A method for preparing a coumarin skeleton compound

Abstract

The application discloses a preparation method of a coumarin skeleton compound, and belongs to the field of organic synthesis. The preparation method comprises the following steps: taking substituted o-coumaric acid as a substrate, taking N,N'-carbonyldiimidazole as a reagent, and reacting in an organic solvent at room temperature for 24 hours, and then performing deimidization and carbon dioxide reaction to obtain the coumarin skeleton compound. The method does not need metal catalysts, photocatalysts and oxidants, has the advantages of wide substrate range, high yield, simple operation and the like, and can be used for synthesis in a kilogram level. The obtained coumarin compound has important application value in the fields of food, medicine, cosmetics, dyes and optical products.

Description

Technical Field

[0001] This invention relates to a method for catalytically preparing coumarin compounds, belonging to the field of organic synthesis technology. Background Technology

[0002] Coumarin compounds are an important class of natural products and synthetic molecular building blocks, possessing diverse physiological, pharmacological, and optical activities. They are widely used in food, pharmaceuticals, cosmetics, dyes, optical products, and fragrances (such as jasmine lactone and coumarin lactone) as compounding agents or as aroma components. Discoumarins, benzylacetone coumarin (warfarin), and acetonitrocoumarins (a new anticoagulant) are important anticoagulant drugs; 4-methylcoumarin derivatives can be used as anticancer drugs; and benzothiazole and benzimidazole coumarins can be used as fluorescent dyes. In recent years, coumarin-based fluorescent ligands have also been applied in fields such as bioimaging and cell tracking, and some coumarin derivatives have exhibited pharmacological activities such as inhibiting the growth of liver cancer. Due to their favorable pharmacokinetic properties and ease of structural modification, coumarins have become an important and advantageous framework in drug discovery and chemical biology.

[0003] Coumarin compounds can be synthesized via methods including the Pechmann reaction, Perkin reaction, Knoevenagel reaction, Refomartsky reaction, and Wittig reaction. The Pechmann method for preparing coumarins with substituents on the benzene ring offers advantages such as readily available and easily stored raw materials. In contrast, the catalysts used in traditional Pechmann reactions are mainly... Equal-strength protic acid or Lewis acids, etc. The above catalysts are corrosive to reaction equipment, require harsh reaction conditions, and produce many byproducts; the post-reaction treatment generates corrosive gases and large amounts of waste liquid, causing serious environmental pollution; some catalysts are sensitive, easily deactivated, and cannot tolerate the sensitive functional groups of the substrate.

[0004] Therefore, developing new synthetic routes and constructing high-yield coumarin compounds under mild conditions plays an important role in promoting drug molecule development and design as well as basic methodological research. Summary of the Invention

[0005] The purpose of this invention is to overcome the aforementioned problems in the prior art and provide a method for preparing coumarin skeleton compounds. This reaction system uses o-coumaric acid as a substrate, N,N'-carbonyldiimidazole as a reagent, and anisole as a solvent. This reaction system has a wide range of applications, is simple to operate, inexpensive and safe, has a high yield, and is environmentally friendly. The synthesized coumarin compounds possess anticoagulant, antitumor, antibacterial, antiviral, and fluorescent probe monitoring effects.

[0006] The present invention discloses a method for preparing a coumarin skeleton compound, comprising the following steps: using substituted o-coumaric acid as a substrate and N,N'-carbonyldiimidazole as a reagent, reacting in an organic solvent, and then reacting with deimidazole and carbon dioxide to obtain the coumarin skeleton compound; the reaction equation is shown below: , Where: R 1 For hydrogen, methyl, methoxy, phenyl, halogen, nitro, acetyl; R 2 For example, hydrogen, methyl, methoxy, halogen, diethylamino; R 3 For hydrogen, halogen, methyl, methoxy; R 4 It can be hydrogen, halogen, methyl, or methoxy.

[0007] Furthermore, in the above technical solution, the substituted o-coumaric acid and N,N′-Carbonyldiimidazole The molar ratio is 1:1.2.

[0008] Furthermore, in the above technical solution, the reaction temperature is 0-30℃; the reaction time is 20-24 hours.

[0009] Furthermore, in the above technical solution, the organic solvent is selected from anisole, toluene, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, acetone, or cyclohexane. Preferably, the organic solvent is anisole or methyl tert-butyl ether.

[0010] Furthermore, in the above technical solution, the reaction products are separated by column chromatography, using a mixed solvent of petroleum ether and ethyl acetate. That is, the reaction solution obtained after the reaction is purified and concentrated by column chromatography to obtain the target product, coumarin compounds. The solvent used in the separation process is preferably a mixed solvent of petroleum ether and ethyl acetate. The mass ratio of petroleum ether to ethyl acetate is 10 / 1 to 2 / 1, preferably 6 / 1 to 3 / 1.

[0011] The method described in this invention can efficiently synthesize coumarin skeleton compounds. This synthesis method does not require a metal catalyst, has mild reaction conditions, short reaction time, simple operation, wide substrate applicability, and high yield (83-99%). Detailed Implementation

[0012] The present invention will be described in detail below through examples, but the scope of protection of the present invention is not limited thereto. In the following examples, the substituted o-coumaric acid is commercially available or prepared by known methods. Example 1

[0013] In a clean round-bottom flask, add coumarin-3-carboxylic acid 1a (0.3 mmol) and condensing agent in sequence. (0.36 mmol) and reaction solvent2 mL of the solution was added and stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was evaporated to dryness, and the product 2a was obtained by column chromatography using a mixture of petroleum ether and ethyl acetate (mass ratio 3:1). The NMR data are as follows: 1 ¹H NMR (400 MHz, CDCl₃) 7.72 (d, J = 9.4 Hz, 1H), 7.59 – 7.46 (m, 2H), 7.34 (d, J = 8.2 Hz, 1H), 7.29 (t, J = 6.9 Hz, 1H), 6.43 (d, J = 9.4 Hz, 1H). The optimized conditions are as follows: A. Screening of condensation reagents

[0014] , .

[0015] B. Screening of reaction solvents , . Example 2

[0016] Add 55 mg (0.3 mmol) of coumarin-3-carboxylic acid as shown in formula (1-1) to a clean round-bottom flask. N,N′- Carbonyl diimidazole 59 mg (0.36 mmol) and 2 mL of anisole was added and stirred at room temperature for 24 hours. After the reaction was completed, the reaction system was evaporated to dryness, and column chromatography was performed using a mixture of petroleum ether and ethyl acetate (mass ratio 3 / 1) to obtain 49.2 mg of the product, with a product yield of 99%.

[0017] , The NMR data of the product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.7 Hz, 1H), 7.49 (dd, J = 15.0, 7.9 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.00 (t, J =8.7 Hz, 1H), 6.46 (d, J = 9.7 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 159.8 (d, J = 7.3 Hz), 157.3, 154.7 (d,J = 5.1 Hz), 136.3 (d, J = 4.1 Hz), 132.2 (d, J =9.6 Hz), 116.8 (d, J = 1.6 Hz), 112.7 (d, J = 4.0 Hz), 110.3 (d, J = 20.0Hz), 109.0 (d, J = 19.2 Hz). Therefore, it can be deduced that the structural formula of the obtained product is as shown in equation (2-1). . Example 3

[0018] Add 84 mg (0.3 mmol) of o-coumaric acid as shown in formula (1-2) sequentially to a clean round-bottom flask. N,N′-carbonyl di Imidazole 59mg (0.36mmol) and 2 mL of anisole was added and stirred at room temperature for 24 hours. After the reaction was completed, the reaction system was evaporated to dryness, and column chromatography was performed using a mixture of petroleum ether and ethyl acetate (mass ratio 3:1) to obtain 75.1 mg of the product, with a product yield of 96%.

[0019] , The NMR data of the product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.64 (d, J = 9.6 Hz, 1H), 7.45 (s, 1H), 6.50 (d, J = 9.6 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 159.0, 149.5, 142.1, 134.7, 129.9, 126.5, 120.6, 118.5, 111.2. HRMS(FTMS-ESI): [M + H]+ calcd for C9H5BrClO2 + : 258.9156; found: 258.9153. Therefore, it can be deduced that the structural formula of the obtained product is as shown in equation (2-2). . Example 4

[0020] Add 62 mg (0.3 mmol) of o-coumaric acid as shown in formula (1-3) sequentially to a clean round-bottom flask. N,N′-carbonyl Diimidazole 59mg (0.36mmol) and 2 mL of anisole was added and stirred at room temperature for 24 hours. After the reaction was completed, the reaction system was evaporated to dryness, and column chromatography was performed using a mixture of petroleum ether and ethyl acetate (mass ratio 3:1) to obtain 55.7 mg of the product, with a product yield of 99%.

[0021] , The NMR data of the product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.13 (s, 2H), 7.80 (d, J = 9.6 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 6.50 (d, J = 9.6 Hz, 1H), 2.66 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 196.0, 159.8, 156.9, 143.2, 133.5, 131.7, 128.6, 118.6, 117.6, 117.3, 26.6. Therefore, the structural formula of the obtained product can be deduced as shown in equation (2-3). . Example 5

[0022] Add 63 mg (0.3 mmol) of o-coumaric acid as shown in formula (1-4) sequentially to a clean round-bottom flask. N,N′-carbonyl di Imidazole 59mg (0.36mmol) and 2 mL of anisole was added and stirred at room temperature for 24 hours. After the reaction was completed, the reaction system was evaporated to dryness, and column chromatography was performed using a mixture of petroleum ether and ethyl acetate (mass ratio 3:1) to obtain 51.1 mg of the product, with a product yield of 89%.

[0023] , The NMR data of the product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 9.5 Hz, 1H), 6.84 (d, J = 4.3 Hz, 2H), 6.29 (d, J = 9.5 Hz, 1H), 6.09 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 161.2, 151.29, 151.26, 144.9, 143.5, 113.4, 112.7, 105.0, 102.4, 98.4. Therefore, the structural formula of the obtained product can be deduced as shown in equation (2-4). . Example 6

[0024] Add 71 mg (0.3 mmol) of o-coumaric acid as shown in formula (1-5) sequentially to a clean round-bottom flask. N,N′-carbonyl di Imidazole 59mg (0.36mmol) and 2 mL of anisole was added and stirred at room temperature for 24 hours. After the reaction was completed, the reaction system was evaporated to dryness, and column chromatography was performed using a mixture of petroleum ether and ethyl acetate (mass ratio 3:1) to obtain 54.6 mg of the product, with a product yield of 83%.

[0025] , The nuclear magnetic resonance data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 9.3Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.51 (s, 1H), 6.05 (d, J = 9.3 Hz, 1H), 3.43 (q, J = 7.0 Hz, 4H), 1.23 (t, J = 7.1 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ 162.3, 156.8, 150.7, 143.7, 128.8, 109.2, 108.7, 108.3, 97.5, 44.8, 12.4. Therefore, the structural formula of the obtained product can be deduced as shown in equation (2-5). . Example 7

[0026] Add 73 mg (0.3 mmol) of coumarin-3-carboxylic acid as shown in formula (1-6) sequentially to a clean round-bottom flask. N,N′- Carbonyl diimidazole 59 mg (0.36 mmol) and2 mL of anisole was added and stirred at room temperature for 24 hours. After the reaction was completed, the reaction system was evaporated to dryness, and column chromatography was performed using a mixture of petroleum ether and ethyl acetate (mass ratio 3:1) to obtain 67.1 mg of the product, with a product yield of 99%.

[0027] , The NMR data of the product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 9.5 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.45 (d, J = 9.5 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 159.7, 150.8, 143.2, 135.4, 127.2, 125.2, 120.1, 117.3, 110.4. Therefore, the structural formula of the obtained product can be deduced as shown in equation (2-6). .

[0028] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing a coumarin skeleton compound, characterized in that, The reaction includes the following steps: using substituted o-coumaric acid as a substrate and N,N'-carbonyldiimidazole as a reagent, the reaction proceeds in an organic solvent, followed by deimidazole reaction and carbon dioxide reaction to yield the coumarin skeleton compound; the reaction equation is shown below: ， Where: R 1 For hydrogen, methyl, methoxy, phenyl, halogen, nitro, acetyl; R 2 For example, hydrogen, methyl, methoxy, halogen, diethylamino; R 3 It can be hydrogen, halogen, methyl, or methoxy; R 4 It can be hydrogen, halogen, methyl, or methoxy.

2. The method for preparing the coumarin skeleton compound according to claim 1, characterized in that: The substituted o-coumaric acid and N,N′-Carbonyldiimidazole The molar ratio is 1:1.

2.

3. The method for preparing the coumarin skeleton compound according to claim 1, characterized in that: The reaction temperature is 0-30℃.

4. The method for preparing the coumarin skeleton compound according to claim 1, characterized in that: The organic solvent is selected from anisole, toluene, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, acetone or cyclohexane.

5. The method for preparing the coumarin skeleton compound according to claim 4, characterized in that: The organic solvent is selected from anisole or methyl tert-butyl ether.

6. The method for preparing the coumarin skeleton compound according to claim 1, characterized in that: The reaction products were separated by column chromatography using a mixture of petroleum ether and ethyl acetate as solvents.

7. The method for preparing the coumarin skeleton compound according to claim 6, characterized in that: The mass ratio of petroleum ether and ethyl acetate mixed solvent is 10 / 1 to 2 / 1.

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