Tetraarylmethane compound with indole and pyrrole skeletons and synthesis method of tetraarylmethane compound

Abstract

The invention relates to a tetraarylmethane compound with indole and pyrrole frameworks and a synthesis method thereof. The chemical structural formula of the compound is shown as a formula 3. The synthesis method comprises the following steps: adding 2-indolyl carbinol and a pyrrole derivative as reaction raw materials into an organic solvent, stirring and reacting at room temperature under the catalysis of Bronsted acid or Lewis acid in the presence of an additive # imgabs0 # molecular sieve, tracking the reaction by TLC until the reaction is complete, filtering, concentrating and purifying to obtain the 2-indolyl carbinol derivative. According to the tetraarylmethane compound with indole and pyrrole frameworks synthesized by the invention, a biological activity test shows that the derivative has relatively high sensitivity and very strong cytotoxic activity on human liver cancer cells HepG2. According to the method, reaction conditions are relatively conventional, the reaction process is mild, simple and convenient, the cost is low, the method is suitable for industrial large-scale production, and the application range of the method is widened; various substrates are used as reactants, products with various structures are obtained, and the yield is high. # imgabs1 #

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a tetraarylmethane compound having both indole and pyrrole skeletons and a synthesis method thereof. Background Art

[0002] Indole, pyrrole and tetraarylmethane compounds are widely present in compounds and natural products with anti-tumor and other drug activities, and have broad application prospects in the field of life sciences. Introducing indole, pyrrole and tetraarylmethane skeletons into one compound is expected to obtain compounds with good anti-tumor activity. Tetraarylmethane compounds with both indole and pyrrole skeletons are a class of compounds that have never been studied, and no one has studied the synthesis methods of these compounds and their cytotoxicity to human liver cancer cells HepG2. Summary of the invention

[0003] One of the purposes of the present invention is to provide a tetraarylmethane compound having both indole and pyrrole skeletons, wherein the tetraarylmethane compound having both indole and pyrrole skeletons has good sensitivity and cytotoxic activity to human liver cancer cells HepG2.

[0004] The second object of the present invention is to provide a method for synthesizing the above-mentioned tetraarylmethane compounds having both indole and pyrrole skeletons, which method has a mild reaction process, is simple, safe and easy to operate, and has the advantages of low cost and high yield.

[0005] To achieve the above object, the technical solution adopted by the present invention is: a tetraarylmethane compound having both indole and pyrrole skeletons, whose chemical structure is shown in Formula 3:

[0006]

[0007] In Formula 3, R is selected from one of hydrogen, C1-C2 alkyl, C1-C2 alkoxy, and halogen; R 1 and R 2 are selected from phenyl, halogen-substituted phenyl, C1-C2 alkyl-substituted phenyl, C1-C2 alkoxy-substituted phenyl, naphthyl, and C1-C2 alkyl; R 3 One selected from hydrogen and C1-C2 alkyl.

[0008] The present invention also provides a method for synthesizing the tetraarylmethane compound having both indole and pyrrole skeletons, which specifically comprises the following steps: adding 2-indole methanol of the compound of formula 1 and the pyrrole derivative of the compound of formula 2 as reaction raw materials into an organic solvent, stirring and reacting for 5-12 hours at room temperature under the catalysis of Bronsted acid or Lewis acid and in the presence of additives, tracking the reaction by TLC until the reaction is complete, filtering, concentrating and purifying to obtain the compound of formula 3;

[0009] The molar ratio of the compound 2-indolecarbinol of formula 1 to the pyrrole derivative of the compound 2 is 1:1.2, the molar ratio of the compound 2-indolecarbinol of formula 1 to the catalyst is 1:(0.05-0.2); the molar ratio of the compound 2-indolecarbinol of formula 1 to the additive is The ratio of molecular sieve is 1.0mmol:1.0g;

[0010] The structural formula of the compound 2-indolecarbinol of formula 1 is In Formula 1, R is selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, and halogen; R 1 and R 2 Each of them is selected from the group consisting 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 the compound of formula 2 is In formula 2, R 3 One selected from hydrogen and C1-C2 alkyl.

[0012] Preferably, the molar ratio of the compound 2-indolemethanol of formula 1 to the catalyst is 1:0.1.

[0013] Preferably, the Bronsted acid is selected from one of diphenylphosphoric acid, benzoic acid, diphenoxyphosphoric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid; and 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 one of acetonitrile, acetone, ethyl acetate, 1,2-dichloroethane, toluene and tetrahydrofuran; the ratio of the volume of the organic solvent to the molar amount of the compound 2-indolemethanol 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 / ethyl acetate in 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 synthesized by the present invention with both indole and pyrrole skeletons have been shown to have high sensitivity and strong cytotoxic activity against human liver cancer cells HepG2 through biological activity tests, indicating that the tetraarylmethane compounds synthesized by the present invention with both indole and pyrrole skeletons are expected to be applied in the medical field;

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

[0022] The present invention is further described in detail below in conjunction with embodiments.

[0023] In the following examples, unless otherwise specified, 2-indolecarbinol, pyrrole derivatives, catalysts and other reagents can be purchased from the market or obtained according to known literature reports; the experimental methods are usually carried out under conventional conditions or conditions recommended by the manufacturer.

[0024] Example 1

[0025] The synthesis route of the tetraarylmethane compound 3aa having both indole and pyrrole skeletons is as follows:

[0026]

[0027] 0.1 mmol of 2-indole methanol (Formula 1a) and 0.12 mmol of pyrrole derivative (Formula 2a) were added as reactants in 1 mL of solvent. 0.005-0.02 mol (5%-20 mol% of 2-indole methanol) of catalyst and 100 mg of In the presence of molecular sieves, the reaction was stirred at room temperature for 5-12 hours, and the reaction was monitored by TLC until completion. 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 of formula 3aa having both indole and pyrrole skeletons. The reaction conditions and yields are shown in Table 1.

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

[0029]

[0030]

[0031] From the data in Table 1, it can be concluded that the optimal reaction conditions are: the catalyst is copper trifluoromethanesulfonate, the catalytic amount is 10% moml, the solvent is 1,2-dichloroethane, and the reaction time is 12 hours.

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

[0033] 0.1 mmol of 2-indolecarbinol 1a and 0.12 mmol of pyrrole derivative 2a were added as reactants in 1 mL of solvent. 0.01 mol (10 mol% of 2-indolecarbinol) of catalyst and 100 mg of In the presence of molecular sieves, the reaction was stirred at room temperature for 12 hours. The reaction was monitored by TLC until completion. 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 of formula 3aa having both indole and pyrrole skeletons.

[0034] The structural characterization data of the product 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 method of Example 2-19 is the same as the steps of obtaining the product 3aa of formula under the optimal reaction conditions in Example 1, except that 2-indole methanol with different structures is used as the raw material.

[0037] The reaction synthesis route is as follows:

[0038]

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

[0040] Table 2 Reaction materials, products, and yields of Examples 1-19

[0041]

[0042] Examples 20-23

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

[0044] The reaction synthesis route is as follows:

[0045]

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

[0047] Table 3 Reaction materials, products, and yields of Examples 1 and 20-23

[0048]

[0049] As can be seen from Tables 2 and 3, the method of the present invention can not only realize the synthesis of tetraarylmethane compounds having both indole and pyrrole skeletons in one step, obtain excellent yield, high atom economy, environmental friendliness, and a wide range of applications, but also has readily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-treatment, and diversified product structures, and thus has great implementation value and potential social and economic benefits.

[0050] The tetraarylmethane compounds having both indole and pyrrole skeletons of the present invention were tested for cytotoxic activity against human liver cancer cells Hep G2 at different concentrations by CCK8 method. The results are shown in Table 4.

[0051] IC 50Test experimental steps: Human liver cancer cells Hep G2 were seeded in a 96-well plate at a density of 5000 cells / 100μL culture medium per well. After the cells were cultured for 24 hours at 37°C and 5% CO2, the test compounds were added to the culture medium at final concentrations of 200, 100, 50, 25, 12.5, and 6.25μg / mL, and the cells were cultured for another 24 hours. Cells without compound addition served as the control group, and cells with only culture medium added served as the blank group. After the compound stimulation was completed, the culture medium was removed, and 100μL of DMEM culture medium containing 10% CCK8 was added to each well, incubated at 37°C for another hour, then the culture plate was shaken for 5s, and the optical density (OD) value was read at 450nm. The experiment was repeated three times, and finally the IC of the test compound was calculated using Originlab software. 50 value.

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

[0053]

[0054]

[0055] Note: IC in Table 4 50 Refers to the half-maximal inhibitory concentration.

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

Claims

1. A tetraarylmethane compound having both an indole and a pyrrole skeleton, characterized in that: Its chemical structure is shown in Formula 3: In Formula 3, R is selected from one of hydrogen, C1-C2 alkyl, C1-C2 alkoxy, and halogen; R 1 and R 2 are selected from phenyl, halogen-substituted phenyl, C1-C2 alkyl-substituted phenyl, C1-C2 alkoxy-substituted phenyl, naphthyl, and C1-C2 alkyl; R 3 One selected from hydrogen and C1-C2 alkyl.

2. A method for synthesizing a tetraarylmethane compound having both an indole and a pyrrole skeleton according to claim 1, characterized in that: The specific steps are: adding 2-indolecarbinol, a compound of formula 1, and a pyrrole derivative, a compound of formula 2, as reaction raw materials into an organic solvent, stirring and reacting for 5-12 hours at room temperature under the catalysis of Bronsted acid or Lewis acid and in the presence of additives, tracking the reaction by TLC until completion, filtering, concentrating, and purifying to obtain a compound of formula 3; The molar ratio of the compound 2-indolecarbinol of formula 1 to the pyrrole derivative of the compound 2 is 1:1.2, the molar ratio of the compound 2-indolecarbinol of formula 1 to the catalyst is 1:(0.05-0.2); the molar ratio of the compound 2-indolecarbinol of formula 1 to the additive is The ratio of molecular sieve is 1.0mmol:1.0g; The structural formula of the compound 2-indolecarbinol of formula 1 is In Formula 1, R is selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, and halogen; R 1 and R 2 Each of them is selected from the group consisting 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 the compound of formula 2 is In formula 2, R 3 One selected from hydrogen and C1-C2 alkyl.

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

1.

4. A method for synthesizing a tetraarylmethane compound having both an indole and a pyrrole skeleton according to claim 2 or 3, characterized in that: The Bronsted 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.

5. The method for synthesizing a tetraarylmethane compound having both indole and pyrrole skeletons according to claim 4, characterized in that: The Lewis acid is copper trifluoromethanesulfonate.

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

7. The method for synthesizing a tetraarylmethane compound having both indole and pyrrole skeletons according to claim 6, characterized in that: The organic solvent is 1,2-dichloroethane.

8. A method for synthesizing a tetraarylmethane compound having both an indole and a pyrrole skeleton according to claim 2 or 3, characterized in that: The reaction time is 12 hours.

9. The method for synthesizing a tetraarylmethane compound having both an indole and a pyrrole skeleton according to claim 2 or 3, characterized in that: The purification is performed by silica gel column chromatography, and the eluent is a petroleum ether / ethyl acetate mixture with a volume ratio of 20:1.

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