Synthesis method of natural molecule 5-(4-hydroxybenzofuran-2-yl) benzene-1, 3-diphenol

Abstract

The invention relates to the technical field of organic synthesis, and discloses a synthesis method of a natural molecule 5-(4-hydroxybenzofuran-2-yl) benzene-1, 3-diphenol, 2-bromo-1, 3-dimethoxybenzene and 3, 5-dimethoxyacetophenone are subjected to a reaction in sodium tert-butoxide and methane sulfonic acid (2-dicyclohexylphosphine-2 ', 4', 6 '-tri-isopropyl-1, 1'-biphenyl) (2 '-amino-1, 3-diphenol), and the reaction product is subjected to a reaction in a solvent to obtain the natural molecule 5-(4-hydroxybenzofuran-2-yl) benzene-1, 3-diphenol. The preparation method comprises the following steps: reacting 2-(2, 6-dimethoxyphenyl)-1-(3, 5-dimethoxyphenyl) ethane-1-ketone in a nitrogen atmosphere under the action of 1, 1 '-biphenyl-2-yl) palladium (II) to generate 2-(2, 6-dimethoxyphenyl)-1-(3, 5-dimethoxyphenyl) ethane-1-ketone; and then carrying out demethylation and cyclization cascade reaction under the action of boron tribromide to generate the 5-(4-hydroxybenzofuran-2-yl) benzene-1, 3-diphenol. The method has the advantages of cheap and easily available raw materials, simple method, mild reaction conditions and high total yield, and is convenient for industrial preparation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol. BACKGROUND

[0002] 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol (Cuspidan B) is an important bioactive natural molecule isolated from the bark of Gnetum cuspidatum, and has good anticancer activity. Its IC50 for human promyelocytic leukemia (HL-60) cells is 33.5 μM. The natural molecule is obtained by extraction from plants, which is low in efficiency and high in cost. Therefore, it is urgent to develop an efficient and simple method to synthesize 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol on a large scale, so as to promote its development and application in the field of biological medicine.

[0003] At present, there are mainly two methods for synthesizing 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol: 1. A method for synthesizing 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol in 7 linear steps was developed by Takayuki Yakura group in Japan, and the key reaction is acid-catalyzed spirocyclopropane ring-opening cyclization reaction. However, starting from tert-butyldimethylsilyl-protected 5-vinyl-1,3-benzene diol, the total yield is only 21%, and the reaction process also involves complicated protection and deprotection reactions, which is not conducive to industrial production (Synthesis 2016, 48, 1892-1901).

[0004] 2. CN110894192A provides another method for synthesizing 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, which utilizes the raw material methyl maltol to generate a disubstituted alkyne intermediate through triflate reaction and Sonogashira coupling reaction. Then, through the key deconstruction and recombination reaction, the benzofuran ring is constructed to obtain 2-(3,5-dimethoxyphenyl)benzofuran-4-ol, and finally the methyl group is removed to obtain 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol. However, this route still needs 4 steps to synthesize the natural molecule, and in addition, the total yield is still not high (29.8%), and the cost and period of large-scale production are longer. SUMMARY

[0005] The present application aims to provide a synthesis method of the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, which is cheap and easy to obtain, simple, mild in reaction conditions, high in total yield, and convenient for industrial production.

[0006] The present application is realized by the following technical scheme: The synthesis method of the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol comprises the following steps: (1) 2-bromo-1,3-dimethoxybenzene and 3,5-dimethoxyacetophenone are reacted under the action of sodium tert-butoxide and methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) in a nitrogen atmosphere to generate 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethan-1-one; (2) 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethan-1-one is subjected to a demethylation and cyclization tandem reaction under the action of boron tribromide to generate 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol.

[0007] Preferably, in step (1), the molar ratio of 2-bromo-1,3-dimethoxybenzene, 3,5-dimethoxyacetophenone, methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-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.

[0008] Preferably, in step (1), the reaction temperature is 80~90℃, and the reaction time is 8~12h.

[0009] Preferably, 2-bromo-1,3-dimethoxybenzene and 3,5-dimethoxyacetophenone are dissolved in 1,4-dioxane for reaction.

[0010] Preferably, in step (1), after the reaction is completed, the reaction solution is diluted with water, an organic solvent is added, the solution is separated, the aqueous phase is extracted with the organic solvent, the organic phases are combined, the solvent is rotary evaporated, and then 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethan-1-one is obtained by silica gel column purification.

[0011] Preferably, in step (2), the molar ratio of 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethan-1-one to boron tribromide is 1:6~8.

[0012] Preferably, in step (2), the reaction temperature is -78~0℃, and the reaction time is 3~5h.

[0013] Preferably, in step (2), 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethan-1-one is dissolved in dichloromethane for reaction.

[0014] Preferably, in step (2), after the reaction is completed, 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, and then the organic phases are combined, the solvent is rotary evaporated, and 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol is obtained by silica gel column purification.

[0015] Compared with the prior art, the present application has the following advantages: 1) The synthetic route of the present application is simple, and 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol can be synthesized in only 2 steps (4-7 steps in the prior art), which greatly shortens the production cycle. The starting materials 2-bromo-1,3-dimethoxybenzene and 3,5-dimethoxyacetophenone are inexpensive and easy to obtain, and the reaction operation is simple. The synthesis process does not require a protecting group and does not involve complicated protection and deprotection reactions. The total yield (up to 67%) is significantly higher than that of the prior art (21%-29.8%), and it is convenient for industrial production.

[0016] 2) The key reaction of the present application is a novel boron tribromide-mediated demethylation / cyclization tandem reaction, which ingeniously cyclizes the α-arylacetophenone structure to obtain a benzofuran natural molecule in one step with high efficiency. In addition to synthesizing 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, the present application also provides a process reference for the synthesis of other benzofuran natural molecules, and compared with the prior art, it has more industrialization promotion prospects. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 The reaction formula of the present application.

[0018] Figure 2 The mass spectrum of 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol prepared by the present application. 1 H-NMR chart.

[0019] Figure 3 The mass spectrum of 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol prepared by the present application. DETAILED DESCRIPTION

[0020] The present application will be further described below in conjunction with examples, but the description of the examples does not impose any limitation on the protection scope of the present application.

[0021] 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 application belongs. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting of the application. 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 application belongs. Although exemplary values are provided in the examples herein, it will be understood that the parameters need not be exactly equal to the respective values, but can be approximated within acceptable error tolerance or design constraints.

[0022] The materials or instruments used in the following examples, if not specifically stated, can be obtained from conventional commercial channels.

[0023] The reaction principle of the present application is shown in Figure 1 .

[0024] Example 1

[0025] (1) 2-bromo-1,3-dimethoxybenzene (2.0 g, 9.22 mmol) and 3,5-dimethoxyacetophenone (1.66 g, 9.22 mmol) were dissolved in 1,4-dioxane (50 mL) solution, and sodium tert-butoxide (1.77 g, 18.44 mmol) and methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-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 completed, it was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (3 x 80 mL). The organic phase was combined and the solvent was evaporated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethan-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] + ; (2) To a stirred solution of 2-(2,6-dimethoxyphenyl)-l-(3,5- dimethoxyphenyl)ethan-l-one (2.0 g, 6.32 mmol) in dichloromethane (40 mL) was added boron tribromide (1.0 M in dichloromethane, 50.6 mL, 50.6 mmol) dropwise at -78 °C and stirred at the same temperature for 2 h and then allowed to warm to room temperature for 1 h. After completion of the reaction, excess boron tribromide was quenched by the addition of ice-cold water (50 mL) and extracted with ethyl acetate (3 x 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-l,3-diol (1.14 g, 75% yield) as a brown solid. Its1H-NMR spectrum is shown in Figure 2 and mass spectrum is shown in Figure 3 . 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] + .

[0026] Example 2

[0027] (1) To a stirred solution of 2-bromo-l,3-dimethoxybenzene (2.0 g, 9.22 mmol) and 3,5-dimethoxyacetophenone (2.49 g, 13.82 mmol) in 1,4-dioxane (50 mL) was added sodium tert-butoxide (2.58 g, 27.66 mmol) and methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl- 1,1'-biphenyl) (2'-amino-l,1'-biphenyl-2-yl)palladium(II) (0.39 g, 0.46 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 8 h under nitrogen atmosphere. After completion of the reaction, it was cooled to room temperature and diluted with water (80 mL) and extracted with ethyl acetate (3 x 80 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 = 4: 1) to give 2-(2,6-dimethoxyphenyl)-l-(3,5-dimethoxyphenyl)ethan-l-one (2.48 g, 85% yield) as a brown solid.

[0028] (2) To a stirred solution of 2-(2,6-dimethoxyphenyl)-1-(3,5- dimethoxyphenyl)ethan-1-one (2.0 g, 6.32 mmol) in dichloromethane (40 mL) was added dropwise boron tribromide (1.0 M in dichloromethane, 37.9 mL, 37.9 mmol) at 0 °C and stirred at the same temperature for 3 h, then stirred at room temperature for 2 h. After completion of the reaction, the excess boron tribromide was quenched by the addition of ice-cold water (50 mL) and extracted with ethyl acetate (3 x 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 (1.21 g, 79% yield) as a brown solid.

[0029] The above examples are only to illustrate the technical concept and characteristics of the present application, and the purpose is to enable those skilled in the art to understand the content of the present application and to implement it, and cannot limit the protection scope of the present application. Any equivalent changes or modifications made according to the spirit and essence of the present application shall be covered within the protection scope of the present application.

Claims

1. A method of synthesis of the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol, characterized in that, Comprising the following steps: Step (1): 2-bromo-1,3-dimethoxybenzene and 3,5-dimethoxyacetophenone are reacted in the presence of sodium tert-butoxide and methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) under a nitrogen atmosphere to form 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethan-1-one; Step (2): 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethan-1-one is subjected to a demethylation and cyclization tandem reaction in the presence of boron tribromide to form 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol.

2. The process for the synthesis of the natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized by: In step (1), the molar ratio of 2-bromo-1,3-dimethoxybenzene, 3,5-dimethoxyacetophenone, methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-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 process for synthesis of natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol as claimed in claim 1, wherein: In step (1), the reaction temperature is 80~90°C, and the reaction time is 8~12h.

4. The process for synthesis of natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol as claimed in claim 1, wherein: In step (1), 2-bromo-1,3-dimethoxybenzene and 3,5-dimethoxyacetophenone are dissolved in 1,4-dioxane for reaction.

5. The method of synthesis of natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized by: In step (1), after the reaction is completed, the reaction solution is diluted with water, an organic solvent is added, the solution is separated, the aqueous phase is extracted with an organic solvent, and the organic phases are combined, the solvent is rotary evaporated, and 2-(2,6-dimethoxyphenyl)-1-(3,5-dimethoxyphenyl)ethan-1-one is obtained by silica gel column purification.

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

7. The method of synthesis of natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized by: In step (2), the reaction temperature is -78~0°C, and the reaction time is 3~5h.

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

9. The method of synthesis of natural molecule 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol according to claim 1, characterized by: In step (2), after the reaction is completed, the reaction is quenched with ice water, an organic solvent is added, the solution is separated, the aqueous phase is extracted with an organic solvent, and the organic phases are combined, the solvent is rotary evaporated, and 5-(4-hydroxybenzofuran-2-yl)benzene-1,3-diol is obtained by silica gel column purification.

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