Angellactone derivative and preparation method thereof

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses an angelica lactone derivative and a preparation method thereof. According to the invention, the 4-vinylpyridine compound and the angelica lactone compound are used as raw materials, and the compound containing the angelica lactone skeleton structure is synthesized by a one-step method, so that the variety of the angelica lactone compound is enriched; the invention provides a novel compound for developing novel medicines with antibacterial, anti-tumor, anti-allergic, anti-inflammatory, analgesic, anti-injury and anti-radiation injury effects and the like, and has very important significance for researching the activity of the compound and expanding the application of the angelica lactone compound in the medical field and industrial production. And a basis is provided for researching novel medicines with high physiological activity.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and particularly relates to an angelica lactone derivative and a preparation method thereof. Background Art

[0002] Angelica is a traditional Chinese medicinal material, which has the effects of enriching blood and promoting blood circulation, regulating menstruation and relieving pain, and is widely used in clinical practice of traditional Chinese medicine. Modern research shows that angelica contains a variety of active ingredients, including volatile oils, polysaccharides, organic acids and lactone compounds, etc. Among them, lactone compounds have received extensive attention in recent years due to their unique chemical structures and significant biological activities.

[0003] Angelica lactone compounds mainly include angelica lactone A, angelica lactone B, etc., and have various biological activities such as anti-inflammatory, antioxidant, and anti-tumor. Research shows that these compounds have potential application values in the treatment of cardiovascular diseases, anti-aging, anti-tumor, etc. However, in the prior art, the extraction and purification methods of angelica lactone compounds have problems such as low efficiency, high cost, and insufficient purity, which limit their large-scale production and application. Natural angelica lactone compounds may have problems such as unstable chemical properties and poor drug-forming properties, and it is necessary to modify and transform their structures through chemical synthesis to improve stability, enhance activity, reduce side effects, etc., to meet the needs of drug research and development.

[0004] Currently, the synthesis methods of angelica lactone derivatives are mainly limited to the catalytic asymmetric Mukaiyama-type reaction using pre-formed silyloxyfurans. In this reaction, under the catalysis of Lewis acid, the enol silyl ether formed by the carbonyl compound first reacts with aldehydes and ketones to generate β-hydroxy aldehydes and ketones. Since the enol silyl ether is an equivalent body of the enolate anion and its nucleophilicity is not strong enough to directly react with aldehydes and ketones, it is necessary to add Lewis acid to activate the carbonyl group. Moreover, the above reaction route also has disadvantages such as complex reaction steps, poor substrate applicability, and lack of economy. Therefore, it is necessary to provide a chemical synthesis method for angelica lactone derivatives with high efficiency, simplicity, and good selectivity. Summary of the Invention

[0005] In order to enrich the types of angelica lactone derivatives and solve the problems that the methods for synthesizing angelica lactone derivatives in the prior art are relatively complex and the yield and purity are relatively low, the present invention provides an angelica lactone derivative and a preparation method thereof.

[0006] To solve the above technical problems, the technical solution provided by the present invention is:

[0007] On the one hand, the present invention provides an angelica lactone derivative, and its structure is shown in formula (I):

[0008]

[0009] Among them, R 1 , R 2 , R 3 , R 4 are each independently selected from H, halogen, methyl or methoxy, and at least two of R 1 , R 2 , R 3 , R 4 are H;

[0010] R 5 is methyl, methoxy, biphenyl or halophenyl.

[0011] Compared with the prior art, the present invention provides an angelica lactone derivative with a novel structure, enriching the types of angelica lactone compounds, providing a new class of compounds for the development of new antibacterial, anti-tumor, anti-allergic, anti-inflammatory and analgesic, anti-injury and anti-radiation injury drugs, and having very important significance for studying the activities of such compounds and expanding the application of angelica lactone compounds in the medical field and industrial production, and providing a basis for studying new drugs with high physiological activity.

[0012] Furthermore, the halogen is F, Cl or Br.

[0013] On the other hand, the present invention also provides a preparation method of the above-mentioned angelica lactone derivative, comprising the following steps:

[0014] Under an inert atmosphere, in the presence of an organic solvent, a Lewis acid and an organic base, the 4-vinylpyridine compound shown in formula (II) and the compound shown in formula (III) are subjected to an addition reaction to obtain the angelica lactone derivative shown in formula (I);

[0015]

[0016] Among them, R 1 , R 2 , R 3 , R 4 are each independently selected from H, halogen, methyl or methoxy, and at least two of R 1 , R 2 , R 3 , R 4 are H;

[0017] R 5 is methyl, methoxy, biphenyl or halophenyl. The specific synthesis route is as follows:

[0018]

[0019] At present, there have been many reports on the preparation methods of compounds containing angelica lactone. However, there is no report on the synthesis of compounds containing the angelica lactone skeleton structure by a one-step method using 4-vinylpyridine compounds and angelica lactone compounds as raw materials. The present invention prepares a novel type of compound containing the angelica lactone skeleton structure through a one-step addition reaction, realizing the diversification of target compounds, which has important value for expanding the application of angelica lactone compounds in the fields of medicine and industrial production.

[0020] It should be noted that the inert atmosphere is provided by conventional inert gases in the art, such as nitrogen, argon, etc.

[0021] Furthermore, the organic solvent is one or more of toluene, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane or dichloroethane.

[0022] Preferably, the organic solvent is 1,4-dioxane.

[0023] Reacting under specific organic solvent conditions can promote the full progress of the reaction between 4-vinylpyridine and the compound shown in formula (Ⅲ), and greatly improve the yield on the premise of ensuring the purity of the target product.

[0024] Furthermore, the Lewis acid is one or more of copper trifluoromethanesulfonate, indium trichloride, bis(triphenylphosphine)palladium dichloride, palladium acetate or scandium trifluoromethanesulfonate.

[0025] Preferably, the Lewis acid is scandium trifluoromethanesulfonate.

[0026] Furthermore, the organic base is one or more of triethylenediamine, triethylamine, pyridine, 2,6-dimethylpyridine, 1,8-diazabicycloundec-7-ene.

[0027] Preferably, the organic base is triethylamine.

[0028] Furthermore, the molar ratio of the 4-vinylpyridine compound to the compound shown in formula (Ⅲ) is 1:(1 - 3).

[0029] Preferably, the molar ratio of the 4-vinylpyridine compound to the compound shown in formula (Ⅲ) is 1:2.5.

[0030] The preferred ratio of reaction substances can ensure the forward progress of the reaction under the condition of less dosage and improve the yield of the target product.

[0031] Furthermore, the molar ratio of the 4-vinylpyridine compound to the Lewis acid is 1:(0.1 - 0.3).

[0032] Preferably, the molar ratio of the 4-vinylpyridine compound to the Lewis acid is 1:0.2.

[0033] Furthermore, the molar volume ratio of the 4-vinylpyridine compound to the organic solvent is 1 mmol:(1 - 5) mL.

[0034] Preferably, the molar volume ratio of the 4-vinylpyridine compound to the organic solvent is 1 mmol:4 mL.

[0035] Furthermore, the molar ratio of the 4-vinylpyridine compound to the organic base is 1:(1 - 3).

[0036] Preferably, the molar ratio of the 4-vinylpyridine compound to the organic base is 1:2.

[0037] Furthermore, the temperature of the addition reaction is 40°C - 110°C.

[0038] The preferred reaction temperature can reduce the occurrence of side reactions on the premise of ensuring the yield, thereby improving the yield and purity of the target product.

[0039] It should be noted that the progress of the addition reaction is monitored by thin-layer chromatography to determine the end time of the reaction.

[0040] Furthermore, the preparation method of the above angelica lactone derivatives further includes a purification step:

[0041] Dichloromethane and water are added to the reaction solution for extraction. The obtained organic phase is dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the angelica lactone derivatives shown in formula (I).

[0042] Specifically, the eluent for column chromatography separation and purification is a mixed solution of dichloromethane and methanol with a volume ratio of (20 - 15):1.

[0043] The present invention provides a novel and simple route for preparing angelica lactone derivatives. The reaction conditions are mild, there is no intermediate separation and purification process, which is suitable for industrial production applications. It provides a basis for the research of new drugs with high antibacterial, anti-tumor, anti-allergic, anti-inflammatory and analgesic activities, and has extremely important value for expanding the application of bis-angelica lactone derivatives in the pharmaceutical field, with extremely high promotion value. Specific Embodiments

[0044] In order to make the objectives, technical solutions and advantages of the present invention clearer, the following examples are used to further illustrate the present invention in detail. It should be understood that the specific examples described herein are only used to explain the present invention and are not used to limit the present invention.

[0045] To better illustrate the present invention, further examples are given below by way of embodiments.

[0046] Example 1

[0047] Preparation of 5-methyl-5-(2-(pyridin-4-yl)ethyl)furan-2(5H)-one:

[0048] To a solvent of dioxane (2.0 mL), 4-vinylpyridine (0.5 mmol, 53 mg), scandium trifluoromethanesulfonate (0.1 mmol, 25 mg), and triethylamine (1.0 mmol, 101.19 mg) were added. Finally, angelica lactone (1.25 mmol, 122.6 mg) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction was monitored by TLC until the reactants were completely converted. Then, the reaction solution was extracted with dichloromethane (3 × 20 mL) and water (15 mL). The obtained organic phase was washed with saturated brine (20 mL), and anhydrous Na 2 SO 4 The solid was dried, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 170 mg of the product with a purity of 94% and a yield of 91%. The reaction equation is as follows:

[0049]

[0050] 1 H NMR (500 MHz, CDCl 3 ): δ 8.51 (s, 2H), 7.51–7.06 (m, 3H), 6.08 (d, J = 5.6 Hz, 1H), 3.18 (s, 3H), 2.20 (s, 2H), 1.37 (s, 3H).

[0051] 13 C NMR (126 MHz, CDCl 3 ): δ 172.28, 159.87, 150.61, 148.66, 124.13, 121.10, 119.03, 38.41, 29.31, 27.72, 26.46, 25.17.

[0052] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, and organic bases, etc. to prepare the above compound can also achieve substantially the same technical effects as above.

[0053] Example 2

[0054] Preparation of 5-(2-(2-chloropyridin-4-yl)ethyl)-5-methylfuran-2(5H)-one:

[0055] To the solvent of dioxane (2.0 mL), add 2-chloro-4-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol). Finally, add angelica lactone (1.25 mmol). Under a nitrogen atmosphere, heat under reflux for 6 h. Monitor the reaction by TLC. After the reactants are completely converted, extract the reaction solution with dichloromethane (3 × 20 mL) and water (15 mL), wash with saturated brine (20 mL), and dry with anhydrous Na 2 SO 4 Solid, filter, concentrate under reduced pressure, and separate by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 109 mg of the product with a purity of 94% and a yield of 92%. The reaction equation is as follows:

[0056]

[0057] 1 H NMR (500 MHz, CDCl 3 ): δ 8.51 (s, 1H), 7.35 - 7.21 (m, 3H), 6.22 (d, J = 8 Hz, 1H), 3.36 (s, 3H), 2.82 (d, 2H), 1.45 (s, 3H).

[0058] 13 C NMR (126 MHz, CDCl 3 ): δ 171.26, 158.88, 151.68, 149.53, 123.53, 122.36, 119.35, 38.54, 29.92, 28.56, 27.48, 26.19.

[0059] Using other reaction conditions, reaction solvents, Lewis acids, and organic bases defined in the specification of the present invention to prepare the above compound can also achieve substantially the same technical effects as above.

[0060] Example 3

[0061] Preparation of 5-(2-(2-fluoropyridin-4-yl)ethyl)-5-methylfuran-2(5H)-one:

[0062] To a solvent of dioxane (2.0 mL), 2-fluoro-4-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) were added. Finally, angelica lactone (1.25 mmol) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction was monitored by TLC. After the reactants were completely converted, the reaction solution was extracted with dichloromethane (3 × 20 mL) and water (15 mL), washed with saturated brine (20 mL), and anhydrous Na 2 SO 4 The solid was dried, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 99 mg of the product with a purity of 93% and a yield of 90%. The reaction equation is as follows:

[0063]

[0064] 1 H NMR (500 MHz, CDCl 3 ): δ 8.31 (s, 1H), 7.55 - 7.64 (m, 3H), 6.80 (d, J = 7.2 Hz, 1H), 3.21 (s, 3H), 2.52 (d, 2H), 1.15 (s, 3H).

[0065] 13 C NMR (126 MHz, CDCl 3 ): δ 172.31, 158.75, 151.77, 147.56, 124.56, 122.21, 120.36, 36.64, 29.62, 28.72, 26.56, 25.86.

[0066] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, and organic bases, etc., to prepare the above compound can also achieve substantially the same technical effects as above.

[0067] Example 4

[0068] Preparation of 5-(2-(2-bromopyridin-4-yl)ethyl)-5-methylfuran-2(5H)-one:

[0069] To a solvent of dioxane (2.0 mL), 2-bromo-4-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) were added. Finally, angelica lactone (1.25 mmol) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction was monitored by TLC. After the reactants were completely converted, the reaction solution was extracted with dichloromethane (3 × 20 mL) and water (15 mL), washed with saturated brine (20 mL), and anhydrous Na2 SO 4 The solid was dried, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 133 mg of the product with a purity of 93% and a yield of 95%. The reaction equation is as follows:

[0070]

[0071] 1 H NMR (500 MHz, CDCl 3 ) : δ 8.49 (s, 1H), 7.62–7.51 (m, 3H), 6.89 (d, J = 6.1 Hz, 1H), 3.61 (s, 3H), 2.45 (d, 2H), 1.52 (s, 3H).

[0072] 13 C NMR (126 MHz, CDCl 3 ) : δ 174.38, 155.74, 153.78, 146.89, 125.67, 122.34, 120.58, 37.85, 29.83, 28.72, 26.65, 25.83.

[0073] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, and organic bases, etc. to prepare the above - mentioned compound can also achieve substantially the same technical effects as above.

[0074] Example 5

[0075] Preparation of 5 - methyl - 5-(2-(2 - methylpyridin - 4 - yl)ethyl)furan - 2(5H)-one:

[0076] To a solvent of dioxane (2.0 mL), 2 - methyl - 4 - vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) were added. Finally, angelica lactone (1.25 mmol) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction was monitored by TLC. After the reactants were completely converted, the reaction solution was extracted with dichloromethane (3×20 mL) and water (15 mL), washed with saturated brine (20 mL), and anhydrous Na 2 SO 4 The solid was dried, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 81 mg of the product with a purity of 93% and a yield of 75%. The reaction equation is as follows:

[0077]

[0078] 1 1H NMR (500 MHz, CDCl 3 3): δ 8.55 (s, 1H), 7.58–7.42 (m, 3H), 6.86 (d, J = 4.8 Hz, 1H), 3.22 (s, 3H), 2.59 (s, 3H), 2.15 (d, 2H), 1.36 (s, 3H).

[0079] 13 13C NMR (126 MHz, CDCl 3 3): δ 175.59, 156.84, 154.76, 147.99, 124.57, 121.36, 121.78, 38.89, 29.74, 28.86, 26.54, 25.55, 24.82.

[0080] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, and organic bases, etc. to prepare the above compounds can also achieve substantially the same technical effects as above.

[0081] Example 6

[0082] Preparation of 5-(2-(2-methoxypyridin-4-yl)ethyl)-5-methylfuran-2(5H)-one:

[0083] To a solvent of dioxane (2.0 mL), add 2-methoxy-4-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), triethylamine (1.0 mmol), and finally add angelica lactone (1.25 mmol). Under a nitrogen atmosphere, heat to reflux for 6 h. Monitor the reaction by TLC. After the reactants are completely converted, extract the reaction solution with dichloromethane (3 × 20 mL) and water (15 mL), wash with saturated brine (20 mL), and dry with anhydrous Na 2 2 4 2SO

[0084]

[0085] 1 1H NMR (500 MHz, CDCl 3):δ 8.55 (s, 1H), 7.63 (s, 1H), 7.61–7.37 (m, 2H), 6.52 (d, J = 4.8 Hz, 1H), 3.79 (s, 3H), 3.31 (d, 2H), 1.85 (s, 2H), 1.38 (s, 3H).

[0086] 13 C NMR (126 MHz, CDCl 3 ):δ 172.6, 163.24, 154.76, 150.76, 147.99, 122.62, 122.36, 121.55, 80.08, 55.12, 38.36, 26.18, 24.77.

[0087] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, and organic bases, etc. to prepare the above compounds can also achieve substantially equivalent technical effects.

[0088] Example 7

[0089] Preparation of 5-(2-(3-chloropyridin-4-yl)ethyl)-5-methylfuran-2(5H)-one:

[0090] To the solvent of dioxane (2.0 mL), add 3-chloro-4-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol). Finally, add angelica lactone (1.25 mmol). Under a nitrogen atmosphere, heat under reflux for 6 h. Monitor the reaction by TLC until the reactants are completely converted. Then, extract the reaction solution with dichloromethane (3 × 20 mL) and water (15 mL), wash with saturated brine (20 mL), and dry with anhydrous Na 2 SO 4 Solid, filter, concentrate under reduced pressure, and separate by silica gel column chromatography (200 - 300 mesh, eluent is a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 105 mg of the product with a purity of 94% and a yield of 88%. The reaction equation is as follows:

[0091]

[0092] 1 H NMR (500 MHz, CDCl 3 ):δ 8.54 (s, 1H), 7.45–7.21 (m, 3H), 6.99 (d, J = 5.8 Hz, 1H), 3.56 (s, 3H), 2.58 (d, 2H), 1.49 (s, 3H).

[0093] 13 C NMR (126 MHz, CDCl3 ):δ 175.65, 155.89, 153.65, 146.55, 125.72, 122.89, 120.78, 37.65, 29.93, 28.89, 26.42, 25.55。

[0094] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, and organic bases, etc., to prepare the above compounds can also achieve substantially equivalent technical effects.

[0095] Example 8

[0096] Preparation of 5-methyl-5-(2-(pyridin-2-yl)ethyl)furan-2(5H)-one:

[0097] Add 2-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) to a solvent of dioxane (2.0 mL). Finally, add angelica lactone (1.25 mmol). Under a nitrogen atmosphere, heat under reflux for 6 h. Monitor the reaction by TLC. After the reactants are completely converted, extract the reaction solution with dichloromethane (3 × 20 mL) and water (15 mL), wash with saturated brine (20 mL), and dry with anhydrous Na 2 SO 4 Solid, filter, concentrate under reduced pressure, and separate by silica gel column chromatography (200 - 300 mesh, eluent is a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 72 mg of the product with a purity of 94% and a yield of 71%. The reaction equation is as follows:

[0098]

[0099] 1 H NMR (500 MHz, CDCl 3 ):δ 8.66 (s, 2H), 7.58–7.32 (m, 3H), 6.21 (d, J = 5.6 Hz, 1H), 3.28 (s, 3H), 2.29 (s, 2H), 1.56 (s, 3H).

[0100] 13 C NMR (126 MHz, CDCl 3 ):δ 173.56, 159.23, 150.55, 148.81, 124.26, 121.54, 119.34, 38.51, 29.81, 27.54, 26.51, 25.22.

[0101] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, organic bases, etc. to prepare the above compounds can also achieve substantially equivalent technical effects as above.

[0102] Example 9

[0103] Preparation of 5-methyl-5-(2-(5-methylpyridin-2-yl)ethyl)furan-2(5H)-one:

[0104] To a solvent of dioxane (2.0 mL), add 5-methyl-2-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), triethylamine (1.0 mmol), and finally add angelica lactone (1.25 mmol). Under a nitrogen atmosphere, heat under reflux for 6 h. Monitor the reaction by TLC. After the reactants are completely converted, extract the reaction solution with dichloromethane (3×20 mL) and water (15 mL), wash with saturated brine (20 mL), and dry with anhydrous Na 2 SO 4 Solid, filter, concentrate under reduced pressure, and separate by silica gel column chromatography (200 - 300 mesh, eluent is a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 70 mg of the product with a purity of 94% and a yield of 65%. The reaction equation is as follows:

[0105]

[0106] 1 H NMR (500 MHz, CDCl 3 ) : δ8.64 (s, 1H), 7.64–7.55 (m, 3H), 6.75 (d, J = 6.38 Hz, 1H), 3.32 (s, 3H), 2.64 (s, 3H), 2.55 (d, 2H), 1.65 (s, 3H).

[0107] 13 C NMR (126 MHz, CDCl 3 ) : δ175.59, 156.84, 154.76, 147.99, 124.57, 121.36, 121.78, 38.89, 29.74, 28.86, 26.54, 25.55, 24.82.

[0108] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, organic bases, etc. to prepare the above compounds can also achieve substantially equivalent technical effects as above.

[0109] Example 10

[0110] Preparation of 5-methyl-5-(2-(3-methylpyridin-2-yl)ethyl)furan-2(5H)-one:

[0111] To a solvent of dioxane (2.0 mL), 3-methyl-2-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) were added. Finally, angelica lactone (1.25 mmol) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction progress was monitored by TLC. After the reactants were completely converted, the reaction solution was extracted with dichloromethane (3 × 20 mL) and water (15 mL), washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 Solid, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 66 mg of the product with a purity of 94% and a yield of 61%. The reaction equation is as follows:

[0112]

[0113] 1 1H NMR (500 MHz, CDCl 3 ) : δ 8.85 (s, 1H), 7.75 - 7.63 (m, 3H), 6.74 (d, J = 7.11 Hz, 1H), 3.41 (s, 3H), 2.54 (s, 3H), 2.43 (d, 2H), 1.69 (s, 3H).

[0114] 13 13C NMR (126 MHz, CDCl 3 ) : δ 175.86, 156.76, 154.55, 147.772, 124.84, 122.85, 121.57, 38.65, 29.85, 28.65, 26.43, 26.65, 23.72.

[0115] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, and organic bases, etc., to prepare the above compound can also achieve substantially the same technical effects as above.

[0116] Example 11

[0117] Preparation of 5-phenyl-5-(2-(pyridin-4-yl)ethyl)furan-2(5H)-one:

[0118] To a solvent of dioxane (2.0 mL), 4-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) were added. Finally, 5-phenylangelica lactone (1.25 mmol) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction was monitored by TLC until the reactants were completely converted. Then, the reaction solution was extracted with dichloromethane (3 × 20 mL) and water (15 mL), washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 The solid was dried, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 92 mg of the product with a purity of 94% and a yield of 70%. The reaction equation is as follows:

[0119]

[0120] 1 H NMR (500 MHz, CDCl 3 ): δ 8.47 (d, J = 4.9 Hz, 2H), 7.67 (d, J = 5.6 Hz, 1H), 7.42–7.35 (m, 5H), 7.04 (d, J = 5.4 Hz, 2H), 6.10 (d, J = 5.6 Hz, 1H), 2.68 (ddd, J = 14.4, 12.3, 5.0 Hz, 1H), 2.50 (dddd, J = 16.6, 13.9, 11.9, 4.6 Hz, 2H), 2.25 (ddd, J = 13.9, 12.0, 5.0 Hz, 1H).

[0121] 13 C NMR (126 MHz, CDCl 3 ): δ 172.01, 159.10, 149.85, 149.80, 149.69, 138.15, 129.09, 128.50, 124.82, 123.70, 120.09, 90.84, 40.21, 29.69, 29.41.

[0122] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, and organic bases, etc., to prepare the above compound can also achieve substantially the same technical effects as above.

[0123] Example 12

[0124] Preparation of 5-([1,1'-biphenyl]-4-yl)-5-(2-(pyridin-4-yl)ethyl)furan-2(5H)-one:

[0125] To the solvent of dioxane (2.0 mL), add 4-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol). Finally, add 5([1,1'-biphenyl]-4-yl)furan-2(3H)-one (1.25 mmol). Under a nitrogen atmosphere, heat under reflux for 6 h. Monitor the reaction by TLC. After the reactants are completely converted, extract the reaction solution with dichloromethane (3 × 20 mL) and water (15 mL), wash with saturated brine (20 mL), and dry with anhydrous Na 2 SO 4 Solid, filter, concentrate under reduced pressure, and separate by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 138 mg of the product with a purity of 94% and a yield of 81%. The reaction equation is as follows:

[0126]

[0127] 1 H NMR (600 MHz, CDCl 3 ): δ 8.41 (d, J = 5.2 Hz, 2H), 7.60 (d, J = 5.6 Hz, 1H), 7.58–7.54 (m, 2H), 7.53–7.48 (m, 2H), 7.42–7.36 (m, 4H), 7.32–7.28 (m, 1H), 7.03–6.95 (m, 2H), 6.06 (d, J = 5.6 Hz, 1H), 2.65 (ddd, J = 13.9, 12.0, 5.0 Hz, 1H), 2.48 (dddd, J = 38.5, 14.1, 11.9, 4.7 Hz, 2H), 2.21 (ddd, J = 14.1, 11.8, 5.0 Hz, 1H).

[0128] 13 C NMR (126 MHz, CDCl 3 ): δ 171.99, 159.02, 149.91, 149.60, 141.50, 140.07, 137.05, 128.93, 127.76, 127.09, 125.33, 123.71, 120.17, 90.78, 40.19, 29.71, 29.45.

[0129] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, and organic bases, etc., to prepare the above compounds can also achieve substantially the same technical effects as above.

[0130] Example 13

[0131] Preparation of 5-(4-chlorophenyl)-5-(2-(pyridin-4-yl)ethyl)furan-2(5H)-one:

[0132] 4-Vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) were added to a solvent of dioxane (2.0 mL). Finally, 5-(4-chlorophenyl)furan-2(3H)-one (1.25 mmol) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction was monitored by TLC until the reactants were completely converted. Then, the reaction solution was extracted with dichloromethane (3 × 20 mL) and water (15 mL), washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 The solid was dried, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 118 mg of the product with a purity of 94% and a yield of 79%. The reaction equation is as follows:

[0133]

[0134] 1 1H NMR (500 MHz, CDCl 3 ):δ8.57–8.41 (m, 2H), 7.63 (d, J=5.6 Hz, 1H), 7.45–7.31 (m, 4H), 7.11–6.98 (m, 2H), 6.12 (s, 1H), 2.67 (ddd, J=13.8, 11.9, 5.0 Hz, 1H), 2.48 (dddd, J=33.2, 14.1, 11.9, 4.7 Hz, 2H), 2.23 (ddd, J=14.1, 11.7, 5.0 Hz, 1H).

[0135] 13 13C NMR (126 MHz, CDCl 3 ):δ171.63, 158.55, 149.87, 149.39, 136.74, 134.54, 129.29, 126.29, 123.66, 120.40, 90.27, 40.14, 29.34.

[0136] Using other reaction conditions defined in the specification of the present invention, as well as reaction solvents, Lewis acids, and organic bases, etc., to prepare the above compound can also achieve substantially the same technical effects as above.

[0137] Example 14

[0138] Preparation of 5-(4-fluorophenyl)-5-(2-(pyridin-4-yl)ethyl)furan-2(5H)-one:

[0139] 4-Vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) were added to dioxane (2.0 mL) solvent. Finally, 5-(4-fluorophenyl)furan-2(3H)-one (1.25 mmol) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction was monitored by TLC. After the reactants were completely converted, the reaction solution was extracted with dichloromethane (3 × 20 mL) and water (15 mL), washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 solid. The mixture was filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 110 mg of the product with a purity of 94% and a yield of 78%. The reaction equation is as follows:

[0140]

[0141] 1 H NMR (500 MHz, CDCl 3 ): δ 8.66–8.59 (m, 2H), 7.59 (d, J = 5.7 Hz, 1H), 7.56–7.28 (m, 4H), 7.13–6.75 (m, 2H), 6.24 (s, 1H), 2.56 (ddd, J = 14.4, 12.4, 5.0 Hz, 1H), 2.55 (dddd, J = 35.5, 13.7, 11.5, 4.9 Hz, 2H), 2.33 (ddd, J = 14.8, 11.7, 5.0 Hz, 1H).

[0142] 13 C NMR (126 MHz, CDCl 3 ): δ 172.55, 158.43, 149.92, 149.55, 136.89, 134.64, 129.72, 126.45, 125.12, 120.55, 89.27, 38.14, 27.56.

[0143] Using other reaction conditions, reaction solvents, Lewis acids, and organic bases defined in the specification of the present invention to prepare the above compound can also achieve substantially the same technical effects as above.

[0144] Example 15

[0145] Preparation of 5-(4-bromophenyl)-5-(2-(pyridin-4-yl)ethyl)furan-2(5H)-one:

[0146] To a solvent of dioxane (2.0 mL), 4-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) were added. Finally, 5-(4-bromophenyl)furan-2(3H)-one (1.25 mmol) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction was monitored by TLC until the reactants were completely converted. Then, the reaction solution was extracted with dichloromethane (3 × 20 mL) and water (15 mL), washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 The solid was dried, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 123 mg of the product with a purity of 94% and a yield of 72%. The reaction equation is as follows:

[0147]

[0148] 1 H NMR (500 MHz, CDCl 3 ): δ 8.57–8.41 (m, 2H), 7.63 (d, J = 5.6 Hz, 1H), 7.45–7.29 (m, 4H), 7.11–6.93 (m, 2H), 6.12 (s, 1H), 2.67 (ddd, J = 13.7, 12.1, 5.0 Hz, 1H), 2.48 (dddd, J = 34.4, 13.2, 10.8, 5.6 Hz, 2H), 2.23 (ddd, J = 13.8, 11.9, 4.9 Hz, 1H).

[0149] 13 C NMR (126 MHz, CDCl 3 ): δ 173.67, 159.56, 148.86, 148.42, 135.82, 135.42, 128.78, 126.56, 125.23, 120.42, 89.65, 38.55, 27.42.

[0150] Using other reaction conditions, reaction solvents, Lewis acids, and organic bases as defined in the specification of the present invention to prepare the above compound can also achieve substantially the same technical effects as above.

[0151] Example 16

[0152] Preparation of 5-(3-chlorophenyl)-5-(2-(pyridin-4-yl)ethyl)furan-2(5H)-one:

[0153] 4-Vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) were added to dioxane (2.0 mL) solvent. Finally, 5-(3-chlorophenyl)furan-2(3H)-one (1.25 mmol) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction was monitored by TLC until the reactants were completely converted. The reaction solution was extracted with dichloromethane (3 × 20 mL) and water (15 mL), washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 The solid was dried, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 116 mg of the product with a purity of 94% and a yield of 78%. The reaction equation is as follows:

[0154]

[0155] 1 H NMR (500 MHz, CDCl 3 ):δ 8.51 (s, 2H), 7.68 (d, J = 5.6 Hz, 1H), 7.44 (d, J = 4.3 Hz, 4H), 7.09 (d, J = 4.7 Hz, 2H), 6.14 (d, J = 5.6 Hz, 1H), 2.72 (dtd, J = 13.9, 6.5, 3.3 Hz, 1H), 2.60–2.47 (m, 2H), 2.28 (ddd, J = 14.0, 11.1, 5.0 Hz, 1H).

[0156] 13 C NMR (126 MHz, CDCl 3 ):δ 175.76, 159.64, 148.75, 148.55, 136.84, 135.23, 129.22, 125.54, 124.23, 121.22, 88.55, 37.56, 28.42.

[0157] Using other reaction conditions, reaction solvents, Lewis acids, and organic bases defined in the specification of the present invention to prepare the above compound can also achieve substantially the same technical effects as above.

[0158] Example 17

[0159] Preparation of 5-(3-bromophenyl)-5-(2-(pyridin-4-yl)ethyl)furan-2(5H)-one:

[0160] To a solvent of dioxane (2.0 mL), 4-vinylpyridine (0.5 mmol), scandium trifluoromethanesulfonate (0.1 mmol), and triethylamine (1.0 mmol) were added. Finally, 5-(3-bromophenyl)furan-2(3H)-one (1.25 mmol) was added. Under a nitrogen atmosphere, the mixture was heated to reflux for 6 h. The reaction was monitored by TLC until the reactants were completely converted. Then, the reaction solution was extracted with dichloromethane (3 × 20 mL) and water (15 mL), washed with saturated brine (20 mL), and dried over anhydrous Na 2 SO 4 The solid was dried, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (200 - 300 mesh, eluent: a mixed solvent of dichloromethane / methanol with a volume ratio of 20:1) to obtain 116 mg of the product with a purity of 94% and a yield of 82%. The reaction equation is as follows:

[0161]

[0162] 1 H NMR (500 MHz, CDCl 3 ): δ 8.47 (d, J = 5.3 Hz, 2H), 7.67 (d, J = 5.6 Hz, 1H), 7.42 (d, J = 4.3 Hz, 4H), 7.08–7.00 (m, 2H), 6.11 (d, J = 5.5 Hz, 1H), 2.68 (dtd, J = 13.0, 6.7, 6.0, 3.9 Hz, 1H), 2.57–2.44 (m, 2H), 2.25 (dtd, J = 13.9, 7.8, 6.9, 3.9 Hz, 1H).

[0163] 13 C NMR (126 MHz, CDCl 3 ): δ 172.56, 158.89, 148.56, 147.54, 146.55, 137.45, 128.12, 127.44, 124.89, 121.24, 120.10, 91.56, 42.45, 30.12, 28.45.

[0164] Using other reaction conditions, reaction solvents, Lewis acids, and organic bases defined in the specification of the present invention to prepare the above compound can also achieve substantially the same technical effects as above.

[0165] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. An angelica lactone derivative, characterized in that: Its structure is shown in formula (I): wherein R1, R2, R3, and R4 are independently selected from H, halogen, methyl, or methoxy, and at least two of R1, R2, R3, and R4 are H; R5 is methyl, methoxy, biphenyl or halogenated phenyl.

2. The angelica lactone derivative according to claim 1, characterized in that: The halogen is F, Cl or Br.

3. A method for preparing the angelica lactone derivatives according to claim 1 or 2, characterized in that: The following steps are involved: Under an inert atmosphere, an organic solvent, a Lewis acid and an organic base, a 4-vinylpyridine compound represented by formula (II) and a compound represented by formula (III) undergo an addition reaction to obtain an angelica lactone derivative represented by formula (I); wherein R1, R2, R3, and R4 are independently selected from H, halogen, methyl, or methoxy, and at least two of R1, R2, R3, and R4 are H; R5 is methyl, methoxy, biphenyl or halogenated phenyl.

4. The method for preparing angelica lactone derivatives according to claim 3, characterized in that: The organic solvent is one or more of toluene, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 1,4-dioxane, dichloromethane or dichloroethane; and / or The Lewis acid is one or more of copper trifluoromethanesulfonate, indium trichloride, bistriphenylphosphine palladium dichloride, palladium acetate or scandium trifluoromethanesulfonate; and / or The organic base is one or more of triethylenediamine, triethylamine, pyridine, 2,6-lutidine, and 1,8-diazabicycloundec-7-ene.

5. The method for preparing angelica lactone derivatives according to claim 4, characterized in that: The organic solvent is 1,4-dioxane; and / or The Lewis acid is scandium trifluoromethanesulfonate; and / or The organic base is triethylamine.

6. The method for preparing angelica lactone derivatives according to claim 3, characterized in that: The molar ratio of the 4-vinylpyridine compound to the compound represented by formula (III) is 1:(1-3).

7. The method for preparing angelica lactone derivatives according to claim 3, characterized in that: The molar ratio of the 4-vinylpyridine compound to the Lewis acid is 1:(0.1-0.3).

8. The method for preparing angelica lactone derivatives according to claim 3, characterized in that: The molar ratio of the 4-vinylpyridine compound to the organic solvent is 1 mmol: (1-5) mL.

9. The method for preparing angelica lactone derivatives according to claim 3, characterized in that: The molar ratio of the 4-vinylpyridine compound to the organic base is 1:(1-3).

10. The method for preparing angelica lactone derivatives according to claim 3, characterized in that: The temperature of the addition reaction is 40°C to 110°C.

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