A chiral tetrahydroindolo[2,3-a]carbazole compound and its synthesis method

Abstract

The present invention discloses a chiral tetrahydroindolo[2,3-a]carbazole compound and a synthesis method thereof. The structural formula of the compound is shown as Formula 3. Using a 2,3-disubstituted indole methanol derivative and indole as reaction raw materials, benzene and its derivatives as reaction solvents, and chiral phosphoric acid as a catalyst, the reaction is stirred at 0 °C. The reaction is tracked by TLC until it is complete, and then filtered, concentrated, and purified to obtain the product. The method of the present invention has a mild reaction process, can obtain products with structural diversity and complexity, and has high enantioselectivity and high yield of the products. Through biological activity tests, it is shown that this type of compound has significant cytotoxic activity against PC-3 cancer cells and has application value in the research and development of new anti-tumor drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and particularly relates to a chiral tetrahydroindolo[3,2-c]carbazole compound and a synthesis method thereof. Background Art

[0002] Chiral tetrahydroindolo[3,2-c]carbazole compounds have broad application prospects in the field of life sciences. At the same time, since it is often one of the enantiomers in the racemate that plays a bioactive role in drug molecules, there is an urgent need to design new chiral tetrahydroindolo[3,2-c]carbazole compounds and develop efficient methods for synthesizing these chiral tetrahydroindolo[3,2-c]carbazole compounds. Currently, for the chiral tetrahydroindolo[3,2-c]carbazole compounds in the prior art, the cytotoxic activity research against PC-3 cancer cells is not sufficient and is almost in a blank stage; moreover, when synthesizing these chiral tetrahydroindolo[3,2-c]carbazole compounds, the reaction conditions are harsh, the steps are lengthy, indirectly resulting in problems such as high cost, low yield and low enantioselectivity. Summary of the Invention

[0003] The object of the present invention is to provide a chiral tetrahydroindolo[3,2-c]carbazole compound, and this kind of compound has significant cytotoxic activity against PC-3 cancer cells.

[0004] Another object of the present invention is to provide a synthesis method of the above chiral tetrahydroindolo[3,2-c]carbazole compound, and this method has mild reaction conditions, low cost and high yield.

[0005] To achieve the above objects, the technical solutions adopted by the present invention are as follows:

[0006] On the one hand, the present invention provides a chiral tetrahydroindolo[3,2-c]carbazole compound, and its chemical structure is as shown in Formula 3:

[0007]

[0008] In the formula, R 1 is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, and halogen; R 2 is selected from one of hydrogen, aryl, heteroaryl, and C1-C3 alkyl; R 3 is selected from one of hydrogen, aryl, heteroaryl, and C1-C3 alkyl; R 4 is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, aryl, ester group, and halogen; R is selected from one of hydrogen and C1-C3 alkyl.

[0009] On the other hand, the present invention also provides a synthesis method of the above chiral tetrahydroindolo[3,2-c]carbazole compound, and the specific steps are as follows:

[0010] Using 2,3-disubstituted indole methanol derivatives and indole as reaction raw materials, benzene and its derivatives as reaction solvents, and chiral phosphoric acid as a catalyst, the reaction is stirred at 0 °C, and the reaction is tracked by TLC until completion. After filtration, concentration, and purification, the compound of formula 3 is obtained;

[0011] Among them, the reaction molar ratio of the 2,3-disubstituted indole methanol derivative to indole is 1:1.2 to 2:1;

[0012] The structural formula of the 2,3-disubstituted indole methanol derivative is In the formula, R 1 is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, and halogen; R 2 is selected from one of hydrogen, aryl, heteroaryl, and C1-C3 alkyl; R 3 is selected from one of hydrogen, aryl, heteroaryl, and C1-C3 alkyl;

[0013] The structural formula of the indole is In the formula, R 4 is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, aryl, ester group, and halogen; R is selected from one of hydrogen and C1-C3 alkyl;

[0014] The chiral phosphoric acid is selected from one or two of binaphthyl skeleton derivatives, octahydrobinaphthyl skeleton derivatives, and spiro skeleton derivatives; among them, the structural formula of the binaphthyl skeleton derivative is In the formula, G is selected from one of 9-anthryl, 9-phenanthryl, 2,4,6-triisopropylphenyl, triphenylsilyl, 2-naphthyl, and 1-naphthyl; the structural formula of the octahydrobinaphthyl skeleton derivative is In the formula, G' is selected from one of 9-anthryl, 9-phenanthryl, 2,4,6-triisopropylphenyl, triphenylsilyl, 2-naphthyl, and 1-naphthyl; the structural formula of the spiro skeleton derivative is In the formula, G'' is selected from one of 9-anthryl, 9-phenanthryl, 2,4,6-triisopropylphenyl, triphenylsilyl, 2-naphthyl, and 1-naphthyl.

[0015] The reaction route is as follows:

[0016]

[0017] Preferably, the structural formula of the chiral phosphoric acid is In the formula, G is selected from 9-anthryl.

[0018] Preferably, the benzene and its derivatives are selected from one of toluene, o-xylene, m-xylene, mesitylene, fluorobenzene, bromobenzene, and chlorobenzene.

[0019] More preferably, the benzene and its derivatives are selected from mesitylene.

[0020] Preferably, the reaction molar ratio of the 2,3-disubstituted indole methanol derivative to indole is 1:1.2.

[0021] Preferably, the purification is carried out by silica gel column chromatography, and the eluent is a mixed solution of petroleum ether / ethyl acetate with a volume ratio of 5:1.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. A chiral tetrahydroindolo[2,3-a]carbazole compound provided by the present invention shows certain cytotoxic activity against PC-3 cancer cells through biological activity tests, indicating that the chiral tetrahydroindolo[2,3-a]carbazole compound synthesized by the present invention has application value in the research and development of new anti-tumor drugs.

[0024] 2. A synthesis method of a chiral tetrahydroindolo[2,3-a]carbazole compound provided by the present invention uses chiral phosphoric acid as a catalyst, which well controls the enantioselectivity of the reaction; in this synthesis method, various types of substrates can be used as reactants to obtain products with structural diversity and complexity; and the products have high enantioselectivity, high yield, and mild reaction process, being suitable for industrial production. Specific Embodiments

[0025] The present invention will be further described in detail below with reference to specific embodiments.

[0026] In the following examples, unless otherwise specified, the experimental methods are usually carried out under conventional conditions or the conditions recommended by the manufacturer.

[0027] The starting material 2,3-disubstituted indole methanol derivative (i.e., compound of formula 1) used in the following examples was synthesized according to the method reported in the literature: Org. Chem. Front. 2018, 5(18), 2657-2667, and the remaining starting materials or reagents can be obtained by commercial purchase.

[0028] The synthesis route of the chiral tetrahydroindolo[2,3-a]carbazole compound 3 is as follows:

[0029]

[0030] In the above reaction, the structural formula of the catalyst chiral phosphoric acid is as follows:

[0031]

[0032] Example 1

[0033] 0.1 mmol of 2,3-disubstituted indole methanol derivative 1a and 0.12 mmol of indole compound 2a were added as reactants to 6 mL of mesitylene, and 0.01 mmol of chiral phosphoric acid (i.e., compound of formula 4) was used as a catalyst. The reaction was carried out at 0 °C for several hours, and the reaction was monitored by TLC until completion. After separation by silica gel column chromatography (the eluent was a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1), chiral tetrahydroindolo[2,3-a]carbazole compound 3aa was obtained.

[0034]

[0035] The structure characterization data of product 3aa in Example 1 are as follows:

[0036] Yield: 92% (47.7 mg); white solid; melting point: 258.3 - 260.1 °C; [α] D 20 = -13.1 (c = 0.90, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.67 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.41 - 7.35 (m, 2H), 7.35 - 7.27 (m, 6H), 7.24 - 7.19 (m, 3H), 7.13 - 7.06 (m, 3H), 7.04 - 6.97 (m, 3H), 6.85 (d, J = 8.0 Hz, 1H), 6.39 (d, J = 7.6 Hz, 1H), 5.92 (s, 1H), 3.69 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 154.4, 146.2, 144.8, 144.5, 138.5, 137.0, 135.0, 134.8, 129.2, 128.92, 128.88, 128.7, 128.5, 127.4, 127.2, 126.4, 125.3, 123.0, 121.8, 119.8, 119.5, 116.5, 116.1, 115.5, 110.8, 104.0, 100.1, 54.6, 52.4, 40.2; IR (KBr): 3057, 3025, 2962, 2835, 1505, 1491, 1344, 1259, 1126, 748; ESI FTMS exact mass calcd for (C 37 18H28 For N2O-H, m / z 515.2129 is required, found m / z 515.2124; enantiomeric excess (ee) value: 95%, HPLC (Daicel Chiralpak OD-H, n-hexane / isopropanol = 95:5, flow rate 1.0 mL / min, T = 30 °C, 254 nm); t R = 9.579 min (major), t R = 14.509 min (minor).

[0037] Examples 2-17

[0038] The reaction synthesis route is as follows:

[0039]

[0040] The reaction raw materials and yields are shown in Table 1:

[0041] Table 1 * Reaction raw materials and yields of Examples 2-17

[0042]

[0043]

[0044] * 0.1 mmol of the compound of formula 1 and 0.12 mmol of the compound of formula 2a are used as reactants, 0.01 mmol of the compound of formula 4 is used as a catalyst, and 1 mL of mesitylene is used as a solvent.

[0045] Examples 18-29

[0046] The reaction synthesis route is as follows:

[0047]

[0048] The reaction raw materials and yields are shown in Table 2:

[0049] Table 2 * Reaction raw materials and yields of Examples 18-29

[0050]

[0051] * 0.1 mmol of the compound of formula 1a and 0.12 mmol of the compound of formula 2 are used as reactants, 0.01 mmol of the compound of formula 4 is used as a catalyst, and 1 mL of mesitylene is used as a solvent.

[0052] Examples 30-34

[0053] Table 3 *Reaction Products and Yields of Examples 30 - 34

[0054]

[0055] *0.1 mmol of the compound of formula 1a and 0.12 mmol of the compound of formula 2 were used as reactants, 0.01 mmol of the compound of formula 4 was used as a catalyst, and 1 mL of mesitylene was used as a solvent.

[0056] As can be seen from Table 1, Table 2, and Table 3, the method of the present invention can not only achieve the synthesis of chiral tetrahydroindolo[2,3 - a]carbazole compounds with high atom economy and environmental friendliness in one step, but also obtain the expected chiral tetrahydroindolo[2,3 - a]carbazole compounds in excellent yields, with high enantioselectivity and diversity. In addition, the reaction raw materials are easily available, the operation is simple and safe, the conditions are mild, and the post - treatment is simple. Therefore, it has great implementation value and potential social and economic benefits.

[0057] The present invention also tested the cytotoxic activities of the chiral tetrahydroindolo[2,3 - a]carbazole compounds synthesized in Examples 1 - 4, Example 7, Example 9, Example 13, Example 18, Example 19, Example 22, and Example 24 on PC - 3 cancer cells by the conventional MTT method in the art, and the results are shown in Table 4. The results show that the compounds synthesized by the present invention have significant cytotoxic activities on PC - 3 cancer cells.

[0058] Table 4 Cytotoxic Activities of the Compounds in the Present Invention on PC - 3 Cancer Cells

[0059]

[0060] The present invention conducted biological activity tests on the prepared chiral tetrahydroindolo[2,3 - a]carbazole compounds, and the results showed that they have significant cytotoxic activities on PC - 3 cancer cells, indicating that this type of compound is a potential drug lead compound in the research and development of new anti - tumor drugs and has inestimable application research value.

[0061] The above - mentioned are only the specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, any modifications, equivalent substitutions, and improvements made within the spirit and principle of the present invention should be covered within the protection scope of the present invention.

Claims

1. A method for synthesizing a chiral tetrahydroindolo[2,3-a]carbazole compound, characterized in that, The specific steps are as follows: Using 2,3-disubstituted indole methanol derivatives and indole as reaction raw materials, benzene or benzene derivatives as reaction solvents, and chiral phosphoric acid as a catalyst, stir and react under 0 o °C, monitor the reaction by TLC until completion, filter, concentrate, and purify to obtain the compound of formula 3; Among them, the structural formula of the compound of Formula 3 is ; The reaction molar ratio of the 2,3-disubstituted indole methanol derivative to indole is 1:1.2 to 2:1; The structural formula of the described 2, 3-disubstituted indole methanol derivative is , where R 1 is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, and halogen; R 2 is selected from one of hydrogen, aryl, heteroaryl, and C1-C3 alkyl; R 3 is selected from one of hydrogen, aryl, heteroaryl, and C1-C3 alkyl; The structural formula of the indole described is , wherein R 4 is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy, aryl, ester group, and halogen; R is selected from one of hydrogen and C1-C3 alkyl; The structural formula of the chiral phosphoric acid is , where G is selected from 9-anthryl; The benzene derivative is selected from one of toluene, o-xylene, m-xylene, mesitylene, fluorobenzene, bromobenzene, and chlorobenzene.

2. The synthesis method of the chiral tetrahydroindolo[2,3-a]carbazole compound according to claim 1, characterized in that, The benzene derivative is selected from mesitylene.

3. The synthesis method of the chiral tetrahydroindolo[3,2-c]carbazole compound according to claim 1, characterized in that, The reaction molar ratio of the 2,3-disubstituted indole methanol derivative to indole is 1:1.

2.

4. The synthesis method of the chiral tetrahydroindolo[2,3-a]carbazole compound according to claim 1, characterized in that, The purification is carried out by silica gel column chromatography, and the eluent is a mixed solution of petroleum ether / ethyl acetate with a volume ratio of 5:1.

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