A method for preparing a 9-alkenyl-substituted acridine derivative

Abstract

This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 9-alkenyl-substituted acridine derivatives. The method involves a one-step reaction of compound II with a combination of 9-carboxyacidine, a palladium catalyst, and a copper catalyst, along with an inorganic base, in a polar organic solvent to obtain compound I. This invention solves the problems of expensive raw materials and long reaction steps, achieving a one-step preparation of 9-alkenyl-substituted acridine derivatives. The raw materials are inexpensive and readily available, the operation is simple, the substrate range is broad, the atom economy is high, and the method is environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing a 9-alkenyl-substituted acridine derivative. Background Technology

[0002] Acridine, also known as 10-azaanthracene, is an important nitrogen-containing heterocyclic organic compound. Its derivatives possess multifunctional biological activities, such as antibacterial, antimalarial, and anticancer effects. Furthermore, the relatively rigid planar conjugated structure of acridine gives it unusual electrochemical and photophysical properties, making acridine derivatives highly promising for applications in organic optoelectronic materials. 9-Alkenyl-substituted acridine derivatives, by introducing a carbon-carbon double bond group widely used in pharmaceutical molecules at the 9-position of acridine, exhibit a certain degree of anticancer activity (Med. Chem. Res., 2017, 26, 2309), representing a highly promising class of novel DNA-targeting drugs.

[0003] The following three methods have been reported for the preparation of 9-alkenyl-substituted acridine derivatives.

[0004] Route 1 uses 9-methylacridine as the starting material: [Prediction by...] 13 The article "C NMR of regioselectivity in 1,3-dipolar cycloadditions of acridin-9-yl dipolarophiles" reports the preparation of (2E)-3-(acridin-9-yl)-prop-2-enoic acid methyl ester via a three-step reaction using 9-methylacridinium and (triphenylphosphine)acetic acid methyl ester as raw materials, with a yield of less than 45% (Magn. Reson. Chem. 2016, 54, 8). This method involves long reaction steps, cumbersome operation, and is atom uneconomical.

[0005]

[0006] Route 2 uses 9-chloroacridin as a starting material: The article "A magnetic nanoparticle-supported N-heter-ocyclic carbene-palladacycle: an efficient and recyclable solid molecular catalyst for Suzuki-Miyaura cross-coupling of 9-chloroacridin" reports the use of 9-chloroacridin and styrylboronic acid as starting materials, SMNP@NHC-Pd (with appendix) Figure 1The catalyst was used to prepare 9-styrylacridine (Chem. Commun., 2017, 53, 13063). The catalyst was prepared through a multi-step reaction and is not commercially available.

[0007]

[0008] Route 3 uses 9-aldehyde acridine as a starting material: The article "Full NMR assignment of new acridinyl-chalcones, pyrazolino-acridines, and spiro[imidazo[1,5-b]pyrazole-4,9'-acridines]" reports the preparation of (2E)-3-(acridin-9-yl)-1-phenyl-2-propen-1-one from 9-aldehyde acridine and acetophenone under strongly alkaline conditions provided by sodium hydroxide and ethanol (Magn. Reson. Chem., 2020, 58, 769). However, the preparation of the starting material 9-aldehyde acridine is complicated and produces many byproducts (Pharmazie, 2010, 65, 239). This reaction is only suitable for 9-aldehyde acridine with aromatic ketones, and the reaction substrate is limited.

[0009]

[0010] In summary, existing preparation methods have the following problems: ① long reaction steps and cumbersome operation; ② special catalysts are not commercially available, and the preparation methods are cumbersome; ③ raw material preparation is cumbersome and commercially expensive. Therefore, there is an urgent need to research and develop new methods for preparing 9-alkenyl-substituted acridine derivatives that use readily available raw materials and have simple reaction steps. Summary of the Invention

[0011] To address the problems and deficiencies of the existing technology, the present invention aims to provide a method for preparing 9-alkenyl-substituted acridine derivatives that is easy to obtain, has simple reaction steps, and is atom-economical.

[0012] To achieve the above objectives, the present invention adopts the following technical solution:

[0013] A method for preparing a 9-alkenyl-substituted acridine derivative includes the following steps:

[0014] Compound of Formula II was prepared by reacting it with 9-carboxyacridine, a combination of palladium and copper catalysts, and an inorganic base in a polar organic solvent under controlled temperature.

[0015]

[0016] R 1 Independently selected from alkoxy, aryl, or substituted aryl groups.

[0017] Preferably, the R 1 The aryl or substituted aryl groups have the following characteristics:

[0018]

[0019] R 2 Independently selected from hydrogen, alkoxy, or halogen.

[0020] More preferably, the R 1 or R 2 The alkoxy group is a C1-C3 alkoxy group, such as methoxy, ethoxy, propoxy, etc.

[0021] To ensure that the raw materials are simple and readily available, the reaction raw material is 9-carboxyacridine.

[0022] The palladium catalyst is selected from palladium acetate or palladium chloride, and the copper catalyst added to the reaction is any one of cuprous oxide, cuprous chloride, or cuprous iodide.

[0023] Furthermore, the molar ratio of 9-carboxyacridine to palladium catalyst and copper catalyst in the reaction is 1:0.005-0.15:0.22-0.01.

[0024] Specifically, the inorganic base is selected from any one of sodium carbonate, potassium carbonate, silver carbonate, copper carbonate, etc.

[0025] Furthermore, the molar ratio of the 9-carboxyacridine to the compound of formula II and the inorganic base is 1:1.1-3:2-5.

[0026] To ensure complete reaction of the raw materials and a good yield of the product, the preferred polar organic solvent is selected from any one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and 1,4-dioxane.

[0027] Furthermore, the mass ratio of the 9-carboxyacridine to the solvent is 1:2.5-10.

[0028] Preferably, the reaction temperature is 100-140℃ and the reaction time is 4-10h.

[0029] Compared with traditional techniques, the preparation method of the present invention has the following advantages:

[0030] This invention develops a novel method for preparing 9-alkenyl-substituted acridine derivatives. Using inexpensive and readily available 9-carboxyacidine as raw material, a combination of common palladium and copper catalysts is used as catalysts for catalysis. The reaction is carried out in a weakly alkaline condition with inorganic bases. The reaction system is simple, has a wide substrate range, is environmentally friendly, has high atom economy, and the yield can reach over 75%. Attached Figure Description

[0031] Figure 1 The SMNP@NHC-Pd structure in the second background technology route;

[0032] Figure 2 The 1H NMR spectrum of methyl 3-(acridin-9-yl)-prop-2-enoate prepared in Example 1. Detailed Implementation

[0033] To further understand the present invention, preferred embodiments are described below with reference to examples. However, it should be understood that these descriptions are merely for illustrating the features and advantages of the present invention and are not intended to limit the scope of the claims. Those skilled in the art can refer to the content of this document to appropriately modify the process parameters. It is particularly important to note that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

[0034] Unless otherwise specified, all raw materials used in the following embodiments are common commercially available products that can be directly purchased in the art, or can be prepared using conventional methods in the art. Room temperature refers to 25±5℃.

[0035] Example 1

[0036] The preparation method of methyl 3-(acridin-9-yl)-prop-2-enoate includes the following steps:

[0037]

[0038] 9-Carboxyacridine (4.4 g, 19.71 mmol), methyl acrylate (3.56 g, 41.39 mmol), cuprous oxide (28 mg, 0.197 mmol), palladium acetate (662 mg, 2.95 mmol), silver carbonate (16.3 g, 59.13 mmol), and dimethyl sulfoxide (44 g) were added sequentially to a reaction flask. The reaction was carried out at 125 °C for 5 h, and then naturally cooled to room temperature. The mixture was extracted with ethyl acetate, filtered, and the filtrate was evaporated to dryness to give 4.36 g of solid, with a yield of 84.0%.

[0039] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.49 (m, 2H), 8.09 (s, 1H), 7.68-7.64 (m, 2H), 7.31 (m, 5H), 3.66 (s, 3H) (attached Figure 2 ).

[0040] Example 2

[0041] The preparation method of 3-(acridin-9-yl)-1-phenyl-2-propen-1-one includes the following steps:

[0042]

[0043] 9-Carboxyacridine (5 g, 22.40 mmol), 1-phenyl-2-propenyl-1-one (8.8 g, 67.19 mmol), cuprous chloride (110 mg, 1.12 mmol), palladium acetate (251 mg, 1.12 mmol), sodium carbonate (4.75 g, 44.80 mmol), and N,N-dimethylformamide (35 g) were added sequentially to a reaction flask. The reaction was carried out at 105 °C for 7 h, and then naturally cooled to room temperature. The mixture was extracted with ethyl acetate, filtered, and the filtrate was evaporated to dryness to give 5.49 g of solid, with a yield of 79.2%.

[0044] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.70 (d, 1H), 8.28-8.25 (m, 2H), 8.10 (d, 2H), 7.83 (m, 2H), 7.55-7.65 (m, 8H).

[0045] Example 3

[0046] The preparation method of 3-(acridin-9-yl)-1-(4-methoxyphenyl)-2-propen-1-one includes the following steps:

[0047]

[0048] 9-Carboxyacridine (2 g, 8.96 mmol), 1-(4-methoxyphenyl)prop-2-en-1-one (2.18 g, 13.44 mmol), cuprous iodide (255 mg, 1.34 mmol), palladium chloride (159 mg, 0.90 mmol), potassium carbonate (6.19 g, 44.80 mmol), and 5 g of mixed solvent (dimethyl sulfoxide / 1,4-dioxane = 1 / 20, v / v) were added sequentially to a reaction flask. The reaction was carried out at 100 °C for 10 h, and then naturally cooled to room temperature. The mixture was extracted with ethyl acetate, filtered, and the filtrate was evaporated to dryness to give 2.46 g of solid, with a yield of 80.9%.

[0049] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.66 (d, 1H), 8.27 (m, 4H), 8.10 (d, 2H), 7.80 (m, 2H), 7.58-7.00 (m, 5H), 3.90 (s, 3H).

[0050] Example 4

[0051] The preparation method of propyl 3-(acridin-9-yl)-prop-2-enoate includes the following steps:

[0052]

[0053] 9-Carboxyacridine (4 g, 17.92 mmol), propyl acrylate (2.25 g, 19.71 mmol), cuprous chloride (390 mg, 3.94 mmol), palladium chloride (16.0 mg, 0.09 mmol), copper carbonate (8.86 g, 71.68 mmol), and 20 g of mixed solvent (dimethyl sulfoxide / N,N-dimethylacetamide = 1 / 4, v / v) were added sequentially to a reaction flask. The reaction was carried out at 140 °C for 4 h, and then naturally cooled to room temperature. The mixture was extracted with ethyl acetate, filtered, and the filtrate was evaporated to dryness to give 4.03 g of solid, with a yield of 77.2%.

[0054] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.57 (d, 1H), 8.31 -8.21 (m, 3H), 7.83 (t, 2H), 7.61 (t, 3H), 6.51 (d, 1H), 4.32 (t, 2H), 1.85 (m, 2H), 1.07 (t, 3H).

[0055] Example 5

[0056] The preparation method of 3-(acridin-9-yl)-1-(4-fluorophenyl)prop-2-en-1-one includes the following steps:

[0057]

[0058] 9-Carboxyacridine (10 g, 44.80 mmol), 1-(4-fluorophenyl)-2-propen-1-one (18.16 g, 120.95 mmol), cuprous oxide (641 mg, 4.48 mmol), palladium acetate (101 mg, 0.45 mmol), copper carbonate (22.1 g, 179.2 mmol), and 100 g of mixed solvent (1,4-dioxane / N,N-dimethylformamide = 1 / 1, v / v) were added sequentially to a reaction flask. The reaction was carried out at 115 °C for 6 h, and then naturally cooled to room temperature. The mixture was extracted with ethyl acetate, filtered, and the filtrate was evaporated to dryness to give 11 g of solid, with a yield of 75.0%.

[0059] 1 H NMR (400MHz, CDCl3): δ (ppm) 8.70 (d, 1H), 8.30-8.25 (m, 4H), 8.15 (m, 2H), 7.84 (m, 2H), 7.60 (m, 2H), 7.57 (d, 1H), 7.22 (t, 2H).

[0060] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing a 9-alkenyl-substituted acridine derivative, characterized in that, Includes the following steps: Compound of Formula II was prepared by reacting it in a polar organic solvent with 9-carboxyacridine, a combination of palladium and copper catalysts, and an inorganic base in a one-step reaction. ； R 1 Independently selected from alkoxy, aryl, or substituted aryl groups; the R 1 The aryl or substituted aryl groups have the following characteristics: ； R 2 Independently selected from hydrogen, alkoxy, or halogen; the R 1 Or R 2 The alkoxy group is a C1-C3 alkoxy group; The palladium catalyst is any one of palladium acetate and palladium chloride, and the copper catalyst is any one of cuprous oxide, cuprous chloride, and cuprous iodide.

2. The method for preparing a 9-alkenyl-substituted acridine derivative according to claim 1, characterized in that, The molar ratio of the 9-carboxyacridine to the palladium catalyst and the copper catalyst is 1:0.005-0.15:0.01-0.

22.

3. The method for preparing a 9-alkenyl-substituted acridine derivative according to claim 1, characterized in that, The inorganic base is selected from any one of sodium carbonate, potassium carbonate, silver carbonate, and copper carbonate.

4. The method for preparing a 9-alkenyl-substituted acridine derivative according to claim 1, characterized in that, The molar ratio of the 9-carboxyacridine to the compound of formula II and the inorganic base is 1:1.1-3:2-5.

5. The method for preparing a 9-alkenyl-substituted acridine derivative according to claim 1, characterized in that, The polar organic solvent is selected from any one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and 1,4-dioxane.

6. The method for preparing a 9-alkenyl-substituted acridine derivative according to claim 1, characterized in that, The mass ratio of the 9-carboxyacridine to the solvent is 1:2.5-10.

7. The method for preparing a 9-alkenyl-substituted acridine derivative according to claim 1, characterized in that, The reaction temperature is 100-140℃, and the reaction time is 4-10h.

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