A method for preparing glabridin

Abstract

The application provides a preparation method of glabriden. The method uses cheap and easily obtained 1,3-dimethoxybenzene as a starting material, and obtains a 3-aryl coumarin analogue intermediate through Friedel-Crafts reaction, Willgerodt reaction and Perkin reaction, and then obtains glabriden through reduction, ring formation and deprotection. Compared with the existing synthesis method, the method has the advantages of cheap and easily obtained raw material, high reaction yield of each step, simple post-treatment and safe and low-toxicity reaction reagent, and is suitable for industrialized preparation of the racemate of glabriden.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing glycyrrhizin. Background Technology

[0002] Glabridin is one of the main flavonoid components in licorice root. It possesses strong antioxidant and anti-atherosclerotic effects, as well as certain lipid-regulating and blood pressure-lowering effects, showing promising research prospects in cardiovascular disease prevention and treatment drugs. Simultaneously, glabridin can inhibit melanin production, thus exhibiting whitening and antioxidant effects, making it one of the most effective and comprehensive cosmetic raw materials currently available.

[0003] Currently, there are three main methods for synthesizing glycyrrhizin. The first route is the synthetic route reported in Japanese Patent JP2006008604A, which uses 2,4-dimethylsulfonyloxyphenylacetic acid as the starting material. The main steps include Friedel-Crafts acylation, pyran ring cyclization, isoflavone ring formation, reduction and decarbonylation, and finally, glycyrrhizin is obtained under alkaline conditions. The synthetic route is as follows:

[0004]

[0005] The method involves 6 steps with an overall yield of 25.8%, but each step involves column chromatography separation, which is costly. Furthermore, the use of highly toxic solvents such as dichloroethane causes significant environmental pollution, making it difficult to scale up for industrial production.

[0006] The second route, reported by Keepyung Nahm et al. (Bull. Korean Chem. Soc., 2007, 28, 481), uses 2,4-dihydroxyacetophenone and 2,4-dihydroxybenzaldehyde as starting materials to synthesize two fragments, respectively. These fragments are then subjected to the Perkin reaction, reduction reaction, and Mitsunobu reaction at -78°C. Finally, the protecting group is removed under acidic conditions to obtain glycyrrhizin. The synthetic route is as follows:

[0007]

[0008] The route is cumbersome and involves many steps, with a yield of only 6.2%. The key step, the condensation reaction of compounds 1 and 2, needs to be carried out at low temperatures, making it unsuitable for large-scale production.

[0009] The third route is the synthetic route reported in patent CN109232603A by Chai Yonghai et al., which uses 7-hydroxycoumarin as a starting material and obtains glycyrrhizin through cyclization, bromination, Suzuki coupling, reduction, Mitsunobu reaction and deprotection. The synthetic route is as follows:

[0010]

[0011] The raw material used in this method, phenylboronic acid derivatives, is expensive, resulting in high production costs when scaled up. Summary of the Invention

[0012] The technical problem to be solved by the present invention is to provide a method for preparing glycyrrhizin with mild reaction conditions, environmental friendliness and low cost, which is in view of the current situation of the prior art, and provides the possibility for large-scale preparation of glycyrrhizin.

[0013] The present invention solves the above-mentioned technical problems by at least one of the following technical solutions.

[0014] This invention provides a method for preparing the above-mentioned glycyrrhizin, and the synthetic route is as follows:

[0015]

[0016] The specific preparation steps of the glycyrrhizin are as follows:

[0017] (1) Under ice bath and argon protection conditions, 1,3-dimethoxybenzene and anhydrous AlCl3 were added to DCM and reacted with acetyl chloride in a Friedel-Crafts reaction. After the reaction, the mixture was quenched, extracted, rotary evaporated and pulped to obtain compound II.

[0018] (2) 2,4-Dimethoxyacetophenone reacts with sulfur powder and morpholine under reflux conditions to undergo the Willgerodt-Kindler reaction. After the reaction, the product is subjected to alkaline hydrolysis with sodium hydroxide, pH adjustment, and filtration to obtain compound III.

[0019] (3) 2,4-Dimethoxyphenylacetic acid, 2,4-dihydroxybenzaldehyde, acetic anhydride, and triethylamine undergo a Perkin reaction under reflux. After the reaction, the mixture is deacetylated with sodium hydroxide, the pH is adjusted, filtered, and pulped to obtain compound IV.

[0020] (4) In a hydrogen atmosphere, 3-arylcoumarin analog intermediate IV, catalyst, and ethanol undergo a hydrogenation reaction to reduce the double bond under pressure and heating. After the reaction, the mixture is filtered, evaporated, and pulped to obtain compound V.

[0021] (5) Under an argon atmosphere, 3-aryldihydrocoumarin analog intermediate V, Lewis acid, aminoborane complex and solvent were reacted at room temperature. After the reaction, the mixture was quenched, extracted and rotary evaporated to obtain compound VI.

[0022] (6) Compound VI reacts with triphenylphosphine and diisopropyl azodicarbonate in THF solvent under an argon atmosphere to generate an ether, thus preparing compound VII.

[0023] (7) Compound VII, anhydrous potassium carbonate, potassium iodide, and 3-chloro-3-methylbutyne were added to dry DMF solvent and reacted under heating conditions. After the reaction was completed, the mixture was filtered, and the filtrate was heated and refluxed for cyclization. After the reaction was completed, the mixture was washed with dilute HCl and water, extracted, dried, evaporated to dryness, and subjected to column chromatography to obtain compound VIII.

[0024] (8) Compound VIII was deprotected with boron tribromide in DCM solvent at -78℃ and under an argon atmosphere to prepare glycyrrhizin IX.

[0025] Further, in step (1), the molar ratio of 1,3-dimethoxybenzene, anhydrous AlCl3, and acetyl chloride is in the range of 1:0.7 to 1:0.7 to 1. Acetyl chloride is added dropwise under ice bath conditions. The quenching is performed by pouring the reaction solution into a large amount of ice water after the reaction is completed.

[0026] In step (2), the molar ratio of 2,4-dimethoxyacetophenone to sulfur powder, morpholine, and sodium hydroxide is 1:2–2.5:2–2.5:0.8–1.2. The Willgerodt-Kindler reaction is carried out at 120°C–140°C for 7–9 hours. The alkaline hydrolysis is performed by adding 10–20 wt% sodium hydroxide solution to the solution and refluxing for 7–9 hours at room temperature. Preferably, the pH is adjusted to 2 using 1.5 mol / L HCl.

[0027] In step (3), the molar ratio of 2,4-dimethoxyphenylacetic acid, 2,4-dihydroxybenzaldehyde, acetic anhydride, triethylamine, and sodium hydroxide ranges from 1:1:3 to 6:1 to 3:1.1 to 1.5. The Perkin reaction temperature is 100℃ to 130℃, and the reaction time is 12h to 24h. The deacetylation is performed by adding 10-20wt% sodium hydroxide solution and refluxing for 7h-9h at room temperature. Preferably, the pH is adjusted to 2 using 1.5mol / L HCl.

[0028] In step (4), the catalyst is any one of Pd / C, Pd(OH)2 / C, Ru / C, and Rh / C. The molar ratio of the catalyst to compound IV is in the range of 0.05 to 0.1:1. The pressure is 0.5 MPa to 1.5 MPa. The temperature is 50℃ to 100℃.

[0029] In step (5), the Lewis acid is any one of anhydrous AlCl3, TiCl4, and BF3·Et2O, and the borane-amine reducing agent is any one of borane-amine complex, borane-dimethylamine complex, and borane-triethylamine complex. The molar ratio of compound V, Lewis acid, and borane-amine complex is in the range of 1:2 to 5:2 to 5. The quenching step involves pouring the reaction solution into a large amount of ice water after the reaction is complete.

[0030] In step (6), the molar ratio of compound VI, triphenylphosphine, and diisopropyl azodicarbonate is in the range of 1:1.1 to 2:1.1 to 2.

[0031] In step (7), the molar ratio of compound VII, anhydrous potassium carbonate, potassium iodide, and 3-chloro-3-methylbutyne is in the range of 1:1.5–3:0.7–1:1.5–3. The temperature for heating to form the alkyne ether is 70°C–90°C. The temperature for heating to cyclize is 140°C–170°C. The column chromatography developing solvent is PE:EA = 25:1.

[0032] In step (8), the molar ratio of compound VIII to boron tribromide is in the range of 1:4 to 6.

[0033] Compared with existing technologies, this invention has the following advantages and technical effects: This invention uses inexpensive and readily available 1,3-dimethoxybenzene as a starting material, and obtains a 3-arylcoumarin analog intermediate through Friedel-Crafts, Willgerodt, and Perkin reactions. Then, it undergoes multiple steps including hydrogenation reduction, borane-amine complex reduction, Mitsunobu reaction, cyclization, and deprotection to obtain the racemic form of glycyrrhizin. Compared with existing synthetic methods, this invention has the advantages of inexpensive starting materials, high yields in each reaction step, simple post-processing, and safe and low-toxicity reaction reagents, making it suitable for industrial-scale production. Attached Figure Description

[0034] Figure 1 The 1H NMR spectrum of intermediate II obtained in step (1) of Example 1;

[0035] Figure 2 The 1H NMR spectrum of intermediate III obtained in step (2) of Example 1;

[0036] Figure 3 The 1H NMR spectrum of intermediate IV obtained in step (3) of Example 1;

[0037] Figure 4 The 1H NMR spectrum of intermediate V obtained in step (4) of Example 1;

[0038] Figure 5 The above is the 1H NMR spectrum of intermediate VI obtained in step (5) of Example 1.

[0039] Figure 6 The 1H NMR spectrum of intermediate VII obtained in step (6) of Example 1;

[0040] Figure 7 The 1H NMR spectrum of intermediate VIII obtained in step (7) of Example 1;

[0041] Figure 8 The 1H NMR spectrum of glycyrrhizin obtained in step (8) of Example 1;

[0042] Figure 9 This is a synthetic route diagram of the preparation method of the present invention.

[0043] Specific implementation methods

[0044] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. It should be noted that any processes not specifically described in detail below are those that can be implemented or understood by those skilled in the art by referring to existing technology. Reagents or instruments whose manufacturers are not specified are considered to be conventional products that can be purchased commercially.

[0045] Example 1

[0046] The preparation method of glycyrrhizin in this embodiment includes the following steps:

[0047] Step (1): Synthesis of 2,4-dimethoxyacetophenone (compound II)

[0048] Under an argon atmosphere, 1,3-dimethoxybenzene (20 mmol, 2.76 g) was dissolved in DCM (40 mL), and anhydrous AlCl3 (20 mmol, 2.67 g) was added. Acetyl chloride (20 mmol, 1.42 mL) was slowly added dropwise using a constant pressure dropping funnel under ice bath conditions. After all the acetyl chloride had been added, the mixture was moved to room temperature and stirred for 3 h. After the reaction was complete, the reaction system was poured into ice water to quench the acetyl chloride. The mixture was extracted three times with DCM, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was slurryed with DCM and PE to give a white solid compound II in 75% yield.

[0049] Step (2): Synthesis of 2,4-dimethoxyphenylacetic acid (compound III)

[0050] Accurately weigh 2,4-dimethoxyacetophenone (15 mmol, 2.70 g) and sulfur powder (30 mmol, 0.96 g) into a 50 mL round-bottom flask. Add morpholine (30 mmol, 2.62 mL) into the flask using a syringe, stir, heat to 130 °C, and react for 7 h. After the reaction is complete, cool to room temperature, add 50 mL of dichloromethane to dissolve, wash with dilute hydrochloric acid, collect the organic phase, and remove the solvent by vacuum distillation to obtain a brown oily substance.

[0051] The oily substance obtained above was dissolved in ethanol, and 20 wt% sodium hydroxide solution was added and stirred under reflux for 7 h. After cooling to room temperature, it was extracted with DCM to remove water-insoluble organic impurities. The aqueous phase was collected, placed in an ice bath, and acidified with 1.5 mol / L HCl to adjust the pH to 2. The solid obtained was collected by filtration to give a light yellow solid compound III, with an overall yield of 67%.

[0052] Step (3): Synthesis of 3-arylcoumarin analog intermediate compound IV

[0053] Accurately weigh 2,4-dihydroxybenzaldehyde (10.0 mmol, 1.38 g) and 2,4-dimethoxyphenylacetic acid (10.0 mmol, 1.96 g) into a 50 mL round-bottom flask. Add 5 mL of acetic anhydride, and under argon atmosphere, add triethylamine (2 mL) through a dropping funnel. Heat under reflux for 24 h, and remove excess solvent by vacuum distillation. Cool the residue to room temperature and dilute with water (100 mL) and tetrahydrofuran (50 mL). After aging for 16 h, collect the precipitate by filtration, wash with THF, and dry to obtain a white solid. Then, suspend the white solid in 2 mol / L NaOH and stir at 50 °C for 7 h. After the reaction is complete, cool the reaction mixture to room temperature and adjust the pH to 2 by adding 1.5 mol / L HCl. Filter the crude product. Recrystallize from ethanol and water to give a pale yellow solid, compound IV, in 76% yield.

[0054] Step (4): Synthesize compound IV to prepare compound V

[0055] Compound IV (2 g) was accurately weighed into a polytetrafluoroethylene liner, dissolved in 30 mL of anhydrous ethanol, and Pd(OH)₂ / C catalyst (10 mmol%) was added. The mixture was placed in a high-pressure reactor, and H₂ was introduced at 1 MPa. The temperature was raised to 80 °C, and the reaction was carried out for 12 h. After the reaction was completed, the filtrate was collected by filtration, and the solid catalyst was collected for recycling. The filtrate was evaporated to dryness, extracted three times with 30 mL of NaHCO₃ aqueous solution and 30 mL of EA, and the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain compound V, with a yield of 80%.

[0056] Step (5): Synthesis of compound V to prepare compound VI

[0057] Compound VI (5 mmol, 1.50 g) was accurately weighed into a 50 mL round-bottom flask, dissolved in THF, and reacted in an ice bath under an argon atmosphere. Anhydrous AlCl3 (10 mmol, 1.33 g) was added, and the mixture was stirred for 10 min. BH3NH3 (10 mmol, 0.31 g) was then added to the reaction system, and the reaction was continued in an ice bath for half an hour, then cooled to room temperature for 6 h. After the reaction was complete, the reaction system was poured into ice water and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a white solid, compound VI, in 95% yield.

[0058] Step (6): Synthesis of compound VI to prepare compound VII

[0059] Compound VI (4 mmol, 1.22 g) and triphenylphosphine (8 mmol, 2.10 g) were accurately weighed into a 25 mL round-bottom flask, dissolved in THF, and placed in an ice-water bath. Then, DIAD (8 mmol, 1.58 mL) was slowly added, and the reaction was allowed to proceed for 10 min, then brought to room temperature and allowed to proceed for 12 h. After the reaction was complete, the mixture was concentrated, diluted with EA, and extracted three times with water. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The residual solid was diluted with 3 mol / L NaOH, extracted three times with EA, and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 6 with dilute HCl, and extracted three times with EA. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness, yielding a pale yellow solid, compound VII, in 85% yield.

[0060] Step (7): Synthesis of compound VII to prepare compound VIII

[0061] Compound VII (3 mmol, 0.86 g), potassium carbonate (6.6 mmol, 0.91 g), potassium iodide (3 mmol, 0.5 g), and 3-chloro-3-methylbutyne (7.5 mmol, 0.84 mL) were accurately weighed and added to dry DMF. The mixture was heated to 80 °C with stirring and reacted for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was directly refluxed for 5 h. After cooling to room temperature, the mixture was diluted with EA, washed with 1.5 mol / L HCl, water, and saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound VIII in 75% yield.

[0062] Step (8): Synthesis of compound VIII to prepare glycyrrhizin

[0063] Compound VIII (2 mmol, 0.7 g) was accurately weighed into a 100 mL round-bottom flask at -78 °C and dissolved in dichloromethane. Under an argon atmosphere, a dichloromethane solution containing BBr3 (20 mmol) was added dropwise, and the mixture was stirred in an ice-water bath for 2 h. After the reaction was complete, the reaction solution was poured into ice water and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was recrystallized from toluene / cyclohexane to give glycyrrhizin, a pale yellow solid, in 87% yield.

[0064] Figure 1 The 1H NMR spectrum of compound II from step (1) of this embodiment is shown below: 1H NMR (400MHz, Chloroform-d) δ 7.79 (d, J = 8.7Hz, 1H), 6.48 (dd, J = 8.8, 2.3Hz, 1H), 6.42 (d, J = 2.3Hz, 1H), 3.83 (d, J = 16.2Hz, 6H), 2.54 (s, 3H).

[0065] Figure 2 The 1H NMR spectrum of compound III from step (2) of this embodiment is as follows: 1H NMR (400MHz, DMSO-d6) δ 12.07 (s, 1H), 7.07 (d, J = 8.2Hz, 1H), 6.54 (d, J = 2.5Hz, 1H), 6.46 (dd, J = 8.3, 2.4Hz, 1H), 3.75 (d, J = 2.4Hz, 6H), 3.41 (s, 2H).

[0066] Figure 3 The 1H NMR spectrum of compound IV from step (3) of this embodiment is shown below: 1H NMR (400MHz, DMSO-d6) δ 10.53 (s, 1H), 7.81 (s, 1H), 7.52 (d, J = 8.4Hz, 1H), 7.22 (d, J = 8.3Hz, 1H), 6.80 (dd, J = 8.4, 2.3Hz, 1H), 6.75 (d, J = 2.3Hz, 1H), 6.64 (d, J = 2.3Hz, 1H), 6.57 (dd, J = 8.4, 2.4Hz, 1H), 3.77 (d, J = 23.2Hz, 6H).

[0067] Figure 4The 1H NMR spectrum of compound V from step (4) of this embodiment is shown below: 1H NMR (400MHz, DMSO-d6) δ 9.66 (s, 1H), 7.12 (d, J = 8.4Hz, 1H), 7.04 (d, J = 8.2Hz, 1H), 6.60 (d, J = 2.4Hz, 1H), 6.55 (dd, J = 8.2, 2.4Hz, 1H), 6.52–6.48 (m, 2H), 4.13 (dd, J = 12.6, 6.4Hz, 1H), 3.76 (d, J = 2.9Hz, 6H), 3.32–3.22 (m, 1H), 2.87 (dd, J = 15.4, 6.4Hz, 1H).

[0068] Figure 5 The 1H NMR spectrum of compound VI from step (5) of this embodiment is shown below: 1H NMR (400MHz, Methanol-d4) δ 7.07 (d, J = 8.3Hz, 1H), 6.66 (d, J = 8.2Hz, 1H), 6.51–6.40 (m, 2H), 6.28 (d, J = 2.4Hz, 1H), 6.14 (dd, J = 8.2, 2.5Hz, 1H), 3.73 (s, 6H), 3.65–3.72 (m, 2H), 3.47 (p, J = 6.8Hz, 1H), 2.97 (dd, J = 13.8, 7.2Hz, 1H), 2.70 (dd, J = 13.8, 7.5Hz, 1H).

[0069] Figure 6 The 1H NMR spectrum of compound VII from step (6) of this embodiment is shown below: 1H NMR (400MHz, Chloroform-d) δ 7.05 (d, J = 8.3Hz, 1H), 6.96 (d, J = 8.1Hz, 1H), 6.52 (d, J = 2.4Hz, 1H), 6.50 (dd, J = 8.3, 2.5Hz, 1H), 6.42 (dd, J = 8.1, 2.6Hz, 1H), 6.39 (d, J = 2.5Hz, 1H), 4.33 ( ddd,J=10.3,3.5,2.0Hz,1H),4.03(t,J=10.1Hz,1H),3.84(d,J=1.6Hz,6H),3.59(tdd,J=10 .2,5.4,3.4Hz,1H),3.00(ddd,J=15.7,10.7,1.0Hz,1H),2.89(ddd,J=15.7,5.4,1.9Hz,1H).

[0070] Figure 7The 1H NMR spectrum of compound VIII from step (7) of this embodiment is shown below. 1H NMR (400MHz, Chloroform-d): δ 7.07 (d, J = 8.2Hz, 1H), 6.87 (d, J = 8.2Hz, 1H), 6.70 (d, J = 9.9Hz, 1H), 6.53 (d, J = 2.4Hz, 1H), 6.51 (dd, J = 8.3, 2.5Hz, 1H), 6.41 (d, J = 8.2Hz, 1H), 5.60 (d, J = 9.9Hz, 1H), 4 .39(ddd,J=10.3,3.4,2.1Hz,1H),4.03(t,J=10.2Hz,1H),3.85(d,J=4.1Hz,6H),3.65-3.55(m,1H ), 3.00(ddd,J=15.6,11.1,1.1Hz,1H),2.87(ddd,J=15.8,5.3,2.0Hz,1H),1.47(d,J=7.9Hz,6H).

[0071] Figure 8 The 1H NMR spectrum of glycyrrhizin obtained in step (8) of this embodiment is as follows: 1H NMR (400MHz, DMSO-d6) δ 9.40 (s, 1H), 9.13 (s, 1H), 6.86 (d, J = 8.4Hz, 1H), 6.82 (d, J = 8.3Hz, 1H), 6.55 (d, J = 9.9Hz, 1H), 6.35 (d, J = 2.4Hz, 1H), 6.29 (d, J = 8.2Hz, 1H), 6.21 (dd, J = 8.3, 2.4Hz). ,1H),4.25(dt,J=10.3,2.6Hz,1H),3.94(t,J=10.2Hz,1H),3.32(ddt,J=14.8,10.1,4.3Hz,1 H), 2.90 (dd, J=15.7, 11.2Hz, 1H), 2.70 (ddd, J=16.0, 5.1, 2.0Hz, 1H), 1.34 (d, J=2.5Hz, 6H).

[0072] Example 2

[0073] The synthesis of compounds II, III, IV, VI, VII, VIII, and glycyrrhizin was the same as in Example 1, except for the preparation of compound V.

[0074] Preparation of compound V: Compound IV (2 g) was accurately weighed into a polytetrafluoroethylene liner, dissolved in 30 mL of anhydrous ethanol, and Ru / C catalyst (10 mmol%) was added. The mixture was placed in a high-pressure reactor, and H2 was introduced at 1 MPa. The temperature was raised to 80 °C, and the reaction was carried out for 12 h. After the reaction was completed, the filtrate was collected by filtration, and the solid catalyst was collected for recycling. The filtrate was evaporated to dryness, and extracted three times with 30 mL of NaHCO3 aqueous solution and 30 mL of EA. The organic layer and the aqueous layer were collected separately. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain compound V, with a yield of 77%.

[0075] Example 3

[0076] The synthesis of compounds II, III, IV, VI, VII, VIII, and glycyrrhizin was the same as in Example 1, except for the preparation of compound V.

[0077] Preparation of compound V: Compound IV (2 g) was accurately weighed into a polytetrafluoroethylene liner, dissolved in 30 mL of anhydrous ethanol, and Rh / C catalyst (10 mmol%) was added. The mixture was placed in a high-pressure reactor, and H2 was introduced at 1 MPa. The temperature was raised to 80 °C, and the reaction was carried out for 12 h. After the reaction was completed, the filtrate was collected by filtration, and the solid catalyst was collected for recycling. The filtrate was evaporated to dryness, and extracted three times with 30 mL of NaHCO3 aqueous solution and 30 mL of EA. The organic layer and the aqueous layer were collected separately. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain compound V, with a yield of 85%.

[0078] Example 4

[0079] The synthesis of compounds II, III, IV, VI, VII, VIII, and glycyrrhizin was the same as in Example 1, except for the preparation of compound V.

[0080] Preparation of compound V: Compound IV (2 g) was accurately weighed into a polytetrafluoroethylene liner, dissolved in 30 mL of anhydrous ethanol, and Pd(OH)₂ / C catalyst (10 mmol%) was added. The mixture was placed in a high-pressure reactor, and H₂ was introduced at 0.5 MPa. The temperature was raised to 80 °C, and the reaction was carried out for 12 h. After the reaction was completed, the filtrate was collected by filtration, and the solid catalyst was collected for recycling. The filtrate was evaporated to dryness, and extracted three times with 30 mL of NaHCO₃ aqueous solution and 30 mL of EA. The organic layer and the aqueous layer were collected separately. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain compound V, with a yield of 50%.

[0081] Example 5

[0082] The synthesis of compounds II, III, IV, VI, VII, VIII, and glycyrrhizin was the same as in Example 1, except for the preparation of compound V.

[0083] Preparation of compound V: Compound IV (2 g) was accurately weighed into a polytetrafluoroethylene liner, dissolved in 30 mL of anhydrous ethanol, and Pd(OH)₂ / C catalyst (10 mmol%) was added. The mixture was placed in a high-pressure reactor, and H₂ was introduced at 1 MPa. The temperature was raised to 50 °C, and the reaction was carried out for 12 h. After the reaction was completed, the filtrate was collected by filtration, and the solid catalyst was collected for recycling. The filtrate was evaporated to dryness, and extracted three times with 30 mL of NaHCO₃ aqueous solution and 30 mL of EA. The organic layer and the aqueous layer were collected separately. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain compound V, with a yield of 80%.

[0084] Example 6

[0085] The synthesis of compounds II, III, IV, VI, VII, VIII, and glycyrrhizin was the same as in Example 1, except for the preparation of compound V.

[0086] Preparation of compound V: Compound IV (2 g) was accurately weighed into a polytetrafluoroethylene liner, dissolved in 30 mL of anhydrous ethanol, and Pd(OH)₂ / C catalyst (10 mmol%) was added. The mixture was placed in a high-pressure reactor, H₂ was introduced at 1 MPa, and the temperature was raised to 100 °C for 12 h. After the reaction was complete, the filtrate was collected by filtration, and the solid catalyst was collected for recycling. The filtrate was evaporated to dryness, and extracted three times with 30 mL of NaHCO₃ aqueous solution and 30 mL of EA. The organic layer and aqueous layer were collected separately. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain compound V, with a yield of 80%.

[0087] Example 7

[0088] The synthesis of compounds II, III, IV, V, VII, VIII, and glycyrrhizin was the same as in Example 1, except for the preparation of compound VI.

[0089] Preparation of compound VI: Compound VI (5 mmol, 1.5 g) was accurately weighed into a 50 mL round-bottom flask, dissolved in THF, and reacted in an ice bath under an argon atmosphere. TiCl4 (10 mmol, 1.1 mL) was added, and the mixture was stirred for 10 min. BH3NH3 (10 mmol, 0.31 g) was then added to the reaction system, and the reaction was continued in an ice bath for half an hour. The mixture was then moved to room temperature and allowed to react for 6 h. After the reaction was complete, the reaction system was poured into ice water and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a white solid, compound VI, in 98% yield.

[0090] Example 8

[0091] The synthesis of compounds II, III, IV, V, VII, VIII, and glycyrrhizin was the same as in Example 1, except for the preparation of compound VI.

[0092] Preparation of compound VI: Compound VI (5 mmol, 1.5 g) was accurately weighed into a 50 mL round-bottom flask, dissolved in THF, and reacted in an ice bath under an argon atmosphere. TiCl4 (10 mmol, 1.1 mL) was added, and the mixture was stirred for 10 min. The borane dimethylamine complex (10 mmol, 0.59 g) was then added to the reaction system. The reaction was continued in an ice bath for half an hour, then cooled to room temperature and allowed to proceed for 6 h. After the reaction was complete, the reaction system was poured into ice water and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a white solid, compound VI, in 80% yield.

[0093] Example 9

[0094] The synthesis of compounds II, III, IV, V, VII, VIII, and glycyrrhizin was the same as in Example 1, except for the preparation of compound VI.

[0095] Preparation of compound VI: Compound VI (5 mmol, 1.5 g) was accurately weighed into a 50 mL round-bottom flask, dissolved in THF, and under an ice bath and argon atmosphere, TiCl4 (10 mmol, 1.1 mL) was added and stirred for 10 min. The borane triethylamine complex (10 mmol, 1.15 g) was then added to the reaction system, and the reaction was continued under ice bath for half an hour, then cooled to room temperature for 6 h. After the reaction was complete, the reaction system was poured into ice water and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a white solid, compound VI, in 53% yield.

[0096] Example 10

[0097] The synthesis of compounds II, III, IV, V, VII, VIII, and glycyrrhizin was the same as in Example 1, except for the preparation of compound VI.

[0098] Preparation of compound VI: Compound VI (5 mmol, 1.5 g) was accurately weighed into a 50 mL round-bottom flask, dissolved in THF, and reacted in an ice bath under an argon atmosphere. BF3·Et2O (10 mmol, 1.23 mL) was added, and the mixture was stirred for 10 min. BH3NH3 (10 mmol, 0.31 g) was then added to the reaction system, and the reaction was continued in an ice bath for half an hour, then cooled to room temperature for 6 h. After the reaction was complete, the reaction system was poured into ice water and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a white solid, compound VI, in 92% yield.

Claims

1. A method for preparing glycyrrhizin, characterized in that: The reaction formula is as follows: (1) Under ice bath and argon protection conditions, 1,3-dimethoxybenzene and anhydrous AlCl3 were added to DCM and reacted with acetyl chloride in a Friedel-Crafts reaction. After the reaction, the mixture was quenched, extracted, rotary evaporated and pulped to obtain compound II. (2) 2,4-Dimethoxyacetophenone reacts with sulfur powder and morpholine under reflux conditions to undergo the Willgerodt-Kindler reaction. After the reaction, the product is subjected to alkaline hydrolysis with sodium hydroxide, pH adjustment, and filtration to obtain compound III. (3) 2,4-Dimethoxyphenylacetic acid, 2,4-dihydroxybenzaldehyde, acetic anhydride, and triethylamine undergo a Perkin reaction under reflux. After the reaction, the mixture is deacetylated with sodium hydroxide, the pH is adjusted, filtered, and pulped to obtain compound IV. (4) In a hydrogen atmosphere, 3-arylcoumarin analog intermediate IV, catalyst, and ethanol undergo hydrogenation under pressure and heating to reduce the double bond. After the reaction, the mixture is filtered, evaporated, and pulped to obtain compound V. (5) Under an argon atmosphere, 3-aryldihydrocoumarin analog intermediate V, Lewis acid, borane-amine reducing agent and solvent react at room temperature. After the reaction, the mixture is quenched, extracted and rotary evaporated to obtain compound VI. (6) In an argon atmosphere, compound VI reacts with triphenylphosphine and diisopropyl azodicarbonate in a THF solvent via the Mitsunobu reaction to generate an ether, thus preparing compound VII; (7) Compound VII, anhydrous potassium carbonate, potassium iodide, and 3-chloro-3-methylbutyne were added to dry DMF solvent and reacted under heating conditions. After the reaction was completed, the mixture was filtered, and the filtrate was heated and refluxed for cyclization. After the reaction was completed, the mixture was washed with dilute HCl and water, extracted, dried, evaporated to dryness, and subjected to column chromatography to obtain compound VIII. (8) Compound VIII was deprotected with boron tribromide in DCM solvent at -78℃ and under an argon atmosphere to prepare glycyrrhizin IX.

2. The method for synthesizing glycyrrhizin according to claim 1, characterized in that: In step (1), the molar ratio of 1,3-dimethoxybenzene, anhydrous AlCl3, and acetyl chloride is in the range of 1:0.7~1:0.7~1.

3. The method for synthesizing glycyrrhizin according to claim 1, characterized in that: In step (2), the molar ratio of 2,4-dimethoxyacetophenone, sulfur powder, morpholine, and sodium hydroxide is 1:2~2.5:2~2.5:0.8~1.

2.

4. The method for synthesizing glycyrrhizin according to claim 1, characterized in that: In step (3), the molar ratio of 2,4-dimethoxyphenylacetic acid, 2,4-dihydroxybenzaldehyde, acetic anhydride, triethylamine, and sodium hydroxide is in the range of 1:1:3~6:1~3:1.1~1.

5.

5. The method for synthesizing glycyrrhizin according to claim 1, characterized in that: In step (4), the catalyst is any one of Pd / C, Pd(OH)2 / C, Ru / C, and Rh / C.

6. The method for synthesizing glycyrrhizin according to claim 1, characterized in that: In step (5), the Lewis acid is any one of anhydrous AlCl3, TiCl4, and BF3·Et2O, and the borane-amine reducing agent is any one of borane-amine complex, borane-dimethylamine complex, and borane-triethylamine complex. The molar ratio of compound V, Lewis acid, and borane-amine complex is in the range of 1:2~5:2~5.

7. The method for synthesizing glycyrrhizin according to claim 1, characterized in that: In step (6), the molar ratio of compound VI, triphenylphosphine, and diisopropyl azodicarbonate is in the range of 1:1.1~2:1.1~2.

8. The method for synthesizing glycyrrhizin according to claim 1, characterized in that: In step (7), the molar ratio of compound VII, anhydrous potassium carbonate, potassium iodide, and 3-chloro-3-methylbutyne is in the range of 1:1.5~3:0.7~1:1.5~3.

9. The method for synthesizing glycyrrhizin according to claim 1, characterized in that: In step (8), the molar ratio of compound VIII to boron tribromide is in the range of 1:4~6.

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