A process for the preparation of r-licorice

Abstract

The application belongs to the technical field of glabridin preparation, and particularly relates to a preparation method of R-glabridin, which comprises the following steps: S1, under a protective gas atmosphere, dissolving a glabridin racemate in an organic solvent A, and reacting with a halogenated reagent through a substitution reaction, and after purification, preparing a halogenated intermediate I; S2, under the protective gas atmosphere, dissolving the halogenated intermediate I prepared in S1 in an organic solvent B, and under alkaline conditions, preparing an intermediate II through a dehalogen olefination reaction, and after purification; S3, under a hydrogen atmosphere, dissolving the intermediate II prepared in S2 in an organic solvent C, and under the action of a catalyst, preparing R-glabridin through an asymmetric hydrogenation reaction, and after purification. The method has the advantages of multiple raw material sources, obvious cost advantage, convenient preparation method, high total yield, less waste and high purity, and is beneficial to industrialization.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of preparing glabridin, and particularly relates to a preparation method of R-glabridin. BACKGROUND

[0002] Glabridin is a flavonoid extracted from a precious plant called glabrous licorice, and is praised as "whitening gold" because of its strong whitening effect. It can eliminate free radicals and melanin in the skin, and is a whitening and anti-aging saint of the skin.

[0003] Glabridin can be prepared by plant extraction method and synthesis method. The plant extraction method is gradually abandoned due to environmental pollution caused by the use of a large amount of Class A solvents, and the organic synthesis method is studied a lot. R-glabridin with a single configuration is less studied. The existing patent CN108440553A discloses a method for asymmetric synthesis of optically pure glabridin catalyzed by a ruthenium complex, and the synthesis route is as follows:

[0004]

[0005]

[0006] The above synthesis route uses an isoflavone protected by an R protecting group as a raw material, which is not easy to obtain. The synthesis route uses toxic and dangerous chemicals, so that the entire synthesis route is not easy to implement and the cost is high.

[0007] CN111362961A reports a direct chiral synthesis of R-type product, and the synthesis route is as follows:

[0008]

[0009] The above synthesis route uses raw materials that are not easy to obtain and has a high cost. Moreover, the synthesis route has many steps, which affects the yield. SUMMARY

[0010] To solve the above technical problems, the application provides a preparation method of R-glabridin.

[0011] The application specifically realizes the technical scheme as follows.

[0012] A preparation method of R-glabridin includes the following steps:

[0013] S1, under a protective gas atmosphere, dissolving glabridin racemate in an organic solvent A, and reacting with a halogenating reagent through a substitution reaction to prepare a halogenated intermediate I after purification;

[0014] S2, under a protective gas atmosphere, the halogenated intermediate I prepared in S1 is dissolved in an organic solvent B, and an intermediate II is prepared by dehalogen olefination reaction under alkaline conditions, and purified.

[0015] S3, under a hydrogen atmosphere, the intermediate II prepared in S2 is dissolved in an organic solvent C, and R-liquiritigenin is prepared by asymmetric hydrogenation reaction under the action of a catalyst, and purified.

[0016] The synthetic route is as follows:

[0017]

[0018] Preferably, in S1, the halogenated reagent is any one or mixture of two of NBS, bromine, hydrogen peroxide + hydrobromic acid, NCS, NIS, I2, Cl2, cyanuric chloride, dibromohydantoin, dichlorohydantoin; the molar ratio of the liquiritigenin racemate and the halogenated reagent is 1:1-5.

[0019] Preferably, in S2, the base used is any one or mixture of two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, and the molar ratio of the halogenated intermediate I and the base is 1:1-5.

[0020] Preferably, in S3, the molar ratio of the intermediate II and the catalyst is 100:1-10; the catalyst is made of a metal salt and an R / S-binol ligand, and the mass ratio of the metal salt and the R / S-binol ligand is 1:1.5, and the structure of the binol ligand is as shown below:

[0021]

[0022] wherein, R1, R2, R3 are respectively selected from alkyl, aryl.

[0023] More preferably, the metal salt is palladium chloride, palladium acetate, ruthenium chloride, rhodium chloride, nickel chloride.

[0024] Preferably, in S3, the hydrogen pressure is 0.1-5 MPa.

[0025] Preferably, the organic solvent A, the organic solvent B, and the organic solvent C are respectively any one of halogenated hydrocarbon solvents, aromatic solvents, ether solvents, ester solvents or alcohol solvents, and strong polar solvents containing heteroatoms.

[0026] The molar ratio of the organic solvent A and the liquiritigenin racemate is 1-10:1, the molar ratio of the organic solvent B and the halogenated intermediate I is 1-10:1, and the molar ratio of the organic solvent C and the intermediate II is 1-10:1.

[0027] More preferably, the halogenated hydrocarbon solvents include dichloromethane and dichloroethane; the aromatic solvents include chlorobenzene, toluene, and xylene; the ether solvents include tetrahydrofuran; the ester solvents include methyl acetate and ethyl acetate; the alcohol solvents include methanol, ethanol, and ethylene glycol; and the heteroatom-containing strongly polar solvents include DMF, DMA, DMSO, NMP, sulfolane, and DMI.

[0028] Preferably, in S1 and S3, the reaction temperature is 0-100℃; in S2, the reaction temperature is -50-150℃.

[0029] More preferably, in S1 and S3, the reaction temperature is 50-80℃, respectively; and in S2, the reaction temperature is -30-10℃.

[0030] Compared with the prior art, the present invention has the following advantages:

[0031] To address the challenges of readily available raw materials and complex synthetic routes in the synthesis of R-glycyrrhizin in existing technologies, this invention provides a method for synthesizing R-glycyrrhizin with readily available raw materials, a simple synthetic route, and ease of industrial production. Specifically, this invention involves a three-step reaction in an organic solvent at a specific temperature, using readily available racemic glycyrrhizin as the raw material, involving halogenation, olefination, and asymmetric hydrogenation reduction to obtain optically pure R-glycyrrhizin. This method offers advantages such as abundant raw material sources, significant cost reduction, more convenient preparation, high overall yield, less waste, and higher purity, making it more suitable for industrial production compared to existing synthetic routes. Detailed Implementation

[0032] To enable those skilled in the art to better understand and implement the technical solutions of the present invention, the present invention will be further described below with reference to specific embodiments and data, but the embodiments are not intended to limit the present invention.

[0033] Unless otherwise specified, the experimental and detection methods described in the following embodiments are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0034] A method for preparing R-glycyrrhizin includes the following steps:

[0035] S1. Under a protective gas atmosphere, the racemic mixture of glycyrrhizin was dissolved in organic solvent A and reacted with a halogenating reagent through a substitution reaction. After purification, halogenated intermediate I was prepared.

[0036] S2. Under a protective gas atmosphere, the halogenated intermediate I prepared in S1 is dissolved in organic solvent B, and under alkaline conditions, it is purified by a dehalogenation olefination reaction to prepare intermediate II.

[0037] S3, under hydrogen atmosphere, the intermediate II prepared in S2 is dissolved in organic solvent C, and R- glabridin is prepared by asymmetric hydrogenation reaction under the action of catalyst and after purification.

[0038] The synthetic route is as follows:

[0039]

[0040] The above is specifically illustrated by the following examples.

[0041] First, the halogenated intermediate I is synthesized, and the synthetic equation is as follows:

[0042]

[0043] The above synthesis is specifically illustrated by the following examples.

[0044] Example 1

[0045] Under nitrogen protection, 500 mL of reaction kettle is put into glabridin racemate 32.4 g (0.10 mol), chlorobenzene 200 mL, NBS 17.8 g (0.1 mol), slowly heated to 50 degrees, and stirred for 24 h, cooled to room temperature, filtered to obtain brominated intermediate I and succinimide by-product, the solid is added with water 100 ml to remove succinimide to obtain brominated intermediate I wet product, oven dried to obtain finished product 33.4 g, yield 83%; the filtered filtrate chlorobenzene (directly used in the next batch of reaction).

[0046] Example 2

[0047] Under nitrogen protection, 500 mL of reaction kettle is put into glabridin racemate 32.4 g (0.10 mol), chlorobenzene 200 mL, bromine 0.1 mol, slowly heated to 50 degrees, and stirred for 24 h, cooled to room temperature, filtered to obtain brominated intermediate I and succinimide by-product, the solid is added with water 100 ml to remove succinimide to obtain brominated intermediate I wet product, yield 23%; the filtered filtrate chlorobenzene (directly used in the next batch of reaction).

[0048] Example 3

[0049] Under nitrogen protection, 500 mL of reaction kettle is put into glabridin racemate 32.4 g (0.10 mol), chlorobenzene 200 mL, hydrogen peroxide + hydrobromic acid 0.1 mol, slowly heated to 50 degrees, and stirred for 24 h, cooled to room temperature, filtered to obtain brominated intermediate I and succinimide by-product, the solid is added with water 100 ml to remove succinimide to obtain brominated intermediate I wet product, yield 35%; the filtered filtrate chlorobenzene (directly used in the next batch of reaction).

[0050] Example 4

[0051] Into a 500 mL reactor, under nitrogen protection, was placed glabratin racemate 32.4 g (0.10 mol), chlorobenzene 200 mL, chlorine 0.1 mol, slowly heated to 50 degrees, and stirred for 24 h. After cooling to room temperature, the brominated intermediate I and succinimide by-product were filtered. The solid was added to 100 mL water to remove the succinimide to obtain the wet product of brominated intermediate I, with a yield of 71%. The filtered chlorobenzene (directly used in the next batch of reaction).

[0052] Example 5

[0053] Into a 500 mL reactor, under nitrogen protection, was placed glabratin racemate 32.4 g (0.10 mol), chlorobenzene 200 mL, NCS 0.1 mol, slowly heated to 50 degrees, and stirred for 24 h. After cooling to room temperature, the brominated intermediate I and succinimide by-product were filtered. The solid was added to 100 mL water to remove the succinimide to obtain the wet product of brominated intermediate I, with a yield of 59%. The filtered chlorobenzene (directly used in the next batch of reaction).

[0054] Example 6

[0055] Into a 500 mL reactor, under nitrogen protection, was placed glabratin racemate 32.4 g (0.10 mol), chlorobenzene 200 mL, NIS 0.1 mol, slowly heated to 50 degrees, and stirred for 24 h. After cooling to room temperature, the brominated intermediate I and succinimide by-product were filtered. The solid was added to 100 mL water to remove the succinimide to obtain the wet product of brominated intermediate I, with a yield of 64%. The filtered chlorobenzene (directly used in the next batch of reaction).

[0056] Example 7

[0057] Into a 500 mL reactor, under nitrogen protection, was placed glabratin racemate 32.4 g (0.10 mol), chlorobenzene 200 mL, I 20.1 mol, slowly heated to 50 degrees, and stirred for 24 h. After cooling to room temperature, the brominated intermediate I and succinimide by-product were filtered. The solid was added to 100 mL water to remove the succinimide to obtain the wet product of brominated intermediate I, with a yield of 8%. The filtered chlorobenzene (directly used in the next batch of reaction).

[0058] Second, the synthesis of intermediate II, the synthesis equation is shown below:

[0059]

[0060] The above synthesis is specifically illustrated by the following examples.

[0061] Example 8

[0062] Under nitrogen protection, 40.2 g (0.10 mol) of brominated intermediate I, 200 mL of ethanol, and 100 mL of water were added to a 500 mL reactor. 0.06 mol of 5% sodium carbonate solution was added dropwise at 0°C. After the addition was complete, the mixture was kept at this temperature for 1 h. The mixture was then filtered, washed with water, and dried to obtain 27.4 g of intermediate II, with a yield of 85% and a purity of 98%.

[0063] Third, R-glycyrrhizin was synthesized, and the synthetic equation is shown below:

[0064]

[0065] The above synthesis is illustrated through the following examples.

[0066] Example 9

[0067] 32.2 g (0.10 mol) of intermediate II, 100 mL of methanol, 1 g of catalyst NiCl2 + 1.5 g (R)-binaphthol were added to a 500 mL high-pressure reactor. After three nitrogen purgings and three hydrogen purgings, the pressure was set to 0.5 MPa, and the mixture was heated to 50 degrees Celsius and stirred for 12 h. The temperature was lowered and the pressure was released. After adding diatomaceous earth to adsorb the catalyst, the mixture was filtered to obtain the mother liquor. Methanol was recovered by atmospheric distillation (directly reused in the next batch of reaction), with a recovery rate of 92%. 50 mL of water was added, and the mixture was extracted with ethyl acetate and desolventized to obtain R-glycyrrhizin with a purity of >96% and an ee of 92%, yielding 83%.

[0068] Example 10

[0069] 32.2 g (0.10 mol) of intermediate II, 100 mL of methanol, 1 g of palladium chloride catalyst, and 1.5 g (R)-binaphthol were added to a 500 mL high-pressure reactor. After three nitrogen purgings and three hydrogen purgings, the pressure was set to 0.5 MPa, and the mixture was heated to 50 degrees Celsius and stirred for 12 h. The temperature was lowered and the pressure was released. After adding diatomaceous earth to adsorb the catalyst, the mixture was filtered to obtain the mother liquor. Methanol was recovered by atmospheric distillation (directly reused in the next batch of reaction), with a recovery rate of 92%. 50 mL of water was added, and the mixture was extracted with ethyl acetate and desolventized to obtain R-glycyrrhizin with a purity of >96% and an ee of 58%, yielding 28%.

[0070] Example 11

[0071] 500ml high pressure reactor, 32.2g of intermediate II (0.10mol), 100ml of methanol, 1g of rhodium chloride + 1.5g of (R)-binol, nitrogen replacement three times, hydrogen replacement three times, set pressure 0.5MPa, heated to 50 degrees, stirring reaction 12h, cooling and pressure relief, add diatomite to adsorb catalyst, pressure filtration to get mother liquor, normal pressure distillation to recover methanol (directly used to the next batch of reaction), recovery rate 92%, add 50ml of water, ethyl acetate extraction, desolventizing to get >96% of R-lumigan, 91%ee, yield 65%.

[0072] Example 12

[0073] 500ml high pressure reactor, 32.2g of intermediate II (0.10mol), 100ml of methanol, 1g of rhodium chloride + 1.5g of (R)-binol, nitrogen replacement three times, hydrogen replacement three times, set pressure 0.5MPa, heated to 50 degrees, stirring reaction 12h, cooling and pressure relief, add diatomite to adsorb catalyst, pressure filtration to get mother liquor, normal pressure distillation to recover methanol (directly used to the next batch of reaction), recovery rate 92%, add 50ml of water, ethyl acetate extraction, desolventizing to get >96% of R-lumigan, 91%ee, yield 65%.

[0074] Example 13

[0075] 500ml high pressure reactor, 32.2g of intermediate II (0.10mol), 100ml of methanol, 1g of rhodium chloride + 1.5g of (R)-binol, nitrogen replacement three times, hydrogen replacement three times, set pressure 0.5MPa, heated to 50 degrees, stirring reaction 12h, cooling and pressure relief, add diatomite to adsorb catalyst, pressure filtration to get mother liquor, normal pressure distillation to recover methanol (directly used to the next batch of reaction), recovery rate 92%, add 50ml of water, ethyl acetate extraction, desolventizing to get >96% of R-lumigan, 91%ee, yield 65%.

[0076] Example 14

[0077] 1000L high pressure reactor, 32.2kg of intermediate II, 300L of methanol, 150g of NiCl2+ 200g of (R)-binol (R3=t-Bu), nitrogen replacement three times, hydrogen replacement three times, set pressure 0.5MPa, heated to 50 degrees, stirring reaction 12h, cooling and pressure relief, add diatomite to adsorb catalyst, pressure filtration to get mother liquor, normal pressure distillation to recover methanol (directly used to the next batch of reaction), recovery rate 95%, add 200L of water, ethyl acetate extraction, desolventizing to get >98% of R-lumigan, 95%ee, yield 88%.

[0078] It will be apparent to those skilled in the art that various modifications and variations can be made to the present application without departing from the spirit or scope of the application. Thus, it is intended that the present application cover modifications and variations of this application provided they come within the scope of the appended claims and their equivalents.

Claims

1. A process for the preparation of R-18a-Glycyrrhizin characterized in that, The method comprises the following steps: S1, dissolving glabriden racemate in organic solvent A under a protective gas atmosphere, and carrying out substitution reaction with a halogenated reagent, and preparing halogenated intermediate I after purification; the molar ratio of glabriden racemate and the halogenated reagent is 1:1-5; the reaction temperature is 50°C; S2, dissolving the halogenated intermediate I prepared in S1 in organic solvent B under a protective gas atmosphere, and carrying out dehalogen olefination reaction under alkaline conditions, and preparing intermediate II after purification; the base used is any one or a mixture of two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium methoxide, sodium tert-butyl alcohol and potassium tert-butyl alcohol; the molar ratio of the halogenated intermediate I and the base is 1:0.6-5; the reaction temperature is 0°C; S3, dissolving the intermediate II prepared in S2 in organic solvent C under a hydrogen atmosphere, and carrying out asymmetric hydrogenation under the action of a catalyst, and preparing R-glabriden after purification; In S3, the molar ratio of the intermediate II and the catalyst is 100:1-10; the catalyst is made of a metal salt and an R-binaphthol ligand, and the mass ratio of the metal salt and the R-binaphthol ligand is 1:1.3-1.5, and the structure of the R-binaphthol ligand is as follows: ； Wherein, R1, R2, R3 are respectively selected from alkyl, aryl; the reaction temperature is 50°C; The metal salt is palladium chloride, palladium acetate, ruthenium chloride, rhodium chloride or nickel chloride; In S1, the halogenated reagent is NBS; The synthesis route is as follows: ； Wherein, X is bromine.

2. The process for the preparation of R-Kaempferol according to claim 1, characterized in that, In S3, the hydrogen pressure is 0.1-5 MPa.

3. The process for the preparation of R-Kaempferol according to claim 1, characterized in that, The organic solvent A, the organic solvent B and the organic solvent C are respectively any one of halogenated hydrocarbon solvents, aromatic solvents, ether solvents, ester solvents or alcohol solvents, and heteroatom-containing polar solvents; The molar ratio of the organic solvent A and the glabriden racemate is 1-10:1, the molar ratio of the organic solvent B and the halogenated intermediate I is 1-10:1, and the molar ratio of the organic solvent C and the intermediate II is 1-10:

1.

4. The process for the preparation of R-Kaempferol according to claim 3, characterized in that, The halogenated hydrocarbon solvents are dichloromethane and dichloroethane, the aromatic solvents are chlorobenzene, toluene and xylene, the ether solvents are tetrahydrofuran, the ester solvents are methyl acetate and ethyl acetate, the alcohol solvents are methanol, ethanol and ethylene glycol, and the heteroatom-containing polar solvents are DMF, DMA, DMSO, NMP and sulfolane.

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