Synthetic method of glabridin

Abstract

The invention discloses a synthetic method of glabridin, which is characterized in that 1, 3-dimethoxybenzene is used as an initial raw material, and the target product glabridin is prepared through a series of reactions. The independently researched and developed glabridin synthesis process has the advantages of cheap and easily available raw materials, simple operation, few side reactions, convenient quality control and the like, and a green organic solvent is adopted in the preparation process, so that post-treatment is simple, recycling can be realized, the emission of three wastes is less, the obtained product is high in yield and purity, and the method is suitable for industrial production and has wide application prospects. And the product has better market competitiveness.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing glabridin, specifically synthesizing glabridin rapidly and efficiently from 1,3-dimethoxybenzene through a nine-step method, belonging to the technical field of organic synthesis. Background Art

[0002] Glabridin is an isoflavanoid compound, which was first isolated from the plant Glycyrrhiza glabra of the family Fabaceae in 1976. Glabridin is the main lipophilic flavonoid in Glycyrrhiza glabra. Total flavonoids can be extracted using organic solvents, and then glabridin can be obtained by repeatedly using column chromatography for separation and repeated recrystallization. However, with the overexploitation of wild Glycyrrhiza glabra resources, the licorice resources have been damaged unprecedentedly and are difficult to recover in a short time. Therefore, in recent years, the state has listed licorice as a protected medicinal material, and licorice has also been obtained through artificial cultivation. However, the analysis of the investigation results shows that geographical distribution, growth years, artificial intervention, etc. are important factors affecting the quality of cultivated licorice medicinal materials. The content of glabridin in artificially cultivated Glycyrrhiza glabra is less than that of wild ones, and the growth cycle is long, generally about 4 years. The uses of glabridin are mainly concentrated in the medical field, showing great application value in aspects such as anti-inflammatory, antioxidant, anti-atherosclerosis, lipid-lowering, blood pressure-lowering, neuroprotection, memory enhancement, and skin whitening, and having extensive biological activities.

[0003] Currently, the main way to obtain glabridin in China is to extract it from the precious plant Glycyrrhiza glabra, and it cannot be obtained in large quantities. In China, Glycyrrhiza glabra mainly grows in the south of Tianshan Mountain. With the implementation of sand prevention and fixation, the harvesting of Glycyrrhiza glabra is restricted, making it particularly important to develop an effective chemical synthesis method for preparing glabridin. Summary of the Invention

[0004] To solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for synthesizing glabridin with cheap, simple and easily available raw materials, an easy-to-implement route, and a high overall yield.

[0005] To achieve the above objectives, the present invention adopts the following technical solutions:

[0006] The present invention first discloses a method for synthesizing glabridin, synthesizing the skeleton in a symmetrical manner, adopting the strategy of selectively removing methyl groups sequentially and then cyclizing, and successively constructing the benzocyclic structure of glabridin to synthesize glabridin. The reaction route is as follows:

[0007]

[0008] Preferably, the foregoing method for synthesizing glabridin includes the following steps:

[0009] S1. Dissolve 1,3 - dimethoxybenzene in an organic solvent, and carry out an acylation reaction with oxalyl chloride or oxalic acid under the catalysis of an acid catalyst to obtain a symmetric dicarbonyl intermediate 2;

[0010] S2. React intermediate 2 with methylmagnesium bromide or methyllithium in a tetrahydrofuran solvent to obtain intermediate 3;

[0011] S3. Use intermediate 3 as a raw material, dissolve it in DCM, and selectively remove the methyl protection and cyclize under the action of aluminum trichloride to obtain intermediate 4;

[0012] S4. Use intermediate 4 and sodium ethanethiolate as raw materials, reflux in DMF, and selectively remove the methyl group to obtain intermediate 5;

[0013] S5. Use intermediate 5, phenylboronic acid, and 3 - methyl - 2 - butenal as raw materials, and carry out a reaction in an organic solvent to obtain intermediate 6;

[0014] S6. Dissolve intermediate 6 in an organic solvent, reduce the carbonyl group and remove the methyl group under the action of lithium aluminum hydride and an acid respectively to obtain the target product 7, i.e., glabridin.

[0015] More preferably, the specific process of the aforementioned step S1 is as follows: First, dissolve 1,3 - dimethoxybenzene in an organic solvent, and the organic solvent is dichloromethane, dichloroethane, benzene, toluene, nitrobenzene, or N,N - dimethylformamide; slowly drop oxalyl chloride or oxalic acid into it at - 20°C to 10°C, add an acid catalyst and reflux and stir for 6 - 24 hours, and the acid catalyst is BF3, SbCl5, FeBr3, AlCl3, FeCl3, SnCl4, TiCl4, ZnCl2, trifluoroacetic anhydride, sulfuric acid, or polyphosphoric acid; the molar ratio of the oxalyl chloride or oxalic acid, 1,3 - dimethoxybenzene, and the acid catalyst is 1:2.0 - 2.4:2.0 - 2.4; after the reaction is complete, quench with dilute hydrochloric acid and extract with dichloromethane, then dry with anhydrous sodium sulfate, and finally distill off the organic solvent under reduced pressure, and purify the crude product by silica gel column chromatography to obtain the dicarbonyl intermediate 2.

[0016] More preferably, the specific process of the aforementioned step S2 is as follows: First, dissolve intermediate 2 in a tetrahydrofuran solvent, and then add methylmagnesium bromide or methyllithium to it, and the molar ratio of intermediate 2 to methylmagnesium bromide or methyllithium is 1:1 - 1.2; stir and react at 0°C for 0.5 - 2 hours, then dropwise add sulfuric acid or trifluoroacetic acid and continue to stir for 1 - 2 hours, quench with a sodium bicarbonate solution, extract the organic phase with DCM and dry, distill off the organic solvent under reduced pressure, and purify with silica gel column chromatography to obtain intermediate 3.

[0017] More preferably, the specific process of the foregoing step S3 is as follows: Dissolve the intermediate 3 in dichloromethane solvent, add aluminum chloride, and react at room temperature for 4 to 8 hours. After the raw materials react completely, add sodium acetate solution and continue stirring for 2 to 4 hours. The reaction mixture is extracted with dichloromethane, the combined organic layers are washed with brine, then dried over anhydrous sodium sulfate, filtered, and the organic solvent is removed by distillation under reduced pressure. The crude product is purified by silica gel column chromatography to obtain intermediate 4.

[0018] Even more preferably, the specific process of the foregoing step S4 is as follows: Dissolve the intermediate 4 in N,N-dimethylformamide, then add sodium ethanethiolate thereto, stir and heat to 60°C to 100°C for reaction. After the raw materials react completely, cool to room temperature, add ammonium chloride solvent to quench, extract with dichloromethane, wash the organic phase with saturated sodium chloride aqueous solution, collect the organic phase, dry over anhydrous sodium sulfate, filter, remove the organic solvent by distillation under reduced pressure, and purify by silica gel column chromatography to obtain intermediate 5.

[0019] Still further preferably, the specific process of the foregoing step S5 is as follows: Dissolve the intermediate 5 in acetic acid / toluene solvent, stir at room temperature and sequentially add phenylboronic acid and 3-methyl-2-butenal, reflux the mixture for 8 to 12 hours. After the raw materials react completely, extract with dichloromethane, wash the extract with sodium bicarbonate aqueous solution and brine in sequence, dry over anhydrous sodium sulfate, remove the organic solvent by distillation under reduced pressure, and purify the crude product by silica gel column chromatography to obtain intermediate 6.

[0020] Even still further preferably, the specific process of the foregoing step S6 is as follows: Dissolve the intermediate 6 in tetrahydrofuran solvent, then add lithium aluminum hydride as a reducing agent and reflux and stir for 6 hours. The molar ratio of the intermediate 6 to lithium aluminum hydride is 1:10 to 20; after the raw materials react completely, quench with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, remove the organic solvent by distillation under reduced pressure, then dissolve the remaining organic matter in acetic acid, add an excessive amount of concentrated hydrochloric acid, hydrobromic acid or hydroiodic acid and reflux for 12 - 24 hours, concentrate to remove the excessive acid, extract with dichloromethane, collect the organic phase, dry over anhydrous sodium sulfate, filter, remove the organic solvent by distillation under reduced pressure, and purify by silica gel column chromatography to obtain the target product 7, i.e., glabridin.

[0021] The present invention also claims glabridin obtained by the synthesis method as described above.

[0022] The beneficial effects of the present invention are as follows: The present invention uses inexpensive and easily available 1,3-dimethoxybenzene as a raw material, and prepares glabridin through a six-step reaction developed independently. The total yield of the product is as high as over 41%, which is higher than the average yield level of 30% in the existing industry. Glabridin is synthesized quickly and efficiently, and the whole process does not involve heavy metals, reducing the synthesis cost and having higher safety.

[0023] Compared with the prior art, in the synthesis process of glabridin of the present invention, the raw materials such as 1,3-dimethoxybenzene, oxalic acid, and sodium ethanethiolate used are all cheap and easily available chemical raw materials. The operation is simple, with few side reactions. Most steps can obtain products through crystallization, without cumbersome post-treatment operations, and quality control is convenient. During the reaction process, green organic solvents are mostly used, making the post-treatment simple and recyclable, with less discharge of three wastes. The whole process does not involve heavy metals, is environmentally friendly, and the obtained product reaches a high purity of 99.7%, which is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is the HPLC purity detection chart of compound 7 (target product) prepared in Example 1 of the present invention;

[0025] Figure 2 It is the 1H NMR spectrum of compound 7 (target product) prepared in Example 1 of the present invention;

[0026] Figure 3 It is the 13C NMR spectrum of compound 7 (target product) prepared in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention will be specifically introduced below in conjunction with the drawings and specific embodiments.

[0028] In the present invention, unless otherwise specified, the raw materials used are all commercially available.

[0029] Example 1

[0030] S1. React oxalyl chloride (2.16 g, 17 mmol) and aluminum trichloride (4.82 g, 36.2 mmol) with 1,3-dimethoxybenzene (5.0 g, 36.2 mmol) in 50 mL of toluene to obtain intermediate 2 (5.14 g, yield 92%). The structure characterization data of the obtained intermediate 2 are as follows: 1 H NMR (400 MHz, Chloroform-d) δ8.05 (d, J = 8.8 Hz, 2H), 6.68–6.60 (m, 2H), 6.43–6.38 (m, 2H), 3.89 (s, 6H), 3.59 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ191.94, 165.86, 162.16, 132.35, 117.13, 106.53, 98.58, 55.80, 55.62. HRMS (ESI + ) [M+H] + Calcd forC 18 H 19O6: 331.1176 m / z, Found: 331.1178 m / z, proving its structural formula is

[0031] S2. Intermediate 2 (3.30 g, 10 mmol) was dissolved in 60 mL of tetrahydrofuran and reacted. Methylmagnesium bromide (3 mol / L, 4 mL, 12 mmol) was added dropwise at 0 °C. After stirring for 1.5 hours, sulfuric acid was added dropwise and stirred for another 1 hour to obtain intermediate 3 (3.02 g, yield 89%). The structural characterization data of the obtained intermediate 3 are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 8.5, 1H), 7.21 (d, J = 8.3, 1H), 6.49–6.39 (m, 2H), 6.34–6.30 (m, 2H), 5.77 (s, 1H), 5.70 (s, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.69 (s, 3H), 3.58 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 195.74, 163.26, 161.02, 159.83, 157.60, 148.80, 132.90, 130.70, 122.62, 121.86, 121.17, 104.68, 104.21, 98.43, 98.37, 55.46, 55.36, 55.33, 55.24. HRMS (ESI + ) [M+H] + Calcd for C 19 H 21 O5: 329.1384 m / z, Found: 329.1378 m / z, proving its structural formula is

[0032] S3. Intermediate 3 (2.40 g, 7.30 mmol) and AlCl3 (1.16 g, 8.76 mmol) were dissolved in 50 mL of dichloromethane and reacted at room temperature for 6 hours under argon protection. Subsequently, an excess of sodium acetate solution was added and stirred for another 4 hours to obtain intermediate 4 (1.97 g, yield 86%). The structural characterization data of the obtained compound 4 are as follows: 11H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 8.8, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.62 (dd, J = 8.8, 1.9 Hz, 1H), 6.50–6.44 (m, 3H), 4.61–4.55 (m, 1H), 4.50 (dd, J = 11.0, 5.4 Hz, 1H), 4.26 (dd, J = 11.5, 5.4 Hz, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 191.56, 165.77, 163.82, 160.53, 158.49, 130.66, 129.39, 116.13, 115.64, 109.79, 104.71, 100.78, 99.19, 71.33, 55.62, 55.55, 55.38, 47.33. HRMS (ESI + ) [M + H] + Calcd for C 18 H 19 O5: 315.1227 m / z, Found: 315.1231 m / z, which proves that its structural formula is

[0033] S4, Intermediate 4 (1.50 g, 4.76 mmol) was reacted with sodium ethanethiolate (0.52 g, 6.18 mmol) in 30 mL of DMF to obtain Intermediate 5 (0.98 g, yield 79%). The structural characterization data of the obtained Intermediate 5 are as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.53 (dt, J = 8.2, 1.4 Hz, 1H), 6.49 (dd, J = 8.4, 2.4 Hz, 1H), 6.36 (m, 1H), 4.54 (t, J = 10.6 Hz, 1H), 4.43 (dd, J = 10.8, 5.2 Hz, 1H), 4.18 (dd, J = 10.8, 5.2 Hz, 1H), 3.76 (s, 3H), 3.72 (s, 3H). 13¹³C NMR (101 MHz, DMSO-d6): δ 190.9, 164.8, 163.7, 160.5, 158.6, 131.2, 129.5, 116.5, 114.5, 111.1, 105.5, 102.8, 99.3, 70.8, 56.1, 55.8, 47.3. HRMS (ESI + ) [M+H] + Calcd for C 17 H 17 O5: 301.1071 m / z, Found: 301.1066 m / z, which proves that its structural formula is

[0034] S5. Add intermediate 5 (0.75 g, 2.5 mmol), phenylboronic acid (0.31 g, 2.5 mmol), 3-methyl-2-butenal (0.25 g, 3 mmol), and dissolve 12 mL of glacial acetic acid in 10 mL of toluene solution. Under an argon atmosphere, stir and reflux the reaction for 12 hours to obtain intermediate 6 (0.80 g, yield 87%). The structural characterization data of the obtained compound 6 are as follows: 1 ¹H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.9 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 10.2 Hz, 1H), 6.44–6.50 (m, 3H), 5.59 (d, J = 10.3 Hz, 1H), 4.59 (t, J = 11.2 Hz, 1H), 4.53 (dd, J = 11.4, 5.4 Hz, 1H), 4.26 (dd, J = 11.4, 5.4 Hz, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 1.48 (s, 3H), 1.43 (s, 3H). 13 ¹³C NMR (101 MHz, Chloroform-d) δ 191.57, 160.47, 159.14, 158.46, 157.96, 130.68, 128.76, 128.49, 116.03, 115.81, 115.46, 110.89, 109.18, 104.58, 99.11, 77.42, 71.26, 55.49, 53.37, 47.18, 28.37, 28.01. HRMS (ESI + ) [M+H] + Calcd for C 22 H 23 O5: 367.1540 m / z, Found: 367.1541 m / z, which proves that its structural formula is

[0035] Intermediate 6 (0.80 g, 2.18 mmol) was reacted with lithium aluminum hydride (0.80 g, 2.18 mmol) in tetrahydrofuran. After quenching, it was redissolved in acetic acid, and excess concentrated hydrochloric acid was added and refluxed to obtain the final compound 7 (0.61 g, yield 86%), namely glabridin. The structural characterization results of the obtained compound 7 are as Figures 1 to 3 shown, and the structural characterization data are: 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.12 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 9.5 Hz, 1H), 6.33 (m, 1H), 6.28 (d, J = 8.2 Hz, 1H), 6.19 (d, J = 8.4 Hz, 1H), 5.64 (d, J = 9.8 Hz, 1H), 4.24 (d, J = 10.2 Hz, 1H), 3.93 (t, J = 10.2 Hz, 1H), 3.36–3.24 (m, 1H), 2.90 (dd, J = 15.6, 11.2 Hz, 1H), 2.70 (dd, J = 16.2, 4.2 Hz, 1H), 1.34 (s, 6H). 13 C NMR (101 MHz, DMSO-d6): δ 157.35, 156.32, 151.70, 149.72, 129.79, 129.63, 128.02, 117.92, 116.89, 115.20, 109.51, 108.56, 106.77, 102.99, 75.67, 70.21, 31.37, 30.46, 27.82, 27.69. HRMS (ESI + ) [M + H] + Calcd for C 20 H 21 O4: 325.1434 m / z, Found: 325.1435 m / z. Finally, the purity of the obtained product glabridin was measured to be 99.7% by HPLC at 254 nm.

[0036] Example 2

[0037] The synthesis of intermediate 3 to glabridin was the same as in Example 1, except for the synthesis of intermediate 2.

[0038] Oxalyl chloride (2.10 g, 16.5 mmol) and trifluoroacetic anhydride (7.28 g, 34.7 mmol) were heated and reacted with 1,3-dimethoxybenzene (4.80 g, 34.7 mmol) to obtain intermediate 2 (4.55 g, yield 82%).

[0039] Example 3

[0040] The synthesis of Intermediate 3 to glabridin is the same as that in Example 1, except for the synthesis of Intermediate 2.

[0041] Oxalic acid (0.90 g, 10.0 mmol) was heated and reacted with 1,3 - dimethoxybenzene (2.76 g, 20 mmol) in 8 mL of polyphosphoric acid to obtain Intermediate 2 (2.61 g, yield 79%).

[0042] Example 4

[0043] The synthesis of Intermediate 3 to glabridin is the same as that in Example 1, except for the synthesis of Intermediate 2.

[0044] Oxalyl chloride (2.05 g, 16.2 mmol) and zinc chloride (4.39 g, 32.3 mmol) were reacted with 1,3 - dimethoxybenzene (4.75 g, 34.39 mmol) in dichloroethane to obtain Intermediate 2 (4.50 g, yield 80%).

[0045] Example 5

[0046] The synthesis of Intermediate 3 to glabridin is the same as that in Example 1, except for the synthesis of Intermediate 2.

[0047] Oxalyl chloride (12.7 g, 10.0 mmol) and iron(III) chloride (3.56 g, 22.0 mmol) were reacted with 1,3 - dimethoxybenzene (2.76 g, 20 mmol) in dichloromethane to obtain Intermediate 2 (2.71 g, yield 82%).

[0048] Example 6

[0049] The synthesis of Intermediate 2, 4, 5, 6 and Compound 7 is the same as that in Example 1, except for the synthesis of Intermediate 3.

[0050] Intermediate 2 (3.30 g, 10 mmol) was dissolved in 60 mL of tetrahydrofuran and reacted. Methyllithium (1.6 mol / L, 6.3 mL, 10 mmol) was added dropwise at 0 °C. After stirring for 1 hour, trifluoroacetic acid was added dropwise and stirred for another 1 hour to obtain Intermediate 3 (2.88 g, yield 85%).

[0051] Example 7

[0052] The synthesis of Intermediate 2, 3, 4, 5, 6 is the same as that in Example 1, except for the synthesis of glabridin.

[0053] Intermediate 6 (1.20 g, 3.27 mmol) was reacted with lithium aluminum hydride (1.20 g, 3.27 mmol) in tetrahydrofuran. After quenching, the organic phase was evaporated to dryness, and excess hydrobromic acid was added and refluxed to obtain the final compound 7 (0.79 g, yield 78%), namely glabridin.

[0054] Example 8

[0055] The synthesis of Intermediates 2, 3, 4, 5, and 6 was the same as that in Example 1, except for the synthesis of glabridin.

[0056] Intermediate 6 (1.20 g, 3.27 mmol) was reacted with lithium aluminum hydride (1.20 g, 3.27 mmol) in tetrahydrofuran. After quenching, the organic phase was evaporated to dryness, and excess hydroiodic acid was added and refluxed to obtain the final compound 7 (0.81 g, yield 80%), namely glabridin.

[0057] In summary, the present invention uses 1,3-dimethoxybenzene, which is inexpensive and easily available, as a raw material, and prepares glabridin through a six-step reaction developed independently. The total yield of the product is as high as over 41%, higher than the average yield level of 30% in the existing industry. Glabridin is synthesized quickly and efficiently. The whole process does not involve heavy metals, the synthesis cost is reduced and the safety is higher. The obtained product has a high purity of 99.7%, is suitable for industrial production and has good market competitiveness.

[0058] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the above embodiments do not limit the present invention in any form. Any technical solutions obtained by using equivalent replacement or equivalent transformation fall within the protection scope of the present invention.

Claims

1. A method for synthesizing glabridin, characterized in that, The skeleton is synthesized in a symmetric manner, and the strategy of selectively removing methyl groups in sequence and then cyclizing is adopted to construct the benzocyclic structure of glabridin successively, and glabridin is synthesized. The reaction route is as follows:

2. The method for synthesizing glabridin according to claim 1, characterized in that, It includes the following steps: S1. Dissolve 1,3-dimethoxybenzene in an organic solvent, and carry out an acylation reaction with oxalyl chloride or oxalic acid under the catalysis of an acid catalyst to obtain a symmetric dicarbonyl intermediate 2. S2. Using intermediate 2 and methylmagnesium bromide or methyllithium as raw materials, react in a tetrahydrofuran solvent to obtain intermediate 3. S3. Using intermediate 3 as a raw material, dissolve it in DCM, and selectively remove the methyl protection and cyclize under the action of aluminum trichloride to obtain intermediate 4. S4. Using intermediate 4 and sodium ethanethiolate as raw materials, reflux in DMF to selectively remove the methyl group to obtain intermediate 5. S5. Using intermediate 5, phenylboronic acid and 3-methyl-2-butenal as raw materials, react in an organic solvent to obtain intermediate 6. S6. Dissolve intermediate 6 in an organic solvent, and reduce the carbonyl group and remove the methyl group under the action of lithium aluminum hydride and an acid respectively to obtain the target product compound 7, that is, glabridin.

3. The method for synthesizing glabridin according to claim 2, characterized in that, In the step S1, the specific process is as follows: First, dissolve 1,3-dimethoxybenzene in an organic solvent, and the organic solvent is dichloromethane, dichloroethane, benzene, toluene, nitrobenzene or N,N-dimethylformamide; slowly drop oxalyl chloride or oxalic acid into it at -20°C to 10°C, add an acid catalyst and reflux and stir for 6-24 hours, and the acid catalyst is BF3, SbCl5, FeBr3, AlCl3, FeCl3, SnCl4, TiCl4, ZnCl2, trifluoroacetic anhydride, sulfuric acid or polyphosphoric acid; the molar ratio of oxalyl chloride or oxalic acid, 1,3-dimethoxybenzene and the acid catalyst is 1:2.0-2.4:2.0-2.4; after the reaction is complete, quench with dilute hydrochloric acid and extract with dichloromethane, then dry with anhydrous sodium sulfate, and finally distill off the organic solvent under reduced pressure, and the crude product is purified by silica gel column chromatography to obtain the dicarbonyl intermediate 2.

4. The method for synthesizing glabridin according to claim 2, characterized in that, In the step S2, the specific process is as follows: First, dissolve intermediate 2 in a tetrahydrofuran solvent, and then add methylmagnesium bromide or methyllithium to it, and the molar ratio of intermediate 2 and methylmagnesium bromide or methyllithium is 1:1-1.2; stir and react at 0°C for 0.5-2 hours, dropwise add sulfuric acid or trifluoroacetic acid and continue to stir for 1-2 hours, quench with sodium bicarbonate solution, extract the organic phase with DCM and dry, distill off the organic solvent under reduced pressure, and purify with silica gel column chromatography to obtain intermediate 3.

5. The method for synthesizing glabridin according to claim 2, characterized in that, In the step S3, dissolve intermediate 3 in a dichloromethane solvent, add aluminum chloride, and react at room temperature for 4-8 hours. After the raw materials react completely, add sodium acetate solution and continue to stir for 2-4 hours. Extract the reaction mixture with dichloromethane, wash the combined organic layers with brine, dry with anhydrous sodium sulfate, filter, distill off the organic solvent under reduced pressure, and purify the crude product by silica gel column chromatography to obtain intermediate 4.

6. The method for synthesizing glabridin according to claim 2, characterized in that, In the step S4, dissolve intermediate 4 in N,N-dimethylformamide, and then add sodium ethanethiolate to it. Stir and heat to react at 60°C to 100°C. After the raw materials have reacted completely, cool to room temperature, add ammonium chloride solvent to quench, extract with dichloromethane, wash the organic phase with saturated sodium chloride aqueous solution, collect the organic phase, dry with anhydrous sodium sulfate, filter, and distill off the organic solvent under reduced pressure. Purify by silica gel column chromatography to obtain intermediate 5.

7. The method for synthesizing glabridin according to claim 2, characterized in that, In the step S5, the intermediate 5 is dissolved in acetic acid / toluene solvent. Stir at room temperature and successively add phenylboronic acid and 3-methyl-2-butenal. React the mixture under reflux for 8 to 12 hours. After the raw materials have reacted completely, extract with dichloromethane. Wash the extract successively with aqueous sodium bicarbonate solution and brine, dry with anhydrous sodium sulfate, distill off the organic solvent under reduced pressure. Purify the crude product by silica gel column chromatography to obtain intermediate 6.

8. The method for synthesizing glabridin according to claim 2, characterized in that, In the step S6, the intermediate 6 is dissolved in tetrahydrofuran solvent, and then lithium aluminum hydride is added as a reducing agent and stirred under reflux for 6 hours. The molar ratio of the intermediate 6 to lithium aluminum hydride is 1:10 to 20; after the raw materials have reacted completely, quench with water, extract with ethyl acetate, dry with anhydrous sodium sulfate, distill off the organic solvent under reduced pressure. Then dissolve the remaining organic matter in acetic acid, add an excess of concentrated hydrochloric acid, hydrobromic acid or hydroiodic acid and reflux for 12 - 24 hours, concentrate to remove the excess acid, extract with dichloromethane, collect the organic phase, dry with anhydrous sodium sulfate, filter, distill off the organic solvent under reduced pressure. Purify by silica gel column chromatography to obtain glabridin.

9. Glabridin prepared by the synthesis method according to any one of claims 1 to 8.

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