Method for constructing 6 (5H)-phenanthridone compound by utilizing natural light to induce carbonylation reaction

Abstract

The invention relates to a method for constructing a 6 (5H)-phenanthridone compound by utilizing natural light to induce carbonylation reaction. According to the method, 2-bromoaniline and phenylboronic acid are taken as reaction raw materials, and the 6 (5H)-phenanthridone compound is successfully constructed through two steps of arylation and natural light induced carbonylation reaction. The method has the characteristics of simple and easily available raw materials, simple synthesis steps, green and mild reaction conditions and simple operation process.

Description

Technical Field

[0001] The present invention relates to the technical fields of medicine, clinic, cell biology and the like, and in particular to a new method for constructing 6(5H)-phenanthridinone by utilizing natural light-induced carbonylation reaction. Background Art

[0002] ‌6(5H)-phenanthridinone is a potent PARP-1 inhibitor and immunomodulator that can inhibit cell proliferation, and therefore has potential application value in cancer research. In addition, it is also used as an organic synthesis reagent in the field of chemical synthesis.

[0003] The chemical structure of 6(5H)-phenanthridinone gives it specific biological activity and can act on specific biological targets. As a PARP-1 inhibitor, it can interfere with the activity of the PARP-1 enzyme and thus affect the cell's DNA repair mechanism, which is of great significance for studying the pathogenesis and treatment strategies of diseases such as cancer. At the same time, due to its immunomodulatory effect, 6(5H)-phenanthridinone may also play an important role in immune-related research.

[0004] In the field of scientific research, the application of 6(5H)-phenanthridinone is not limited to cancer research. It can also be used to explore treatments for other diseases and as a basic compound for the development of new drugs. Due to its specific chemical structure and biological activity, 6(5H)-phenanthridinone has become an important object of study for chemists and biologists in order to discover more about its mechanism of action and potential applications.

[0005] In general, 6(5H)-phenanthridinone has shown potential application value in cancer research and immune regulation through its unique chemical structure and biological activity, providing new ideas and directions for future drug development and disease treatment.

[0006] Under this research background, we proposed a method to construct 6(5H)-phenanthridinone compounds by using natural light-induced carbonylation reaction. The synthetic route is as follows:

[0007]

[0008] The 6(5H)-phenanthridinone synthesized by the present invention has the following structural formula:

[0009]

[0010] This invention synthesizes 6(5H)-phenanthridinone by a two-step method of natural light-induced carbonylation reaction, providing a novel synthetic route for the synthesis of this type of compound. The raw materials involved in this route are cheap and easily available, the reaction conditions are green and mild, and the reaction route is simple. Summary of the invention

[0011] The present invention relates to a method for constructing a 6(5H)-phenanthridinone compound by using a natural light-induced carbonylation reaction. The method uses 2-bromoaniline and phenylboronic acid as reaction raw materials to successfully construct a 6(5H)-phenanthridinone compound by two steps of arylation and natural light carbonylation reaction. The method has the characteristics of simple and easy-to-obtain raw materials, concise synthesis steps, green and mild reaction conditions, and simple operation process.

[0012] The technical solution of the present invention is as follows.

[0013] 6(5H)-phenanthridinone was synthesized by a two-step method using natural light-induced carbonylation reaction. The synthetic route is as follows:

[0014]

[0015] In the above method, the 6(5H)-phenanthridinone is prepared by two reaction steps of arylation and natural light-induced carbonylation of compound 1 (2-bromoaniline) and compound 2 (phenylboronic acid); the specific steps are as follows:

[0016] (1) Compound 1 (2-bromoaniline) is placed in a container, and compound 2 (phenylboric acid), cesium carbonate, and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex are added, and the mixture is heated to 110 degrees Celsius in a solvent mixture (tetrahydrofuran / water = 10:1) and stirred and refluxed for 16 hours. After the reaction is completed, the mixture is cooled to room temperature, extracted, separated and purified to obtain compound 3 ([1,1'-biphenyl]-2-amine), thereby achieving the arylation process.

[0017] (2) Compound 3 ([1,1'-biphenyl]-2-amine) was placed in a test tube, and a catalyst, additive, and solvent were added. A balloon filled with carbon monoxide gas was placed on the tube, and the reaction was stirred under natural light. After the reaction was completed, the balloon was removed, and the reaction solution was purified by column chromatography to obtain 6(5H)-phenanthridinone.

[0018] In the above method: the reaction container of the specific step (2) is a test tube; the metal palladium is palladium acetate, palladium trifluoroacetate, palladium chloride, tetrakis(triphenylphosphine)palladium; the additive is tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hexafluorophosphate, tetraethylammonium bromide.

[0019] In the above method, the solvent in the specific step (2) is acetonitrile.

[0020] In the above method, the reaction temperature in the specific step (2) is room temperature.

[0021] Compared with the prior art, the advantages of the present invention are: the method has a novel synthesis method, and 6(5H)-phenanthridinone is successfully synthesized by utilizing natural light-induced carbonylation reaction. The reaction raw materials are simple and easy to obtain, and the reaction conditions are mild, which meets the development requirements of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of compound 3 ([1,1'-biphenyl]-2-amine) obtained in Example 1;

[0023] Figure 2 is the carbon NMR spectrum of compound 3 ([1,1'-biphenyl]-2-amine) obtained in Example 1;

[0024] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of 6(5H)-phenanthridinone obtained in Example 2-12;

[0025] Figure 4 is the carbon nuclear magnetic resonance spectrum of 6(5H)-phenanthridinone obtained in Example 2-12; DETAILED DESCRIPTION

[0026] The invention will be further described below through specific embodiments.

[0027] Example 1

[0028] Synthesis of compound 3 ([1,1'-biphenyl]-2-amine)

[0029] In a 100 mL round-bottom flask, 1 mmol of 2-bromoaniline and 1 mmol of phenylboronic acid were added, followed by 3 mmol of cesium carbonate and 0.1 mmol of [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex. 10 ml of tetrahydrofuran and 1 ml of water were added, and the mixture was heated to 110 degrees Celsius and refluxed with stirring for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. Compound 3 ([1,1'-biphenyl]-2-amine) was obtained with a yield of 52%.

[0030] The structural characterization data of compound 3 ([1,1'-biphenyl]-2-amine) obtained in Example 1 are as follows: (see Figure 1 and Figure 2 )

[0031] 1 H NMR (500 MHz, CDCl3) δ 7.52-7.44 (m, 4H), 7.42-7.35 (m, 1H), 7.22-7.16 (m, 2H), 6.87 (td, J = 7.4, 1.2 Hz, 1H), 6.82 (dd, J = 8.0, 1.2 Hz, 1H).

[0032] 13 C NMR (125 MHz, CDCl3) δ 143.39, 139.50, 130.51, 129.14, 128.85,128.54, 127.75, 127.22, 118.78, 115.71.

[0033] Based on the above data, the structure of compound 3 ([1,1'-biphenyl]-2-amine) is as follows:

[0034]

[0035] Example 2

[0036] Synthesis of 6(5H)-phenanthridinone

[0037] Add 0.1 mmol of compound 3 ([1,1'-biphenyl]-2-amine), 0.005 mmol of palladium acetate, 0.1 mmol of tetrabutylammonium bromide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain compound 6 (5H) - phenanthridinone with a yield of 67%.

[0038] Example 3

[0039] Add 0.1 mmol of compound 3 ([1,1'-biphenyl]-2-amine), 0.005 mmol of palladium trifluoroacetate, 0.1 mmol of tetrabutylammonium bromide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain compound 6 (5H) - phenanthridinone with a yield of 32%.

[0040] Example 4

[0041] Add 0.1 mmol of compound 3 ([1,1'-biphenyl]-2-amine), 0.005 mmol of palladium chloride, 0.1 mmol of tetrabutylammonium bromide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain compound 6 (5H) - phenanthridinone with a yield of 0%.

[0042] Example 5

[0043] Add 0.1 mmol of compound 3 ([1,1'-biphenyl]-2-amine), 0.005 mmol of tetrakis(triphenylphosphine)palladium, 0.1 mmol of tetrabutylammonium bromide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain compound 6 (5H)-phenanthridinone with a yield of 51%.

[0044] Example 6

[0045] Add 0.1 mmol of compound 3 ([1,1'-biphenyl]-2-amine), 0.005 mmol of palladium acetate, 0.1 mmol of tetrabutylammonium iodide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain compound 6 (5H) - phenanthridinone with a yield of 60%.

[0046] Example 7

[0047] Add 0.1 mmol of compound 3 ([1,1'-biphenyl]-2-amine), 0.005 mmol of palladium acetate, 0.1 mmol of tetrabutylammonium acetate, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain compound 6 (5H) - phenanthridinone with a yield of 33%.

[0048] Example 8

[0049] Add 0.1 mmol of compound 3 ([1,1'-biphenyl]-2-amine), 0.005 mmol of palladium acetate, 0.1 mmol of tetraethylammonium bromide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain compound 6 (5H) - phenanthridinone with a yield of 63%.

[0050] The structural characterization data of 6(5H)-phenanthridinone obtained in Example 2-9 are as follows: (see Figure 3 and Figure 4 )

[0051] 1H NMR (500 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.40 (s, 1H), 7.38 (s, 1H), 7.36-7.29 (m, 1H), 7.23(d, J = 7.7 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H);

[0052] 13 C NMR (125 MHz, DMSO-d6) δ 154.02, 139.17, 136.10, 133.91, 130.79,129.67, 129.51, 129.18, 128.16, 127.79, 124.76, 124.26, 118.43.

[0053] The structure of 6(5H)-phenanthridinone obtained based on the above data is as follows:

[0054]

Claims

1. A method for constructing a 6(5H)-phenanthridinone compound by using a natural light-induced carbonylation reaction, characterized in that: The synthetic route is as follows: 。 2. The method for constructing a 6(5H)-phenanthridinone compound by utilizing a natural light-induced carbonylation reaction according to claim 1, characterized in that: The 6(5H)-phenanthridinone is prepared by two steps of arylation and photoinduced carbonylation of compound 1 (2-bromoaniline) and compound 2 (phenylboronic acid); the compound 1 is 2-bromoaniline and the compound 2 is phenylboronic acid; The specific steps are as follows: (1) Compound 1 (2-bromoaniline) is placed in a container, compound 2 (phenylboric acid), cesium carbonate, and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex are added, and the mixture is heated to 110 degrees Celsius in a solvent mixture (tetrahydrofuran / water = 10:1) and stirred and refluxed for 16 hours. After the reaction is completed, the mixture is cooled to room temperature, extracted, separated and purified to obtain compound 3 ([1,1'-biphenyl]-2-amine), thereby achieving the arylation process; (2) Compound 3 ([1,1'-biphenyl]-2-amine) was placed in a test tube, and a catalyst, additive, and solvent were added. A balloon filled with carbon monoxide gas was placed on the tube, and the reaction was stirred under natural light. After the reaction was completed, the balloon was removed, and the reaction solution was purified by column chromatography to obtain 6(5H)-phenanthridinone.

3. The method for constructing a 6(5H)-phenanthridinone compound by utilizing natural light-induced carbonylation reaction according to claim 2, characterized in that: The reaction container of the specific step (2) is a test tube; the metal palladium is palladium acetate, palladium trifluoroacetate, palladium chloride, tetrakis(triphenylphosphine)palladium; and the additive is tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hexafluorophosphate, and tetraethylammonium bromide.

4. The method for constructing a 6(5H)-phenanthridinone compound by utilizing a natural light-induced carbonylation reaction according to claim 2, characterized in that: In the specific step (2), the solvent is acetonitrile.

5. The method for constructing a 6(5H)-phenanthridinone compound by utilizing natural light-induced carbonylation reaction according to claim 2, characterized in that: The reaction temperature in the specific step (2) is room temperature.

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