Preparation method of glabridin

Abstract

The invention provides a preparation method of glabridin. According to the method, 1, 3-dimethoxybenzene which is low in price and easy to obtain is used as a starting raw material, a 3-aryl coumarin analogue intermediate is obtained through a Friedel-Crafts reaction, a Willgerodt reaction and a Perkin reaction, and then glabridin is obtained through the steps of reduction, ring formation, deprotection and the like. Compared with an existing synthesis mode, the method has the advantages that the raw materials are cheap and easy to obtain, the reaction yield in each step is high, aftertreatment is simple, and the reaction reagent is safe and low in toxicity, and is suitable for industrial preparation of the glabridin raceme.

Description

Technical Field

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

[0002] Glabridin is one of the main flavonoid components in Glycyrrhiza glabra. Glabridin has strong antioxidant, anti-atherosclerotic and certain lipid-regulating and blood pressure-lowering effects, and shows good research prospects in the research of cardiovascular disease prevention and treatment drugs. At the same time, glabridin can inhibit melanin and thus has whitening and antioxidant effects. It is one of the cosmetic raw materials with good efficacy and comprehensive functions.

[0003] There are three main methods for synthesizing glabridin. The first route is the synthesis route reported in Japanese patent JP2006008604A, which uses 2,4-dimethylsulfonyloxyphenylacetic acid as the starting material, and mainly includes Friedel-Crafts acylation reaction, pyran ring annulation reaction, isoflavone ring formation, reduction and removal of carbonyl, and finally obtains glabridin under alkaline conditions. The synthesis route is as follows:

[0004]

[0005] The method has 6 steps and a total yield of 25.8%, but each step of the reaction involves column chromatography separation, which is costly, and the use of highly toxic solvents such as dichloroethane causes great pollution to the environment, making it difficult to carry out industrial production.

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

[0007]

[0008] This route is cumbersome, has many steps, and has 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, which is not suitable for large-scale production.

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

[0010]

[0011] The raw material phenylboronic acid derivative used in this method is expensive, and the production cost is high when it is scaled up for production. Summary of the invention

[0012] The technical problem to be solved by the present invention is to provide a preparation method of glabridin with mild reaction conditions, environmental protection and low cost in view of the current status of the prior art, so as to provide the possibility for large-scale preparation of glabridin.

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

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

[0015]

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

[0017] (1) Under ice bath and argon protection, 1,3-dimethoxybenzene and anhydrous AlCl 3 Add it into DCM and react with acetyl chloride to produce Friedel-Crafts reaction. After the reaction, it is quenched, extracted, rotary evaporated and beaten to obtain compound II.

[0018] (2) 2,4-dimethoxyacetophenone reacts with sulfur powder and morpholine under heating and reflux to produce a Willgerodt-Kindler reaction, followed by alkaline hydrolysis with sodium hydroxide, pH adjustment, and filtration to obtain compound III;

[0019] (3) 2,4-dimethoxyphenylacetic acid and 2,4-dihydroxybenzaldehyde, acetic anhydride and triethylamine undergo Perkin reaction under heating and reflux conditions, followed by deacetylation with sodium hydroxide, pH adjustment, filtration and pulping to obtain compound IV;

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

[0021] (5) Under an argon atmosphere, 3-aryldihydrocoumarin analog intermediate V, Lewis acid, ammonia borane complex and solvent are reacted at room temperature, and after the reaction, the reaction is quenched, extracted and rotary evaporated to obtain compound VI;

[0022] (6) Compound VI reacts with triphenylphosphine and diisopropyl azodicarboxylate in THF solvent to generate an ether by Mitsunobu reaction in an argon atmosphere to obtain compound VII;

[0023] (7) Compound VII, anhydrous potassium carbonate, potassium iodide, and 3-chloro-3-methylbutyne are added to a dry DMF solvent and reacted under heating conditions. After the reaction is completed, the mixture is filtered and the filtrate is heated under reflux for cyclization. After the reaction is completed, the mixture is washed with dilute HCl, extracted, dried, spin-dried, and subjected to column chromatography to obtain Compound VIII;

[0024] (8) Compound VIII was subjected to a deprotection reaction with boron tribromide in DCM solvent at -78°C in an argon atmosphere to obtain glabridin IX.

[0025] Furthermore, in step (1), 1,3-dimethoxybenzene, anhydrous AlCl 3 The molar ratio of acetyl chloride is in the range of 1:0.7 to 1:0.7 to 1. Acetyl chloride is added dropwise in an ice bath. The quenching is to pour 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 in the range of 1:2-2.5:2-2.5:0.8-1.2. The temperature of the Willgerodt-Kindler reaction is 120°C-140°C, and the reaction time is 7-9h. The alkaline hydrolysis is performed by adding 10-20wt% sodium hydroxide solution at room temperature and refluxing for 7h-9h. Preferably, the pH value is adjusted to pH=2 using 1.5mol / L HCl.

[0027] 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. The temperature of the Perkin reaction is 100°C-130°C, and the reaction time is 12h-24h. The deacetylation is performed by adding 10-20wt% sodium hydroxide solution at room temperature and refluxing for 7h-9h. Preferably, the pH value is adjusted to pH=2 using 1.5mol / L HCl.

[0028] In step (4), the catalyst is Pd / C, Pd(OH) 2 / C, Ru / C, Rh / C. The molar ratio of the catalyst to the 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°C to 100°C.

[0029] In step (5), the Lewis acid is anhydrous AlCl 3 、TiCl 4 , BF 3 ·Et 2O, the borane-amine reducing agent is any one of borane ammonia complex, borane dimethylamine complex, borane triethylamine complex, and the molar ratio of the compound V, Lewis acid, and borane-amine complex is 1:2 to 5:2 to 5. The quenching is to pour the reaction solution into a large amount of ice water after the reaction is completed.

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

[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 acetylene ether is 70°C-90°C. The temperature for heating cyclization 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 1:4-6.

[0033] Compared with the prior art, the present invention has the following advantages and technical effects: the present invention uses cheap and readily available 1,3-dimethoxybenzene as a starting material, obtains a 3-aryl coumarin analog intermediate through Friedel-Crafts reaction, Willgerodt reaction, and Perkin reaction, and then obtains a glabridin racemate through hydrogenation reduction, borane-amine complex reduction, Mitsunobu reaction, cyclization, and deprotection. Compared with the existing synthesis method, the present invention has the advantages of cheap raw materials, high yield per step, simple post-treatment, and safe and low-toxic reaction reagents, and is suitable for industrialized scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the intermediate II obtained in step (1) of Example 1;

[0035] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the intermediate III obtained in step (2) of Example 1;

[0036] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the intermediate IV obtained in step (3) of Example 1;

[0037] Figure 4 is the hydrogen nuclear magnetic resonance spectrum of the intermediate V obtained in step (4) of Example 1;

[0038] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of the intermediate VI obtained in step (5) of Example 1.

[0039] Figure 6 This is the hydrogen nuclear magnetic resonance spectrum of the intermediate VII obtained in step (6) of Example 1;

[0040] Figure 7 is the hydrogen nuclear magnetic resonance spectrum of the intermediate VIII obtained in step (7) of Example 1;

[0041] Figure 8 is the hydrogen nuclear magnetic resonance spectrum of glabridin obtained in step (8) of Example 1;

[0042] Fig. 9 The figure is a synthetic route diagram of the preparation method of the present invention.

[0043] Specific embodiment

[0044] The present invention is further described in detail below in conjunction with the examples, but the embodiments of the present invention are not limited thereto. It should be noted that if there are processes that are not particularly described in detail below, they can be implemented or understood by those skilled in the art with reference to the prior art. If the manufacturer of the reagents or instruments used is not indicated, they are deemed to be conventional products that can be purchased commercially.

[0045] Example 1

[0046] The preparation method of glabridin in this embodiment comprises the following steps:

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

[0048] Under argon atmosphere, 1,3-dimethoxybenzene (20 mmol, 2.76 g) was dissolved in DCM (40 mL) and anhydrous AlCl 3 (20mmol, 2.67g), acetyl chloride (20mmol, 1.42mL) was slowly added with a constant pressure dropping funnel under ice bath conditions, and after all the acetyl chloride was added, it was moved to room temperature and stirred for 3h. After the reaction was completed, the reaction system was poured into ice water to quench the acetyl chloride. It was extracted with DCM 3 times, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, the solvent was spin-dried, and the residue was slurried with DCM and PE to obtain a white solid compound II with a yield of 75%.

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

[0050] Accurately weigh 2,4-dimethoxyacetophenone (15mmol, 2.70g) and sulfur powder (30mmol, 0.96g) in a 50mL round-bottom flask, add morpholine (30mmol, 2.62mL) into the flask with a syringe, stir, heat to 130°C, react for 7h, cool to room temperature after the reaction is completed, add 50mL of dichloromethane to dissolve, wash with dilute hydrochloric acid, collect the organic phase, and distill under reduced pressure to remove the solvent to obtain a brown oil.

[0051] The oily substance obtained above was dissolved in ethanol, and a 20 wt % sodium hydroxide solution was added, stirred and refluxed for 7 h, cooled to room temperature, extracted with DCM to remove water-insoluble organic impurities, and the aqueous phase was collected, ice-bathed, and 1.5 mol / L HCl was added to acidify, and the pH was adjusted to 2. The obtained solid was collected by filtration to obtain a light yellow solid compound III with a total yield of 67%.

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

[0053] Accurately weigh 2,4-dihydroxybenzaldehyde (10.0mmol, 1.38g) and 2,4-dimethoxyphenylacetic acid (10.0mmol, 1.96g) in a 50mL round-bottom flask, add 5mL of acetic anhydride, add triethylamine (2mL) through a dropping funnel under an argon atmosphere, heat to reflux for 24h, and remove excess solvent by reduced pressure distillation. The residue was cooled to room temperature and then diluted with water (100mL) and tetrahydrofuran (50mL). After aging for 16h, the precipitate was collected by filtration, washed with THF, and dried to obtain a white solid. The white solid was then suspended in 2mol / LNaOH and stirred at 50°C for 7h. After the reaction was completed, the reaction mixture was cooled to room temperature and 1.5mol / L HCl was added to adjust the pH to 2. The crude product was obtained by filtration. Recrystallization from ethanol water gave a pale yellow solid compound IV with a yield of 76%.

[0054] Step (4): Synthesis of Compound IV to Prepare Compound V

[0055] Accurately weigh compound IV (2 g) into a polytetrafluoroethylene liner, dissolve it in 30 mL of anhydrous ethanol, and add Pd(OH) 2 / C catalyst (10 mmol%) was placed in a high pressure reactor and 1 MPa H 2 , heat to 80°C and react for 12 hours. After the reaction is completed, filter and collect the filtrate, and collect the solid catalyst for recycling. The filtrate is dried and washed with 30 mL of NaHCO 3 The aqueous solution was extracted with 30 mL EA for three times, and the organic layer was collected and dried over anhydrous sodium sulfate. The solvent was spin-dried to obtain compound V with a yield of 80%.

[0056] Step (5): Synthesis of Compound V to Prepare Compound VI

[0057] Accurately weigh compound VI (5 mmol, 1.50 g) in a 50 mL round-bottom flask, dissolve it in THF, place it in an ice bath, and under the protection of an argon atmosphere, add anhydrous AlCl 3 (10 mmol, 1.33 g), stirred for 10 min, and BH 3 NH 3 (10mmol, 0.31g) was added to the reaction system, reacted in an ice bath for half an hour and then moved to room temperature for 6 hours. After the reaction was completed, the reaction system was poured into ice water and extracted with EA three times. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was dried to obtain a white solid compound VI with a yield of 95%.

[0058] Step (6): Synthesis of Compound VI to Prepare Compound VII

[0059] Accurately weigh compound VI (4mmol, 1.22g) and triphenylphosphine (8mmol, 2.10g) in a 25mL round-bottom flask, dissolve with THF, place in an ice-water bath, then slowly add DIAD (8mmol, 1.58mL), react for 10min, move to room temperature, and react for 12h. After the reaction is completed, concentrate, dilute with EA, extract with water 3 times, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, spin dry the solvent, dilute the residual solid with 3mol / LNaOH, extract with EA 3 times, collect the aqueous phase, adjust the pH of the aqueous phase to 6 with dilute HCl, extract with EA 3 times, collect the organic phase, dry the organic phase with anhydrous sodium sulfate, spin dry the solvent, and obtain a light yellow solid compound VII with a yield of 85%.

[0060] Step (7): Synthesis of Compound VII to Prepare Compound VIII

[0061] Accurately weigh compound VII (3mmol, 0.86g), potassium carbonate (6.6mmol, 0.91g), potassium iodide (3mmol, 0.5g) and 3-chloro-3-methylbutyne (7.5mmol, 0.84mL) and add them to dry DMF, heat to 80°C with stirring, react for 16h, cool to room temperature, filter, and directly heat the filtrate to reflux for 5h. Cool to room temperature, add EA to dilute, wash with 1.5mol / L HCl, wash with water and wash with saturated salt water. Collect the organic phase, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the residue by column chromatography to obtain compound VIII with a yield of 75%.

[0062] Step (8): Synthesis of Compound VIII to Prepare Glabridin

[0063] At -78 °C, accurately weigh compound VIII (2 mmol, 0.7 g) in a 100 mL round-bottom flask, dissolve it in dichloromethane, and dropwise add BBr under argon atmosphere. 3 After the reaction was completed, the reaction solution was poured into ice water, extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was spin-dried, and the crude product was recrystallized from toluene / cyclohexane to obtain light yellow solid glabridin, with a yield of 87%.

[0064] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of compound II in step (1) of this example, 1H NMR (400 MHz, Chloroform-d) δ7.79 (d, J = 8.7 Hz, 1H), 6.48 (dd, J = 8.8, 2.3 Hz, 1H), 6.42 (d, J = 2.3 Hz, 1H), 3.83 (d, J = 16.2 Hz, 6H), 2.54 (s, 3H).

[0065] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of compound III in step (2) of this example, 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 6.46 (dd, J = 8.3, 2.4 Hz, 1H), 3.75 (d, J = 2.4 Hz, 6H), 3.41 (s, 2H).

[0066] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of compound IV in step (3) of this example, 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.81 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.80 (dd, J = 8.4, 2.3 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), 6.57 (dd, J = 8.4, 2.4 Hz, 1H), 3.77 (d, J = 23.2 Hz, 6H).

[0067] Figure 4This is the hydrogen nuclear magnetic resonance spectrum of compound V in step (4) of this example, 1H NMR (400 MHz, DMSO-d6) δ9.66 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 8.2, 2.4 Hz, 1H), 6.52-6.48 (m, 2H), 4.13 (dd, J = 12.6, 6.4 Hz, 1H), 3.76 (d, J = 2.9 Hz, 6H), 3.32-3.22 (m, 1H), 2.87 (dd, J = 15.4, 6.4 Hz, 1H).

[0068] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of compound VI in step (5) of this example, 1H NMR (400 MHz, Methanol-d4) δ7.07 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.51-6.40 (m, 2H), 6.28 (d, J = 2.4 Hz, 1H), 6.14 (dd, J = 8.2, 2.5 Hz, 1H), 3.73 (s, 6H), 3.65-3.72 (m, 2H), 3.47 (p, J = 6.8 Hz, 1H), 2.97 (dd, J = 13.8, 7.2 Hz, 1H), 2.70 (dd, J = 13.8, 7.5 Hz, 1H).

[0069] Figure 6 The hydrogen nuclear magnetic resonance spectrum of compound VII in step (6) of this embodiment is as follows: 1H NMR (400 MHz, Chloroform-d) δ7.05 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 8.3, 2.5 Hz, 1H), 6.42 (dd, J = 8.1, 2.6 Hz, 1H), 6.39 (d, J = 2.5 Hz, 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 hydrogen nuclear magnetic resonance spectrum of compound VIII in step (7) of this embodiment is as follows: 1H NMR (400 MHz, Chloroform-d) δ7.07 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 9.9 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.3, 2.5 Hz, 1H), 6.41 (d, J = 8.2 Hz, 1H), 5.60 (d, J = 9.9 Hz, 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 This is the hydrogen nuclear magnetic resonance spectrum of glabridin in step (8) of this embodiment, 1H NMR (400 MHz, DMSO-d6) δ9.40 (s, 1H), 9.13 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 9.9 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.29 (d, J = 8.2 Hz, 1H), 6.21 (dd, J = 8.3, 2.4 Hz ,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 syntheses of compounds II, III, IV, VI, VII, VIII and glabridin were the same as those in Example 1, except for the preparation of compound V.

[0074] Preparation of compound V: accurately weigh compound IV (2 g) in a polytetrafluoroethylene liner, dissolve it in 30 mL of anhydrous ethanol, add Ru / C catalyst (10 mmol%), put it into a high-pressure reactor, and pass 1 MPa H 2, heat to 80°C and react for 12 hours. After the reaction is completed, filter and collect the filtrate, and collect the solid catalyst for recycling. The filtrate is dried and washed with 30 mL of NaHCO 3 The solution was extracted with 30 mL of EA for three times, and the organic layer and the aqueous layer were collected respectively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain compound V with a yield of 77%.

[0075] Example 3

[0076] The syntheses of compounds II, III, IV, VI, VII, VIII and glabridin were the same as those in Example 1, except for the preparation of compound V.

[0077] Preparation of compound V: accurately weigh compound IV (2 g) in a polytetrafluoroethylene liner, dissolve it in 30 mL of anhydrous ethanol, add Rh / C catalyst (10 mmol%), put it in a high-pressure reactor, and pass 1 MPa H 2 , heat to 80°C and react for 12 hours. After the reaction is completed, filter and collect the filtrate, and collect the solid catalyst for recycling. The filtrate is dried and washed with 30 mL of NaHCO 3 The solution was extracted with 30 mL of EA for three times, and the organic layer and the aqueous layer were collected respectively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain compound V with a yield of 85%.

[0078] Example 4

[0079] The syntheses of compounds II, III, IV, VI, VII, VIII and glabridin were the same as those in Example 1, except for the preparation of compound V.

[0080] Preparation of compound V: accurately weigh compound IV (2 g) in a polytetrafluoroethylene liner, dissolve it in 30 mL of anhydrous ethanol, add Pd(OH) 2 / C catalyst (10 mmol%) was placed in a high pressure reactor and passed through 0.5 MPa H 2 , heat to 80°C and react for 12 hours. After the reaction is completed, filter and collect the filtrate, and collect the solid catalyst for recycling. The filtrate is dried and washed with 30 mL of NaHCO 3 The solution was extracted with 30 mL of EA for three times, and the organic layer and the aqueous layer were collected respectively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain compound V with a yield of 50%.

[0081] Example 5

[0082] The syntheses of compounds II, III, IV, VI, VII, VIII and glabridin were the same as those in Example 1, except for the preparation of compound V.

[0083] Preparation of compound V: accurately weigh compound IV (2 g) in a polytetrafluoroethylene liner, dissolve it in 30 mL of anhydrous ethanol, add Pd(OH)2 / C catalyst (10 mmol%) was placed in a high pressure reactor and 1 MPa H 2 , heat to 50°C and react for 12 hours. After the reaction is completed, filter and collect the filtrate, and collect the solid catalyst for recycling. The filtrate is spin-dried and washed with 30 mL of NaHCO 3 The solution was extracted with 30 mL of EA for three times, and the organic layer and the aqueous layer were collected respectively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain compound V with a yield of 80%.

[0084] Example 6

[0085] The syntheses of compounds II, III, IV, VI, VII, VIII and glabridin were the same as those in Example 1, except for the preparation of compound V.

[0086] Preparation of compound V: accurately weigh compound IV (2 g) in a polytetrafluoroethylene liner, dissolve it in 30 mL of anhydrous ethanol, add Pd(OH) 2 / C catalyst (10 mmol%) was placed in a high pressure reactor and 1 MPa H 2 , heat to 100°C and react for 12 hours. After the reaction is completed, filter and collect the filtrate, and collect the solid catalyst for recycling. The filtrate is dried and washed with 30 mL of NaHCO 3 The solution was extracted with 30 mL of EA for three times, and the organic layer and the aqueous layer were collected respectively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain compound V with a yield of 80%.

[0087] Example 7

[0088] The syntheses of compounds II, III, IV, V, VII, VIII and glabridin were the same as those in Example 1, except for the preparation of compound VI.

[0089] Preparation of compound VI: Accurately weigh compound VI (5 mmol, 1.5 g) in a 50 mL round-bottom flask, dissolve it in THF, place it in an ice bath, and add TiCl 4 (10 mmol, 1.1 mL), stirred for 10 min, and BH 3 NH 3 (10mmol, 0.31g) was added to the reaction system, reacted in an ice bath for half an hour, then moved to room temperature and reacted for 6 hours. After the reaction was completed, the reaction system was poured into ice water, extracted with EA three times, the organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was dried to obtain a white solid compound VI with a yield of 98%.

[0090] Example 8

[0091] The syntheses of compounds II, III, IV, V, VII, VIII and glabridin were the same as those in Example 1, except for the preparation of compound VI.

[0092] Preparation of compound VI: Accurately weigh compound VI (5 mmol, 1.5 g) in a 50 mL round-bottom flask, dissolve it in THF, place it in an ice bath, and add TiCl 4 (10mmol, 1.1mL), stirred for 10min, added borane dimethylamine complex (10mmol, 0.59g) to the reaction system, reacted under ice bath for half an hour and then moved to room temperature for 6h. After the reaction was completed, the reaction system was poured into ice water, extracted with EA 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was spin-dried to obtain white solid compound VI with a yield of 80%.

[0093] Example 9

[0094] The syntheses of compounds II, III, IV, V, VII, VIII and glabridin were the same as those in Example 1, except for the preparation of compound VI.

[0095] Preparation of compound VI: Accurately weigh compound VI (5 mmol, 1.5 g) in a 50 mL round-bottom flask, dissolve it in THF, place it in an ice bath, and add TiCl 4 (10mmol, 1.1mL), stirred for 10min, added borane triethylamine complex (10mmol, 1.15g) to the reaction system, reacted under ice bath for half an hour and then moved to room temperature for 6h. After the reaction was completed, the reaction system was poured into ice water, extracted with EA 3 times, the organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was spin-dried to obtain white solid compound VI with a yield of 53%.

[0096] Example 10

[0097] The syntheses of compounds II, III, IV, V, VII, VIII and glabridin were the same as those in Example 1, except for the preparation of compound VI.

[0098] Preparation of compound VI: accurately weigh compound VI (5 mmol, 1.5 g) in a 50 mL round-bottom flask, dissolve it in THF, place it in an ice bath, and add BF 3 ·Et 2 O (10 mmol, 1.23 mL), stirred for 10 min, and BH 3 NH 3 (10mmol, 0.31g) was added to the reaction system, reacted in an ice bath for half an hour, then moved to room temperature and reacted for 6 hours. After the reaction was completed, the reaction system was poured into ice water, extracted with EA three times, the organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was dried to obtain a white solid compound VI with a yield of 92%.

Claims

1. A method for preparing glabridin, characterized in that: The raw material 1,3-dimethoxybenzene undergoes Friedel-Crafts reaction, Willgerodt reaction, and Perkin reaction to obtain a 3-arylcoumarin analog intermediate, and then the double bond of the intermediate is hydrogenated and reduced, and the lactone is reduced using a borane-amine reducing agent, and then undergoes a Mitsunobu reaction to form an ether ring closure, and then cyclization and deprotection are performed after the reaction to obtain glycyrrhizin.

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

3. The method for synthesizing glabridin according to claim 2, 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 to 1:0.7 to 1.

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

2.

5. The method for synthesizing glabridin according to claim 2, 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 to 6:1 to 3:1.1 to 1.

5.

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

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

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

9. The method for synthesizing glabridin according to claim 2, 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.

10. The method for synthesizing glabridin according to claim 2, 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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