Synthetic method of glabridin

Abstract

The invention discloses a synthetic method of glabridin with optical purity, which comprises the following steps: by taking (R)-3-acetoxyl-2-(2, 4-dimethoxyphenyl) propanol and 2-isopentenyl resorcinol as raw materials, carrying out Mitsunobu reaction to obtain a key intermediate compound I, then carrying out hydrolysis and iodination to obtain an intermediate compound II, and then carrying out cyclization to obtain the glabridin with optical purity. Reducing and removing a protecting group to obtain glabridin. By introducing the isopentene side chain, the reaction activity of an olefin functional group is reserved, a key site is provided for subsequent cyclization conversion, the precise spatial configuration of the product is ensured, and finally glabridin with optical purity is prepared. The method is short in route, low in cost, mild in reaction condition and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing optically pure glabridin. Background Art

[0002] Glabridin is an isoprenylated isoflavone with a unique molecular structure and various biological activities. It has been confirmed that glabridin purified from natural sources exists only in the C3R configuration. In addition to the well-known whitening effect, glabridin has also been proven to have various effects such as antioxidant, anti-microbial, anti-inflammatory, anti-cancer, anti-osteoporosis, and neuroprotective effects.

[0003] The unique structure of glabridin limits the development of its chemical synthesis. Currently, glabridin is mainly obtained by extraction from Glycyrrhiza glabra L. The limited planting area and the low content of glabridin (about 0.1%-0.3%) limit its large-scale application. The unique three-dimensional structure of glabridin determines its biological activity. However, when chemically synthesized, it faces great challenges in precisely constructing its specific stereoconfiguration.

[0004] WO2005037815A1 discloses a method for preparing isoflavone derivatives in three steps starting from a cis-benzene-cinnamate compound. This method can only obtain racemic products, and the raw materials are difficult to obtain. Hazardous lithium reagents are also used in the reaction process, and it involves a hydrogenation reduction reaction with a high risk factor.

[0005] CN103030647A discloses a six-step synthesis method for glabridin. This method uses environmentally unfriendly reagents such as sulfur powder, morpholine, and Pd / C, and the post-treatment is cumbersome, which is not suitable for industrial production.

[0006] CN109232603A discloses a method for synthesizing glabridin in seven steps starting from 7-hydroxycoumarin. The liquid bromine used in this route has strong corrosiveness and toxicity, requires special protection, has high requirements for equipment, and limits its industrial application.

[0007] CN111362961A discloses a method for synthesizing glabridin in seven steps starting from 7-hydroxy-chromane-4-one. This method uses an R-dicyclohexylnaphthyloxyphosphine ligand, the synthesis is complex and expensive, and expensive palladium catalysts are used multiple times in the route, resulting in great cost pressure.

[0008] In summary, although there have been some studies on the total synthesis of glabridin, the racemization of the product, high cost, and harsh experimental conditions greatly limit its industrial scale-up production and application. Developing a simple, efficient, mild, and low-cost chemical synthesis method for glabridin is particularly crucial. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to provide a synthesis method which is simple and efficient in process, mild in reaction conditions, low in production cost, capable of obtaining the target stereoconfiguration in high yield, and suitable for large-scale production of high-purity glabridin in view of the deficiencies of the prior art.

[0010] To solve the above technical problems, the technical solutions adopted by the present invention are as follows: The present invention provides a synthesis method of optically pure glabridin, comprising the following steps: (1) Using (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol and 2-isoprenylresorcinol as raw materials, adding an activation reagent to carry out the Mitsunobu reaction to obtain the following compound I ; (2) After the hydrolysis of compound I in alcohol, the hydrolysis product reacts with triphenylphosphine and an iodination reagent to carry out an iodination reaction to obtain the following iodinated compound II ; (3) Compound II undergoes two cyclizations to obtain the cyclization product compound III ; (4) Adding triphenylphosphine to the organic solution of compound III and heating to carry out an elimination reaction to obtain compound IV ; (5) Removing the protecting group from compound IV under acidic conditions to obtain optically pure glabridin .

[0011] Preferably, in step (1), the solvent used is any one or a mixed solution of more than one of tetrahydrofuran, toluene, dichloromethane, and N,N-dimethylformamide, and toluene is more preferred.

[0012] Preferably, in step (1), the activation reagent for the Mitsunobu reaction used is triphenylphosphine and diethyl azodicarboxylate or triphenylphosphine and diisopropyl azodicarboxylate, and triphenylphosphine and diisopropyl azodicarboxylate are more preferred.

[0013] Preferably, in step (1), the molar ratio of (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol to 2-isoprenylresorcinol is 1:1 to 1:1.5, and 1:1.3 is more preferred.

[0014] Preferably, in step (1), the molar ratio of (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol to the activation reagent is 1:1.1 to 1:1.5, and 1:1.3 is more preferred.

[0015] Preferably, in step (2), the alcohol is methanol or ethanol, more preferably ethanol.

[0016] Preferably, in step (2), the iodinating reagent is N-iodosuccinimide or iodine, more preferably N-iodosuccinimide.

[0017] Preferably, in step (2), the molar ratio of compound I to the iodinating reagent is 1:1 to 1:1.5, more preferably 1:1 to 1:1.1.

[0018] Preferably, in step (3), the temperature of the first ring-closing reaction is 0°C to 30°C, more preferably 15°C to 25°C, and most preferably 25°C.

[0019] Preferably, in step (3), the solvent used for the first ring-closing is any one or a mixed solution of two or more of N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, toluene, and dichloromethane, more preferably N,N-dimethylformamide.

[0020] Preferably, in step (3), the mediating reagent for the first ring-closing is sodium hydride.

[0021] Preferably, in step (3), the molar ratio of compound II to sodium hydride is 1:2 to 1:3, more preferably 1:2.5.

[0022] Preferably, in step (3), the temperature of the second ring-closing reaction is -20°C to 25°C, more preferably -10°C to 25°C, and most preferably 0°C to 25°C.

[0023] Preferably, in step (3), the solvent used for the second ring-closing is any one or a mixed solution of two or more of acetonitrile, ethanol, dichloromethane, chloroform, and hexane, more preferably acetonitrile.

[0024] Preferably, in step (3), the reagent used for the second ring-closing is any one of hydrogen peroxide, m-chloroperoxybenzoic acid, and potassium hydrogen persulfate, more preferably potassium hydrogen persulfate.

[0025] Preferably, in step (3), the molar ratio of compound II to the second ring-closing reagent is 1:1.5 to 1:3, more preferably 1:2.

[0026] Preferably, in step (4), the organic solvent is any one or a mixed solution of two or more of acetonitrile, carbon tetrachloride, toluene, tetrahydrofuran, and triethylamine, more preferably a mixed solution of acetonitrile and carbon tetrachloride or tetrahydrofuran, and most preferably a 1:1 mixed solution of acetonitrile and carbon tetrachloride.

[0027] Preferably, in step (4), the reaction temperature is 50°C to 90°C, more preferably 60°C to 80°C, and most preferably 70°C to 80°C.

[0028] Preferably, in step (4), the molar ratio of compound Ⅲ to triphenylphosphine is 1:2 to 1:6, more preferably 1:4.

[0029] Preferably, in step (5), the acid used is any one or a mixture of two of boron tribromide, hydrochloric acid, hydrobromic acid, and trifluoroacetic acid, more preferably boron tribromide.

[0030] Preferably, in step (5), the molar ratio of compound Ⅳ to the acid used is 1:2 to 1:3, more preferably 1:2.5.

[0031] The reaction process of the present invention is as follows:

[0032] The beneficial effects of the present invention are mainly reflected in: (1) Using (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol as the raw material, the raw material is cheap and easily available, with high chiral purity and stable configuration; (2) By introducing an isopentenyl side chain in the present invention, the reaction activity of the olefin functional group is retained, providing a key site for subsequent cyclization and ensuring the precise stereoconfiguration of the product; (3) The route realizes the high-purity synthesis of glabridin through 5-step reactions, with a short reaction route and high reaction yield; (4) The reaction conditions are mild, the equipment requirements in production are low, and compared with the existing synthesis routes, it is suitable for scale-up preparation and industrial production. Description of the Drawings

[0033] Figure 1 It is the liquid-phase purity spectrum of glabridin prepared in Example 1 of the present invention Figure 2 It is the liquid-phase chiral purity spectrum of glabridin prepared in Example 1 of the present invention Figure 3 It is the 1H NMR spectrum of glabridin prepared in Example 1 of the present invention Detailed Embodiments

[0034] The present invention will be further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to the following content. Example 1

[0035] (1) Synthesis of Intermediate Ⅰ Under nitrogen protection, (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol (2.4 g, 9.4 mmol), triphenylphosphine (3.22 g, 12.3 mmol), and 2-isoprenylresorcinol (2.19 g, 12.3 mmol) were taken and dissolved in 25 ml of toluene by stirring for 10 min. Then, a solution of diisopropyl azodicarboxylate (2.48 g, 12.3 mmol) diluted with 20 ml of toluene was slowly added dropwise, and the reaction was carried out at room temperature for 16 h. After the reaction was complete, 40 ml of water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 40 ml of n-heptane was added to dissolve the residue, and the mixture was stirred for crystallization for 2 h. The insoluble impurities were removed by filtration, and the filtrate was concentrated to obtain 3.37 g of a colorless oily substance with a yield of 86%. 1 H NMR (400 MHz, DMSO) δ 9.20 (s, 1H),7.18 (d, J = 8.4 Hz, 1H), 6.89 (t, J = 8.2 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H),6.49 (dd, J = 8.4, 2.4 Hz, 1H), 6.40 (t, J = 7.4 Hz, 2H), 5.06 – 4.95 (m,1H), 4.38 (dd, J = 10.8, 6.7 Hz, 1H), 4.29 (dd, J = 10.8, 6.8 Hz, 1H), 4.08(d, J = 6.2 Hz, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.73 – 3.68 (m, 1H), 3.13(d, J = 7.0 Hz, 2H), 1.95 (s, 3H), 1.64 (s, 3H), 1.56 (s, 3H). (2) Synthesis of Intermediate II Take intermediate Ⅰ (2.06 g, 5.0 mmol), add 20 ml of ethanol and 5 ml of water, stir to dissolve, then add sodium hydroxide (0.2 g, 5.0 mmol), and keep the reaction at room temperature for 3 h. After the reaction is complete, adjust the pH to 7 - 8 with 2N hydrochloric acid, distill off ethanol under reduced pressure, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent to obtain a crude product as a light brown oil. Under nitrogen protection, take the above crude product and triphenylphosphine (1.55 g, 5.5 mmol), add 33 ml of dichloromethane and stir to dissolve. After the solution is clear, cool the reaction system to 0 °C, add N-iodosuccinimide (1.33 g, 5.5 mmol) to the system in batches, continue to react at 0 °C for 2 h, and then transfer the reaction system to room temperature and react for 3 h. After the reaction is complete, quench the reaction by dropping saturated sodium sulfite solution, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent to obtain a crude product. Dissolve the crude product in 30 ml of tetrahydrofuran, add calcium bromide (2.2 g, 11 mmol), stir and crystallize for 3 h, filter to remove insoluble impurities, concentrate the filtrate to obtain 2.19 g of a brown oil, with a yield of 91%. 1 H NMR (400 MHz, DMSO) δ 9.22 (s, 1H), 7.17 (d, J = 8.5Hz, 1H), 6.90 (t, J = 8.2 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.51 (dd, J =8.4, 2.4 Hz, 1H), 6.41 (dd, J = 10.6, 8.2 Hz, 2H), 5.14 – 4.94 (m, 1H), 4.07(ddd, J = 9.9, 8.2, 4.4 Hz, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.66 (dt, J =9.3, 4.6 Hz, 1H), 3.59 (dt, J = 14.8, 6.8 Hz, 2H), 3.16 (d, J = 6.7 Hz, 2H),1.67 (s, 3H), 1.59 (s, 3H). (3)Synthesis of intermediate Ⅲ Under nitrogen protection, dissolve intermediate Ⅱ (0.46 g, 1.0 mmol) in 20 ml of N,N-dimethylformamide and stir. Slowly add sodium hydride (95 mg, 2.5 mmol) to the system in batches at room temperature, and keep the reaction at room temperature for 16 h. After the reaction is complete, add 20 ml of water to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent to obtain a crude product as a colorless oil.

[0036] The crude product was added with 29 mL of acetonitrile and 7 mL of water and stirred until dissolved. After the internal temperature was lowered to 0 °C, potassium peroxymonosulfate (1.42 g, 2.0 mmol) was added to the system in portions, and the reaction was carried out at 0 °C for 0.5 h. After the reaction was complete, the insoluble salts were removed by filtration. The filtrate was concentrated under reduced pressure to remove acetonitrile. The remaining aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and 10 mL of petroleum ether was added and stirred for crystallization. 315 mg of white solid was obtained by filtration, with a yield of 85%. 1 H NMR (400 MHz, DMSO) δ 7.08 (dd, J = 8.4, 1.9 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 8.3, 2.2 Hz, 1H), 6.26 (d, J = 8.3 Hz, 1H), 5.08 – 5.03 (m, 1H), 4.22 (d, J = 10.1 Hz, 1H), 3.95 (td, J = 10.2, 2.6 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.59 (dq, J = 8.0, 5.4 Hz, 1H), 3.42 – 3.33 (m,1H), 2.99 – 2.86 (m, 1H), 2.79 – 2.72 (m, 1H), 2.70 (d, J = 6.3 Hz, 1H), 2.35 (dd, J = 17.2, 6.0 Hz, 1H), 1.25 (s, 3H), 1.12 (s, 3H). (4)Synthesis of Intermediate Ⅳ Under nitrogen protection, Intermediate III (0.28 g, 0.8 mmol) was dissolved in a mixed solvent of 3 mL of carbon tetrachloride and 3 mL of acetonitrile, then triphenylphosphine (0.8 g, 3.2 mmol) was added, and the reaction was carried out at 80 °C for 2 h. After the reaction was complete, 5 mL of water and 5 mL of ethyl acetate were added for liquid separation. The ethyl acetate was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and 2 mL of petroleum ether and 2 mL of methyl tert-butyl ether were added and stirred for crystallization. 230 mg of white solid was obtained by filtration, with a yield of 81%. 11H NMR (400 MHz, DMSO) δ 7.08 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 9.9 Hz, 1H), 6.50 (dd, J = 8.4, 2.4 Hz, 1H), 6.29 (d, J = 8.2 Hz, 1H), 5.65 (d, J = 9.9 Hz, 1H), 4.27 – 4.17 (m, 1H), 3.98 (t, J = 10.1 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.38 (td, J = 10.7, 5.8 Hz, 1H), 2.91 (dd, J = 15.6, 11.0 Hz, 1H), 2.79 – 2.68 (m, 1H), 1.35 (s, 3H), 1.34 (s, 3H). (5) Synthesis of Glabridin Under nitrogen protection, intermediate Ⅳ (0.21 g, 0.56 mmol) was taken and added to 10 ml of dichloromethane and stirred until dissolved. The temperature was lowered to -78 °C, and boron tribromide (0.35 g, 1.4 mmol) was slowly added dropwise. The system was maintained at -78 °C for reaction for 4 h, and then transferred to room temperature for reaction for 2 h. After the reaction was complete, 5 ml of ice water was added and stirred for 0.5 h to quench the reaction. It was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, a crude white solid was obtained. The above crude product was dissolved in 5 ml of toluene. After dissolving clearly, 5 ml of methyl tert-butyl ether was added and the temperature was lowered to 0 °C for crystallization. The white solid was filtered to obtain 168 mg, with a yield of 95% and 99.9% ee. 11H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 9.10 (s, 1H), 6.84 (dd, J = 11.8, 8.4 Hz, 2H), 6.54 (d, J = 9.9 Hz, 1H), 6.30 (dd, J = 15.0, 5.3 Hz, 2H), 6.18 (dd, J = 8.3, 2.4 Hz, 1H), 5.65 (d, J = 9.9 Hz, 1H), 4.23 (d, J = 10.3 Hz, 1H), 3.93 (t, J = 10.2 Hz, 1H), 3.26 (s, 1H), 2.89 (dd, J = 15.5, 11.3 Hz, 1H), 2.69 (dd, J = 16.1, 3.5 Hz, 1H), 1.34 (s, 3H), 1.34 (s, 3H). Example 2

[0037] (1) Synthesis of Intermediate I Under nitrogen protection, (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol (50 g, 0.2 mol), triphenylphosphine (67.05 g, 0.26 mol), and 2-isoprenylresorcinol (45.55 g, 0.26 mol) were taken and dissolved in 500 ml of toluene by stirring for 5 min. Then, a solution of diisopropyl azodicarboxylate (51.69 g, 0.26 mol) diluted with 500 ml of toluene was slowly added dropwise to the system. After the addition was complete, the reaction was carried out at room temperature for 16 h. After the reaction was complete, 500 ml of water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, 500 ml of n-heptane was added to dissolve the residue, and the mixture was stirred and crystallized for 2 h. Insoluble impurities were removed by filtration, and the filtrate was concentrated to obtain 68.81 g of a colorless oily substance with a yield of 83%.

[0038] (2) Synthesis of Intermediate II Take the intermediate Ⅰ (50 g, 0.12 mol), add 400 ml of ethanol and 100 ml of water, stir to dissolve, then add sodium hydroxide (7.24 g, 0.18 mol), and keep the reaction at room temperature for 3 h. After the reaction is complete, adjust the pH to 7 - 8 with 2N hydrochloric acid, distill off ethanol under reduced pressure, extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and remove the solvent to obtain a light brown oily crude product. Under nitrogen protection, take the above crude product and triphenylphosphine (31.64 g, 0.12 mol), add 320 ml of dichloromethane and stir to dissolve. After the solution is clear, cool the reaction system to 0 °C, add N-iodosuccinimide (27.14 g, 0.12 mol) to the system in batches, continue to react at 0 °C for 2 h, and then transfer the reaction to room temperature and react for 3 h. After the reaction is complete, add saturated sodium sulfite solution dropwise to quench the reaction, extract with dichloromethane, combine the organic phases, wash the organic phase with saturated brine, dry with anhydrous magnesium sulfate, remove the solvent to obtain a crude product, add 300 ml of tetrahydrofuran to dissolve the crude product, then add calcium bromide (47.97 g, 0.24 mol), stir to crystallize for 3 h, filter to remove insoluble impurities, concentrate the filtrate to obtain 52.37 g of a brown oily substance, with a yield of 90%.

[0039] (3)Synthesis of Intermediate Ⅲ Under nitrogen protection, take the intermediate Ⅱ (50 g, 0.1 mol), add 1000 ml of N,N-dimethylformamide, stir to dissolve for 5 min, slowly add sodium hydride (10.36 g, 0.25 mol) to the system in batches, and keep the reaction at room temperature for 16 h. After the reaction is complete, add 200 ml of water to quench the reaction, extract with ethyl acetate, combine the organic phases, wash the organic phase with saturated brine, dry with anhydrous magnesium sulfate, and remove the solvent to obtain a colorless oily crude product.

[0040] Take the above crude product, add 300 ml of acetonitrile and 50 ml of water, stir to dissolve, cool to an internal temperature of 0 °C, add potassium peroxymonosulfate (122.94 g, 0.2 mol) to the system in batches, keep the reaction at 0 °C for 0.5 h, and then transfer the system to room temperature and react for 6 h. After the reaction is complete, filter to remove insoluble salts, distill off acetonitrile from the filtrate under reduced pressure, extract the obtained aqueous phase with ethyl acetate, combine the organic phases, wash the organic phase with saturated brine, dry with anhydrous magnesium sulfate, evaporate the solvent, add 200 ml of petroleum ether, stir to crystallize, and filter to obtain 32.23 g of a white solid, with a yield of 87%.

[0041] (4)Synthesis of Intermediate IV Under nitrogen protection, take intermediate III (30 g, 0.08 mol), add it to 300 ml of tetrahydrofuran and stir to dissolve. Then add triphenylphosphine (83.93 g, 0.32 mol) to the reaction solution, heat to 70 °C and reflux for 2 h. After the reaction is complete, add 200 ml of water and 200 ml of ethyl acetate for liquid separation. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent is evaporated, and then 100 ml of petroleum ether and 100 ml of methyl tert-butyl ether are added and stirred at room temperature for crystallization. Filter to obtain 23.4 g of white solid, with a yield of 83%.

[0042] (5)Synthesis of Glabridin Under nitrogen protection, take intermediate IV (20 g, 0.06 mol), add it to 200 ml of dichloromethane and stir to dissolve. Then cool the system to -78 °C, slowly add boron tribromide (37.57 g, 0.15 mol) dropwise to the system, and keep the system reacting at -78 °C for 4 h. Transfer the system to room temperature and react for 2 h until the reaction is complete. Add 200 ml of ice water and stir vigorously for 1 h to quench the reaction. Extract with dichloromethane, combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous magnesium sulfate, and then remove the solvent to obtain the crude white solid. Dissolve the above crude product in 100 ml of toluene, then add 100 ml of methyl tert-butyl ether and cool to 0 °C for crystallization. Filter to obtain 17.49 g of white solid, with a yield of 95% and 99.9% ee.

Claims

1. A method for synthesizing glabridin, characterized in that, It includes the following steps: (1) Using (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol and 2-isopentenylresorcinol as raw materials, adding an activation reagent to carry out the Mitsunobu reaction to obtain the following compound I ； (2) After the compound I is hydrolyzed in alcohol, the hydrolysis product undergoes an iodination reaction with triphenylphosphine and an iodinating reagent to obtain the following iodinated compound II ； (3) The compound II undergoes two cyclization reactions to obtain the cyclization product compound III ； (4) Adding triphenylphosphine to the organic solution of compound III and heating to carry out an elimination reaction to obtain compound IV ； (5) Removing the protecting group from compound IV under acidic conditions to obtain optically pure glabridin 。 2. The synthesis method of glabridin according to claim 1, characterized in that, In step (1), the solvent used is any one or a mixture of more than one of tetrahydrofuran, toluene, dichloromethane, and N,N-dimethylformamide.

3. The synthesis method of glabridin according to claim 1, wherein, In step (1), the activation reagent is triphenylphosphine and diethyl azodicarboxylate or triphenylphosphine and diisopropyl azodicarboxylate.

4. The synthetic method of glabridin according to claim 1, characterized in that, In step (1), the molar ratio of (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol to 2-isopentenylresorcinol is 1:1 to 1:1.5; the molar ratio of (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol to the activation reagent is 1:1.1 to 1:1.

5.

5. The synthesis method of glabridin according to claim 1, wherein, In step (2), the alcohol is methanol or ethanol; the iodinating reagent is N-iodosuccinimide or iodine; the molar ratio of compound I to the iodinating reagent is 1:1.1 to 1:1.

5.

6. The synthetic method of glabridin according to claim 1, wherein In step (3), the reaction temperature of the first cyclization reaction is 0°C to 30°C; the reaction temperature of the second cyclization reaction is -20°C to 25°C.

7. The synthesis method of glabridin according to claim 1, characterized in that, In step (3), the solvent used for the first cyclization is any one or a mixture of more than one of N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, toluene, and dichloromethane.

8. The synthetic method of glabridin according to claim 1, characterized in that, In step (3), the mediating reagent for the first cyclization is sodium hydride; the molar ratio of compound II to the mediating reagent is 1:2 to 1:

3.

9. The synthetic method of glabridin according to claim 1, characterized in that, In step (3), the solvent used for the second cyclization is any one or a mixture of more than one of acetonitrile, ethanol, dichloromethane, chloroform, and hexane.

10. The synthetic method of glabridin according to claim 1, characterized in that, In step (3), the reagent used for the second cyclization is any one of hydrogen peroxide, m-chloroperbenzoic acid, and potassium peroxymonosulfate; the molar ratio of compound II to the reagent used is 1:1.5 to 1:

3.

11. The synthesis method of glabridin according to claim 1, wherein, In step (4), the organic solvent used is any one or a mixture of more than one of acetonitrile, carbon tetrachloride, toluene, tetrahydrofuran, and triethylamine.

12. The synthesis method of glabridin according to claim 1, wherein, In step (4), the reaction temperature is 50 to 90°C.

13. The synthesis method of glabridin according to claim 1, characterized in that, In step (4), the molar ratio of compound III to triphenylphosphine is 1:2 to 1:

6.

14. The synthetic method of glabridin according to claim 1, wherein In step (5), the acid used is any one or a mixture of two of boron tribromide, hydrochloric acid, hydrobromic acid, and trifluoroacetic acid.

15. The synthesis method of glabridin according to claim 1, characterized in that, In step (5), the molar ratio of compound IV to the acid used is 1:2 to 1:3.

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