Asymmetric synthesis method of (R)-glabridin

Abstract

The invention provides an asymmetric synthesis method of (R)-glabridin, which comprises the following steps: synthesizing 5-hydroxy-6-hydroxymethyl-2, 2-dimethylchroman-4-ketone by using 2, 6-dihydroxyacetophenone as a raw material, then carrying out nuclear substitution reaction, Wittig reaction, asymmetric hydrogenation reaction, protecting group removal and carbonyl reduction reaction, and finally dehydrating under an acidic condition to obtain the (R)-glabridin. The chiral center is constructed by a method of catalyzing asymmetric hydrogenation through a chiral metal catalyst, the addition amount is as low as 0.5 mol%, the reaction selectivity is good (eegt, 98%), the conversion rate is high (the yield gt, 89%), and the problem of low construction efficiency of the chiral center in asymmetric synthesis of glabridin is solved. The asymmetric synthesis route of (R)-glabridin provided by the invention is novel and efficient, the reaction 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 an asymmetric synthesis method of (R)-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 methods have several limitations: glycyrrhizin content in *Glycyrrhiza glabra* is only 1-3‰ at most, and the plant contains a large number of structurally similar flavonoids, making separation and purification techniques complex and costly. These factors limit the acquisition of 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 dihydropyran 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 (R)-glycyrrhizin in patent CN 113651832 B. This method involves constructing a chiral center via enzymatic catalysis, followed by a chemical transformation to prepare (R)-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 (R)-glycyrrhizin is obtained by demethylation. However, this route resulted in very low yields when using enzymatic catalysis to construct the chiral center and in the Friedel-Crafts alkylation cyclization 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 during the construction of the dihydropiperanone ring, and the synthetic route design is relatively simple. However, this route is a synthetic route for racemic glycyrrhizin and requires multiple use 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 expensive.

[0015]

[0016] In 2025, Tianjin Taipu disclosed a method for synthesizing (R)-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 design 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 cyclization reactions. In particular, the asymmetric synthetic routes for (R)-glycyrrhizin face challenges such as low efficiency in constructing chiral centers and low conversion rates in enzymatically catalyzed chiral center construction. Currently, there is still no suitable synthetic route for industrial-scale production, resulting in high costs associated with the chemical synthesis of (R)-glycyrrhizin. Therefore, it is necessary to design new asymmetric synthetic routes to efficiently construct the chiral centers of glycyrrhizin and address the high costs associated with current asymmetric synthesis of (R)-glycyrrhizin. Summary of the Invention

[0019] To overcome the shortcomings of existing synthetic methods for (R)-glycyrrhizin, the present invention aims to provide a method for constructing chiral centers of glycyrrhizin through asymmetric hydrogenation catalyzed by a metal catalyst, and to apply this method to the asymmetric synthetic route of glycyrrhizin, thereby solving the industry problem that the asymmetric synthesis of (R)-glycyrrhizin is difficult to industrialize.

[0020] In view of this, one object of the present invention is to provide an asymmetric synthesis method for (R)-glycyrrhizin, comprising the following steps:

[0021] 1) Add intermediate 1 and intermediate 2 to acetone, stir to dissolve, place in an ice bath, add potassium carbonate, react at room temperature after addition, quench the reaction after the reaction is complete, and separate and purify to obtain intermediate 3.

[0022] 2) Add intermediate 3 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, and filter to obtain intermediate phosphine salt. Add phosphine salt to ethanol, stir to dissolve, place under ice bath, add sodium ethoxide, and react at room temperature after the addition is complete. After the reaction is complete, quench the reaction and purify to obtain intermediate 4.

[0023] 3) Add intermediate 4 to a high-pressure reactor, add dichloromethane and stir to dissolve; add a chiral metal catalyst, introduce hydrogen gas and heat to react, and after the reaction is complete, separate and purify to obtain intermediate 5;

[0024] 4) Add intermediate 5 to dichloromethane, add boron tribromide dropwise at -78 ℃, and react at -78 ℃. After the reaction is complete, separate and purify to obtain intermediate 6.

[0025] 5) Add intermediate 6 to methanol, stir to dissolve, place in an ice bath, add sodium borohydride, react at room temperature after the addition is complete, quench the reaction after the reaction is complete, and separate and purify to obtain intermediate 7.

[0026] 6) Add intermediate 7 to toluene and stir to dissolve. Add p-toluenesulfonic acid monohydrate and heat to react. Separate and purify to obtain (R)-glycyrrhizin.

[0027] Steps 1) through 6) are all performed under nitrogen protection;

[0028] Step 3) The chiral metal catalyst described has the structure shown in general formula (I):

[0029] (I)

[0030] Wherein, R1 is a C1-6 straight-chain or branched alkyl group, a benzene ring, or a 5-8 membered unsaturated carbon ring or heterocycle; R2 is a C1-7 straight-chain or branched alkyl group, or a benzene ring.

[0031] The method includes the following synthetic route:

[0032] ,

[0033] The numbers 1-7 in the synthesis route are intermediates 1-7.

[0034] The intermediate 1 is 5-hydroxy-6-hydroxymethyl-2,2-dimethylchroman-4-one;

[0035] The intermediate 2 is 1-(2,4-bisbenzyloxyphenyl)-2-bromoethyl ketone;

[0036] The intermediate 3 is 5-(2-(2,4-bisbenzyloxyphenyl)-2-oxoethoxy)-6-hydroxymethyl-2,2-dimethylchroman-4-one;

[0037] The intermediate 4 is 3-(2,4-dibenzyloxyphenyl)-8,8-dimethyl-8,9-dihydro-2H,10H-pirano[2,3-f]chromene-10-one;

[0038] The intermediate 5 is (R)-3-(2,4-dibenzyloxyphenyl)-8,8-dimethyl-3,4,8,9-tetrahydro-2H,10H-pirano[2,3-f]chromene-10-one;

[0039] The intermediate 6 is (R)-3-(2,4-dihydroxyphenyl)-8,8-dimethyl-3,4,8,9-tetrahydro-2H,10H-pirano[2,3-f]chromene-10-one;

[0040] The intermediate 7 is (3R)-3-(2,4-dihydroxyphenyl)-8,8-dimethyl-3,4,9,10-tetrahydro-2H,8H-pirano[2,3-f]chromene-10-ol;

[0041] Furthermore, in the chiral metal catalyst of general formula (Ⅰ), R1 = -CH(CH3)2, R2 = -Bn,

[0042] Right now ;

[0043] Or R1 = -CH3, R2 = -Ph,

[0044] Right now ;

[0045] Or R1=-CH3, R2=-Bn,

[0046] Right now ;

[0047] Preferably, in the chiral metal catalyst of general formula (Ⅰ), R1 = -CH(CH3)2, R2 = -Bn,

[0048] Right now .

[0049] Preferably, the molar ratio of intermediate 1 and intermediate 2 and potassium carbonate in step 1) is 1:1:1.2;

[0050] And / or the molar ratio of intermediate 3 and triphenylphosphine hydrobromide and sodium ethoxide in step 2) is 1:1:1;

[0051] And / or the amount of the chiral metal catalyst in step 3) is not less than 0.5 mol% of intermediate 4.

[0052] And / or the molar ratio of intermediate 5 and boron tribromide in step 4) is 1:2.5;

[0053] And / or the molar ratio of intermediate 6 and sodium borohydride in step 5) is 3:14;

[0054] And / or the molar ratio of intermediate 7 and p-toluenesulfonic acid monohydrate in step 6) is 1:2;

[0055] Furthermore, the room temperature reaction described in step 1) is carried out for 24 hours;

[0056] Furthermore, the heating reaction described in step 2) is to heat to 80 °C and react for 2 h;

[0057] Furthermore, step 2) includes a step of vacuum drying at 40 °C for 5 h after filtration;

[0058] Furthermore, the room temperature reaction described in step 2) is carried out for 12 hours;

[0059] Furthermore, the hydrogen gas introduced in step 3) is to achieve a pressure of 1 MPa;

[0060] Furthermore, the heating reaction described in step 3) is to heat to 40 °C and react for 24 h;

[0061] Furthermore, the -78°C reaction described in step 4) is carried out for 3 hours;

[0062] Furthermore, the room temperature reaction described in step 5) is carried out for 2 hours;

[0063] Furthermore, the heating reaction described in step 6) is to heat to 90°C and react for 1 hour.

[0064] A second objective of this invention is to provide the application of any of the chiral metal catalysts described above in the catalytic asymmetric hydrogenation of intermediate 4 to construct the (R)-glycyrrhizin chiral center.

[0065] Furthermore, the amount of the chiral metal catalyst is not less than 0.5 mol of the intermediate 4.

[0066] A third objective of this invention is to provide a method for constructing a (R)-glycyrrhizin chiral center, comprising the step of catalytic asymmetric hydrogenation of intermediate 4 by any of the chiral metal catalysts described above.

[0067] Preferably, the method includes the step of catalytic asymmetric hydrogenation of the intermediate 4 using the chiral metal catalyst of claim 3, wherein the molar ratio of the chiral metal catalyst of claim 3 to the intermediate 4 is 200:1.

[0068] The fourth objective of this invention is to provide an intermediate compound for the synthesis of (R)-glycyrrhizin, the structural formula of which is:

[0069] ,

[0070] The compound is named 5-hydroxy-6-hydroxymethyl-2,2-dimethylchroman-4-one;

[0071] Or:

[0072] ,

[0073] The compound is named 5-(2-(2,4-bisbenzyloxyphenyl)-2-oxoethoxy)-6-hydroxymethyl-2,2-dimethylchroman-4-one;

[0074] Or:

[0075] ,

[0076] The compound is named 3-(2,4-dibenzyloxyphenyl)-8,8-dimethyl-8,9-dihydro-2H,10H-pirano[2,3-f]chromene-10-one;

[0077] Or:

[0078] ,

[0079] The compound is named (R)-3-(2,4-dibenzyloxyphenyl)-8,8-dimethyl-3,4,8,9-tetrahydro-2H,10H-pirano[2,3-f]chromene-10-one;

[0080] Or:

[0081] ,

[0082] The compound is named (R)-3-(2,4-dihydroxyphenyl)-8,8-dimethyl-3,4,8,9-tetrahydro-2H,10H-pirano[2,3-f]chromene-10-one;

[0083] Or:

[0084] ,

[0085] The compound is named (3R)-3-(2,4-dihydroxyphenyl)-8,8-dimethyl-3,4,9,10-tetrahydro-2H,8H-pirano[2,3-f]chromene-10-ol.

[0086] The fifth objective of this invention is to provide the application of any of the aforementioned intermediate compounds in the synthesis of glycyrrhizin.

[0087] This invention has the following advantages over existing synthesis methods:

[0088] (1) The present invention constructs a chiral center by asymmetric hydrogenation catalyzed by a chiral metal catalyst. The reaction has good selectivity (ee>98%) and high conversion rate (yield>89%). It overcomes the difficulties and poor selectivity of asymmetric catalytic hydrogenation of multisubstituted olefins with no nearby positioning functional groups, and solves the problem of low construction efficiency of chiral center in the asymmetric synthesis of glycyrrhizin.

[0089] (2) The conversion rate and selectivity of the reaction are still very good when the amount of metal catalyst added is as low as 0.5 mol%, and the amount of catalyst used is extremely low, which significantly reduces the cost.

[0090] (3) In the asymmetric synthesis route of glycyrrhizin, the present invention solves the problem of poor selectivity of the key ring-closing reaction by pre-constructing a dimethylpyranone ring, and also avoids the problem of the dimethylpyranone ring being hydrogenated during catalytic hydrogenation. Finally, the dimethyl dihydropyranone ring can be obtained by simple reduction elimination.

[0091] (4) The asymmetric synthetic route of (R)-glycyrrhizin provided by the present invention is novel and efficient, with mild reaction conditions, avoiding the use of dangerous reducing reagents such as lithium aluminum hydride and ultra-low temperature equipment. Compared with existing synthetic routes, it is more suitable for industrial scale-up production. Attached Figure Description

[0092] Figure 1 Synthetic route diagram of (R)-glycyrrhizin of this invention;

[0093] Figure 2 This is a chiral HPLC liquid phase diagram of intermediate 5 in Example 1 of the present invention;

[0094] Figure 3 This is the chiral HPLC liquid phase diagram of intermediate 5 in Example 2 of the present invention;

[0095] Figure 4 This is the chiral HPLC liquid phase diagram of intermediate 5 in Example 3 of the present invention;

[0096] Figure 5 This is the chiral HPLC liquid phase diagram of intermediate 5 in Example 4 of the present invention;

[0097] Figure 6 This is the chiral HPLC liquid phase diagram of intermediate 5 in Example 5 of the present invention;

[0098] Figure 7 This is the chiral HPLC liquid phase diagram of intermediate 5 in Example 7 of the present invention;

[0099] Figure 8 This is the chiral HPLC liquid phase diagram of intermediate 5 in Example 9 of the present invention;

[0100] Figure 9This is the chiral HPLC liquid phase of the glycyrrhizin of this invention. Detailed Implementation

[0101] 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.

[0102] The chiral metal catalysts C1, C2, and C3 used in this invention were all purchased from Beijing Bailingwei Technology Co., Ltd.

[0103] The synthetic route for (R)-glycyrrhizin provided by this invention is as follows: Figure 1 As shown, numbers 1-7 in the synthetic route refer to intermediates 1-7 in the examples, wherein intermediate 1 is 5-hydroxy-6-hydroxymethyl-2,2-dimethylchroman-4-one; intermediate 2 is 1-(2,4-bisbenzyloxyphenyl)-2-bromoethylone; intermediate 3 is 5-(2-(2,4-bisbenzyloxyphenyl)-2-oxoethoxy)-6-hydroxymethyl-2,2-dimethylchroman-4-one; intermediate 4 is 3-(2,4-bisbenzyloxyphenyl)-8,8-dimethyl-8,9-dihydro-2H,10H-pirano[2,3-f]chromen-10-one; and intermediate 5 is (R)-3-(2,4-bisbenzyloxyphenyl)-8,8-dimethyl-3,4,8,9-tetrahydro-2H,10H-pirano[2,3-f]chromen-10-one. Intermediate 6 is (R)-3-(2,4-dihydroxyphenyl)-8,8-dimethyl-3,4,8,9-tetrahydro-2H,10H-pirano[2,3-f]chromeno-10-one; Intermediate 7 is (3R)-3-(2,4-dihydroxyphenyl)-8,8-dimethyl-3,4,9,10-tetrahydro-2H,8H-pirano[2,3-f]chromeno-10-ol;

[0104] The synthesis steps of intermediate 1 of the present invention include the following synthetic route:

[0105]

[0106] Specifically, the steps include the following:

[0107] (1) Synthesis of intermediate 1b

[0108] Under nitrogen protection, 2,6-dihydroxyacetophenone 1a (30 g, 19.7 mmol) and acetone (22.9 g, 39.4 mmol) were added to 300 mL of toluene and stirred until dissolved. Tetrahydropyrrole (42.1 g, 59.2 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 1b (5-hydroxy-2,2-dimethylchroman-4-one), 37 g of gray solid, 98% yield. 1 H NMR (400 MHz, CDCl3) δ 11.66 (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).

[0109] (2) Synthesis of intermediate 1c

[0110] Under nitrogen protection, intermediate 1b (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 and chloroform were simultaneously 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 1c (5-hydroxy-2,2-dimethyl-4-oxo-chroman-6-carboxaldehyde), 19.5 g of yellow solid, yield 78%. 1 H NMR (400 MHz, CDCl3) δ 12.41 (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).

[0111] (3) Synthesis of intermediate 1 of the present invention

[0112] Under nitrogen protection, intermediate 1c (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 (50.5 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 obtain intermediate 1 (5-hydroxy-6-hydroxymethyl-2,2-dimethylchroman-4-one), a gray solid of 15.9 g, with a yield of 90%. 1 H NMR (400MHz, 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).

[0113] Example 1

[0114] (1) Synthesis of intermediate 5

[0115] Under nitrogen protection, intermediate 4 (4.7 g, 9 mmol) was added to a high-pressure reactor, and 100 mL of dichloromethane was added and stirred to dissolve. Catalyst C1 (159 mg, 0.09 mmol) was added to the reactor. After the addition was complete, the reactor was purged with hydrogen three times, and hydrogen was introduced into the reactor until the pressure reached 1 MPa. The temperature was raised to 40 °C and the reaction was carried out for 24 h. The reaction solution was cooled to room temperature, and 60 mL of water was added. The mixture was extracted and separated. The organic phase was washed once with 50 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 5, 3.8 g of white solid, yield 82%, ee 96%. Figure 2 ).

[0116] Example 2

[0117] (2) Synthesis of intermediate 5

[0118] Under nitrogen protection, intermediate 4 (4.7 g, 9 mmol) was added to a high-pressure reactor, followed by the addition of 100 mL of dichloromethane and stirring to dissolve. Catalyst C2 (156 mg, 0.09 mmol) was then added to the reactor. After the addition was complete, the reactor was purged with hydrogen three times, and hydrogen was introduced into the reactor until the pressure reached 1 MPa. The temperature was raised to 40 °C and the reaction proceeded for 24 h. The reaction solution was cooled to room temperature, and 60 mL of water was added. The mixture was extracted and separated. The organic phase was washed once with 50 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 5, a white solid of 4.2 g, yield 90%, ee 94%. Figure 3 ).

[0119] Example 3

[0120] (3) Synthesis of intermediate 5

[0121] Under nitrogen protection, intermediate 4 (4.7 g, 9 mmol) was added to a high-pressure reactor, and 100 mL of dichloromethane was added and stirred to dissolve. Catalyst C3 (161 mg, 0.09 mmol) was then added to the reactor. After the addition was complete, the reactor was purged with hydrogen three times, and hydrogen was introduced into the reactor until the pressure reached 1 MPa. The temperature was raised to 40 °C and the reaction was carried out for 24 h. The reaction solution was cooled to room temperature, and 60 mL of water was added. The mixture was extracted and separated. The organic phase was washed once with 50 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 5, 4.3 g of white solid, yield 92%, ee 99%. Figure 4 ).

[0122] Example 4

[0123] (4) Synthesis of intermediate 5

[0124] Under nitrogen protection, intermediate 4 (4.7 g, 9 mmol) was added to a high-pressure reactor, and 100 mL of dichloromethane was added and stirred to dissolve. Catalyst C3 (81 mg, 0.045 mmol) was then added to the reactor. After the addition was complete, the reactor was purged with hydrogen three times, and hydrogen was introduced into the reactor until the pressure reached 1 MPa. The temperature was raised to 40 °C and the reaction was carried out for 24 h. The reaction solution was cooled to room temperature, and 60 mL of water was added. The mixture was extracted and separated. The organic phase was washed once with 50 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 5, 4.2 g of white solid, yield 89%, ee 98% ( Figure 5 ).

[0125] Example 5

[0126] (5) Synthesis of intermediate 5

[0127] Under nitrogen protection, intermediate 4 (4.7 g, 9 mmol) was added to a high-pressure reactor, followed by the addition of 100 mL of dichloromethane and stirring to dissolve. Catalyst C3 (41 mg, 0.023 mmol) was then added to the reactor. After the addition was complete, the reactor was purged with hydrogen three times, and hydrogen was introduced into the reactor until the pressure reached 1 MPa. The mixture was then heated to 40 °C and reacted for 24 h. The reaction solution was cooled to room temperature, and 60 mL of water was added. The mixture was extracted and separated. The organic phase was washed once with 50 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 5, a white solid of 3.7 g, yield 80%, ee 95%. Figure 6 ).

[0128] Example 6

[0129] (6) Synthesis of intermediate 5

[0130] Under nitrogen protection, intermediate 4 (4.7 g, 9 mmol) was added to a high-pressure reactor, and 100 mL of dichloromethane was added and stirred to dissolve. Ru catalyst ([R-RuOAc2(BINAP)], CAS 325146-81-4, 76 mg, 0.09 mmol) was added to the reactor. After the addition was complete, the reactor was purged with hydrogen three times, and hydrogen was introduced into the reactor until the pressure reached 1 MPa. The temperature was raised to 40 °C and the reaction was carried out for 24 h. The reaction solution was cooled to room temperature, and TLC monitoring showed no product formation.

[0131] Example 7

[0132] (7) Synthesis of intermediate 5

[0133] Under nitrogen protection, intermediate 4 (4.7 g, 9 mmol) was added to a high-pressure reactor, and 100 mL of dichloromethane was added and stirred to dissolve. Rh catalyst (Rh(COD)((S,S)-Et-DUPHOS)BF4, cas213343-64-7, 59 mg, 0.09 mmol) was added to the reactor. After the addition was complete, hydrogen was purged three times, and hydrogen was introduced into the reactor until the pressure reached 1 MPa. The temperature was raised to 40 °C and the reaction was carried out for 24 h. The reaction solution was cooled to room temperature, and 60 mL of water was added. The mixture was extracted and separated. The organic phase was washed once with 50 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 5, 0.4 g of white solid, yield 8%, ee 35%. Figure 7 ).

[0134] Example 8

[0135] (8) Synthesis of intermediate 5

[0136] Under nitrogen protection, intermediate 4 (4.7 g, 9 mmol) was added to a high-pressure reactor, followed by the addition of 100 mL of dichloromethane and stirring to dissolve. Pd catalyst (Pd(R-BINAP)Cl2, CAS 115826-95-4, 72 mg, 0.09 mmol) was then added to the reactor. After the addition was complete, the reactor was purged with hydrogen three times, and hydrogen gas was introduced into the reactor until the pressure reached 1 MPa. The reactor was then heated to 40 °C and reacted for 24 h. The reaction solution was cooled to room temperature, and TLC monitoring revealed no product formation.

[0137] Example 9: Asymmetric Synthesis of Glycyrrhizin

[0138] (1) Synthesis of intermediate 3

[0139] Under nitrogen protection, intermediate 1 (10 g, 48.5 mmol) and intermediate 2 (12.6 g, 48.5 mmol) were added to 150 mL of acetone, stirred until dissolved, and then placed in an ice bath. Potassium carbonate (8 g, 58.2 mmol) was added to the reaction solution in three portions. After the additions were complete, the reaction was allowed to proceed 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 3, 15.5 g of gray solid, in 83% yield.1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz, 1H), 7.43-7.30 (m, 11H), 6.70-6.61 (m, 2H), 6.56 (d, J = 2.1 Hz, 1H), 5.28 (s,2H), 5.09 (d, J = 5.9 Hz, 4H), 4.60 (s, 2H), 2.50 (s, 2H), 1.36 (s, 6H).

[0140] (2) Synthesis of intermediate 4

[0141] Under nitrogen protection, intermediate 3 (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 acetonitrile was removed by concentration under reduced pressure. 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.

[0142] 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, and the reaction was allowed to proceed at room temperature for 12 h after each addition. The reaction was quenched by slowly adding 50 mL of saturated ammonium chloride solution to the reaction 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 4, 8.1 g of gray solid, in 85% yield. 1 H NMR (400 MHz, CDCl3) δ 7.45-7.28 (m, 10H), 7.22 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 8.4 Hz,1H), 6.62-6.55 (m, 2H), 6.50 (s, 1H), 6.45 (d, J = 8.4 Hz, 1H), 5.13 (s, 2H), 5.04 (d, J = 7.0 Hz, 4H), 2.68 (s, 2H), 1.44 (s, 6H).

[0143] (3) Synthesis of intermediate 5

[0144] Under nitrogen protection, intermediate 4 (6.2 g, 12 mmol) was added to a high-pressure reactor, followed by the addition of 110 mL of dichloromethane and stirring to dissolve. Catalyst C3 (107 mg, 0.06 mmol) was then added to the reactor. After the addition was complete, the reactor was purged with hydrogen three times, and hydrogen was introduced into the reactor until the pressure reached 1 MPa. The mixture was then heated to 40 °C and reacted for 24 h. The reaction solution was cooled to room temperature, and 60 mL of water was added. The mixture was extracted and separated. The organic phase was washed once with 50 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 5, a white solid of 5.7 g, yield 91%, ee 99%. Figure 8 ). 1 H NMR (400 MHz, CDCl3) δ 7.43-7.26 (m,10H), 7.20 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.64-6.57 (m, 2H), 6.47 (d, J = 8.4 Hz, 1H), 5.15 (s, 2H), 5.06 (d, J = 7.0 Hz, 4H), 4.63-4.48(m, 1H), 4.04 (m, 1H), 3.65-3.53 (m, 1H), 2.97 (dd, J = 15.4, 11.7 Hz, 1H), 2.82 (m, 1H), 2.74-2.61 (m, 2H), 1.43 (s, 6H).

[0145] (4) Synthesis of intermediate 6

[0146] Under nitrogen protection, intermediate 5 (4.2 g, 8 mmol) was added to 50 mL of dichloromethane and stirred to dissolve. The reaction solution was cooled to -78 °C, and 1 mol / L boron tribromide (20 mL, 20 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 (hexane / ethyl acetate = 80 / 20) to give intermediate 6, 2.3 g of white solid, yield 83%. 1HNMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.85 (d, J =8.4 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 6.32 (dd, J= 8.4, 2.4 Hz, 1H), 5.63 (s, 1H), 4.50 (dt, J = 10.3, 3.0 Hz, 1H), 3.94 (t, J= 10.2 Hz, 1H), 3.63-3.45 (m, 1H), 3.01 (dd, J = 15.6, 11.1 Hz, 1H), 2.86-2.74 (m, 1H), 2.74-2.61 (m, 2H), 1.45 (s, 3H), 1.41 (s, 3H).

[0147] (5) Synthesis of intermediate 7

[0148] Under nitrogen protection, intermediate 6 (2.0 g, 6 mmol) was added to 50 mL of methanol, stirred until dissolved, and then placed in an ice bath. Sodium borohydride (1.1 g, 28 mmol) was added to the reaction solution in three portions, and the reaction was allowed to proceed at room temperature for 2 h after each addition. The reaction was quenched by slowly adding 10 mL of saturated ammonium chloride solution to the reaction 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 = 80 / 20) to give intermediate 7, 2.0 g of gray solid, in 96% yield. 1HNMR (400 MHz, DMSO-d6) δ 9.42-9.33 (m, 1H), 9.17-9.08 (m, 1H), 6.93-6.82 (m,2H), 6.32 (dd, J = 2.2, 1.1 Hz, 1H), 6.25 (dd, J = 8.3, 1.3 Hz, 1H), 6.19(ddd, J = 8.3, 5.9, 2.4 Hz, 1H), 4.84-4.71 (m, 1H), 4.56 (dd, J = 10.3, 3.5Hz, 1H), 4.33 -4.18 (m, 1H), 3.42-3.21 (m, 1H), 3.02-2.81 (m, 1H), 2.79-2.60(m, 1H), 1.94-1.78 (m, 2H), 1.35 (s, 3H), 1.29 (s, 3H).

[0149] (6) Synthesis of glycyrrhizin

[0150] Under nitrogen protection, intermediate 7 (1.7 g, 5 mmol) was added to 50 mL of toluene and stirred until dissolved. p-Toluenesulfonic acid monohydrate (1.9 g, 10 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 = 80 / 20) to give (R)-glycyrrhizin, 1.5 g of white solid, yield 91%, ee 97%. Figure 9 ). 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, 2.4 Hz, 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).

[0151] In summary, this invention utilizes a chiral metal catalyst-catalyzed asymmetric hydrogenation to construct the chiral center of glycyrrhizin, thereby improving the synthesis efficiency of the asymmetric synthesis of glycyrrhizin. Preferred metal catalysts include C1, C2, and C3, with product yields all exceeding 80% and ee all exceeding 94%. Furthermore, the minimum required metal catalyst equivalent is only 0.5 mol%, significantly reducing material costs. The optimal conditions are described in Example 3 of this invention, achieving an optimal yield of 92% and an ee of 99%.

[0152] The conventional techniques and undescribed solutions in the above embodiments are all well known in the art, and therefore will not be described in detail 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. An asymmetric synthesis method for (R)-glycyrrhizin, characterized in that, It includes the following steps: 1) Add intermediate 1 and intermediate 2 to acetone, stir to dissolve, place in an ice bath, add potassium carbonate, react at room temperature after addition, quench the reaction after the reaction is complete, and separate and purify to obtain intermediate 3. 2) Add intermediate 3 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, and filter to obtain intermediate phosphine salt. Add phosphine salt to ethanol, stir to dissolve, place under ice bath, add sodium ethoxide, and react at room temperature after the addition is complete. After the reaction is complete, quench the reaction and purify to obtain intermediate 4. 3) Add intermediate 4 to a high-pressure reactor, add dichloromethane and stir to dissolve; add a chiral metal catalyst, introduce hydrogen gas and heat to react, and after the reaction is completed, separate and purify to obtain intermediate 5; 4) Add intermediate 5 to dichloromethane, add boron tribromide dropwise at -78 ℃, and react at -78 ℃. After the reaction is complete, separate and purify to obtain intermediate 6. 5) Add intermediate 6 to methanol, stir to dissolve, place in an ice bath, add sodium borohydride, react at room temperature after the addition is complete, quench the reaction after the reaction is complete, and separate and purify to obtain intermediate 7. 6) Add intermediate 7 to toluene and stir to dissolve. Add p-toluenesulfonic acid monohydrate and heat to react. Separate and purify to obtain (R)-glycyrrhizin. Steps 1) through 6) are all performed under nitrogen protection; Step 3) The chiral metal catalyst described has the structure shown in general formula (I): （Ⅰ） Wherein, R1 is a C1-6 straight-chain or branched alkyl group, a benzene ring, or a 5-8 membered unsaturated carbon ring or heterocycle; R2 is a C1-7 straight-chain or branched alkyl group, or a benzene ring. The method includes the following synthetic route: ； The numbers 1-7 in the synthesis route are intermediates 1-7.

2. The method as described in claim 1, characterized in that, In the chiral metal catalyst of general formula (Ⅰ), R1=-CH(CH3)2, R2=-Bn or R1=-CH3, R2=-Ph or R1=-CH3, R2=-Bn.

3. The method as described in claim 2, characterized in that, In the chiral metal catalyst of general formula (Ⅰ), R1=-CH(CH3)2 and R2=-Bn.

4. The method according to any one of claims 1-3, characterized in that, In step 1), the molar ratio of intermediate 1 and intermediate 2 to potassium carbonate is 1:1:1.

2. And / or the molar ratio of intermediate 3 and triphenylphosphine hydrobromide and sodium ethoxide in step 2) is 1:1:1; And / or the amount of the chiral metal catalyst in step 3) is not less than 0.5 mol% of intermediate 4. And / or the molar ratio of intermediate 5 and boron tribromide in step 4) is 1:2.5; And / or the molar ratio of intermediate 6 and sodium borohydride in step 5) is 3:14; And / or the molar ratio of intermediate 7 and p-toluenesulfonic acid monohydrate in step 6) is 1:

2.

5. The use of the chiral metal catalyst according to any one of claims 1-3 in the catalytic asymmetric hydrogenation of intermediate 4 to construct the (R)-glycyrrhizin chiral center.

6. The application as described in claim 5, characterized in that, The amount of the chiral metal catalyst is not less than 0.5 mol of the intermediate 4.

7. A method for constructing (R)-glycyrrhizic chiral centers, characterized in that, The step includes the catalytic asymmetric hydrogenation of intermediate 4 using a chiral metal catalyst as described in any one of claims 1-3.

8. The method as described in claim 7, characterized in that, The method includes the step of catalytic asymmetric hydrogenation of the intermediate 4 using the chiral metal catalyst of claim 3, wherein the molar ratio of the chiral metal catalyst of claim 3 to the intermediate 4 is 200:

1.

9. An intermediate compound for the synthesis of (R)-glycyrrhizin, characterized in that, The structural formula of the intermediate compound is: ； Or: ； Or: ； Or: ； Or: ； Or: 。 10. The use of the intermediate compound of claim 9 in the synthesis of glycyrrhizin.

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