Total synthesis preparation method of wedelolactone or norwedelolactone

Abstract

The invention belongs to the technical field of traditional Chinese medicine plant chemistry, and particularly relates to a total synthetic preparation method of wedelolactone or norwedelolactone. Raw materials (6-hydroxybenzo[2,1-d][1,3]dioxolan-5-yl) methyl acetate and 2,4,6-trimethoxybenzoic acid are used for synthesis to obtain an intermediate compound, and wedelolactone and norwedelolactone are synthesized respectively through the intermediate compound. The preparation method of the invention avoids the use of a metal catalyst (palladium catalyst, copper catalyst, etc.), reduces costs, has a simple reaction, and a short route, thus facilitating subsequent further efficacy research on wedelolactone and norwedelolactone.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine plant chemistry, and particularly relates to a total synthetic preparation method of wedelolactone or norwedelolactone. Background Art

[0002] The dried part of the plant Channa spp., belonging to the genus Channa of the Asteraceae family, is a common Chinese medicine. It contains a large number of natural active ingredients and has been shown to protect the liver (Am J Chin Med. 2018.46(4):819-833.) and resist snake venom (Basic Clin Pharmacol Toxicol. 2009.104(4):293-9.) in traditional Chinese medicine. Modern research has found that wedelolactone and norwedelolactone have anti-tumor and anti-immunosuppressive effects, and some of the effects of wedelolactone and its derivative norwedelolactone need further study.

[0003] However, the content of wedelolactone and norwedelolactone in Herba Lycopersici and other natural plants is low, and traditional extraction methods are still difficult and often lack purity. Therefore, it is very necessary to synthesize wedelolactone and norwedelolactone through efficient chemical methods, which can greatly reduce costs, improve purity, and facilitate subsequent biological activity research.

[0004] However, the currently published synthesis methods for the natural product wedelia lactone mainly include the following two methods: synthesis using phenylacetylene as raw material (J Org Chem. 2003. 68(22): 8500-4.); synthesis using pyrogallol as raw material (Tetrahedron. 2008. 64(17): 3661-3666.; Molecules. 2019. 24(22): 4130.).

[0005] The synthesis method from phenylacetylene is limited by the difficulty of synthesizing phenylacetylene and the long actual reaction route. The use of precious metal catalysts in the reaction process using pyrogallol as the raw material leads to increased actual production costs. Furthermore, this method, after optimization, forms a longer reaction route, making it even less suitable for industrial production. The above methods also have problems such as difficulty in preparing raw materials, the use of metal catalysts, long reaction routes, high costs, and difficulty in achieving industrial production levels, which have a certain impact on the progress of the synthesis and environmental protection. Summary of the Invention

[0006] The present invention aims to solve the problems existing in the prior art and provides a method for the total synthesis of the natural product wedelaractone or norwedelaractone.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] In a first aspect, an intermediate compound for preparing wedelolactone or norwedelolactone is provided, wherein the intermediate compound is methyl 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylate, and its structural formula is as follows:

[0009]

[0010] The preparation method is specifically as follows:

[0011] Step A: Compound 1, Compound 2, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 4-dimethylaminopyridine were dissolved in dichloromethane at a molar ratio of Compound 1: Compound 2: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 4-dimethylaminopyridine = 1:1:1:0.05, and reacted at 60° C. for 12 hours; then separated and purified by column chromatography to obtain Compound 3;

[0012] Step B: Compound 3 was dissolved in tetrahydrofuran at a molar ratio of compound 3: potassium tert-butoxide = 1:5, and then placed at -78°C. Potassium tert-butoxide was added, and the mixture was taken out and stored at room temperature overnight after 2 hours. The pH was adjusted to ≤ 7 with 1M hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 4.

[0013] Step C: Compound 4 was dissolved in methanol, sulfuric acid was added, and the mixture was stirred at 90° C. for 8 hours; saturated sodium bicarbonate solution was added to neutralize the mixture to a pH of 7, and the methanol in the solution was removed by distillation under reduced pressure. The mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain compound 5, i.e., methyl 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylate;

[0014] The reaction route is as follows:

[0015]

[0016] Compound 1 is methyl (6-hydroxybenzo[2,1-d][1,3]dioxolan-5-yl)acetate;

[0017] Compound 2 is 2,4,6-trimethoxybenzoic acid;

[0018] Compound 3 is methyl (6-{[(2,4,6-trimethoxyphenyl)carbonyl]oxy}benzo[2,1-d][1,3]dioxolan-5-yl)acetate;

[0019] Compound 4 is 7-[(Z)-hydroxy(2,4,6-trimethoxyphenyl)methylene]furo[2',3':1,2]benzo[4,5-d][1,3]dioxolan-6-one.

[0020] In a second aspect, the present invention provides a method for preparing wedelolactone, which is specifically as follows: according to the molar ratio of 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylic acid methyl ester: boron tribromide = 1:10, 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylic acid methyl ester: boron tribromide = 1:10, Methyl ':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylate was dissolved in dichloromethane and stirred at -20°C. Boron tribromide was diluted with dichloromethane and added to the reaction solution, and stirred at -20°C for 40 minutes. Methanol was added to quench the excess boron tribromide, and the dichloromethane was removed by concentration. After recrystallization from dichloromethane and petroleum ether, the filter cake was filtered and dried under infrared irradiation to obtain the final product 6, i.e., wedelolide.

[0021] In a third aspect, the present invention provides a method for preparing wedelolactone, which is specifically as follows:

[0022] According to the molar ratio of 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylic acid methyl ester: boron tribromide = 1:10, 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylic acid methyl ester was dissolved in dichloromethane and placed at -20°C. Boron tribromide was diluted with dichloromethane and added to the reaction solution, and the temperature was raised to 40°C and refluxed for 8 hours. Methanol was added to quench the excess boron tribromide, and the product was concentrated to remove dichloromethane. The product was separated and purified by chromatography, and concentrated under reduced pressure to obtain the final product 7, i.e., demethylwedelactone.

[0023] The present invention has the following technical effects: (1) The method for the total synthesis of the natural products wedelia lactone and norwedelia lactone uses a more readily available raw material (6-hydroxybenzo[2,1-d][1,3]dioxolane-5-yl)acetic acid methyl ester to prepare 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylic acid methyl ester, and solves the problems of difficulty in obtaining raw materials, high cost of using precious metal catalysts (palladium catalysts, copper catalysts, etc.), and long reaction routes in preparing wedelia lactone and norwedelia lactone by using the method; at the same time, it provides convenience for subsequent further research on the efficacy of wedelia lactone and norwedelia lactone.

[0024] (2) The total synthesis preparation method of the natural products wedeli lactone and demethyl wedeli lactone of the present invention has higher purity than that obtained by extracting from traditional Chinese medicine. Other products may exist when extracted from traditional Chinese medicine, while only this product can be obtained by chemical synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The reaction route diagram for the intermediate compound;

[0026] Figure 2 Reaction route of the natural product wedelilactone;

[0027] Figure 3 This is the reaction route of demethylwedelactone. DETAILED DESCRIPTION

[0028] The contents and drawings of the present invention will be described in detail below. This embodiment is implemented based on the technical solution of the present invention and involves detailed implementation plans and operating procedures. However, the scope of protection of the present invention is not limited to the following specific embodiments. The terms used in the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0029] Example 1 Preparation method of natural product wedelolactone

[0030] Step A: Compound 1 [methyl (6-hydroxybenzo[2,1-d][1,3]dioxolan-5-yl)acetate] (210 mg, 1 mmol), compound 2 [2,4,6-trimethoxybenzoic acid] (212 mg, 1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (191.7 mg, 1 mmol), and 4-dimethylaminopyridine (6.1 mg, 0.05 mmol) were dissolved in dichloromethane (5 ml) and reacted at 60°C for 12 hours. The product was separated and purified by column chromatography (silica, eluent: dichloromethane) to obtain compound 3 [methyl (6-{[(2,4,6-trimethoxyphenyl)carbonyl]oxy}benzo[2,1-d][1,3]dioxolan-5-yl)acetate] (210 mg, 51.98%). 1H NMR (400MHz, Chloroform-d) δ6.83 (s, 1H), 6.75 (s, 1H), 6.17 (s, 2H), 6.01 (s, 2H), 3.88 (d, J = 6.5Hz, 9H), 3.69 (d, J = 3.3Hz, 5H).

[0031] Step B: Compound 3 (404 mg, 1 mmol) was dissolved in tetrahydrofuran (20 ml) and potassium tert-butoxide (560 mg, 5 mmol) was added at -78°C. The mixture was reacted at -78°C for 2 hours and then allowed to stand at room temperature (25°C) overnight. The pH was adjusted to ≤ 7 with 1 M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (silica, eluent: petroleum ether / ethyl acetate = 4 / 1) to obtain compound 4[7-[(Z)-hydroxy(2,4,6-trimethoxyphenyl)methylidene]furo[2',3':1,2]benzo[4,5-d][1,3]dioxolan-6-one] (213 mg, 50.5%). 1H NMR (400MHz, DMSO-d6) δ12.27(s,1H),7.23(s,1H),6.87(s,1H),6.29(s,2H),6.00(s,2H),3.84(s,3H),3.72(s,6H).

[0032] Step C: Compound 4 (213 mg, 0.505 mmol) was dissolved in methanol (5 mL), and a catalytic amount of sulfuric acid was added. The mixture was stirred at 90°C for 8 hours. Saturated sodium bicarbonate solution was added to neutralize the mixture to a pH of 7. The methanol was removed by distillation under reduced pressure, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (silica, eluent: dichloromethane) to obtain compound 5 [methyl 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolan-7-carboxylate] (146.3 mg, 74.8%). 1H NMR (400MHz, Chloroform-d) δ7.47(s,1H),7.03(s,1H),6.21(s,2H),6.02(s,2H),3.89(s,3H),3.80(s,3H),3.76(s,6H).

[0033] Step D: Dissolve compound 5 (38.6 mg, 0.1 mmol) in dichloromethane (10 mL) and place at -20°C. Dilute boron tribromide (250 mg, 1 mmol) with 2 mL of dichloromethane and add the resulting mixture to the reaction mixture. Stir at -20°C for 40 minutes. Add a small amount of methanol to quench the excess boron tribromide, and concentrate to remove the dichloromethane. Recrystallize the mixture from dichloromethane and petroleum ether, filter, and dry under infrared spectroscopy to obtain the final product 6 (wedelactone) (26.8 mg, 85%). 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.43(s,1H),9.38(s,1H),7.25(s,1H),7.17(s,1H),6.64(d,J=2.3Hz,1H),6.47(d,J=2.3Hz,1H),3.83(s,3H).

[0034] Reaction route such as Figure 2 shown.

[0035] Example 2 Preparation method of norwedelactone

[0036] Step A: Compound 1 [methyl (6-hydroxybenzo[2,1-d][1,3]dioxolan-5-yl)acetate] (210 mg, 1 mmol), compound 2 [2,4,6-trimethoxybenzoic acid] (212 mg, 1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (191.7 mg, 1 mmol), and 4-dimethylaminopyridine (6.1 mg, 0.05 mmol) were dissolved in dichloromethane (5 ml) and reacted at 60°C for 12 hours. The product was separated and purified by column chromatography (silica, eluent: dichloromethane) to obtain compound 3 (210 mg, 51.98%). 1H NMR (400MHz, Chloroform-d) δ6.83 (s, 1H), 6.75 (s, 1H), 6.17 (s, 2H), 6.01 (s, 2H), 3.88 (d, J = 6.5Hz, 9H), 3.69 (d, J = 3.3Hz, 5H).

[0037] Step B: Compound 3 (404 mg, 1 mmol) was dissolved in tetrahydrofuran (20 ml) and potassium tert-butoxide (560 mg, 5 mmol) was added at -78°C. The mixture was reacted at -78°C for 2 hours and then allowed to stand at room temperature (25°C) overnight. The pH was adjusted to ≤7 with 1 M hydrochloric acid solution and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (silica, eluent: petroleum ether / ethyl acetate = 4 / 1) to yield compound 4 (213 mg, 50.5%). 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 7.23 (s, 1H), 6.87 (s, 1H), 6.29 (s, 2H), 6.00 (s, 2H), 3.84 (s, 3H), 3.72 (s, 6H).

[0038] Step C: Compound 4 (213 mg, 0.505 mmol) was dissolved in methanol (5 mL), and a catalytic amount of sulfuric acid was added. The mixture was stirred at 90°C for 8 hours. Saturated sodium bicarbonate solution was added to neutralize the mixture to a pH of 7. The methanol was removed by distillation under reduced pressure, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (silica, eluent: dichloromethane) to obtain compound 5 (146.3 mg, 74.8%). 1H NMR (400 MHz, Chloroform-d) δ 7.47 (s, 1H), 7.03 (s, 1H), 6.21 (s, 2H), 6.02 (s, 2H), 3.89 (s, 3H), 3.80 (s, 3H), 3.76 (s, 6H).

[0039] Step E: Compound 5 (38.6 mg, 0.1 mmol) was dissolved in dichloromethane (10 mL) and placed at -20°C. Boron tribromide (250 mg, 1 mmol) diluted with dichloromethane and added to the reaction mixture, which was then heated to 40°C and refluxed for 8 hours. A small amount of methanol was added to quench the excess boron tribromide. The mixture was concentrated to remove dichloromethane and purified by column chromatography (silica, eluent: petroleum ether / ethyl acetate = 1 / 2). After concentration under reduced pressure, the final product 7 (demethylwedelactone) (4.7 mg, 15%) was obtained. 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),10.41(s,1H),9.36(d,J=16.0Hz,2H),7.22(s,1H),7.15(s,1H),6.40(d,J=2.1Hz,1H),6.36(d,J=2.1Hz,1H).

[0040] Reaction route such as Figure 2 shown.

[0041] The above description of the disclosed embodiments is intended to enable those skilled in the art to use the present invention. Furthermore, the above embodiments are intended only to illustrate the technical concepts of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications based on the technical solutions proposed in accordance with the technical concepts of the present invention fall within the scope of protection of the present invention.

Claims

1. An intermediate compound for preparing wedelolactone or norwedelolactone, characterized in that: The intermediate compound is methyl 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylate, and its structural formula is as follows:

2. The method for preparing the intermediate compound according to claim 1, characterized in that: The preparation method is specifically as follows: Step A: Compound 1, Compound 2, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 4-dimethylaminopyridine were dissolved in dichloromethane at a molar ratio of Compound 1: Compound 2: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 4-dimethylaminopyridine = 1:1:1:0.05, and reacted at 60° C. for 12 hours; then separated and purified by column chromatography to obtain Compound 3; Step B: Compound 3 was dissolved in tetrahydrofuran at a molar ratio of compound 3: potassium tert-butoxide = 1:5, and then placed at -78°C. Potassium tert-butoxide was added, and the mixture was taken out and stored at room temperature overnight after 2 hours. The pH was adjusted to ≤ 7 with 1M hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 4. Step C: Compound 4 was dissolved in methanol, sulfuric acid was added, and the mixture was stirred at 90° C. for 8 hours; saturated sodium bicarbonate solution was added to neutralize the mixture to a pH of 7, and the methanol in the solution was removed by distillation under reduced pressure. The mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain compound 5, i.e., methyl 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylate; The reaction route is as follows: Compound 1 is methyl (6-hydroxybenzo[2,1-d][1,3]dioxolan-5-yl)acetate; Compound 2 is 2,4,6-trimethoxybenzoic acid; Compound 3 is methyl (6-{[(2,4,6-trimethoxyphenyl)carbonyl]oxy}benzo[2,1-d][1,3]dioxolan-5-yl)acetate; Compound 4 is 7-[(Z)-hydroxy(2,4,6-trimethoxyphenyl)methylene]furo[2',3':1,2]benzo[4,5-d][1,3]dioxolan-6-one.

3. A method for preparing wedelolactone using the intermediate compound according to claim 1, characterized in that: The method is specifically as follows: according to the molar ratio of 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylic acid methyl ester: boron tribromide = 1:10, 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylic acid methyl ester is dissolved in dichloromethane and then stirred at -20°C; boron tribromide is diluted with dichloromethane and added to the reaction solution, and stirred at -20°C for 40 minutes; methanol is added to quench excess boron tribromide, and dichloromethane is removed by concentration; after recrystallization with dichloromethane and petroleum ether, the filter cake is filtered to obtain a final product 6, i.e., wedelolide.

4. A method for preparing norwedelactone using the intermediate compound according to claim 1, characterized in that: The method is specifically as follows: According to the molar ratio of 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylic acid methyl ester: boron tribromide = 1:10, 6-(2,4,6-trimethoxyphenyl)-6,7-dihydrofuro[2',3':1,2]benzo[4,5-d][1,3]dioxolane-7-carboxylic acid methyl ester was dissolved in dichloromethane and placed at -20°C. Boron tribromide was diluted with dichloromethane and added to the reaction solution, and the temperature was raised to 40°C and refluxed for 8 hours. Methanol was added to quench the excess boron tribromide, and the product was concentrated to remove dichloromethane. The product was separated and purified by chromatography, and concentrated under reduced pressure to obtain the final product 7, i.e., demethylwedelactone.

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