structures are used as raw materials.

[0044] The reaction synthesis route is shown below:

[0045]

[0046] The products and yields are shown in Table 3 below:

[0047] Table 3. Reactants, products, and yields in Examples 1 and 20-23

[0048]

[0049] As shown in Tables 2 and 3, the method of the present invention can not only achieve the synthesis of tetraarylmethane compounds with both indole and pyrrole skeletons in one step, obtain excellent yields, high atom economy, environmental friendliness, and wide applicability, but also has readily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-processing, and diversified product structures. Therefore, it has great implementation value and potential social and economic benefits.

[0050] The tetraarylmethane compounds of the present invention, which possess both indole and pyrrole skeletons, were used to test the cytotoxic activity of the compounds synthesized in some examples against Hep G2 human liver cancer cells at different concentrations using the CCK8 method. The results are shown in Table 4.

[0051] IC 50Experimental Procedure: Hep G2 liver cancer cells were seeded at a density of 5000 cells / 100 μL of medium in 96-well plates and cultured at 37°C with 5% CO2 for 24 hours. Then, the test compound was added to the medium at concentrations of 200, 100, 50, 25, 12.5, and 6.25 μg / mL, and the cells were cultured for another 24 hours. Cells without the compound served as the control group, and cells with only medium served as the blank group. After the compound stimulation, the culture medium was removed, and 100 μL of DMEM medium containing 10% CCK8 was added to each well. The cells were incubated at 37°C for another hour, followed by shaking the plate for 5 seconds. The optical density (OD) value was read at 450 nm. The experiment was repeated three times. Finally, the IC50 of the test compound was calculated using Originlab software. 50 value.

[0052] Table 4. Cytotoxic activity of the compounds in this invention against HepG2 human liver cancer cells.

[0053]

[0054]

[0055] Note: IC in Table 4 50 The half-maximal inhibitory concentration (MCI) is the concentration of the inhibitory component of a drug.

[0056] As shown in Table 4, the tetraarylmethane compounds of the present invention, which possess both indole and pyrrole skeletons, exhibit excellent cytotoxic activity against Hep G2 human liver cancer cells, IC50. 50 The lowest value was 7.78 μg / mL.

Claims

1. A method for synthesizing a tetraarylmethane compound possessing both indole and pyrrole skeletons, characterized in that, The specific steps are as follows: Compound 2-indole methanol of Formula 1 and pyrrole derivative of Formula 2 are added to an organic solvent as reaction raw materials. Under the catalysis of Lewis acid copper trifluoromethanesulfonate and in the presence of 3Å molecular sieve additive, the reaction is stirred at room temperature for 5-12 hours. The reaction is monitored by TLC until complete. After filtration, concentration and purification, compound of Formula 3 is obtained. The molar ratio between compound 2-indole methanol of formula 1 and the pyrrole derivative of formula 2 is 1:1.2, the molar ratio between compound 2-indole methanol of formula 1 and the catalyst is 1:(0.05-0.2), and the ratio between compound 2-indole methanol of formula 1 and the additive 3Å molecular sieve is 1.0 mmol:1.0 g. The structural formula of compound 2-indolemethyl is as follows: In Formula 1, R is selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, and halogen; R 1 and R 2 It is selected from one of phenyl, halogen-substituted phenyl, C1-C2 alkyl-substituted phenyl, C1-C2 alkoxy-substituted phenyl, naphthyl, and C1-C2 alkyl; The structural formula of the pyrrole derivative of compound 2 is as follows: In Equation 2, R 3 Selected from hydrogen and C1-C2 alkyl groups; The chemical structural formula of compound 3 is as follows: In formula 3, R is selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, and halogen; R 1 and R 2 Each of the following is selected from phenyl, halogen-substituted phenyl, C1-C2 alkyl-substituted phenyl, C1-C2 alkoxy-substituted phenyl, naphthyl, and C1-C2 alkyl; R 3 It is selected from hydrogen and C1-C2 alkyl groups.

2. The method for synthesizing a tetraarylmethane compound possessing both indole and pyrrole skeletons according to claim 1, characterized in that, The molar ratio of compound 2-indole-methanol of Formula 1 to the catalyst is 1:0.

1.

3. A method for synthesizing a tetraarylmethane compound possessing both indole and pyrrole skeletons according to claim 1 or 2, characterized in that, The organic solvent is selected from acetonitrile, acetone, ethyl acetate, 1,2-dichloroethane, toluene, and tetrahydrofuran; the volume ratio of the organic solvent to the molar amount of compound 2-indole methanol of Formula 1 is 10 mL: 1 mmol.

4. The method for synthesizing a tetraarylmethane compound possessing both indole and pyrrole skeletons according to claim 3, characterized in that, The organic solvent is 1,2-dichloroethane.

5. A method for synthesizing a tetraarylmethane compound possessing both indole and pyrrole skeletons according to claim 1 or 2, characterized in that, The reaction time is 12 hours.

6. A method for synthesizing a tetraarylmethane compound possessing both indole and pyrrole skeletons according to claim 1 or 2, characterized in that, The purification was performed by silica gel column chromatography, with the eluent being a mixture of petroleum ether and ethyl acetate at a volume ratio of 20:1.

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