Synthetic method of glabridin

Abstract

The invention provides a method for synthesizing glabridin, which comprises the following steps: by taking 2, 6-dihydroxyacetophenone as a raw material, carrying out condensation reaction, formylation reaction, selective reduction reaction, nucleophilic substitution reaction, Wittig reaction, catalytic hydrogenation reaction, carbonyl reduction reaction, dehydration under an acidic condition and deprotection to obtain the glabridin. The synthetic route is novel and efficient, the total yield is 34%, and the purity is up to 99% or above. According to the synthesis route provided by the invention, starting raw materials are cheap and easy to obtain, reaction reagents are common commercial reagents, the route conditions are mild, and technical support is provided for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the fields of organic synthesis and fine chemical technology, and specifically relates to a method for synthesizing glycyrrhizin. Background Technology

[0002] Glabridin is a flavonoid extracted from the plant *Glycyrrhiza glabra*. It possesses significant antioxidant properties and melanin-inhibiting whitening effects, making it a highly effective and comprehensive cosmetic ingredient. Originally introduced to the market by Japanese cosmetic companies, glabridin is now widely used in whitening cosmetics and is known as "whitening gold." Furthermore, glabridin exhibits strong anti-atherosclerotic effects and certain lipid-regulating and blood pressure-lowering effects, showing promising research prospects in cardiovascular disease prevention and treatment drugs.

[0003] Currently, glycyrrhizin is mainly extracted from the plant *Glycyrrhiza glabra*. However, plant extraction has several limitations: First, in my country, *Glycyrrhiza glabra* primarily grows south of the Tianshan Mountains, and with the implementation of my country's desertification control policies, its availability is restricted. Second, the highest concentration of glycyrrhizin in *Glycyrrhiza glabra* is only 1-3‰, and the plant contains a large number of structurally similar flavonoids, making separation and purification techniques complex and costly. These factors limit the ability to obtain large quantities of glycyrrhizin through plant extraction. Therefore, developing methods for the chemical synthesis of glycyrrhizin is particularly important.

[0004] In 2006, Japanese Patent JP2006008604A first reported a route for synthesizing the racemic form of glycyrrhizin. However, this route had poor selectivity for the ring-closing site when constructing the dihydropiperane ring, and the two isomers formed by cyclization were difficult to separate, resulting in low synthesis efficiency.

[0005]

[0006] In 2007, Keepyung Nahm et al. from South Korea reported (Bull. Korean Chem. Soc., 2007, 28, 481) a nine-step synthetic route to obtain the racemic form of glycyrrhizin from 2,4-dihydroxyacetophenone. However, this route requires the use of highly toxic MOMCl reagents and harsh reaction conditions of anhydrous and oxygen-free environments.

[0007]

[0008] In 2013, Ji Wenhua et al. (Synthetic Communications, 2014, 44, 540-546) reported a method for preparing racemic glycyrrhizin from resorcinol via a 10-step reaction. However, this route also suffers from poor selectivity of the ring-closing site when constructing the dihydropiperan ring, and the difficulty in separating the two isomers formed by cyclization.

[0009]

[0010] In 2021, Gu Guoxian et al. from Hebei University of Technology disclosed a method for synthesizing optically pure glycyrrhizin in patent CN 113651832 B. This method involves constructing a chiral center via enzymatic catalysis, followed by a chemical transformation method to prepare optically pure glycyrrhizin. The key step involves using lipase to catalyze the formation of a monoacylated chiral intermediate from a diol compound, followed by bromination to obtain the crucial intermediate. This crucial intermediate is then converted to methyl-protected glycyrrhizin via nucleophilic substitution and Friedel-Crafts reaction, after which the methyl group is removed to obtain glycyrrhizin. However, this route resulted in very low yields when using enzymatic catalysis to construct the chiral center and the Friedel-Crafts alkylation ring-closing reaction.

[0011]

[0012] In 2024, Shenzhen Chuangyuan disclosed a method for preparing glycyrrhizin in patent CN 117964633 A. This method uses 2,4-dihydroxybenzaldehyde as the starting material and employs Perkin condensation as the key step to construct the isoflavone skeleton of glycyrrhizin. Subsequent simple modifications yield glycyrrhizin. This route solves the problem of poor selectivity at the ring-closing site when constructing the dihydropiperanone ring, and the synthetic route design is relatively simple. However, this route requires multiple uses of ultra-low temperature reaction conditions (-78℃), making it unsuitable for large-scale production.

[0013]

[0014] In 2020, Jiang Deqi et al. from Yulin Normal University disclosed a method for preparing (R)-glycyrrhizin using 7-hydroxychroman-4-one as a starting material in patent document CN111362961A. This route also suffers from poor selectivity at the ring-closing site during the construction of the dihydropiperanone ring, making it difficult to separate the two isomers formed by cyclization. Furthermore, the starting material 7-hydroxychroman-4-one is not a widely available chemical product and is relatively expensive.

[0015]

[0016] In 2025, Tianjin Taipu disclosed a method for synthesizing optically pure glycyrrhizin in patent CN 120289477A. ​​This method uses (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol and 2-isopentenylresorcinol as starting materials. The key intermediate, an aryl alkyl ether, is obtained through a Mitsunobu reaction. This intermediate is then hydrolyzed and iodinated to obtain an iodinated intermediate, which is subsequently cyclized, reduced, and deprotected to obtain (R)-glycyrrhizin. While the route is relatively simple, both starting materials require multiple reaction steps, resulting in a relatively long overall synthetic route.

[0017]

[0018] In summary, current synthetic routes for glycyrrhizin generally suffer from cumbersome procedures and poor selectivity in key ring-closing reactions, resulting in low overall synthetic efficiency and persistently high costs. Therefore, it is necessary to design new synthetic routes for glycyrrhizin to address the industry's current challenge of high costs. Summary of the Invention

[0019] In view of this, one of the objectives of the present invention is to provide a method for synthesizing glycyrrhizin, comprising the following steps:

[0020] 1) Add intermediate 1 and acetone to toluene and stir to dissolve. Add tetrahydropyrrole dropwise and heat to react. After the reaction is complete, quench the reaction and separate and purify to obtain intermediate 2.

[0021] 2) Add intermediate 2 to methanol and stir to dissolve. Under heating conditions, sodium hydroxide solution and chloroform are added dropwise simultaneously. After the addition is complete, the reaction is kept at the temperature. After the reaction is completed, intermediate 3 is obtained by separation and purification.

[0022] 3) Add intermediate 3 to ethanol, stir to dissolve, place in an ice bath, add sodium triacetate borohydride, react at room temperature after addition, quench the reaction after it is complete, and separate and purify to obtain intermediate 4.

[0023] 4) Add intermediates 4 and 5 to acetone, stir to dissolve, place in an ice bath, add potassium carbonate, react at room temperature after addition, quench the reaction after it is complete, and separate and purify to obtain intermediate 6.

[0024] 5) Add intermediate 6 to acetonitrile and stir to dissolve. Add triphenylphosphine hydrobromide and heat to react. After the reaction is complete, concentrate under reduced pressure. Add ethyl acetate to the concentrate, stir to disperse evenly, filter and dry to obtain intermediate phosphine salt. Add intermediate phosphine salt to ethanol, stir to dissolve, place under ice bath, add sodium ethoxide, and react at room temperature after the addition is complete. Quench the reaction after the reaction is complete, separate and purify to obtain intermediate 7.

[0025] 6) Add intermediate 7 to methanol and stir to dissolve. Add palladium on carbon, replace with hydrogen and heat to react. After the reaction is complete, filter, concentrate under reduced pressure, and separate and purify to obtain intermediate 8.

[0026] 7) Add intermediate 8 to methanol, stir to dissolve, place under ice bath, add sodium borohydride, react at room temperature after addition, quench the reaction after the reaction is complete, concentrate under reduced pressure, and separate and purify to obtain intermediate 9.

[0027] 8) Add intermediate 9 to toluene and stir to dissolve. Add p-toluenesulfonic acid monohydrate and heat to react. After the reaction is complete, separate and purify to obtain intermediate 10.

[0028] 9) Add intermediate 10 to dichloromethane and stir to dissolve. Cool to below -78℃ and add boron tribromide dropwise to react. After the reaction is complete, quench the reaction and separate and purify to obtain glycyrrhizin.

[0029] Steps 1)-9) are all performed under nitrogen protection;

[0030] The method includes the following synthetic route:

[0031] ,

[0032] The numbers 1-10 in the synthesis route are intermediates 1-10;

[0033] Intermediate 1 is 2,6-dihydroxyacetophenone;

[0034] The intermediate 2 is 5-hydroxy-2,2-dimethylchroman-4-one;

[0035] The intermediate 3 is 5-hydroxy-2,2-dimethyl-4-oxo-chroman-6-carboxaldehyde;

[0036] The intermediate 4 is 5-hydroxy-6-hydroxymethyl-2,2-dimethylchroman-4-one;

[0037] The intermediate 5 is 2-bromo-1-(2,4-dimethoxyphenyl)ethyl-1-one;

[0038] The intermediate 6 is 5-(2-(2,4-dimethoxyphenyl)-2-oxoethoxy)-6-(hydroxymethyl)-2,2-dimethylchroman-4-one;

[0039] The intermediate 7 is 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-8,9-dihydro-2H,10H-pirano[2,3-f]chromene-10-one;

[0040] The intermediate 8 is 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-3,4,8,9-tetrahydro-2H,10H-pirano[2,3-f]chromene-10-one;

[0041] The intermediate 9 is 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-3,4,9,10-tetrahydro-2H,8H-pirano[2,3-f]chromene-10-ol;

[0042] The intermediate 10 is 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-3,4-dihydro-2H,8H-pirano[2,3-f]chromene.

[0043] Further, in step 1), the molar ratio of intermediate 1 to acetone and tetrahydropyrrole is 1:2:3;

[0044] And / or the molar ratio of intermediate 2 and sodium hydroxide solution and chloroform in step 2) is 1:2:2;

[0045] And / or the molar ratio of intermediate 3 and sodium triacetate borohydride in step 3) is 1:3;

[0046] And / or the molar ratio of intermediate 4 and intermediate 5 and potassium carbonate in step 4) is 1:1:1.2;

[0047] And / or the molar ratio of intermediate 6 and triphenylphosphine hydrobromide and sodium ethoxide in step 5) is 1:1:1;

[0048] And / or the mass ratio of intermediate 7 and palladium on carbon in step 6) is 1.1:0.1;

[0049] And / or the molar ratio of intermediate 8 and sodium borohydride in step 7) is 1:3.5;

[0050] And / or the molar ratio of intermediate 9 and p-toluenesulfonic acid monohydrate in step 8) is 1:2;

[0051] And / or the molar ratio of intermediate 10 and boron tribromide in step 9) is 1:2.5.

[0052] Furthermore, the heating reaction described in step 1) is to heat to 50°C and react for 12 hours;

[0053] Furthermore, the heating condition described in step 2) is to heat to 70°C;

[0054] Furthermore, the heat preservation reaction described in step 2) is a reaction at 70°C for 3 hours;

[0055] Furthermore, the room temperature reaction described in step 3) is carried out for 12 hours;

[0056] Furthermore, the room temperature reaction described in step 4) is carried out for 24 hours;

[0057] Furthermore, the heating reaction described in step 5) is to heat to 80°C and react for 2 hours;

[0058] Furthermore, the drying described in step 5) is performed at 40°C for 5 hours;

[0059] Furthermore, the room temperature reaction described in step 5) is carried out for 12 hours;

[0060] Furthermore, the heating reaction described in step 6) is to heat to 60°C and react for 6 hours;

[0061] Furthermore, the room temperature reaction described in step 7) is carried out for 2 hours;

[0062] Furthermore, the heating reaction described in step 8) is to heat to 90°C and react for 1 hour;

[0063] Furthermore, the boron tribromide addition reaction described in step 9) is carried out for 3 hours;

[0064] Furthermore, step 3) includes a vacuum concentration step prior to separation and purification;

[0065] Furthermore, step 4) includes a vacuum concentration step prior to separation and purification;

[0066] Furthermore, step 5) includes a vacuum concentration step prior to separation and purification.

[0067] A second objective of this invention is to provide an intermediate compound for the synthesis of glycyrrhizin, the structural formula of which is:

[0068] ;

[0069] The compound is named 5-hydroxy-2,2-dimethylchroman-4-one;

[0070] Or:

[0071] ;

[0072] The compound is named 5-hydroxy-2,2-dimethyl-4-oxo-chroman-6-carboxaldehyde;

[0073] Or:

[0074] ;

[0075] The compound is named 5-hydroxy-6-hydroxymethyl-2,2-dimethylchroman-4-one;

[0076] Or:

[0077] ;

[0078] The compound is named 5-(2-(2,4-dimethoxyphenyl)-2-oxoethoxy)-6-(hydroxymethyl)-2,2-dimethylchroman-4-one;

[0079] Or:

[0080] ;

[0081] The compound is named 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-8,9-dihydro-2H,10H-pirano[2,3-f]chromene-10-one;

[0082] Or:

[0083] ;

[0084] The compound is named 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-3,4,8,9-tetrahydro-2H,10H-pirano[2,3-f]chromene-10-one;

[0085] Or:

[0086] ;

[0087] The compound is named 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-3,4,9,10-tetrahydro-2H,8H-pirano[2,3-f]chromene-10-ol;

[0088] Or:

[0089] ;

[0090] The compound is named 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-3,4-dihydro-2H,8H-pirano[2,3-f]chromene.

[0091] A third objective of this invention is to provide the application of the aforementioned intermediate compound in the synthesis of glycyrrhizin.

[0092] This invention has the following advantages over existing synthesis methods:

[0093] (1) This invention uses 2,6-dihydroxyacetophenone, which is inexpensive and readily available, as the starting material. The molecular skeleton of glycyrrhizin is efficiently constructed through the convergent synthesis of two fragments. Then, the artificial synthesis of glycyrrhizin is achieved through a total of 9 steps of functional group transformation and deprotection. The total yield is 34% and the purity is as high as 99% or more.

[0094] (2) This invention uses the reaction of the 2-position acetyl group introduced in the starting material with acetone to directionally construct a dimethylpyranone ring, which solves the problem of poor selectivity of the ring-closing reaction position and only obtaining a small half product that is common in the synthesis route of glycyrrhizin, and significantly improves the synthesis efficiency.

[0095] (3) In this invention, the ketone carbonyl group that preferentially constructs the dimethylbinone ring is used as a substitute group for the double bond, which avoids the simultaneous hydrogenation of the two double bonds in the molecule during catalytic hydrogenation. Finally, the dimethylbinone ring can be obtained by simple reductive elimination to obtain the dimethyldihydrobinone ring. At the same time, the preferentially constructed dimethylbinone ring also improves the overall stability of the molecule.

[0096] (4) The synthetic route of this invention is novel and efficient. The reaction raw materials and reagents are all common commercial reagents. Moreover, the route is under mild conditions, avoiding the use of dangerous reagents such as lithium aluminum hydride and ultra-low temperature equipment. Compared with existing synthetic routes, it is more suitable for industrial-scale production. Attached Figure Description

[0097] Figure 1 This is a schematic diagram of the synthetic route for glycyrrhizin in this invention;

[0098] Figure 2 The NMR spectrum of intermediate 2 in this embodiment of the invention;

[0099] Figure 3 The NMR spectrum of intermediate 3 in the embodiments of the present invention;

[0100] Figure 4 The NMR spectrum of intermediate 4 in this embodiment of the invention;

[0101] Figure 5 The NMR spectrum of intermediate 6 in this embodiment of the invention;

[0102] Figure 6 The NMR spectrum of intermediate 7 in this embodiment of the invention;

[0103] Figure 7 The NMR spectrum of intermediate 8 in this embodiment of the invention;

[0104] Figure 8 The NMR spectrum of intermediate 9 in this embodiment of the invention;

[0105] Figure 9The NMR spectrum of intermediate 10 in this embodiment of the invention;

[0106] Figure 10 This is the NMR spectrum of glycyrrhizin in an embodiment of the present invention. Detailed Implementation

[0107] The present invention will be described in detail below with reference to embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of application of the present invention. The present invention is not limited to the following embodiments or examples. Any modifications and variations made without departing from the spirit of the present invention should be included within the scope of the present invention. Unless otherwise specified, the experimental materials or reagents used in the following embodiments are commercially available.

[0108] The synthetic route of glycyrrhizin in this invention is as follows: Figure 1 As shown, numbers 1-10 in the synthetic route refer to intermediates 1-10 in the examples, wherein intermediate 1 is 2,6-dihydroxyacetophenone; intermediate 2 is 5-hydroxy-2,2-dimethylchroman-4-one; intermediate 3 is 5-hydroxy-2,2-dimethyl-4-oxo-chroman-6-carboxaldehyde; intermediate 4 is 5-hydroxy-6-hydroxymethyl-2,2-dimethylchroman-4-one; intermediate 5 is 2-bromo-1-(2,4-dimethoxyphenyl)ethyl-1-one; intermediate 6 is 5-(2-(2,4-dimethoxyphenyl)-2-oxoethoxy)-6-(hydroxymethyl)-2,2-dimethylchroman-4-one; intermediate 7 is 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-8,9-dihydro-2H,10H-pyrano[2, Intermediate 8 is 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-3,4,8,9-tetrahydro-2H,10H-pirano[2,3-f]chromene-10-one; Intermediate 9 is 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-3,4,9,10-tetrahydro-2H,8H-pirano[2,3-f]chromene-10-ol; Intermediate 10 is 3-(2,4-dimethoxyphenyl)-8,8-dimethyl-3,4-dihydro-2H,8H-pirano[2,3-f]chromene.

[0109] Example

[0110] (1) Synthesis of intermediate 2

[0111] Under nitrogen protection, 2,6-dihydroxyacetophenone (30 g, 197 mmol) and acetone (22.9 g, 394 mmol) were added to 300 mL of toluene and stirred until dissolved. Tetrahydropyrrole (42.1 g, 592 mmol) was added dropwise to the reaction mixture, and the mixture was heated to 50 °C and reacted for 12 h. The reaction was quenched by adding 200 mL of 2 N hydrochloric acid solution, and the mixture was separated, retaining the organic phase. The aqueous layer was extracted once with 200 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed once with 100 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (n-hexane / ethyl acetate = 90 / 10) to give intermediate 2, 37 g of gray solid, yield 98%. Figure 2 ). 1 H NMR (400 MHz, CDCl3) δ11.66 (s, 1H), 7.33 (t, J = 8.3 Hz, 1H), 6.46 (dd, J = 8.3, 0.9 Hz, 1H), 6.38(dd, J = 8.3, 0.9 Hz, 1H), 2.74 (s, 2H), 1.46 (s, 7H).

[0112] (2) Synthesis of intermediate 3

[0113] Under nitrogen protection, intermediate 2 (20 g, 113.5 mmol) was added to 100 mL of methanol and stirred until dissolved. While heating the reaction solution to 70 °C, sodium hydroxide solution (9.1 g, 227 mmol sodium hydroxide dissolved in 25 g water) and chloroform (27.1 g, 227 mmol) were added dropwise. After the addition was complete, the reaction was maintained at 70 °C for 3 h. The reaction solution was cooled to room temperature, and the pH was adjusted to 6-7 by adding 1 N hydrochloric acid solution. The reaction solution was extracted three times with ethyl acetate (80 mL x 3), and the organic phases were combined. The organic phases were washed once with 50 mL of saturated sodium bicarbonate solution and once with 50 mL of saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (n-hexane / ethyl acetate = 90 / 10) to give intermediate 3, a yellow solid of 19.5 g, yield 78%. Figure 3 ). 1 H NMR (400 MHz, CDCl3) δ12.41 (s, 1H), 10.31 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 6.47 (dd, J = 8.8,0.8 Hz, 1H), 2.80 (s, 2H), 1.51 (s, 6H).

[0114] (3) Synthesis of intermediate 4

[0115] Under nitrogen protection, intermediate 3 (17.5 g, 79.4 mmol) was added to 250 mL of ethanol, stirred until dissolved, and then placed in an ice bath. Sodium triacetoxyborohydride (50.4 g, 238 mmol) was added to the reaction solution in three portions. After each addition, the reaction was allowed to proceed at room temperature for 12 h. The reaction was quenched by slowly adding 50 mL of saturated ammonium chloride solution, and the ethanol was removed by concentration under reduced pressure. 50 mL of water and 100 mL of ethyl acetate were added to the residue, and the mixture was extracted and separated. The aqueous phase was extracted again with 100 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed once with 80 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (n-hexane / ethyl acetate = 90 / 10) to give intermediate 4, a gray solid of 15.9 g, in 90% yield. Figure 4 ). 1 H NMR (400 MHz, CDCl3) δ 12.03 (s, 1H), 7.38 (d, J =8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 4.63 (s, 2H), 2.74 (s, 2H), 1.46 (s,6H).

[0116] (4) Synthesis of intermediate 6

[0117] Under nitrogen protection, intermediate 4 (10 g, 48.5 mmol) and intermediate 5 (12.6 g, 48.5 mmol) were added to 150 mL of acetone. After stirring and dissolving, the mixture was placed in an ice bath. Potassium carbonate (8 g, 58.2 mmol) was added to the reaction solution in three portions. After each addition, the mixture was allowed to react at room temperature for 24 h. The reaction was quenched by adding 50 mL of saturated ammonium chloride solution, and the acetone was removed by concentration under reduced pressure. 50 mL of water and 80 mL of ethyl acetate were added to the residue, and the mixture was extracted and separated. The aqueous phase was extracted again with 80 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed once with 80 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (n-hexane / ethyl acetate = 90 / 10) to give intermediate 6, 15.5 g of gray solid, in 83% yield. Figure 5 ). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 8.8, 2.3Hz, 1H), 6.42 (d, J = 2.2 Hz, 1H), 5.30 (s, 2H), 4.65 (s, 2H), 3.86 (d, J =1.3 Hz, 6H), 2.71 (s, 2H), 1.45 (s, 6H).

[0118] (5) Synthesis of intermediate 7

[0119] Under nitrogen protection, intermediate 6 (10.4 g, 26 mmol) was added to 100 mL of acetonitrile and stirred until dissolved. Triphenylphosphine hydrobromide (8.9 g, 26 mmol) was added to the reaction solution in three portions. After the additions were complete, the mixture was heated to 80 °C and reacted for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the acetonitrile. 100 mL of ethyl acetate was added to the residue and stirred until evenly dispersed. The mixture was filtered, and the filter cake was dried under vacuum at 40 °C for 5 h to obtain the intermediate phosphine salt.

[0120] Under nitrogen protection, the intermediate phosphine salt was added to 100 mL of ethanol, stirred until dissolved, and then placed in an ice bath. Sodium ethoxide (1.8 g, 26 mmol) was added to the reaction solution in three portions. After the addition was complete, the reaction was allowed to proceed at room temperature for 12 h. The reaction was quenched by slowly adding 50 mL of saturated ammonium chloride solution, and the ethanol was removed by concentration under reduced pressure. 50 mL of water and 50 mL of ethyl acetate were added to the residue, and the mixture was extracted and separated. The aqueous phase was extracted again with 50 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed once with 40 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (n-hexane / ethyl acetate = 90 / 10) to give intermediate 7, 8.1 g of gray solid, in 85% yield. Figure 6 ). 1 H NMR (400MHz, CDCl3) δ 7.20 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.52-6.42(m, 3H), 5.15 (d, J = 1.2 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 2.69 (s, 2H), 1.44 (s, 6H).

[0121] (6) Synthesis of intermediate 8

[0122] Under nitrogen protection, intermediate 7 (4.4 g, 12 mmol) was added to 60 mL of methanol and stirred until dissolved. 10% palladium on carbon (0.4 g) was added to the reaction mixture, followed by nitrogen purging once and hydrogen purging three times. The mixture was heated to 60 °C and reacted for 6 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to remove methanol. 50 mL of water and 50 mL of ethyl acetate were added to the residue, and the mixture was extracted and separated. The aqueous phase was extracted again with 50 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed once with 40 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (n-hexane / ethyl acetate = 90 / 10) to give intermediate 8, 4.3 g of gray solid, yield 97%. Figure 7 ). 1 H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.52 -6.40 (m,3H), 4.61 - 4.47 (m, 1H), 4.02 (t, J = 10.5 Hz, 1H), 3.80 (d, J = 2.3 Hz, 6H), 3.66-3.50 (m, 1H), 2.99 (dd, J = 15.4, 11.7 Hz, 1H), 2.80 (ddd, J =15.6, 4.9, 2.2 Hz, 1H), 2.76-2.60 (m, 2H), 1.45 (s, 3H), 1.42 (s, 3H).

[0123] (7) Synthesis of intermediate 9

[0124] Under nitrogen protection, intermediate 8 (3.7 g, 10 mmol) was added to 50 mL of methanol, stirred until dissolved, and then placed in an ice bath. Sodium borohydride (1.3 g, 35 mmol) was added to the reaction solution in three portions. After each addition, the reaction was allowed to proceed at room temperature for 2 h. The reaction was quenched by slowly adding 10 mL of saturated ammonium chloride solution, and the methanol was removed by concentration under reduced pressure. 20 mL of water and 30 mL of ethyl acetate were added to the residue, and the mixture was extracted and separated. The aqueous phase was extracted again with 30 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed once with 20 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (n-hexane / ethyl acetate = 90 / 10) to give intermediate 9, 3.6 g of gray solid, with a yield of 97%. Figure 8 ). 1H NMR (400 MHz, DMSO-d6) δ 6.95-6.83 (m, 2H), 6.35 (dd, J = 2.2, 1.1 Hz,1H), 6.27 (dd, J = 8.3, 1.3 Hz, 1H), 6.17 (ddd, J = 8.3, 5.9, 2.4 Hz, 1H),4.84-4.71 (m, 1H), 4.36 (dd, J = 10.3, 3.5 Hz, 1H), 4.12-3.98 (m, 1H), 3.82(s, 3H), 3.80 (s, 3H), 3.67-3.52 (m, 1H), 3.02-2.81 (m, 1H), 2.79-2.60 (m,1H), 1.96-1.79 (m, 2H), 1.35 (s, 3H), 1.30 (s, 3H).

[0125] (8) Synthesis of intermediate 10

[0126] Under nitrogen protection, intermediate 9 (3.0 g, 8 mmol) was added to 50 mL of toluene and stirred until dissolved. p-Toluenesulfonic acid monohydrate (3.0 g, 16 mmol) was added to the reaction mixture, and the mixture was heated to 90 °C for 1 h. The reaction mixture was cooled to room temperature, and the pH was adjusted to 5-6 by adding 1 N sodium hydroxide solution. The residue was extracted with 50 mL of water. The aqueous phase was extracted again with 50 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed once with 40 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (n-hexane / ethyl acetate = 90 / 10) to give intermediate 10, 2.5 g of white solid, 90% yield. Figure 9 ). 1H NMR (400 MHz, CDCl3) δ 7.03(d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 9.9 Hz, 1H), 6.52- 6.43 (m, 2H), 6.36 (d, J = 8.2 Hz, 1H), 5.56 (d, J = 9.9 Hz, 1H), 4.35 (d,J = 10.3 Hz, 1H), 3.99 (t, J = 10.1 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.61- 3.50 (m, 1H), 3.05-2.91 (m, 1H), 2.83 (dd, J = 15.6, 4.9 Hz, 1H), 1.43 (s, 3H), 1.41 (s, 3H).

[0127] (9) Synthesis of glycyrrhizin

[0128] Under nitrogen protection, intermediate 10 (2.1 g, 6 mmol) was added to 50 mL of dichloromethane and stirred until dissolved. The reaction solution was cooled to -78 °C, and boron tribromide (3.8 g, 15 mmol) was slowly added dropwise. After the addition was complete, the reaction was continued at -78 °C for 3 h. After the reaction was complete, 10 mL of ice water was added and stirred for 0.5 h to quench the reaction. 40 mL of water was added to the reaction solution, and the mixture was extracted and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (n-hexane / ethyl acetate = 90 / 10) to give 1.6 g of white solid, yield 83%. Figure 10 ). 1H NMR(400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.10 (s, 1H), 6.84 (dd, J = 12.8, 8.3 Hz,2H), 6.54 (d, J = 9.9 Hz, 1H), 6.35 - 6.25 (m, 2H), 6.18 (dd, J = 8.3, 2.4Hz, 1H), 5.64 (d, J = 9.9 Hz, 1H), 4.29 - 4.17 (m, 1H), 3.93 (t, J = 10.2 Hz,1H), 3.36 - 3.23 (m, 1H), 2.89 (dd, J = 15.6, 11.2 Hz, 1H), 2.75-2.62 (m,1H), 1.34 (s, 3H), 1.33 (s, 3H).

[0129] The conventional techniques and solutions not described in detail in the above embodiments are all well known in the art, and therefore will not be elaborated upon here. The above embodiments and / or experimental examples describe the preferred embodiments of the present invention in detail. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. A method for synthesizing glycyrrhizin, characterized in that, It includes the following steps: 1) Add intermediate 1 and acetone to toluene and stir to dissolve. Add tetrahydropyrrole dropwise and heat to react. After the reaction is complete, quench the reaction and separate and purify to obtain intermediate 2. 2) Add intermediate 2 to methanol and stir to dissolve. Under heating conditions, sodium hydroxide solution and chloroform are added dropwise simultaneously. After the addition is complete, the reaction is kept at the temperature. After the reaction is completed, intermediate 3 is obtained by separation and purification. 3) Add intermediate 3 to ethanol, stir to dissolve, place in an ice bath, add sodium triacetate borohydride, react at room temperature after addition, quench the reaction after it is complete, and separate and purify to obtain intermediate 4. 4) Add intermediates 4 and 5 to acetone, stir to dissolve, place in an ice bath, add potassium carbonate, react at room temperature after addition, quench the reaction after it is complete, and separate and purify to obtain intermediate 6. 5) Add intermediate 6 to acetonitrile and stir to dissolve. Add triphenylphosphine hydrobromide and heat to react. After the reaction is complete, concentrate under reduced pressure, add ethyl acetate, stir to disperse evenly, filter and dry to obtain intermediate phosphine salt. Add intermediate phosphine salt to ethanol, stir to dissolve, place under ice bath, add sodium ethoxide, react at room temperature after addition, quench the reaction after it is complete, separate and purify to obtain intermediate 7. 6) Add intermediate 7 to methanol and stir to dissolve. Add palladium on carbon, replace with hydrogen and heat to react. After the reaction is complete, filter, concentrate under reduced pressure, and separate and purify to obtain intermediate 8. 7) Add intermediate 8 to methanol and stir to dissolve. Place the mixture in an ice bath and add sodium borohydride. After the addition is complete, react at room temperature. After the reaction is complete, quench the reaction, concentrate under reduced pressure, and separate and purify to obtain intermediate 9. 8) Add intermediate 9 to toluene and stir to dissolve. Add p-toluenesulfonic acid monohydrate and heat to react. After the reaction is complete, separate and purify to obtain intermediate 10. 9) Add intermediate 10 to dichloromethane and stir to dissolve. Add boron tribromide dropwise at -78°C and react. Quench the reaction after it is complete and separate and purify to obtain glycyrrhizin. Steps 1)-9) are all performed under nitrogen protection; The method includes the following synthetic route: ； The numbers 1-10 in the synthesis route are intermediates 1-10.

2. The method as described in claim 1, characterized in that, In step 1), the molar ratio of intermediate 1 to acetone and tetrahydropyrrole is 1:2:

3. And / or the molar ratio of intermediate 2 and sodium hydroxide solution and chloroform in step 2) is 1:2:2; And / or the molar ratio of intermediate 3 and sodium triacetate borohydride in step 3) is 1:3; And / or the molar ratio of intermediate 4 and intermediate 5 and potassium carbonate in step 4) is 1:1:1.2; And / or the molar ratio of intermediate 6 and triphenylphosphine hydrobromide and sodium ethoxide in step 5) is 1:1:1; And / or the mass ratio of intermediate 7 and palladium on carbon in step 6) is 1.1:0.1; And / or the molar ratio of intermediate 8 and sodium borohydride in step 7) is 1:3.5; And / or the molar ratio of intermediate 9 and p-toluenesulfonic acid monohydrate in step 8) is 1:2; And / or the molar ratio of intermediate 10 and boron tribromide in step 9) is 1:2.

5.

3. An intermediate compound for the synthesis of glycyrrhizin, characterized in that, The structural formula of the intermediate compound is: ； Or: ； Or: ； Or: ； Or: ； Or: ； Or: ； Or: 。 4. The use of the intermediate compound of claim 3 in the synthesis of glycyrrhizin.

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