Search

CN-121991088-A - Synthesis method of (R) -glabridin with high optical purity

CN121991088ACN 121991088 ACN121991088 ACN 121991088ACN-121991088-A

Abstract

The invention discloses a method for synthesizing (R) -glabridin with high optical purity, belonging to the technical field of organic synthesis. The synthesis method comprises the steps of dissolving methyl-protected isoflavone in a solvent, adding boron tribromide for deprotection reaction, then enabling a reaction product to generate asymmetric hydrogen transfer reaction in an acid-base mixed solution under the action of a chiral ruthenium catalyst, and finally enabling the reaction product and a silane reagent to conduct dehydroxylation reaction in the solvent in the presence of acid to obtain (R) -glabridin. The invention synthesizes (R) -glabridin with high efficiency and high selectivity by three steps of simple reaction, has high total yield and excellent optical purity, and has mild condition and simple post-treatment method, thereby being suitable for large-scale production.

Inventors

  • LU YAN
  • WANG GUANGCHAO
  • YU HONGMENG
  • WANG FAPING

Assignees

  • 山东梅奥华卫科技有限公司
  • 美丽序章(山东)生物科技有限公司
  • 上海交通大学

Dates

Publication Date
20260508
Application Date
20260130

Claims (10)

  1. 1. The synthesis method of the (R) -glabridin with high optical purity is characterized by comprising the following steps: S1, dissolving a compound shown in a formula (I) in a solvent, and adding boron tribromide to carry out deprotection reaction to obtain a compound shown in a formula (II); Formula (I); Formula (II); S2, carrying out asymmetric hydrogen transfer reaction on a compound shown in a formula (II) in an acid-base mixed solution under the action of a chiral ruthenium catalyst to obtain a compound shown in a formula (III); formula (III); S3, in the presence of acid, carrying out dehydroxylation reaction on the compound shown in the formula (III) and a silane reagent in a solvent to obtain (R) -glabridin.
  2. 2. The synthesis method according to claim 1, wherein the deprotection reaction of step S1 is carried out under the protection of inert gas at-78 to-20 ℃, and the solvent in step S1 is at least one selected from dichloromethane, chloroform or 1, 2-dichloroethane.
  3. 3. The synthesis method according to claim 1, wherein in step S1, the molar ratio of the compound represented by formula (I) to boron tribromide is 1 (2-4).
  4. 4. The method of claim 1, wherein in the step S2, the acid in the acid-base mixture is at least one selected from formic acid, acetic acid and propionic acid, the base is at least one selected from triethylamine, diethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene, the molar ratio of the acid to the base is (0.4-3): 1, the solvent of the acid-base mixture is at least one selected from methyl acetate, ethyl acetate, propyl acetate and ethyl propionate, and the molar ratio of the compound represented by the formula (II) to the base is (5-20).
  5. 5. The synthetic method of claim 1 wherein the chiral ruthenium catalyst is selected from at least one of the following structures: 。
  6. 6. the synthesis method according to claim 5, wherein the chiral ruthenium catalyst has an addition amount of 0.5-3.0 mol% of a compound represented by formula (II), and has the following structure: 。
  7. 7. the synthesis method according to claim 1, wherein the asymmetric hydrogen transfer reaction in step S2 is performed at a reaction temperature of 40 to 80 ℃ for 15 to 30 hours.
  8. 8. The synthesis method according to claim 1, wherein in step S3, the acid is at least one selected from trifluoroacetic acid, boron trifluoride diethyl etherate, anhydrous aluminum chloride, anhydrous ferric chloride, anhydrous zinc chloride and anhydrous nickel chloride, and the amount of the acid added is 2 to 6 equivalents of the compound represented by formula (III).
  9. 9. The synthesis method according to claim 1, wherein in step S3, the silane reagent is at least one selected from triethylsilane, tributylsilane, triphenylsilane and triisopropylsilane, and the addition amount of the silane reagent is 1 to 5 equivalents of the compound represented by formula (III).
  10. 10. The synthesis method according to claim 1, wherein the solvent in the step S3 is at least one selected from dichloromethane, chloroform and 1, 2-dichloroethane, the temperature of the dehydroxylation reaction in the step S3 is 10 to 40 ℃, and the reaction time is 0.5 to 3 hours.

Description

Synthesis method of (R) -glabridin with high optical purity Technical Field The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing (R) -glabridin with high optical purity. Background The information disclosed in the background of the invention is only for enhancement of understanding of the general background of the invention and is not necessarily to be taken as an admission or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art. Glabridin is an important flavonoid compound extracted from glabra licorice, has remarkable whitening, anti-inflammatory, antioxidant and antibacterial activities, and has important application value in the fields of high-end cosmetics and medicines. At present, the high-purity glabridin is mainly obtained by plant extraction, but the high-purity glabridin has extremely low content in plants and is often coexistent with structural analogues, so that the separation and purification are difficult, the cost is high, the purity of common extracts is usually only about 40%, and the large-scale requirements are difficult to meet. In order to fundamentally solve the source problem, chemical synthesis methods become an important research direction. However, both naturally occurring and active glabridin are in the (R) -configuration, and have the following structural formula: 。 However, most of the existing chemical synthesis methods can only obtain racemate, the biological activity of which is obviously different from that of natural products, and the application value of the existing chemical synthesis methods is limited. Although a plurality of methods capable of synthesizing optical purity R-configuration glabridin are reported at present, the methods still generally have some outstanding problems restricting the industrial application, such as the need of using expensive chiral catalysts or noble metals, leading to great increase of production cost, longer synthetic route, more reaction steps, lower total yield and complex operation, and the severe reaction conditions of partial methods, such as the need of extremely high hydrogen pressure, ultra-low temperature environment or special catalyst systems, high requirements on equipment and safe production, or the use of cheap raw materials, but the problems of insufficient stereoselectivity, undefined catalysts, poor reproducibility and the like of the whole process, and the realization of stable, efficient and economic mass production is difficult. Therefore, developing a synthesis method of (R) -glabridin with high optical purity, which is based on cheap and easily available raw materials, has simple reaction steps, mild conditions, high stereoselectivity, proper cost and easy amplification, is still a technical problem to be solved in the field. Disclosure of Invention In view of the above, the present invention provides a method for synthesizing (R) -glabridin with high optical purity, which synthesizes (R) -glabridin efficiently and selectively in three steps with a simple reaction, has a high total yield and excellent optical purity, and is suitable for mass production under mild conditions. The invention provides a method for synthesizing (R) -glabridin with high optical purity, which comprises the following steps: S1, dissolving a compound shown in a formula (I) in a solvent, and adding boron tribromide to carry out deprotection reaction to obtain a compound shown in a formula (II); Formula (I); Formula (II); S2, carrying out asymmetric hydrogen transfer reaction on a compound shown in a formula (II) in an acid-base mixed solution under the action of a chiral ruthenium catalyst to obtain a compound shown in a formula (III); formula (III); S3, in the presence of acid, carrying out dehydroxylation reaction on the compound shown in the formula (III) and a silane reagent in a solvent to obtain (R) -glabridin. Preferably, the deprotection reaction of the step S1 is carried out under the protection of inert gas at-78 to-20 ℃, and the solvent in the step S1 is selected from at least one of dichloromethane, chloroform or 1, 2-dichloroethane. Preferably, in the step S1, the molar ratio of the compound shown in the formula (I) to the boron tribromide is 1 (2-4). Preferably, in the step S2, the acid in the acid-base mixed solution is at least one selected from formic acid, acetic acid and propionic acid, the base is at least one selected from triethylamine, diethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene, the molar ratio of the acid to the base is (0.4-3): 1, the solvent of the acid-base mixed solution is at least one selected from methyl acetate, ethyl acetate, propyl acetate and ethyl propionate, and the molar ratio of the compound shown in the formula (II) to the base is (5-20). Preferably, the chiral ruthenium catalyst is selected from at least one of the following structures: 。 Further, the addition amount