A method for synthesizing a natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol

Abstract

This invention relates to the field of organic synthesis technology and discloses a method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diphenol. 2-Bromo-1,3-dimethoxybenzene and 3,5-dimethoxyacetophenone react under a nitrogen atmosphere with sodium tert-butoxide and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) to generate 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one. Subsequently, a demethylation and cyclization tandem reaction occurs under the action of boron tribromide to generate 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diphenol. The method of this invention requires inexpensive and readily available raw materials, is simple, has mild reaction conditions, and a high overall yield, making it suitable for industrial-scale preparation.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol. Background Technology

[0002] 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol (Cuspidan B) is an important bioactive natural molecule isolated from the bark of the plant *Gnetum cuspidatum*. It exhibits good anticancer activity, with an IC50 of 33.5 μM against human promyelocytic leukemia (HL-60) cells. However, obtaining this natural molecule solely through plant extraction is inefficient and costly. Therefore, there is an urgent need to develop efficient and concise methods for the large-scale synthesis of 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, thereby promoting its development and application in the biomedical field.

[0003] Currently, there are two main methods for synthesizing 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol:

[0004] 1. The Takayuki Yakura group in Japan developed a 7-step linear method for the synthesis of 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, with the key reaction being an acid-catalyzed ring-opening cyclization reaction of spirocyclopropane. However, starting from tert-butyldimethylsilyl-protected 5-vinyl-1,3-benzenediol, the overall yield is only 21%, and the reaction involves cumbersome protection and deprotection reactions, which is not conducive to industrial-scale preparation (Synthesis 2016, 48, 1892-1901).

[0005] 2. CN110894192A provides another method for synthesizing 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, which utilizes methyl maltol as a starting material via trifluoromethanesulfonation and a Sonogashira coupling reaction to generate a disubstituted alkyne intermediate. Then, through a key destructive-recombination reaction, a benzofuran ring is constructed to obtain 2-(3,5-dimethoxyphenyl)benzofuran-4-phenol, and finally, the methyl group is removed to yield 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol. However, this route still requires four steps to synthesize the natural molecule, and the overall yield remains low (29.8%), with long production costs and timelines for large-scale production. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, which requires inexpensive and readily available raw materials, is simple, has mild reaction conditions, high overall yield, and is convenient for industrial preparation.

[0007] This invention is achieved through the following technical solution:

[0008] A method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, comprising the following steps:

[0009] (1) 2-Bromo-1,3-dimethoxyphenyl and 3,5-dimethoxyacetophenone react in a nitrogen atmosphere under the action of sodium tert-butoxide and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) to generate 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one;

[0010] (2) 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one undergoes a series of demethylation and cyclization reactions under the action of boron tribromide to generate 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol.

[0011] Preferably, in step (1), the molar ratio of 2-bromo-1,3-dimethoxybenzene, 3,5-dimethoxyacetophenone, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) and sodium tert-butoxide is 1:1~1.5:0.05~0.2:2~3.

[0012] Preferably, in step (1), the reaction temperature is 80℃~90℃ and the reaction time is 8~12h.

[0013] Preferably, 2-bromo-1,3-dimethoxybenzene and 3,5-dimethoxyacetophenone are dissolved in 1,4-dioxane for the reaction.

[0014] Preferably, in step (1), after the reaction is complete, water is added to dilute the reaction solution, an organic solvent is added, the liquid is separated, the aqueous phase is extracted with an organic solvent, the organic phases are combined, the solvent is evaporated, and then purified by silica gel column chromatography to obtain 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one.

[0015] Preferably, in step (2), the molar ratio of 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one to boron tribromide is 1:6~8.

[0016] Preferably, in step (2), the reaction temperature is -78℃ to 0℃ and the reaction time is 3 to 5 hours.

[0017] Preferably, in step (2), 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one is dissolved in dichloromethane for the reaction.

[0018] Preferably, in step (2), after the reaction is complete, ice water is added to quench the reaction, an organic solvent is added, the liquid is separated, the aqueous phase is extracted with an organic solvent, the organic phases are combined, the solvent is evaporated, and the product is purified by silica gel column chromatography to obtain 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol.

[0019] Compared with existing technical solutions, the present invention has the following advantages:

[0020] 1) The synthetic route of this invention is simple, requiring only two reaction steps (compared to four to seven steps in existing processes) to synthesize 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, significantly shortening the production cycle. The starting materials, 2-bromo-1,3-dimethoxybenzene and 3,5-dimethoxyacetophenone, are inexpensive and readily available, and the reaction operation is simple. The synthesis process does not require protecting groups and does not involve cumbersome protection and deprotection reactions. The overall yield (up to 67%) is significantly higher than that of existing processes (21%~29.8%), facilitating industrial production.

[0021] 2) The key reaction of this invention is a novel boron tribromide-mediated demethylation / cyclization tandem reaction, which ingeniously and efficiently cyclizes α-arylacetophenone structures in one step to obtain benzofuran-like natural molecules. Besides synthesizing 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, it also provides a process reference for the synthesis of other benzofuran-like natural molecules, and compared with existing processes, it has greater prospects for industrialization. Attached Figure Description

[0022] Figure 1 This is the reaction formula of the present invention.

[0023] Figure 2 The 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol prepared in this invention 1 H-NMR spectrum.

[0024] Figure 3 The mass spectrum of 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol prepared in this invention is shown. Detailed Implementation

[0025] The present invention will be further described below with reference to the embodiments, but the description of the embodiments does not limit the scope of protection of the present invention in any way.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. Furthermore, while this document may provide examples of parameters containing specific values, it should be understood that the parameters need not be exactly equal to the corresponding values, but may approximate the corresponding values ​​within acceptable error tolerances or design constraints.

[0027] Unless otherwise specified, all substances or instruments used in the following examples can be obtained from conventional commercial sources.

[0028] The reaction principle of this invention is as follows: Figure 1 As shown.

[0029] Example 1

[0030] (1) At room temperature, 2-bromo-1,3-dimethoxybenzene (2.0 g, 9.22 mmol) and 3,5-dimethoxyacetophenone (1.66 g, 9.22 mmol) were dissolved in 50 mL of 1,4-dioxane. Sodium tert-butoxide (1.77 g, 18.44 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.56 g, 1.84 mmol) were added with stirring. The resulting mixture was stirred at 80 °C for 12 h under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, diluted with 80 mL of water, and extracted with ethyl acetate (3 × 80 mL). The organic phases were combined and the solvent was evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one (2.36 g, 81% yield) as a brown solid. 1 H NMR (400MHz, CDCl3) δ 7.22 – 7.17 (m, 3H), 6.62 (t, J = 2.3 Hz, 1H), 6.57 (s, 1H), 6.55 (s, 1H), 4.28 (s, 2H), 3.81 (s, 6H), 3.75 (s, 6H). ESI-MS m / z = 317.22[M+H] + ;

[0031] (2) Boron tribromide (1.0 M dichloromethane solution, 50.6 mL, 50.6 mmol) was added dropwise to a stirred solution of 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one (2.0 g, 6.32 mmol) in 40 mL of dichloromethane at -78 °C, and the mixture was stirred at the same temperature for 2 h, then heated to room temperature and stirred for 1 h. After the reaction was complete, excess boron tribromide was quenched with ice-cold water (50 mL), and the mixture was extracted with ethyl acetate (3 × 60 mL). The organic phases were combined and the solvent was evaporated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to give 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol (1.14 g, 75% yield), as a brown solid. Its 1H-NMR spectrum is shown below. Figure 2 As shown, the mass spectrum is as follows Figure 3 As shown. 1 HNMR (400 MHz, CD3OD) δ 7.09 – 7.01 (m, 2H), 6.96 (d, J = 8.2 Hz, 1H), 6.77(d, J = 2.2 Hz, 2H), 6.56 (d, J = 7.8 Hz, 1H), 6.23 (t, J = 2.2 Hz, 1H). ESI-MS m / z = 243.13 [M+H] + .

[0032] Example 2

[0033] (1) At room temperature, 2-bromo-1,3-dimethoxybenzene (2.0 g, 9.22 mmol) and 3,5-dimethoxyacetophenone (2.49 g, 13.82 mmol) were dissolved in 50 mL of 1,4-dioxane. Sodium tert-butoxide (2.58 g, 27.66 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.39 g, 0.46 mmol) were added with stirring. The resulting mixture was stirred at 90 °C for 8 h under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, diluted with 80 mL of water, and extracted with ethyl acetate (3 × 80 mL). The organic phases were combined and the solvent was evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to give 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one (2.48 g, 85% yield) as a brown solid.

[0034] (2) At 0 °C, boron tribromide (1.0 M dichloromethane solution, 37.9 mL, 37.9 mmol) was added dropwise to a stirred solution of 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one (2.0 g, 6.32 mmol) in 40 mL of dichloromethane and stirred at the same temperature for 3 h, then heated to room temperature and stirred for 2 h. After the reaction was complete, excess boron tribromide was quenched with ice-cold water (50 mL) and extracted with ethyl acetate (3 × 60 mL). The organic phases were combined and the solvent was evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to give 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol (1.21 g, 79% yield) as a brown solid.

[0035] The above embodiments are only for illustrating the technical concept and features of the present invention. Their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be used to limit the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, characterized in that, Includes the following steps: Step (1): 2-bromo-1,3-dimethoxyphenyl and 3,5-dimethoxyacetophenone react in a nitrogen atmosphere under the action of sodium tert-butoxide and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) to generate 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one; Step (2): 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one undergoes a demethylation and cyclization tandem reaction in the presence of boron tribromide to generate 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol.

2. The method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized in that: In step (1), the molar ratio of 2-bromo-1,3-dimethoxybenzene, 3,5-dimethoxyacetophenone, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) and sodium tert-butoxide is 1:1~1.5:0.05~0.2:2~3.

3. The method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized in that: In step (1), the reaction temperature is 80℃~90℃ and the reaction time is 8~12h.

4. The method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized in that: In step (1), 2-bromo-1,3-dimethoxybenzene and 3,5-dimethoxyacetophenone are dissolved in 1,4-dioxane for the reaction.

5. The method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized in that: In step (1), after the reaction is complete, water is added to dilute the reaction solution, an organic solvent is added, the liquid is separated, the aqueous phase is extracted with an organic solvent, the organic phases are combined, the solvent is evaporated, and then purified by silica gel column chromatography to obtain 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one.

6. The method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized in that: In step (2), the molar ratio of 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one to boron tribromide is 1:6~8.

7. The method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized in that: In step (2), the reaction temperature is -78℃ to 0℃ and the reaction time is 3 to 5 hours.

8. The method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized in that: In step (2), 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethane-1-one is dissolved in dichloromethane for the reaction.

9. The method for synthesizing the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized in that: In step (2), after the reaction is complete, ice water is added to quench the reaction, an organic solvent is added, the liquid is separated, the aqueous phase is extracted with an organic solvent, the organic phases are combined, the solvent is evaporated, and the solution is purified by silica gel column chromatography to obtain 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol.

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