CN106554254B - A kind of synthetic method of 2,3 ', 4,5 '-tetrahydroxy of natural products bibenzyl - Google Patents

Abstract

The invention discloses a kind of natural products 2,3 ', 4, the synthetic method of 5 '-tetrahydroxy bibenzyls is with 3,5- dihydroxyphenyl acetic acid and 2,4- 4-dihydroxy benzaldehyde is raw material, and condensation reaction occurs in the presence of a base and obtains 3- (3,5-dihydroxy phenyl)-umbelliferone, again after the open loop decarboxylic reaction under alkaline condition, E-2 is obtained, 3 ', 4,5 '-tetrahydroxystilbenes, last hydrogenated reaction obtain natural products 2,3 ', 4,5 '-tetrahydroxy bibenzyls.This method raw material is simple and easy to get, and reaction route is simple and direct, and Atom economy is high, simple in after-treatment, and yield is higher.

Description

A kind of synthetic method of natural product 2,3',4,5'-tetrahydroxybibenzyl

technical field

The invention relates to the field of organic synthesis, in particular to a method for synthesizing a natural product 2,3',4,5'-tetrahydroxybibenzyl.

Background technique

2,3',4,5'-Tetrahydroxybibenzyl is a natural product (Pholidota) isolated from the genus Rhododendron, and its existence is also found in the plant species of Caryophyllaceae. It is a natural product E. - Hydrogenated derivatives of 2,3',4,5'-tetrahydroxystilbene. 2,3',4,5'-Tetrahydroxybibenzyl has strong tyrosinase (Tyrosinase) inhibitory activity and antioxidant (Antioxidant) activity, and studies have also found that it can be used as γ-aminobutyric acid type A receptor Modulators (Nat.Prod.Rep.2009,26,916; Nat.Prod.Rep.2012,29; J.Nat.Prod.2012,752261; J.Phytochemistry 2008,69,1084; Bioorg.Med.Chem.2014, 22, 1276–1284; Bioorg.Med.Chem.Lett.2006,16,5650–5653), therefore, 2,3',4,5'-tetrahydroxybibenzyl holds promise for anticonvulsant, antihypertensive and headache treatment. , gastroenteritis, bronchitis are widely used. Regarding the synthesis of 2,3',4,5'-tetrahydroxybibenzyl compounds, it is generally reported in the literature that E-2,3 is first prepared by methods such as Wittig reaction, Wittig-Horner reaction, Suzuki cross-coupling reaction and Perkin condensation reaction. ',4,5'-tetrahydroxystilbene, and then prepare 2,3',4,5'-tetrahydroxybibenzyl by hydrogenation, but these methods have long reaction steps, high cost, catalyst can not be recycled, intermediate However, it has disadvantages such as the need for protection and deprotection, poor atom economy, and difficulty in large-scale preparation.

SUMMARY OF THE INVENTION

The purpose of the present invention is to overcome the shortcoming existing in the prior art, and provide a kind of synthetic method of natural product 2,3',4,5'-tetrahydroxybibenzyl which is environmentally friendly, low in cost and simple in process.

The object of the present invention is achieved through the following technical solutions:

A synthetic method of natural product 2,3',4,5'-tetrahydroxybibenzyl, comprising the following steps:

(1) Using 3,5-dihydroxyphenylacetic acid (structural formula 1) and 2,4-dihydroxybenzaldehyde (structural formula 2) as raw materials, in solvent A, in the presence of base A, a condensation reaction occurs to obtain 3-( 3,5-dihydroxyphenyl)-7-hydroxycoumarin (structural formula 3);

(2) In solvent B, under the condition of base B, 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin undergoes a ring-opening decarboxylation reaction, and after post-treatment, E-2,3', 4,5'-tetrahydroxystilbene (structural formula 4);

(3) In solvent C, under the action of catalyst C, E-2,3',4,5'-tetrahydroxystilbene undergoes hydrogenation reaction to obtain natural product 2,3',4,5'-tetrahydroxyl Bibenzyl (Structure 5).

In step (1), the reaction solution obtained after the condensation reaction is poured into ice water, stirred, suction filtered, the filter cake is washed with water, the filter cake is dissolved with an aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid to pH=3～ 4. Precipitate the solid, filter with suction, wash with water, collect the filter cake, and dry to obtain 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin.

In step (2), the post-treatment is to cool the reaction solution obtained by the decarboxylation reaction to room temperature, acidify to pH=3-4 with hydrochloric acid, extract with ethyl acetate, collect the organic phase, dry, remove the solvent, and use ethanol-water Recrystallization gave E-2,3',4,5'-tetrahydroxystilbene.

In step (3), the reaction mixture obtained by the hydrogenation reaction is subjected to suction filtration, the catalyst is recovered, the filtrate is collected, dried, the solvent is removed, and ethyl acetate-petroleum ether is recrystallized to obtain the natural product 2,3',4,5'-tetrakis. Hydroxybibenzyl.

In step (1), solvent A includes but is not limited to acetic anhydride, propionic anhydride, butyric anhydride, preferably solvent A is acetic anhydride; base A includes but is not limited to sodium acetate, sodium ethoxide, triethylamine, 1,8- Diazabicycloundec-7-ene (DBU), preferably the base A is triethylamine.

In step (1), the temperature of the condensation reaction is 100-140°C, preferably the reaction temperature is 110°C; the reaction time is 5-9 hours, preferably 7 hours.

In step (1), the molar ratio of 3,5-dihydroxyphenylacetic acid, 2,4-dihydroxybenzaldehyde and alkali A is 1:(1.0-1.2):(2-4), preferably 3,5-dihydroxybenzaldehyde The molar ratio of hydroxyphenylacetic acid, 2,4-dihydroxybenzaldehyde and base A was 1:1:3.

In step (2), alkali B includes but is not limited to sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, tripotassium phosphate, triethylamine, preferably alkali B is Potassium hydroxide; solvent B includes but is not limited to distilled water, dimethyl sulfoxide (DMSO), polyethylene glycol-400 (PEG-400), ethylene glycol, dimethyl sulfoxide-water (volume ratio is 3:1 ), N,N-dimethylformamide, preferably solvent B is dimethyl sulfoxide-water (volume ratio is 3:1).

In step (2), the temperature of the decarboxylation reaction is 100-180° C., preferably the reaction temperature is 160° C.; the reaction time is 1-3 hours, and the preferably reaction time is 2 hours.

In step (2), the molar ratio of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin and base B is 1:(5-15), preferably 3-(3,5-dihydroxy The molar ratio of phenyl)-7-hydroxycoumarin and base B is 1:10.

In step (3), the hydrogenation reaction time is 1 to 8 hours, and the preferred reaction time is 3 hours.

In step (3), solvent C includes but not limited to methanol, ethanol, isopropanol, acetone, tetrahydrofuran, preferably solvent is methanol; catalyst C includes but not limited to Raney nickel, palladium carbon, preferably catalyst is palladium carbon.

The chemical reaction formula involved in the present invention is as follows:

Compared with the prior art, the present invention has the following advantages and effects:

(1) The reaction process of the present invention does not require noble metal catalysis, does not require functional group protection, is easy to operate, high in yield, and has good atom economy, and the overall process is green and environmentally friendly.

(2) The starting materials, reagents and solvents of the present invention are cheap and easy to obtain, and the intermediates can be put into the next reaction without complicated separation and purification, which is favorable for large-scale preparation.

Description of drawings

Figure 1 is the H NMR spectrum of 2,3',4,5'-tetrahydroxybibenzyl (400MHz, DMSO-d ₆ );

Figure 2 is the carbon nuclear magnetic resonance spectrum (100 MHz, DMSO-d ₆ ) of 2,3',4,5'-tetrahydroxybibenzyl.

Detailed ways

The present invention will be described in further detail below with reference to the examples, but the embodiments of the present invention are not limited thereto.

Example 1

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round bottom flask was added 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.07 g, 15 mmol), triethylamine (4.55 g, 45 mmol), acetic anhydride (10 mL) ), stirred, heated to 110° C. in an oil bath, and reacted for 7 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, dried to obtain a light yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 3.24g , the yield is 80%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

Put 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin (1.35 g, 5 mmol), potassium hydroxide (2.80 g, 50 mmol), dimethyl sulfoxide-water (15 ml) into a round-bottomed flask -5ml), refluxed in oil bath at 160°C for 2h, the reaction was completed, diluted with 50ml of water, acidified with hydrochloric acid to pH=3～4, extracted with ethyl acetate (10ml×3), collected the organic layer, dried over anhydrous sodium sulfate, evaporated to dryness The solvent was recrystallized from ethanol-water to obtain E-2,3',4,5'-tetrahydroxystilbene, with a weight of 0.93 g and a yield of 76%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.58(s, 1H), 9.40(s, 1H), 9.15(s, 2H), 7.34(d, J=8.4Hz, 1H), 7.14(d, J＝16.4Hz, 1H), 6.76(d, J＝16.5Hz, 1H), 6.33(d, J＝5.6Hz, 3H), 6.24(d, J＝8.1Hz, 1H), 6.07(s, 1H) ; ¹³ C NMR (100MHz, DMSO-d ₆ ) δ 158.96, 158.58, 156.49, 140.49, 127.61, 125.08, 123.64, 115.72, 107.68, 104.45, 103.03, 101.82.

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

To the round-bottomed flask was added E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol), then 10ml of methanol was added to stir and dissolve, and 10% palladium on carbon (61mg) was added under ice bath conditions. ), reacted at room temperature in a hydrogen atmosphere under one atmosphere for 3 hours, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural products 2,3',4, 5'-Tetrahydroxybibenzyl, weight 1.11 g, yield 90%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.13(s, 1H), 9.05(s, 2H), 8.97(s, 1H), 6.79(d, J=8.2Hz, 1H), 6.27(d, J=2.3Hz, 1H), 6.11(dd, J=8.1, 2.3Hz, 1H), 6.07(d, J=2.0Hz, 2H), 6.01(t, J=2.0Hz, 1H), 2.56(dt, J = 9.1, 5.3 Hz, 4H) (as shown in Figure 1). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 158.61, 156.74, 156.15, 144.79, 130.40, 118.83, 106.78, 106.28, 102.80, 100.43, 36.59, 31.61 (as shown in Figure 2).

Example 2

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round bottom flask was added 3,5-dihydroxyphenylacetic acid (2.52g, 15mmol), 2,4-dihydroxybenzaldehyde (2.07g, 15mmol), triethylamine (4.55g, 45mmol), propionic anhydride (10mL) ), stirred, heated to 110° C. in an oil bath, and reacted for 7 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, and dried to obtain a pale yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 2.75g , the yield is 68%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

Put 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin (1.35 g, 5 mmol), potassium hydroxide (2.80 g, 50 mmol), dimethyl sulfoxide-water (20 ml) into a round-bottomed flask , 3:1), the oil bath was refluxed at 120°C for 2h, the reaction was completed, diluted with 50ml of water, acidified with hydrochloric acid to PH=3～4, extracted with ethyl acetate (10ml×3), the organic layer was collected, dried over anhydrous sodium sulfate, The solvent was evaporated to dryness and recrystallized from ethanol-water to obtain E-2,3',4,5'-tetrahydroxystilbene, with a weight of 0.60 g and a yield of 49%.

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

To the round-bottomed flask was added E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol), then 10ml of ethanol was added to stir and dissolve, and 10% palladium on carbon (61mg) was added under ice bath conditions. ), reacted at room temperature for 3 hours in a hydrogen atmosphere under one atmosphere, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural product 2,3',4 ,5'-tetrahydroxybibenzyl, weight 1.08g, yield 88%.

Example 3

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round bottom flask was added 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.07 g, 15 mmol), triethylamine (4.55 g, 45 mmol), acetic anhydride (10 mL) ), stirred, heated to 110° C. in an oil bath, and reacted for 9 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, and dried to obtain a light yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 2.87g , the yield is 71%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

Put 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin (1.35 g, 5 mmol), potassium hydroxide (2.80 g, 50 mmol), dimethyl sulfoxide-water (20 ml) into a round-bottomed flask , 3:1), react at 180°C for 2h, after the reaction is completed, add 50ml of water to dilute, acidify with hydrochloric acid to pH=3～4, extract with ethyl acetate (10ml×3), collect the organic layer, dry over anhydrous sodium sulfate, evaporate The dry solvent was recrystallized from ethanol-water to obtain E-2,3',4,5'-tetrahydroxystilbene, with a weight of 1.04 g and a yield of 70%.

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

To the round-bottomed flask was added E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol), then 10ml of ethanol was added to stir and dissolve, and 10% palladium on carbon (61mg) was added under ice bath conditions. ), reacted at room temperature for 1 hour in a hydrogen atmosphere under one atmosphere, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural product 2,3',4 ,5'-tetrahydroxybibenzyl, weight 0.86g, yield 70%.

Example 4

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round-bottom flask, add 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.07 g, 15 mmol), triethylamine (4.55 g, 45 mmol), acetic anhydride ( 10 mL), stirred, heated to 110° C. in an oil bath, and reacted for 5 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, and dried to obtain a light yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 2.03g , the yield is 50%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

Put 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin (1.35 g, 5 mmol), potassium hydroxide (2.80 g, 50 mmol), dimethyl sulfoxide-water (20 ml) into a round-bottomed flask , 3:1), the oil bath was refluxed at 160 °C for 1 h, the reaction was completed, diluted with 50 ml of water, acidified with hydrochloric acid to PH = 3~4, extracted with ethyl acetate (10 ml × 3), the organic layer was collected, dried over anhydrous sodium sulfate, The solvent was evaporated to dryness and recrystallized from ethanol-water to obtain E-2,3',4,5'-tetrahydroxystilbene, with a weight of 0.52 g and a yield of 43%.

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

To the round-bottomed flask was added E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol), then 10ml of ethanol was added to stir to dissolve, and 10% palladium on carbon (61mg) was added under ice bath conditions. ), reacted at room temperature for 3 hours in a hydrogen atmosphere under one atmosphere, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural product 2,3',4 ,5'-tetrahydroxybibenzyl, weight 1.11g, yield 90%.

Example 5

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round bottom flask was added 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.07 g, 15 mmol), triethylamine (3.03 g, 30 mmol), acetic anhydride (10 mL) ), stirred, heated to 110° C. in an oil bath, and reacted for 7 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, and dried to obtain a pale yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 2.97g , the yield is 73%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

Put 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin (1.35 g, 5 mmol), potassium hydroxide (2.80 g, 50 mmol), dimethyl sulfoxide-water (20 ml) into a round-bottomed flask , 3:1), the oil bath was refluxed at 160°C for 3h, the reaction was completed, diluted with 50ml of water, acidified with hydrochloric acid to PH=3～4, extracted with ethyl acetate (10ml×3), collected the organic layer, dried over anhydrous sodium sulfate, The solvent was evaporated to dryness and recrystallized from ethanol-water to obtain E-2,3',4,5'-tetrahydroxystilbene, with a weight of 0.72 g and a yield of 59%.

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

To the round-bottomed flask was added E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol), then 10ml of ethanol was added to stir and dissolve, and 10% palladium on carbon (61mg) was added under ice bath conditions. ), reacted at room temperature for 3 hours in a hydrogen atmosphere under one atmosphere, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural product 2,3',4 ,5'-tetrahydroxybibenzyl, weight 1.11g, yield 90%.

Example 6

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round bottom flask was added 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.07 g, 15 mmol), triethylamine (6.06 g, 60 mmol), acetic anhydride (10 mL) ), stirred, heated to 110° C. in an oil bath, and reacted for 7 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, and dried to obtain a pale yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 2.75g , the yield is 68%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin (1.35 g, 5 mmol), cesium hydroxide (2.80 g, 50 mmol), DMSO-H ₂ O (20 ml, 3:1), the oil bath was refluxed at 160°C for 2h, the reaction was completed, diluted with 50ml of water, acidified with hydrochloric acid to PH=3～4, extracted with ethyl acetate (10ml×3), the organic layer was collected, dried over anhydrous sodium sulfate, evaporated The dry solvent was recrystallized from ethanol-water to obtain E-2,3',4,5'-tetrahydroxystilbene, with a weight of 0.79 g and a yield of 65%.

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl (5)

To the round-bottomed flask was added E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol), then 10ml of ethanol was added to stir and dissolve, and 10% palladium on carbon (61mg) was added under ice bath conditions. ), reacted at room temperature for 3 hours in a hydrogen atmosphere under one atmosphere, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural product 2,3',4 ,5'-tetrahydroxybibenzyl, weight 1.11g, yield 90%.

Example 7

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round-bottomed flask, add 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.50 g, 18 mmol), triethylamine (4.55 g, 45 mmol), acetic anhydride ( 10 mL), stirred, heated to 110° C. in an oil bath, and reacted for 7 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, dried to obtain a light yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 3.16g , the yield is 78%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

3-(3,5-Dihydroxyphenyl)-7-hydroxycoumarin (1.35 g, 5 mmol), sodium carbonate (5.30 g, 50 mmol), dimethyl sulfoxide-water (20 ml, 3 mmol) were put into a round bottom flask : 1), the oil bath was refluxed at 160°C for 2h, the reaction was completed, diluted with 50ml of water, acidified with hydrochloric acid to PH=3～4, extracted with ethyl acetate (10ml×3), the organic layer was collected, dried over anhydrous sodium sulfate, evaporated to dryness The solvent was recrystallized from ethanol-water to obtain E-2,3',4,5'-tetrahydroxystilbene (4) with a weight of 0.44 g and a yield of 36%.

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

Add E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol) to the round-bottomed flask, then add 10ml methanol and stir to dissolve, add 150μm Raney nickel dispersed in water under ice bath conditions (61mg), reacted at room temperature in a hydrogen atmosphere under one atmosphere for 3 hours, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural product 2,3', 4,5'-Tetrahydroxybibenzyl, weight 1.06g, yield 86%.

Example 8

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin (3)

To a round-bottomed flask was added 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.07 g, 15 mmol), sodium acetate (3.69 g, 45 mmol), acetic anhydride (10 mL) ), stirred, heated to 110° C. in an oil bath, and reacted for 7 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, and dried to obtain a pale yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 0.93g , the yield is 23%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

3-(3,5-Dihydroxyphenyl)-7-hydroxycoumarin (1.35g, 5mmol), potassium carbonate (6.90g, 50mmol), dimethyl sulfoxide-water (20ml, 3 : 1), the oil bath was refluxed at 160°C for 2h, the reaction was completed, diluted with 50ml of water, acidified with hydrochloric acid to pH=3～4, extracted with ethyl acetate (10ml×3), the organic layer was collected, dried over anhydrous sodium sulfate, evaporated to dryness Solvent, ethanol-water recrystallization to obtain E-2,3',4,5'-tetrahydroxystilbene, weight 0.56, yield 46%.

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

Add E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol) to the round-bottomed flask, then add 10ml of tetrahydrofuran and stir to dissolve, add 150μm Raney nickel dispersed in water under ice bath conditions (61mg), reacted at room temperature in a hydrogen atmosphere under one atmosphere for 3 hours, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural product 2,3', 4,5'-Tetrahydroxybibenzyl, weight 0.97g, yield 79%.

Example 9

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round bottom flask was added 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.07 g, 15 mmol), DBU (6.84 g, 45 mmol), acetic anhydride (10 mL), With stirring, the oil bath was heated to 110°C, and the reaction was carried out for 7 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, and dried to obtain a light yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 1.42g , the yield is 35%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

Put 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin (1.35g, 5mmol), potassium hydroxide (2.80g, 50mmol), ethylene glycol (20ml) into a round bottom flask, oil bath Reflux at 160°C for 2 hours, after the reaction is completed, add 50ml of water to dilute, acidify with hydrochloric acid to pH=3～4, extract with ethyl acetate (10ml×3), collect the organic layer, dry with anhydrous sodium sulfate, evaporate the solvent to dryness, and weigh the mixture with ethanol-water. Crystallized to obtain E-2,3',4,5'-tetrahydroxystilbene, weight 0.81 g, yield 66%.

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

Add E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol) to the round-bottomed flask, then add 10ml of tetrahydrofuran and stir to dissolve, add 150μm Raney nickel dispersed in water under ice bath conditions (61mg), reacted at room temperature in a hydrogen atmosphere under one atmosphere for 3 hours, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural product 2,3', 4,5'-Tetrahydroxybibenzyl, weight 0.97g, yield 79%.

Example 10

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round bottom flask was added 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.07 g, 15 mmol), triethylamine (4.55 g, 45 mmol), acetic anhydride (10 mL) ), stirred, heated to 110° C. in an oil bath, and reacted for 7 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, dried to obtain a light yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 3.24g , the yield is 80%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

Put 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin (1.35g, 5mmol), potassium hydroxide (2.80g, 50mmol), DMSO (20ml) into a round-bottomed flask, oil bath at 160°C Refluxed for 2h, the reaction was completed, diluted with 50ml of water, acidified with hydrochloric acid to pH=3～4, extracted with ethyl acetate (10ml×3), collected the organic layer, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethanol-water, Obtained E-2,3',4,5'-tetrahydroxystilbene, weight 0.77g, yield 63%

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol) was added to the round-bottomed flask, then 10ml of methanol was added to stir to dissolve, and 10% palladium on carbon (61mg) was added under ice bath conditions. ), reacted at room temperature for 3 hours in a hydrogen atmosphere under one atmosphere, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural products 2,3',4, 5'-Tetrahydroxybibenzyl, weight 1.11 g, yield 90%.

Example 11

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round bottom flask was added 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.07 g, 15 mmol), triethylamine (4.55 g, 45 mmol), acetic anhydride (10 mL) ), stirred, heated to 110° C. in an oil bath, and reacted for 7 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, dried to obtain a light yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 3.24g , the yield is 80%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

3-(3,5-Dihydroxyphenyl)-7-hydroxycoumarin (1.35 g, 5 mmol), potassium hydroxide (1.40 g, 25 mmol), DMSO-H ₂ O (20 ml, 3 mmol) were placed in a round bottom flask : 1), the oil bath was refluxed at 160°C for 2h, the reaction was completed, diluted with 50ml of water, acidified with hydrochloric acid to pH=3～4, extracted with ethyl acetate (10ml×3), the organic layer was collected, dried over anhydrous sodium sulfate, evaporated to dryness Solvent, ethanol-water recrystallization to obtain E-2,3',4,5'-tetrahydroxystilbene, weight 0.46g, yield 38%

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol) was added to the round-bottomed flask, then 10ml of methanol was added to stir to dissolve, and 10% palladium on carbon (61mg) was added under ice bath conditions. ), reacted at room temperature for 3 hours in a hydrogen atmosphere under one atmosphere, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural products 2,3',4, 5'-Tetrahydroxybibenzyl, weight 1.11 g, yield 90%.

Example 12

(1) Preparation of 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin

To a round bottom flask was added 3,5-dihydroxyphenylacetic acid (2.52 g, 15 mmol), 2,4-dihydroxybenzaldehyde (2.07 g, 15 mmol), triethylamine (4.55 g, 45 mmol), acetic anhydride (10 mL) ), stirred, heated to 110° C. in an oil bath, and reacted for 7 hours. After the completion of the reaction, the reaction solution was poured into 50 mL of ice water while still hot, stirred, and a solid was precipitated, suction filtered, washed the filter cake with water, and collected the filter cake. The filter cake was dissolved in aqueous sodium hydroxide solution, washed with ethyl acetate, and acidified with hydrochloric acid. To pH=3～4, a solid was precipitated, suction filtered, washed with water, the filter cake was collected, dried to obtain a light yellow solid, which was 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin, weight 3.24g , the yield is 80%.

(2) Preparation of E-2,3',4,5'-tetrahydroxystilbene

Into a round bottom flask was placed 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin (1.35g, 5mmol), potassium hydroxide (4.2g, 75mmol), DMSO- _H2O (20ml, 3 : 1), the oil bath was refluxed at 160°C for 2h, the reaction was completed, diluted with 50ml of water, acidified with hydrochloric acid to pH=3～4, extracted with ethyl acetate (10ml×3), the organic layer was collected, dried over anhydrous sodium sulfate, evaporated to dryness The solvent was recrystallized from ethanol-water to obtain E-2,3',4,5'-tetrahydroxystilbene, with a weight of 0.51 g and a yield of 42%.

(3) Preparation of natural product 2,3',4,5'-tetrahydroxybibenzyl

E-2,3',4,5'-tetrahydroxystilbene (1.22g, 5mmol) was added to the round-bottomed flask, then 10ml of methanol was added to stir to dissolve, and 10% palladium on carbon (61mg) was added under ice bath conditions. ), reacted at room temperature for 3 hours in a hydrogen atmosphere under one atmosphere, suction filtered, recovered palladium carbon, dried over anhydrous sodium sulfate, evaporated to dryness, and recrystallized from ethyl acetate-petroleum ether to obtain natural products 2,3',4, 5'-Tetrahydroxybibenzyl, weight 1.11 g, yield 90%.

Claims (5)

1. a synthetic method of natural product 2,3',4,5'-tetrahydroxybibenzyl, is characterized in that comprising the following steps: (1) Using 3,5-dihydroxyphenylacetic acid and 2,4-dihydroxybenzaldehyde as raw materials, in solvent A, in the presence of base A, a condensation reaction occurs to obtain 3-(3,5-dihydroxyphenyl) )-7-hydroxycoumarin; solvent A is acetic anhydride, propionic anhydride or butyric anhydride, base A is sodium acetate, sodium ethoxide, triethylamine or 1,8-diazabicycloundec-7-ene ; The molar ratio of 3,5-dihydroxyphenylacetic acid, 2,4-dihydroxybenzaldehyde and base A is 1:(1.0～1.2):(2～4); the temperature of condensation reaction is 100～140℃, and the reaction The time is 5 to 9 hours; (2) In solvent B, under the condition of base B, 3-(3,5-dihydroxyphenyl)-7-hydroxycoumarin undergoes a ring-opening decarboxylation reaction, and after post-treatment, E-2,3', 4,5'-Tetrahydroxystilbene; base B is sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, tripotassium phosphate or triethylamine, solvent B is Distilled water, dimethyl sulfoxide, polyethylene glycol-400, ethylene glycol, dimethyl sulfoxide-water or N,N-dimethylformamide; 3-(3,5-dihydroxyphenyl)-7- The molar ratio of hydroxycoumarin and alkali B is 1:(5～15); the temperature of decarboxylation reaction is 100～180℃, and the reaction time is 1～3 hours; (3) In solvent C, under the action of catalyst C, E-2,3',4,5'-tetrahydroxystilbene undergoes hydrogenation reaction to obtain natural product 2,3',4,5'-tetrahydroxyl Bibenzyl; solvent C is methanol, ethanol, isopropanol, acetone or tetrahydrofuran, catalyst C is Raney nickel or palladium carbon. 2. the synthetic method of natural product 2,3',4,5'-tetrahydroxybibenzyl according to claim 1, is characterized in that: in step (1), the reaction solution obtained after the condensation reaction is poured into ice water , stir, filter with suction, wash the filter cake with water, dissolve the filter cake with aqueous sodium hydroxide solution, wash with ethyl acetate, acidify with hydrochloric acid to pH=3~4, precipitate out solid, filter with suction, wash with water, collect the filter cake, and dry to obtain 3-(3,5-Dihydroxyphenyl)-7-hydroxycoumarin. 3. the synthetic method of natural product 2,3',4,5'-tetrahydroxybibenzyl according to claim 1, is characterized in that: in step (2), described post-processing is the reaction obtained by decarboxylation reaction The liquid was cooled to room temperature, acidified with hydrochloric acid to pH=3～4, extracted with ethyl acetate, collected the organic phase, dried, removed the solvent, and recrystallized with ethanol-water to obtain E-2,3',4,5'-tetra Hydroxystilbene. 4. the synthetic method of natural product 2,3',4,5'-tetrahydroxybibenzyl according to claim 1, is characterized in that: in step (3), the reaction mixture that hydrogenation reaction obtains is carried out suction filtration, recovery catalyst, collect the filtrate, dry, remove the solvent, and recrystallize from ethyl acetate-petroleum ether to obtain the natural product 2,3',4,5'-tetrahydroxybibenzyl. 5. The synthetic method of natural product 2,3',4,5'-tetrahydroxybibenzyl according to claim 1, characterized in that: in step (3), the hydrogenation reaction time is 1-8 hours.