Preparation method of isoliquiritin and artificially synthesized liquiritin

Abstract

The invention discloses a preparation method of isoliquiritin and artificially synthesized liquiritin, which is characterized by comprising the following steps: carrying out aldol condensation reaction on 2, 4-dihydroxyacetophenone of which hydroxyl is protected by acyl and 4-hydroxybenzaldehyde to obtain acyl-protected isoliquiritigenin as a precursor; the preparation method comprises the following steps: carrying out glycosylation reaction on a precursor and an acyl-protected glucosyl donor in the presence of an accelerant to obtain acyl-protected isoliquiritin, then carrying out deprotection to obtain isoliquiritin and artificially synthesized liquiritin at the same time, and further carrying out alkali catalysis ring closing on the isoliquiritin to obtain the artificially synthesized liquiritin. Compared with a method for directly extracting liquiritin and isoliquiritin from licorice roots in the prior art, the method has very obvious technical and industrial advantages, raw materials are cheap and easy to obtain, reaction conditions are mild, product purity is high, the defects that an existing isoliquiritin synthesis method is low in yield, large in workload and the like are overcome, artificially synthesized liquiritin can be further obtained, and the method is suitable for industrial production. The method has a very good industrialization prospect and a great prospect of modernization of traditional Chinese medicines through chemical modification and transformation.

Description

Technical Field

[0001] The invention relates to the technical field of compound synthesis, in particular to a preparation method of isoliquiritigenin, a liquorice active ingredient, and artificially synthesized liquiritigenin. Background Art

[0002] Licorice (scientific name: Glycyrrhiza uralensis, English: Licorice), also known as Ural licorice, raw grass, raw licorice, powdered grass, powdered licorice, moxibustion grass, Guolao, sweet grass root, is a perennial herbaceous plant of the Leguminosae family. As a traditional Chinese medicinal material, licorice has a wide range of uses and is said to be "nine herbs in ten prescriptions". There are three recognized licorice medicinal plants, namely Ural licorice (Glycyrrhiza uralensis Fisch.), inflated licorice (G. inflata Bat.) and glabra L., and their roots and rhizomes are used for medicinal purposes. Licorice tastes sweet and is neutral in nature. It enters the heart, lung, spleen, and stomach meridians. It has the effects of tonifying the spleen and replenishing qi, clearing away heat and detoxifying, removing phlegm and relieving cough, relieving urgency and pain, and harmonizing various medicines. It is commonly used for weak spleen and stomach, fatigue, palpitations and shortness of breath, cough with sputum, cramps and pain in the abdomen and limbs, carbuncles and sores, and to relieve the toxicity and potency of drugs.

[0003] Liquiritin ((2S)-7-hydroxy-11-O-β-D-pyranoglucoside-dihydroflavone) and isoliquiritin ((E)-1-(2,4-dihydroxy-phenyl)-3-(4-O-β-D-pyranoglucoside phenyl) prop-2-en-1-one) are flavonoid compounds and are also two important active ingredients contained in licorice. Liquiritin, white crystal, molecular formula: C 21 H 22 O9, molecular weight: 418.39, soluble in organic solvents such as methanol, ethanol, n-propanol, isopropanol, melting point: 212℃~213℃. Isoliquiritin is an isomer of liquiritin, yellow crystal, molecular formula: C 21 H 22 O9, molecular weight: 418.39, soluble in organic solvents such as methanol, ethanol, n-propanol, isopropanol, melting point: 148℃~150℃. Many domestic and foreign literatures report that liquiritin and isoliquiritin have multiple pharmacological effects such as antioxidant, anti-tumor, anti-ulcer, anti-depression, anti-HIV, anti-virus, anti-inflammatory, neuroprotective, adjuvant treatment of diabetes, whitening, etc.

[0004] The structural formulas of the liquiritin and isoliquiritin are shown in (IV) to (V) below:

[0005]

[0006] There is no literature report on the chemical synthesis method of liquiritin, and the main method of obtaining it is separation and extraction from licorice herbs.

[0007] Chinese patent "CN101289480" a method for separating and preparing liquiritin: by water extraction, alcohol precipitation, membrane separation, and then using macroporous resin to separate liquiritin; Chinese patent "CN10205085A1" liquiritin and its preparation method: extract liquiritin from glycyrrhizic acid powder, extract with dilute ammonia water, extract with organic solvent, and then use polyamide resin to separate liquiritin. Chinese patent CN102336791 discloses a preparation method for extracting isoliquiritin from licorice, and the method for obtaining isoliquiritin is also mainly to separate and extract from licorice medicinal materials. The latest journal paper Green Chem.2024, 26, 9186 reports the use of carbohydrase for direct glycosylation of aglycones, but it requires expensive artificially modified glycosyltransferases to achieve.

[0008] The literature reports the total synthesis reaction of isoliquiritigenin: p-hydroxybenzaldehyde and bromoacetyl glucose are used as raw materials to react in the presence of a phase transfer catalyst to generate glycoside (i.e., acetyl glucose benzaldehyde glycoside, with a synthesis yield of 60-82%), and then the protected isoliquiritigenin (with an aldol condensation yield of 37%) is obtained by the aldol condensation reaction of acetyl glucose benzaldehyde glycoside and 2,4-dihydroxyacetophenone catalyzed by boric acid / piperidine / diethylene glycol diethyl ether. The yield is low, the reaction conditions are severe, the repeatability is poor, and it is not suitable for industrial production. Summary of the invention

[0009] The object of the present invention is to provide a method for preparing isoliquiritigenin and artificially synthesized liquiritigenin in view of the deficiencies of the prior art. The method adopts a convergent synthesis strategy, uses 2,4-dihydroxyacetophenone and 4-hydroxybenzaldehyde as starting materials, firstly protects the hydroxyl group on 2,4-dihydroxyacetophenone with acyl group, and then reacts the obtained product with 4-hydroxybenzaldehyde to obtain acyl-protected isoliquiritigenin as a precursor of the synthesis route, and reacts the product with an acyl-protected glucose donor in the presence of a promoter to obtain acyl-protected isoliquiritigenin, and then removes the protecting group to obtain isoliquiritigenin, an active ingredient of licorice, and artificially synthesized liquiritigenin, and further alkali-catalyzes the ring closure of isoliquiritigenin to obtain artificially synthesized liquiritigenin. The synthesis method has a novel route, cheap and easy-to-obtain raw materials, mild reaction conditions, high purity of the obtained product, easier quality control, simple operation, solves the disadvantages of low yield and large workload in the existing isoliquiritigenin synthesis method, and can further obtain artificially synthesized liquiritigenin. Compared with the currently reported method of directly extracting liquiritin and isoliquiritin from licorice, it has very obvious technical and industrial advantages. It can not only effectively save and protect Chinese medicine resources, but also has very good industrialization prospects and broad prospects for realizing the modernization of Chinese medicine through chemical modification and transformation.

[0010] The object of the present invention is achieved by: a method for preparing isoliquiritigenin and artificially synthesized liquiritigenin, wherein the reaction path of the preparation method is as shown in the following formula (I):

[0011]

[0012] The preparation method of isoliquiritigenin and artificially synthesized liquiritigenin comprises the following steps:

[0013] 1) Compound A and compound B are reacted under the action of a promoter to obtain compound C; the compound A is a sugar donor compound of pyranose glucose synthesized using glucose as a raw material, and B is protected isoliquiritigenin.

[0014] 2) Compound C is deprotected from the hydroxyl and phenolic hydroxyl groups to obtain compound D (isoliquiritigenin) and compound E (synthetic liquiritigenin).

[0015] 3) Compound D (isoliquiritigenin) reacts under the action of a promoter to obtain compound E (artificially synthesized liquiritigenin).

[0016] X in the compound A is a leaving group, preferably X is a halogen atom, an acetoxy group, a thioether group, a trichloroacetimidate, a phenyltrifluoroacetimidate, a trifluoroacetate, a silyl ether group, a sulfoxide group, an alkoxy group, an o-alkyl acetylene benzoate, an o-cycloalkyl acetylene benzoate, an o-aryl acetylene benzoate, a phosphonate or a phosphite; the structure of the X group is one of the structures shown in the following formula (II):

[0017]

[0018] In the compound A, compound B and compound C, preferably R1 is benzoyl, p-methylbenzoyl, or a C2-C6 alkyl substituted acyl group.

[0019] The synthesis step of the compound B comprises taking compound F as a raw material, first protecting the 2 and 4 hydroxyl groups thereof to obtain compound G, and then subjecting compound G and compound H to an aldol condensation reaction under the action of a promoter to obtain compound B. The synthesis route is shown in the following formula (III):

[0020]

[0021] R1 in the compound G is preferably benzoyl, p-methylbenzoyl, or a C2-C6 alkyl substituted acyl group.

[0022] The accelerator of the aldol condensation reaction includes but is not limited to potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, piperidine, pyrrole, acetic acid, acetyl chloride, hydrochloric acid, hydrogen chloride, thionyl chloride, tetraisopropoxytitanium and mixtures thereof; the reaction solvent includes but is not limited to water, ethanol, methanol, isopropanol, dichloromethane, 1,4-dioxane, 1,2-dichloroethane, tetrahydrofuran and mixtures thereof.

[0023] The accelerator for synthesizing compound C from compound A and compound B is trimethylsilyl trifluoromethanesulfonate, boron trifluoride ethyl ether, elemental iodine, N-bromosuccinimide, trifluoromethanesulfonic acid, silver trifluoromethanesulfonate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, copper trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, silver perchlorate, triphenylphosphine gold (I) bis (trifluoromethanesulfonyl) imide salt, triphenylphosphine gold (I) trifluoromethanesulfonate or trifluoromethanesulfonic anhydride.

[0024] The molar ratio of the sugar donor (compound A) to the sugar acceptor (compound B) is 1:1-4:1, the molar ratio of the promoter to the sugar acceptor (compound B) is 0.005:1-8:1, the reaction temperature is -78-50°C, and the reaction time is 0.5-24 hrs.

[0025] In the reaction from compound C to compound D and compound E, the deprotecting base used includes: sodium methoxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate and cesium carbonate, the reaction solvent is water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide or hexafluoroacetone and a mixture thereof, the reaction temperature is 0 to 50°C, and the reaction time is 0.5 to 24 hrs.

[0026] In the reaction from compound D to compound E, the promoter is triethylamine, diisopropylethylamine, dimethylamine, diethylamine, piperidine, tetrahydropyrrole, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, acetic acid or boric acid and a mixture thereof, the promoter equivalent is 1.0 to 20, the reaction solvent is water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or hexafluoroacetone and a mixture thereof, the reaction temperature is 0 to 100° C., and the reaction time is 0.5 to 48 hrs.

[0027] Compared with the prior art, the invention has the advantages of novel synthesis method, cheap and readily available raw materials, mild reaction conditions, high purity of the obtained product, easier quality control, simple operation, and solves the disadvantages of low yield and large workload in the existing isoliquiritigenin synthesis method, and can further obtain artificially synthesized liquiritigenin. Moreover, compared with the currently reported physical extraction of liquiritigenin and isoliquiritigenin from licorice, the invention has very obvious advantages, has very good industrialization prospects and chemical modification and transformation prospects, and can also save and protect licorice resources. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The H NMR spectrum of the liquiritin prepared in Example 5;

[0029] Figure 2 This is the hydrogen nuclear magnetic spectrum of isoliquiritigenin prepared in Example 6. DETAILED DESCRIPTION

[0030] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods.

[0031] The present invention selects the synthesis process under the preferred conditions to illustrate the specific synthesis method of the compound molecule involved in the present invention, wherein the substituent R1 is selected from acetyl and benzoyl, and the leaving group is selected from bromine atom and trichloroacetimidyl ester, but the selection of the embodiment does not mean any limitation of the preparation method of the present invention.

[0032] Example 1

[0033] The synthesis of 4-acetyl-1,3-diphenylene-dibenzoate is shown in the following formula (a):

[0034]

[0035] Under nitrogen protection in a 10-degree water bath, 5.76 mL of benzoyl chloride was added dropwise to a 15 mL pyridine solution of 3.04 g of 2,4-dihydroxy-acetophenone. The reaction solution was stirred at 10-25 degrees for 3 hours. After the reaction was completed by TLC monitoring, the reaction solution was poured into a mixture of 80 g and 3 mL of concentrated hydrochloric acid, extracted with 150 mL of ethyl acetate, and the extract was washed with 150 mL of water twice, washed once with a saturated sodium bicarbonate aqueous solution, and washed once with 150 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation. The crude product was washed with petroleum ether to obtain 7.28 g of a white solid product, which was 4-acetyl-1,3-diphenylene-dibenzoate, with a yield of 99%.

[0036] The data of the product analyzed by NMR spectrum are as follows:

[0037] 1 H NMR(400MHz, CDCl3)δ8.21(td,J=8.2,1.2Hz,4H),7.98(d,J=8.6Hz,1H),7.69–7.63(m, 2H),7.56–7.50(m,4H),7.29(dd,J=8.6,2.3Hz,1H),7.23(d,J=2.2Hz,1H),2.57(s,3H).

[0038] Example 2

[0039] The synthesis of (E)-4-(3-(4-hydroxyphenyl)acryloyl)-1,3-diphenylene-dibenzoate is shown in the following formula (b):

[0040]

[0041] Under the protection of ice bath argon, 2.4 mL of dichlorothionyl was added dropwise to a mixed solvent of 7.22 g of 4-acetyl-1,3-diphenylene-dibenzoate and 2.68 g of 4-hydroxybenzaldehyde in 15 mL of dichloromethane and 15 mL of isopropanol. The reaction solution was stirred at 5 degrees for 4 hours. 200 mL of ethyl acetate was added to the reaction solution, and then washed twice with 100 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was quickly purified by silica gel column to obtain 8.0 g of a light orange solid product, which was (E)-4-(3-(4-hydroxyphenyl)acryloyl)-1,3-diphenylene-dibenzoate, with a yield of 86%.

[0042] The data of the product analyzed by NMR spectrum are as follows:

[0043] 1 H NMR (400MHz, DMSO) δ10.12(s,1H),8.22–8.15(m,2H),8.12–8.06(m,2H),8.01(d,J=8.5Hz,1H),7.79(t,J=7.4Hz,1H),7.71( t,J=7.5Hz,1H),7.64(t,J=7.8Hz,2H),7.58–7.51(m,5H),7.51–7.43(m,2H),7.30(d,J=15.7Hz,1H),6.77(d,J=8.6Hz,2H).

[0044] Example 3

[0045] The synthesis of 2,3,4,6-D-tetraacetylpyranose-1-O-trichloroimide is shown in the following formula (c):

[0046]

[0047] Under the protection of argon in an ice bath, 50 mg of DBU was added dropwise to 3.48 g of 1-hydroxy-2,3,4,6-OD-tetraacetylpyranose and 2.2 mL of trichloroacetonitrile in 40 mL of dichloromethane. The reaction solution was stirred at room temperature for 2 hours. The dichloromethane was removed by rotation, and the crude product was purified by rapid silica gel column to obtain 4.0 g of colorless liquid, which solidified into a white solid product at low temperature, which was 2,3,4,6-D-tetraacetylpyranose-1-O-trichloroimide ester, with a yield of 81%.

[0048] The data of the product analyzed by NMR spectrum are as follows:

[0049] 1 H NMR (400MHz, CDCl3) δ8.70 (s, 1H), 6.56 (d, J = 3.3Hz, 1H), 5.57 (t, J = 9.9Hz, 1H), 5.19 (t, J = 9.9Hz, 1H), 5.14 (dd, J = 10.2, 3.7Hz, 1H) ,4.28(dd,J=12.3,4.1Hz,1H),4.25–4.18(m,1H),4.14(dd,J=12.3,2.0Hz,1H),2.08(s,3H),2.05(s,3H),2.04(s,3H),2.02(s,3H).

[0050] Example 4

[0051] The synthesis of 4-((E)-3-(2,4-dibenzoyloxyphenyl)-3-oxa-prop-1-enyl)phenyl-1-O-β-D-2,3,4,6-O-tetraacetylpyranoglucoside is shown in the following formula (d):

[0052]

[0053] Under the protection of argon in an ice bath, 46 mg of trimethylsilyl trifluoromethanesulfonate was added dropwise to a 22 mL dry dichloromethane solution of 980 mg of (E)-4-(3-(4-hydroxyphenyl)acryloyl)-1,3-diphenylene-dibenzoate and 1.91 g of 2,3,4,6-OD-tetraacetylpyranose-1-O-trichloroimide. The reaction solution was reacted at 5 degrees for 1 hour and then at 25 degrees for 2 hours. The reaction solution was diluted with 100 mL of ethyl acetate, washed twice with 100 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was quickly passed through a silica gel column to obtain 1.56 g of a white foamy solid product, 4-((E)-3-(2,4-dibenzoyloxyphenyl)-3-oxa-prop-1-enyl)phenyl-1-O-β-D-2,3,4,6-O-tetraacetylpyranoglucoside, with a yield of 93%.

[0054] The data of the product analyzed by NMR spectrum are as follows:

[0055] 1 H NMR (400MHz, CDCl3) δ8.26–8.19(m,2H),8.15–8.10(m,2H),7.87–7.83(m,1H),7.66(d,J=7.4Hz,1H ),7.61–7.51(m,4H),7.44–7.37(m,4H),7.33–7.30(m,2H),7.09(d,J=15.9Hz,1H),6.92(d,J=8.7Hz ,2H),5.30(dd,J=8.5,5.2Hz,2H),5.17(t,J=9.5Hz,1H),5.12(d,J=7.4Hz,1H),4.30(dd,J=12.3,5. 4Hz,1H),4.21–4.15(m,1H),3.93–3.85(m,1H),2.07(s,3H),2.06(s,3H),2.06(s,3H),2.05(s,3H).

[0056] Example 5

[0057] Artificially synthesized liquiritin (7-hydroxy-11-O-β-D-pyranoglucoside-dihydroflavone) is shown in the following formula (e):

[0058]

[0059] Under the protection of nitrogen in an ice bath, 306 mg of sodium methoxide was added to a mixed solution of 5 mL of dichloromethane and 20 mL of methanol of 1.50 g of 4-((E)-3-(2,4-dibenzoyloxyphenyl)-3-oxa-prop-1-enyl)phenyl-1-O-β-D-2,3,4,6-O-tetraacetylpyranoglucoside. The reaction solution was slowly heated to 25 degrees and stirred for 2 hours. The solvent was vortexed. 20 mL of ethanol and 1 mL of triethylamine were added. The reaction solution was heated to reflux at 85 degrees for 18 hours. The solvent was vortexed, and 30 mL of an aqueous solution of 1 mL of formic acid was added to the residue, filtered, and the filter residue was recrystallized with ethanol to obtain 260 mg of an off-white solid product. The filtrate was purified by a C18 column to obtain 70 mg of a white solid product, which was liquiritin, with a total yield of 41%.

[0060] See also Figure 1 The data of the product liquiritin analyzed by NMR spectrum are as follows:

[0061] 1H NMR (400MHz, DMSO) δ10.59(s,1H),7.65(d,J=8.6Hz,1H),7.45(d,J=8.7Hz,2H),7.06(d,J= 8.5Hz,2H),6.51(dd,J=8.7,2.2Hz,1H),6.35(d,J=2.2Hz,1H),5.53(dd,J=12.7,2.6Hz,1H) ,5.32(bs,1H),5.04(bs,2H),4.89(d,J=7.2Hz,1H),4.56(bs,1H),3.69(d,J=10.4Hz,1H), 3.46(dd,J=11.8,5.7Hz,1H), 3.30–3.21(m,2H), 3.19–3.08(m,2H), 2.67(d,J=16.8Hz,1H).

[0062] Example 6

[0063] The synthesis of isoliquiritigenin ((E)-1-(2,4-dihydroxy-phenyl)-3-(4-O-β-D-pyranoglucopyranoside phenyl) prop-2-en-1-one) and synthetic liquiritigenin (7-hydroxy-11-O-β-D-pyranoglucopyranoside-dihydroflavone) is shown in the following formula (f):

[0064]

[0065] Under the protection of nitrogen in an ice bath, 153 mg of sodium methoxide was added to a mixed solution of 750 mg of 4-((E)-3-(2,4-dibenzoyloxyphenyl)-3-oxa-prop-1-enyl)phenyl-1-O-β-D-2,3,4,6-O-tetraacetylpyranoglucoside in 5 mL of dichloromethane and 20 mL of methanol. The reaction solution was slowly heated to 25 degrees and stirred for 2 hours. 1.1 g of strong acid cationic resin was added to pH ~ 5, filtered, the filtrate was spin-dried, and the residue was purified by C18 column to obtain 260 mg of yellow solid product (Isoliquiritigenin), with a yield of 65%, and 54 mg of white solid product (synthetic liquiritigenin) was obtained at the same time, with a yield of 13.6%.

[0066] See also Figure 2 The data of the product isoliquiritigenin analyzed by NMR spectrum are as follows:

[0067] 1H NMR (400MHz, DMSO) δ13.52(s,1H),10.77(s,1H),8.19(d,J=9.0Hz,1H),7.86(d,J=8.8Hz,2H),7.86(d,J=1 5.1Hz,1H),7.77(d,J=15.4Hz,1H),7.10(d,J=8.7Hz,2H),6.41(dd,J=8.9,2.2Hz,1H),6.29(d,J=2.2Hz,1H ),5.38(d,J=4.8Hz,1H),5.13(d,J=4.4Hz,1H),5.07(d,J=5.3Hz,1H),4.97(d,J=7.3Hz,1H),4.62(t,J=5. 6Hz,1H),3.70(dd,J=10.6,5.0Hz,1H),3.50–3.36(m,2H),3.33–3.23(m,2H),3.17(dt,J=14.1,7.1Hz,1H).

[0068] Example 7

[0069] The synthesis of 4-((E)-3-(2,4-dibenzoyloxyphenyl)-3-oxa-prop-1-enyl)phenyl-1-O-β-D-2,3,4,6-O-tetraacetyl glucopyranoside is shown in the following formula (g):

[0070]

[0071] Under the protection of argon in an ice bath, 462 mg of silver (I) oxide was added to a 20 mL dry acetonitrile solution of 465 mg of (E)-4-(3-(4-hydroxyphenyl) acryloyl)-1,3-diphenylene-dibenzoate and 822 mg of 1-bromo-2,3,4,6-D-tetraacetylpyranose. The reaction solution was reacted at 5 degrees for 2 hours. The reaction solution was diluted with 100 mL of ethyl acetate, filtered through diatomaceous earth, and the filtrate was washed twice with 100 mL of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was quickly passed through a silica gel column to obtain 180 mg of a white foamy solid product, which was 4-((E)-3-(2,4-dibenzoyloxyphenyl)-3-oxa-prop-1-enyl)phenyl-1-O-β-D-2,3,4,6-O-tetraacetylpyranose, with a yield of 22%.

[0072] Example 8

[0073] The synthesis of 4-((E)-3-(2,4-dibenzoyloxyphenyl)-3-oxa-prop-1-enyl)phenyl-1-O-β-D-2,3,4,6-O-tetrabenzoylpyranoglucoside is shown in the following formula (h):

[0074]

[0075] Under the protection of argon in an ice bath, 6 mg of boron trifluoride ether was added dropwise to a 1.5 mL dry dichloromethane solution of 23 mg of (E)-4-(3-(4-hydroxyphenyl)acryloyl)-1,3-diphenylene-dibenzoate and 70 mg of 2,3,4,6-D-tetrabenzoylpyranose-1-O-(N-phenyltrifluoroimide). The reaction solution was reacted at 5 degrees for 1 hour and then at room temperature overnight. The reaction solution was diluted with 10 mL of ethyl acetate, washed once with 10 mL of 5% NaHCO3 aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was quickly purified by silica gel column to obtain 28 mg of light yellow foamy solid product, which was 4-((E)-3-(2,4-dibenzoyloxyphenyl)-3-oxa-prop-1-enyl)phenyl-1-O-β-D-2,3,4,6-O-tetrabenzoylpyranoglucoside, with a yield of 52%.

[0076] The data of the product analyzed by NMR spectrum are as follows:

[0077] 1 H NMR (400MHz, CDCl3) δ8.25–8.19(m,2H),8.11–8.06(m,2H),8.03–7.99(m,2H),7.95(dd,J=11.9,4.2Hz,4H) ,7.89–7.83(m,3H),7.67(t,J=7.4Hz,1H),7.61–7.28(m,20H),7.20(d,J=8.8Hz,2H),7.02(d,J=15.9Hz,1H ),6.91(d,J=8.7Hz,2H),6.01(t,J=9.5Hz,1H),5.81(dd,J=9.5,7.7Hz,1H),5.71(t,J=9.6Hz,1H),5.43(d, J=7.7Hz, 1H), 4.68 (dd, J=12.1, 2.9Hz, 1H), 4.55 (dd, J=12.1, 6.8Hz, 1H), 4.37 (ddd, J=9.7, 6.8, 2.9Hz, 1H).

[0078] Example 9

[0079] The synthesis of 4-((E)-3-(2,4-dibenzoyloxyphenyl)-3-oxa-prop-1-enyl)phenyl-1-O-β-D-2,3,4,6-O-tetrabenzoylpyranoglucoside is shown in the following formula (i):

[0080]

[0081] Under argon protection, 23 mg of (E)-4-(3-(4-hydroxyphenyl)acryloyl)-1,3-diphenylene-dibenzoate, 78 mg of 2,3,4,6-D-tetrabenzoylpyranose-1-O-(2-(1-hexyn-1-yl)benzoate) and 12 mg of triphenylphosphine gold (I) bis (trifluoromethanesulfonyl) imide salt was added to 1.5 mL of dry dichloromethane solution of molecular sieve. The reaction solution was reacted at 25 degrees for 12 hours. The reaction solution was quenched with 6 mg of triethylamine and spin-dried to obtain a crude product. The crude product was quickly passed through a silica gel column to obtain 36 mg of a light yellow foamy solid product, which was 4-((E)-3-(2,4-dibenzoyloxyphenyl)-3-oxa-prop-1-enyl)phenyl-1-O-β-D-2,3,4,6-O-tetrabenzoylpyranoglucoside, with a yield of 67%.

[0082] The above description is only a general embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing isoliquiritigenin and artificially synthesized liquiritigenin, characterized in that: Compound A and compound B are subjected to glycosylation reaction under the action of a promoter to obtain compound C, which is then deprotected to obtain isoliquiritigenin D and synthetic liquiritigenin E. Isoliquiritigenin D is cyclized under the base catalysis of the promoter to obtain synthetic liquiritigenin E. The preparation process is shown in the structural reaction formula (I) below: The molar ratio of compound A to compound B is 1:1 to 4:1; the molar ratio of the accelerator to compound B is 0.005:1 to 8:1, the reaction temperature is -78 to 50°C, and the reaction time is 0.5 to 24 hours; the deprotection group of compound C is removed by alkali at a temperature of -15 to 45°C for 15 to 180 minutes; the base-catalyzed ring-closure reaction temperature of isoliquiritigenin D is 0 to 100°C, and the reaction time is 0.5 to 48 hours; The compound A is an acyl protected glucosyl donor synthesized from glucose; the compound B is acyl protected isoliquiritigenin; the compound C is acyl protected isoliquiritigenin D and artificially synthesized liquiritigenin E; The accelerator for synthesizing compound C from compound A and compound B is trimethylsilyl trifluoromethanesulfonate, boron trifluoride ethyl ether, elemental iodine, N-bromosuccinimide, trifluoromethanesulfonic acid, silver trifluoromethanesulfonate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, copper trifluoromethanesulfonate, ferrous trifluoromethanesulfonate, silver perchlorate, triphenylphosphine gold (I) bis (trifluoromethanesulfonyl) imide salt, triphenylphosphine gold (I) trifluoromethanesulfonate or trifluoromethanesulfonic anhydride; In the reaction of compound C to compound D and compound E, the base used for deprotection includes sodium methoxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate or cesium carbonate, the reaction solvent is water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide or hexafluoroacetone and mixtures thereof, the reaction temperature is 0 to 50°C, and the reaction time is 0.5 to 24 hrs; In the reaction of compound D to compound E, the promoter is triethylamine, diisopropylethylamine, dimethylamine, diethylamine, piperidine, tetrahydropyrrole, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, acetic acid or boric acid and a mixture thereof, the promoter equivalent is 1.0 to 20, the reaction solvent is water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane or N,N-dimethylformamide, dimethyl sulfoxide, hexafluoroacetone and a mixture thereof, the reaction temperature is 0 to 100°C, and the reaction time is 0.5 to 48 hrs.

2. The method for preparing isoliquiritigenin and artificially synthesized liquiritigenin according to claim 1, characterized in that: X in the compound A is a halogen atom, an acetoxy group, a thioether group, a trichloroacetimidate, a phenyltrifluoroacetimidate, a trifluoroacetate, a silyl ether group, a sulfoxide group, an alkoxy group, an o-alkyl acetylene benzoate, an o-cycloalkyl acetylene benzoate, an o-aryl acetylene benzoate, a phosphonate or an X leaving group of a phosphite.

3. The method for preparing isoliquiritigenin and synthetic liquiritigenin according to claim 1, characterized in that: The X leaving group is one of the structures shown in the following formula (II):

4. The method for preparing isoliquiritigenin and synthetic liquiritigenin according to claim 1, characterized in that: R1 in the compound A, compound B and compound C is benzoyl, p-methylbenzoyl or a C2-C6 alkyl substituted acyl group.

5. The method for preparing isoliquiritigenin and synthetic liquiritigenin according to claim 1, characterized in that: The synthesis step of the compound B comprises: protecting the 2 and 4 hydroxyl groups of the compound F to obtain the compound G, and subjecting the compound G and the compound H to an aldol condensation reaction under the action of a promoter to obtain the compound B, whose structural reaction formula is shown in the following formula (III): The compound F is 2,4-dihydroxyacetophenone; the compound G is 2,4-diacylated acetophenone, wherein R1 is benzoyl, p-methylbenzoyl or C2-C6 alkyl substituted acyl. The accelerator of the aldol condensation reaction is potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, piperidine, tetrahydropyrrole, acetic acid, acetyl chloride, hydrochloric acid, hydrogen chloride, dichlorothionyl or tetraisopropoxytitanium and a mixture thereof; the reaction solvent is water, ethanol, methanol, isopropanol, dichloromethane, 1,4-dioxane, 1,2-dichloroethane or tetrahydrofuran and a mixture thereof.

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