A synthetic method of glabridin

Abstract

The present invention discloses a method for synthesizing optically pure glabridin. The method uses (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol and 2-isopentenylresorcinol as raw materials to obtain a key intermediate compound I through a Mitsunobu reaction, and then obtains an intermediate compound II through hydrolysis and iodination. The intermediate compound II is then cyclized, reduced, and protected by removal to obtain glabridin. The present invention retains the reactivity of the olefin functional group by introducing an isopentyl side chain, provides a key site for subsequent cyclization, ensures the precise stereoconfiguration of the product, and ultimately obtains optically pure glabridin. The present invention has a short route, low cost, mild reaction conditions, and is suitable for industrial production.

Description

Technical Field

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

[0002] Glabridin is a prenylated isoflavone with a unique molecular structure and diverse biological activities. Glabridin purified from natural sources has been shown to exist only in the C3R configuration. In addition to its well-known whitening properties, glabridin has also been shown to possess antioxidant, antimicrobial, anti-inflammatory, anti-cancer, anti-osteoporosis, and neuroprotective properties.

[0003] The unique structure of glabridin has limited the development of its chemical synthesis. Currently, glabridin is primarily extracted from Glycyrrhiza glabra. Limited planting area and the low glabridin content (approximately 0.1%-0.3%) restrict its large-scale application. Glabridin's unique three-dimensional structure determines its biological activity, but precisely constructing its specific three-dimensional configuration during chemical synthesis presents significant challenges.

[0004] WO2005037815A1 discloses a method for preparing isoflavone derivatives using a cis-phenyl-cinnamate compound as a starting material through three steps. This method can only produce racemic products, and the raw materials are difficult to obtain. The reaction also uses dangerous lithium reagents and involves a hydrogenation reduction reaction, which is highly risky.

[0005] CN103030647A discloses a six-step synthesis method for preparing glabridin. This method uses environmentally unfriendly reagents such as sulfur powder, morpholine, and Pd / C, and the post-processing is cumbersome, making it unsuitable for industrial production.

[0006] CN109232603A discloses a method for synthesizing glabridin in seven steps using 7-hydroxycoumarin as a raw material. The liquid bromine used in this route is highly corrosive and toxic, requiring special protection and high requirements for equipment, which limits its industrial application.

[0007] CN111362961A discloses a method for synthesizing glabridin using 7-hydroxychroman-4-one as a raw material through a seven-step reaction. This method uses R-dicyclohexylnaphthyloxyphosphine ligand, and the synthesis is complex and expensive. In addition, expensive palladium catalysts are used multiple times in the route, which puts great cost pressure.

[0008] In summary, although some research has been conducted on the total synthesis of glabridin, the racemization of the product, high costs, and stringent experimental conditions have greatly limited its industrial production and application. Developing a simple, efficient, mild, and low-cost chemical synthesis method for glabridin is crucial. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to address the deficiencies of the existing technology and provide a synthesis method for glabridin with simple and efficient process, mild reaction conditions, low production cost, high yield and suitable for large-scale production of high-purity glabridin.

[0010] In order to solve the above technical problems, the technical solutions adopted by the present invention are as follows:

[0011] The present invention provides a method for synthesizing optically pure glycyrrhizin, comprising the following steps:

[0012] (1) Using (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol and 2-isoprenylated resorcinol as raw materials, an activating agent was added to carry out a Mitsunobu reaction to obtain the following compound I

[0013] ;

[0014] (2) After compound I is hydrolyzed in alcohol, the hydrolysis product reacts with triphenylphosphine and an iodine reagent to produce the iodinated compound II of the following formula:

[0015] ;

[0016] (3) Compound II undergoes two cyclizations to obtain the cyclization product Compound III

[0017] ;

[0018] (4) Add triphenylphosphine to the organic solution of compound III and heat to eliminate the reaction to obtain compound IV

[0019] ;

[0020] (5) Compound IV was deprotected under acidic conditions to obtain optically pure glycyrrhizin

[0021] .

[0022] Preferably, in step (1), the solvent used is a mixed solution of any one or more of tetrahydrofuran, toluene, dichloromethane, and N,N-dimethylformamide, more preferably toluene.

[0023] Preferably, in step (1), the Mitsunobu reaction activation reagent used is triphenylphosphine and diethyl azodicarboxylate or triphenylphosphine and diisopropyl azodicarboxylate, more preferably triphenylphosphine and diisopropyl azodicarboxylate.

[0024] 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, more preferably 1:1.3.

[0025] Preferably, in step (1), the molar ratio of the (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol to the activation reagent is 1:1.1 to 1:1.5, more preferably 1:1.3.

[0026] Preferably, in step (2), the alcohol is methanol or ethanol, more preferably ethanol.

[0027] Preferably, in step (2), the iodine reagent is N-iodosuccinimide or elemental iodine, more preferably N-iodosuccinimide.

[0028] Preferably, in step (2), the molar ratio of compound I to the iodine reagent is 1:1 to 1:1.5, more preferably 1:1 to 1:1.1.

[0029] 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.

[0030] Preferably, in step (3), the solvent used for the first ring-closure is a mixed solution of any one or more of N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, toluene, and dichloromethane, more preferably N,N-dimethylformamide.

[0031] Preferably, in step (3), the mediating reagent for the first ring closure is sodium hydride.

[0032] Preferably, in step (3), the molar ratio of compound II to sodium hydride is 1:2 to 1:3, more preferably 1:2.5.

[0033] 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.

[0034] Preferably, in step (3), the solvent used for the second ring closure is a mixed solution of any one or more of acetonitrile, ethanol, dichloromethane, chloroform, and hexane, more preferably acetonitrile.

[0035] Preferably, in step (3), the reagent used for the second ring closure is any one of hydrogen peroxide, m-chloroperbenzoic acid, and potassium persulfate, more preferably potassium persulfate.

[0036] Preferably, in step (3), the molar ratio of compound II to the second cyclization reagent is 1:1.5 to 1:3, more preferably 1:2.

[0037] Preferably, in step (4), the organic solvent is a mixed solution of any one 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.

[0038] 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.

[0039] Preferably, in step (4), the molar ratio of compound III to triphenylphosphine is 1:2 to 1:6, more preferably 1:4.

[0040] Preferably, in step (5), the acid used is any one of boron tribromide, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, or a mixture of two thereof, more preferably boron tribromide.

[0041] 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.

[0042] The reaction process of the present invention is as follows:

[0043]

[0044] The beneficial effects of the present invention are mainly reflected in the following aspects: (1) (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol is used as the raw material, which is cheap and easy to obtain, has high chiral purity and stable configuration; (2) the present invention retains the reactivity of the olefin functional group by introducing the isopentene side chain, provides a key site for subsequent cyclization, and ensures the precise stereoconfiguration of the product; (3) the route realizes the high-purity synthesis of glycyrrhizin through 5 steps of reaction, the reaction route is short, and the reaction yield is high; (4) the reaction conditions are mild, and the equipment requirements in production are low. Compared with the synthetic route in the prior art, the present invention is suitable for scale-up preparation and industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 Liquid phase purity spectrum of glabridin prepared in Example 1 of the present invention

[0046] Figure 2 This is the liquid phase chiral purity spectrum of glabridin prepared in Example 1 of the present invention

[0047] Figure 3 This is the H NMR spectrum of glabridin prepared in Example 1 of the present invention DETAILED DESCRIPTION

[0048] The present invention will be further described below with reference to the embodiments, but the protection scope of the present invention is not limited to the following contents. Example 1

[0049] (1) Synthesis of intermediate I

[0050] Under nitrogen, (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 added to 25 ml of toluene and stirred for 10 minutes. A solution of diisopropyl azodicarboxylate (2.48 g, 12.3 mmol) diluted with 20 ml of toluene was then slowly added dropwise and allowed to react at room temperature for 16 hours. After completion, 40 ml of water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Dissolved in 40 ml of n-heptane, the mixture was stirred for 2 hours, and insoluble impurities were removed by filtration. The filtrate was then desolvated to obtain 3.37 g of a colorless oil in an 86% yield. 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).

[0051] (2) Synthesis of intermediate II

[0052] Intermediate I (2.06 g, 5.0 mmol) was dissolved in 20 ml of ethanol and 5 ml of water, and stirred. Sodium hydroxide (0.2 g, 5.0 mmol) was then added and the reaction was maintained at room temperature for 3 hours. After the reaction was complete, 2N hydrochloric acid was added to adjust the pH to 7-8. The ethanol was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and desolvated to obtain a crude light-brown oil. Under nitrogen, the crude product and triphenylphosphine (1.55 g, 5.5 mmol) were added to 33 ml of dichloromethane and stirred to dissolve. After the solution cleared, the reaction system was cooled to 0°C, and N-iodosuccinimide (1.33 g, 5.5 mmol) was added portionwise. The reaction was maintained at 0°C for 2 hours, and then the reaction system was transferred to room temperature for 3 hours. After the reaction was complete, a saturated sodium sulfite solution was added dropwise to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then desolvated to obtain a crude product. The crude product was dissolved in 30 ml of tetrahydrofuran, and calcium bromide (2.2 g, 11 mmol) was added and stirred for crystallization for 3 h. The insoluble impurities were removed by filtration, and the filtrate was concentrated 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).

[0053] (3) Synthesis of intermediate III

[0054] Under nitrogen, Intermediate II (0.46 g, 1.0 mmol) was dissolved in 20 mL of N,N-dimethylformamide with stirring. Sodium hydride (95 mg, 2.5 mmol) was slowly added portionwise at room temperature and allowed to react for 16 h. Upon completion, 20 mL of water was added to quench the reaction. The organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and desolvated to yield a crude colorless oil.

[0055] The crude product was dissolved in 29 ml of acetonitrile and 7 ml of water by stirring. After the internal temperature dropped to 0°C, potassium persulfate (1.42 g, 2.0 mmol) was added portionwise to the system and the reaction was maintained at 0°C for 0.5 h. After the reaction was complete, insoluble salts were removed by filtration. The filtrate was concentrated under reduced pressure to remove the acetonitrile. The remaining aqueous phase was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and 10 ml of petroleum ether was added with stirring to induce crystallization. Filtration afforded 315 mg of a white solid, yielding 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 = 2.4Hz, 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).

[0056] (4) Synthesis of intermediate IV

[0057] Under nitrogen, intermediate III (0.28 g, 0.8 mmol) was dissolved in a mixture of 3 mL of carbon tetrachloride and 3 mL of acetonitrile. Triphenylphosphine (0.8 g, 3.2 mmol) was then added and heated to 80°C for 2 h. After the reaction was complete, 5 mL of water and 5 mL of ethyl acetate were added for separation. The organic phase was extracted with ethyl acetate, washed with saturated brine, and 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, stirred, and crystallized. Filtering afforded 230 mg of a white solid in an 81% yield. 1H 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).

[0058] (5) Synthesis of glabridin

[0059] Under nitrogen, Intermediate IV (0.21 g, 0.56 mmol) was added to 10 ml of dichloromethane with stirring to dissolve. The mixture was cooled to -78°C and slowly added dropwise with boron tribromide (0.35 g, 1.4 mmol). The reaction was maintained at -78°C for 4 hours, then transferred to room temperature for 2 hours. After completion, 5 ml of ice water was added and stirred for 0.5 hours to quench the reaction. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and desolventized to obtain a crude white solid. The crude product was dissolved in 5 ml of toluene. After the solution became clear, 5 ml of methyl tert-butyl ether was added, the temperature was lowered to 0°C for crystallization, and filtration afforded 168 mg of a white solid in a 95% yield and 99.9% ee. 1H 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 = 10.2Hz, 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

[0060] (1) Synthesis of intermediate I

[0061] Under nitrogen, (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol (50g, 0.2mol), triphenylphosphine (67.05g, 0.26mol), and 2-isoprenylresorcinol (45.55g, 0.26mol) were added to 500ml of toluene and stirred for 5 minutes. A solution of diisopropyl azodicarboxylate (51.69g, 0.26mol) diluted with 500ml of toluene was then slowly added dropwise to the system. After addition, the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, 500ml of water was added to quench the reaction, followed by extraction with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The mixture was dissolved in 500ml of n-heptane and stirred for 2 hours to allow crystallization. Insoluble impurities were removed by filtration, and the filtrate was desolvated to obtain 68.81g of a colorless oil in an 83% yield.

[0062] (2) Synthesis of intermediate II

[0063] Intermediate I (50g, 0.12mol) was dissolved in 400ml of ethanol and 100ml of water, and stirred. Sodium hydroxide (7.24g, 0.18mol) was then added and the reaction was maintained at room temperature for 3 hours. After the reaction was complete, 2N hydrochloric acid was added to adjust the pH to 7-8. The ethanol was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and desolvated to obtain a crude light-brown oil. Under nitrogen, the crude product and triphenylphosphine (31.64g, 0.12mol) were added to 320ml of dichloromethane and stirred to dissolve. After the solution cleared, the reaction system was cooled to 0°C, and N-iodosuccinimide (27.14g, 0.12mol) was added portionwise. The reaction was maintained at 0°C for 2 hours, and then the reaction was transferred to room temperature for 3 hours. After the reaction was complete, a saturated sodium sulfite solution was added dropwise to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then desolvated to obtain a crude product. 300 ml of tetrahydrofuran was added to dissolve the crude product, and calcium bromide (47.97 g, 0.24 mol) was added and stirred for crystallization for 3 h. The insoluble impurities were removed by filtration, and the filtrate was concentrated to obtain 52.37 g of a brown oil with a yield of 90%.

[0064] (3) Synthesis of intermediate III

[0065] Under nitrogen, Intermediate II (50 g, 0.1 mol) was added to 1000 ml of N,N-dimethylformamide and stirred for 5 minutes. Sodium hydride (10.36 g, 0.25 mol) was then slowly added portionwise to the system. The reaction was maintained at room temperature for 16 hours. After the reaction was complete, 200 ml of water was added to quench the reaction. The product was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and desolvated to obtain a crude colorless oil.

[0066] The crude product was added to 300ml of acetonitrile and 50ml of water, stirred and dissolved. The internal temperature was lowered to 0°C, and potassium persulfate (122.94g, 0.2mol) was added portionwise. The reaction was maintained at 0°C for 0.5h, and then the system was transferred to room temperature for 6h. After the reaction was complete, insoluble salts were removed by filtration. The acetonitrile was evaporated under reduced pressure from the filtrate. The resulting aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. After addition of 200ml of petroleum ether, the mixture was stirred and crystallized. Filtration afforded 32.23g of a white solid, yielding 87%.

[0067] (4) Synthesis of Intermediate IV

[0068] Under nitrogen, Intermediate III (30 g, 0.08 mol) was added to 300 ml of tetrahydrofuran and stirred to dissolve. Triphenylphosphine (83.93 g, 0.32 mol) was then added to the reaction mixture, and the mixture was heated to 70°C and refluxed for 2 h. After the reaction was complete, 200 ml of water and 200 ml of ethyl acetate were added for separation. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, 100 ml of petroleum ether and 100 ml of methyl tert-butyl ether were added, stirred at room temperature, and crystallized. Filtering afforded 23.4 g of a white solid in an 83% yield.

[0069] (5) Synthesis of glabridin

[0070] Under nitrogen, intermediate IV (20 g, 0.06 mol) was added to 200 ml of dichloromethane and stirred to dissolve. The system was then cooled to -78°C and slowly added dropwise with boron tribromide (37.57 g, 0.15 mol). The reaction was maintained at -78°C for 4 hours, and the system was transferred to room temperature for 2 hours to complete. The reaction was quenched by adding 200 ml of ice water and stirring vigorously for 1 hour. The reaction was then extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and desolventized to obtain a crude white solid. This crude product was dissolved in 100 ml of toluene, then added with 100 ml of methyl tert-butyl ether, cooled to 0°C for crystallization, and filtered to obtain 17.49 g of a white solid with a yield of 95% and 99.9% ee.

Claims

1. A method for synthesizing glabridin, characterized in that: The following steps are involved: (1) Using (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol and 2-isopentenylresorcinol as raw materials, an activating agent was added to carry out Mitsunobu reaction to obtain the following compound I ； (2) After compound I is hydrolyzed in alcohol, the hydrolysis product reacts with triphenylphosphine and an iodine reagent to produce the iodinated compound II of the following formula: ； (3) Compound II undergoes two cyclizations to obtain the cyclization product Compound III ； (4) Add triphenylphosphine to the organic solution of compound III and heat to eliminate the reaction to obtain compound IV ； (5) Compound IV was deprotected under acidic conditions to obtain optically pure glycyrrhizin 。 2. The method for synthesizing glabridin according to claim 1, wherein In step (1), the solvent used is a mixed solution of any one or more of tetrahydrofuran, toluene, dichloromethane, and N,N-dimethylformamide.

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

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

5.

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

5.

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

7. The method for synthesizing glabridin according to claim 1, wherein: In step (3), the solvent used for the first ring-closure is a mixed solution of any one or more of N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, toluene, and dichloromethane.

8. The method for synthesizing glabridin according to claim 1, wherein: In step (3), the mediating reagent for the first ring closure is sodium hydride; the molar ratio of compound II to the mediating reagent is 1:2 to 1:

3.

9. The method for synthesizing glabridin according to claim 1, wherein In step (3), the solvent used for the second ring closure is a mixed solution of any one or more of acetonitrile, ethanol, dichloromethane, chloroform, and hexane.

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

3.

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

12. The method for synthesizing glabridin according to claim 1, characterized in that: In step (4), the reaction temperature is 50-90°C.

13. The method for synthesizing glabridin according to claim 1, wherein: In step (4), the molar ratio of compound III to triphenylphosphine is 1:2 to 1:

6.

14. The method for synthesizing glabridin according to claim 1, characterized in that: In step (5), the acid used is any one of boron tribromide, hydrochloric acid, hydrobromic acid, and trifluoroacetic acid, or a mixture of two thereof.

15. The method for synthesizing 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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