Glabridin synthesis method of asymmetric gasification system

Abstract

The invention relates to the technical field of glabridin synthesis, and discloses a glabridin synthesis method of an asymmetric gasification system.The asymmetric gasification system can effectively control the stereochemical process in the glabridin synthesis process through an well-designed asymmetric catalyst, so that the product has high optical purity. Compared with the traditional method, the high stereoselectivity can obviously improve the quality and biological activity of glabridin, so that the glabridin can be more effectively applied to the fields of medicines, cosmetics and the like.

Description

Technical Field

[0001] The invention relates to the technical field of glabridin synthesis, and more specifically to a method for synthesizing glabridin in an asymmetric gasification system. Background Art

[0002] Glabridin is mainly found in plants such as licorice. It has excellent antioxidant and whitening physiological activities. In the cosmetics industry, it is regarded as a highly effective natural whitening ingredient that can inhibit the activity of tyrosinase and reduce the production of melanin. In the medical field, studies have also shown that it may have potential medicinal value such as anti-inflammatory and anti-cancer.

[0003] Traditional methods for synthesizing glabridin usually require multi-step reactions, including complex functional group protection and deprotection processes, and often have stringent requirements on reaction conditions, such as requiring high temperature, high pressure, or the use of highly toxic reagents. In addition, the total yield of these methods is usually not high, resulting in high production costs, which limits the large-scale production and application of glabridin. Therefore, it is of great practical significance to develop a more efficient, more environmentally friendly and high-yield synthesis method. For this purpose, we propose a method for synthesizing glabridin using an asymmetric gasification system. Summary of the invention

[0004] In order to overcome the deficiencies of the prior art, the present invention provides a method for synthesizing glabridin in an asymmetric gasification system to solve the problems raised in the above background technology.

[0005] To achieve the above object, the present invention provides the following technical solution: a method for synthesizing glabridin in an asymmetric gasification system, comprising the following steps;

[0006] S1: Synthesis of compound Ⅰ;

[0007] Raw materials: 2,2-dimethyl-2H-chromen-5-ol and levorotatory epichlorohydrin;

[0008] Reaction conditions: The reaction is carried out under alkaline conditions. The base used can be any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or a mixture of two thereof. The molar ratio of 2,2-dimethyl-2H-chromen-5-ol to the base is 1:1.0-2.0, preferably 1:1.1-1.3, to obtain compound I.

[0009] S2: cyclization to generate compound II;

[0010] Raw materials: Compound Ⅰ;

[0011] Reaction conditions: The cyclization reaction is carried out under acidic heating conditions. The acid used can be any one of gold trichloride, silver trifluoromethanesulfonate, ferric chloride, ferric bromide, boron trifluoride etherate, dichlorotitanocene, p-toluenesulfonic acid, tin tetrachloride, or a mixture of two thereof, preferably a mixture of gold trichloride and silver trifluoromethanesulfonate. The reaction temperature is 70°C to 100°C to obtain compound II.

[0012] S3: generate sulfonylated product III;

[0013] Raw materials: Compound II;

[0014] Reaction conditions: Add pyridine-2-sulfonyl fluoride and sodium bis(trimethylsilyl)amide to an organic solution of compound II at low temperature, react under stirring, the reaction temperature is -40°C to -80°C, to obtain sulfonylated compound III;

[0015] S4: generating coupling compound IV;

[0016] Raw materials: sulfonylated compound III;

[0017] Reaction conditions: under low temperature conditions, add a metal catalyst and an aryl Grignard reagent to an organic solution of compound III, and react under stirring conditions to obtain a coupling compound IV, wherein R is a protecting group. The metal catalyst is any one of copper trifluoromethanesulfonate, copper dimethanol, copper acetate, copper acetylacetonate, and cuprous iodide, preferably copper trifluoromethanesulfonate; the aryl Grignard reagent is selected from 2,4-disubstituted phenylmagnesium bromide, 2,4-disubstituted phenylmagnesium chloride, 2,4-disubstituted phenylmagnesium iodide, more preferably 2,4-dimethoxyphenylmagnesium bromide, and the reaction temperature is -40 to 0°C;

[0018] S5: deprotection to generate glabridin;

[0019] Raw materials: Compound IV;

[0020] Reaction conditions: Compound IV is deprotected under acidic or alkaline conditions to obtain optically pure glabridin. When R is one of methyl, methoxymethylene, and benzyl, compound IV is deprotected under acidic conditions, and the acid used is selected from any one of boron tribromide, hydrobromic acid, and acetic acid, or a mixture of two of them, more preferably boron tribromide; when R is one of triethylsilyl and tert-butyldimethylsilyl, compound IV is deprotected under alkaline conditions, and the base used is selected from any one of lithium hydroxide, potassium carbonate, and tetrabutylammonium fluoride, more preferably tetrabutylammonium fluoride.

[0021] As a preferred technical solution of the present invention, the asymmetric gasification reaction is carried out under relatively mild temperature (40-80° C.) and pressure (0.5-2 MPa) conditions.

[0022] As a preferred technical solution of the present invention, the reaction container adopts a pressure-resistant stainless steel reactor.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. The asymmetric gasification system of the present invention can effectively control the stereochemical process in the synthesis of glabridin through a carefully designed asymmetric catalyst, so that the product has a high optical purity. Compared with traditional methods, this high stereoselectivity can significantly improve the quality and biological activity of glabridin, making its application in the fields of medicine and cosmetics more effective.

[0025] 2. The asymmetric gasification reaction of the present invention is carried out under relatively mild temperature (40-80°C) and pressure (0.5-2MPa) conditions, avoiding the harsh conditions such as high temperature and high pressure that may be required in traditional synthesis methods. This not only reduces the requirements for reaction equipment, but also reduces energy consumption and safety risks, which is conducive to industrial production.

[0026] 3. The method of the present invention can achieve a higher yield of glabridin by optimizing the reaction system and synthesis steps. Compared with the traditional method, the increase in yield can reduce production costs, making the large-scale production of glabridin more economical and feasible, thereby meeting the growing market demand. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] Example 1: A method for synthesizing glabridin in an asymmetric gasification system, comprising the following steps:

[0029] S1: Synthesis of compound Ⅰ;

[0030] Raw materials: 2,2-dimethyl-2H-chromen-5-ol and levorotatory epichlorohydrin;

[0031] Reaction conditions: The reaction is carried out under alkaline conditions. The base used can be any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or a mixture of two thereof. The molar ratio of 2,2-dimethyl-2H-chromen-5-ol to the base is 1:1.0-2.0, preferably 1:1.1-1.3, to obtain compound I.

[0032] S2: cyclization to generate compound II;

[0033] Raw materials: Compound Ⅰ;

[0034] Reaction conditions: The cyclization reaction is carried out under acidic heating conditions. The acid used can be any one of gold trichloride, silver trifluoromethanesulfonate, ferric chloride, ferric bromide, boron trifluoride etherate, dichlorotitanocene, p-toluenesulfonic acid, tin tetrachloride, or a mixture of two thereof, preferably a mixture of gold trichloride and silver trifluoromethanesulfonate. The reaction temperature is 70°C to obtain compound II.

[0035] S3: generate sulfonylated product III;

[0036] Raw materials: Compound II;

[0037] Reaction conditions: under low temperature conditions, add pyridine-2-sulfonyl fluoride and sodium bis(trimethylsilyl)amide to the organic solution of compound II, react under stirring conditions, and the reaction temperature is -40°C to obtain sulfonyl compound III;

[0038] S4: generating coupling compound IV;

[0039] Raw materials: sulfonylated compound III;

[0040] Reaction conditions: under low temperature conditions, add a metal catalyst and an aryl Grignard reagent to the organic solution of compound III, and react under stirring conditions to obtain a coupling compound IV, wherein R is a protecting group. The metal catalyst is any one of copper trifluoromethanesulfonate, copper dimethanol, copper acetate, copper acetylacetonate, and cuprous iodide, preferably copper trifluoromethanesulfonate; the aryl Grignard reagent is selected from 2,4-disubstituted phenylmagnesium bromide, 2,4-disubstituted phenylmagnesium chloride, 2,4-disubstituted phenylmagnesium iodide, more preferably 2,4-dimethoxyphenylmagnesium bromide, and the reaction temperature is -40;

[0041] S5: deprotection to generate glabridin;

[0042] Raw materials: Compound IV;

[0043] Reaction conditions: Compound IV is deprotected under acidic or alkaline conditions to obtain optically pure glabridin. When R is one of methyl, methoxymethylene, and benzyl, compound IV is deprotected under acidic conditions, and the acid used is selected from any one of boron tribromide, hydrobromic acid, and acetic acid, or a mixture of two of them, more preferably boron tribromide; when R is one of triethylsilyl and tert-butyldimethylsilyl, compound IV is deprotected under alkaline conditions, and the base used is selected from any one of lithium hydroxide, potassium carbonate, and tetrabutylammonium fluoride, more preferably tetrabutylammonium fluoride.

[0044] Among them, the asymmetric gasification reaction is carried out under relatively mild temperature (40-80°C) and pressure (0.5-2MPa) conditions, avoiding the harsh conditions such as high temperature and high pressure that may be required in traditional synthesis methods. This not only reduces the requirements for reaction equipment, but also reduces energy consumption and safety risks, which is conducive to industrial production.

[0045] The reaction vessel is a pressure-resistant stainless steel reactor.

[0046] Example 2: A method for synthesizing glabridin in an asymmetric gasification system, comprising the following steps:

[0047] S1: Synthesis of compound Ⅰ;

[0048] Raw materials: 2,2-dimethyl-2H-chromen-5-ol and levorotatory epichlorohydrin;

[0049] Reaction conditions: The reaction is carried out under alkaline conditions. The base used can be any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or a mixture of two thereof. The molar ratio of 2,2-dimethyl-2H-chromen-5-ol to the base is 1:1.0-2.0, preferably 1:1.1-1.3, to obtain compound I.

[0050] S2: cyclization to generate compound II;

[0051] Raw materials: Compound Ⅰ;

[0052] Reaction conditions: The cyclization reaction is carried out under acidic heating conditions. The acid used can be any one of gold trichloride, silver trifluoromethanesulfonate, ferric chloride, ferric bromide, boron trifluoride etherate, dichlorotitanocene, p-toluenesulfonic acid, tin tetrachloride, or a mixture of two thereof, preferably a mixture of gold trichloride and silver trifluoromethanesulfonate. The reaction temperature is 100°C to obtain compound II.

[0053] S3: generate sulfonylated product III;

[0054] Raw materials: Compound II;

[0055] Reaction conditions: Add pyridine-2-sulfonyl fluoride and sodium bis(trimethylsilyl)amide to the organic solution of compound II at low temperature, react under stirring, the reaction temperature is -80°C, to obtain sulfonyl compound III;

[0056] S4: generating coupling compound IV;

[0057] Raw materials: sulfonylated compound III;

[0058] Reaction conditions: under low temperature conditions, add a metal catalyst and an aryl Grignard reagent to an organic solution of compound III, and react under stirring conditions to obtain a coupling compound IV, wherein R is a protecting group. The metal catalyst is any one of copper trifluoromethanesulfonate, copper dimethanol, copper acetate, copper acetylacetonate, and cuprous iodide, preferably copper trifluoromethanesulfonate; the aryl Grignard reagent is selected from 2,4-disubstituted phenylmagnesium bromide, 2,4-disubstituted phenylmagnesium chloride, 2,4-disubstituted phenylmagnesium iodide, more preferably 2,4-dimethoxyphenylmagnesium bromide, and the reaction temperature is 0°C;

[0059] S5: deprotection to generate glabridin;

[0060] Raw materials: Compound IV;

[0061] Reaction conditions: Compound IV is deprotected under acidic or alkaline conditions to obtain optically pure glabridin. When R is one of methyl, methoxymethylene, and benzyl, compound IV is deprotected under acidic conditions, and the acid used is selected from any one of boron tribromide, hydrobromic acid, and acetic acid, or a mixture of two of them, more preferably boron tribromide; when R is one of triethylsilyl and tert-butyldimethylsilyl, compound IV is deprotected under alkaline conditions, and the base used is selected from any one of lithium hydroxide, potassium carbonate, and tetrabutylammonium fluoride, more preferably tetrabutylammonium fluoride.

[0062] Example 3: A method for synthesizing glabridin in an asymmetric gasification system, comprising the following steps:

[0063] S1: Synthesis of compound Ⅰ;

[0064] Raw materials: 2,2-dimethyl-2H-chromen-5-ol and levorotatory epichlorohydrin;

[0065] Reaction conditions: The reaction is carried out under alkaline conditions. The base used can be any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or a mixture of two thereof. The molar ratio of 2,2-dimethyl-2H-chromen-5-ol to the base is 1:1.0-2.0, preferably 1:1.1-1.3, to obtain compound I.

[0066] S2: cyclization to generate compound II;

[0067] Raw materials: Compound Ⅰ;

[0068] Reaction conditions: The cyclization reaction is carried out under acidic heating conditions. The acid used can be any one of gold trichloride, silver trifluoromethanesulfonate, ferric chloride, ferric bromide, boron trifluoride ethyl ether, dichlorotitanocene, p-toluenesulfonic acid, tin tetrachloride, or a mixture of two thereof, preferably a mixture of gold trichloride and silver trifluoromethanesulfonate. The reaction temperature is 83°C to obtain compound II.

[0069] S3: generate sulfonylated product III;

[0070] Raw materials: Compound II;

[0071] Reaction conditions: Add pyridine-2-sulfonyl fluoride and sodium bis(trimethylsilyl)amide to the organic solution of compound II at low temperature, react under stirring, the reaction temperature is -60°C, to obtain sulfonylated compound III;

[0072] S4: generating coupling compound IV;

[0073] Raw materials: sulfonylated compound III;

[0074] Reaction conditions: under low temperature conditions, add a metal catalyst and an aryl Grignard reagent to an organic solution of compound III, and react under stirring conditions to obtain a coupling compound IV, wherein R is a protecting group. The metal catalyst is any one of copper trifluoromethanesulfonate, copper dimethanol, copper acetate, copper acetylacetonate, and cuprous iodide, preferably copper trifluoromethanesulfonate; the aryl Grignard reagent is selected from 2,4-disubstituted phenylmagnesium bromide, 2,4-disubstituted phenylmagnesium chloride, 2,4-disubstituted phenylmagnesium iodide, more preferably 2,4-dimethoxyphenylmagnesium bromide, and the reaction temperature is -20°C;

[0075] S5: deprotection to generate glabridin;

[0076] Raw materials: Compound IV;

[0077] Reaction conditions: Compound IV is deprotected under acidic or alkaline conditions to obtain optically pure glabridin. When R is one of methyl, methoxymethylene, and benzyl, compound IV is deprotected under acidic conditions, and the acid used is selected from any one of boron tribromide, hydrobromic acid, and acetic acid, or a mixture of two of them, more preferably boron tribromide; when R is one of triethylsilyl and tert-butyldimethylsilyl, compound IV is deprotected under alkaline conditions, and the base used is selected from any one of lithium hydroxide, potassium carbonate, and tetrabutylammonium fluoride, more preferably tetrabutylammonium fluoride.

[0078] Reaction mechanism: In the asymmetric gasification system, the active gas released by the gasifier undergoes an electrophilic addition reaction with the substrate molecule. In the presence of an asymmetric catalyst, the active sites of the substrate molecule (such as double bonds or phenolic hydroxyl groups, etc.) are activated, and the chiral environment of the catalyst guides the active gas to attack the substrate molecule from a specific direction, thereby achieving stereoselective control. For example, when the active gas is a hydrogen halide, it undergoes an addition reaction with the double bond of the flavonoid compound to form an intermediate with a halogen atom. Under the action of the catalyst, this intermediate undergoes further condensation reaction with the compound containing phenolic hydroxyl groups, and after a series of intramolecular rearrangement and cyclization reactions, the molecular structure of glabridin is gradually constructed. Throughout the reaction process, the asymmetric catalyst always controls the stereochemical process of the reaction, ensuring that the generated glabridin has a high optical purity.

[0079] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0080] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing glabridin in an asymmetric gasification system, characterized in that: The steps include: S1: Synthesis of compound Ⅰ; Raw materials: 2,2-dimethyl-2H-chromen-5-ol and levorotatory epichlorohydrin; Reaction conditions: The reaction is carried out under alkaline conditions. The base used can be any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or a mixture of two thereof. The molar ratio of 2,2-dimethyl-2H-chromen-5-ol to the base is 1:1.0-2.0, preferably 1:1.1-1.3, to obtain compound I. S2: cyclization to generate compound II; Raw materials: Compound Ⅰ; Reaction conditions: The cyclization reaction is carried out under acidic heating conditions. The acid used can be any one of gold trichloride, silver trifluoromethanesulfonate, ferric chloride, ferric bromide, boron trifluoride etherate, dichlorotitanocene, p-toluenesulfonic acid, tin tetrachloride, or a mixture of two thereof, preferably a mixture of gold trichloride and silver trifluoromethanesulfonate. The reaction temperature is 70°C to 100°C to obtain compound II. S3: generate sulfonylated product III; Raw materials: Compound II; Reaction conditions: Add pyridine-2-sulfonyl fluoride and sodium bis(trimethylsilyl)amide to an organic solution of compound II at low temperature, react under stirring, the reaction temperature is -40°C to -80°C, to obtain sulfonylated compound III; S4: generating coupling compound IV; Raw materials: sulfonylated compound III; Reaction conditions: under low temperature conditions, add a metal catalyst and an aryl Grignard reagent to an organic solution of compound III, and react under stirring conditions to obtain a coupling compound IV, wherein R is a protecting group. The metal catalyst is any one of copper trifluoromethanesulfonate, copper dimethanol, copper acetate, copper acetylacetonate, and cuprous iodide, preferably copper trifluoromethanesulfonate; the aryl Grignard reagent is selected from 2,4-disubstituted phenylmagnesium bromide, 2,4-disubstituted phenylmagnesium chloride, 2,4-disubstituted phenylmagnesium iodide, more preferably 2,4-dimethoxyphenylmagnesium bromide, and the reaction temperature is -40 to 0°C; S5: deprotection to generate glabridin; Raw materials: Compound IV; Reaction conditions: Compound IV is deprotected under acidic or alkaline conditions to obtain optically pure glabridin. When R is one of methyl, methoxymethylene, and benzyl, compound IV is deprotected under acidic conditions, and the acid used is selected from any one of boron tribromide, hydrobromic acid, and acetic acid, or a mixture of two of them, more preferably boron tribromide; when R is one of triethylsilyl and tert-butyldimethylsilyl, compound IV is deprotected under alkaline conditions, and the base used is selected from any one of lithium hydroxide, potassium carbonate, and tetrabutylammonium fluoride, more preferably tetrabutylammonium fluoride.

2. The method for synthesizing glabridin in an asymmetric gasification system according to claim 1, characterized in that: The asymmetric gasification reaction is carried out under relatively mild temperature (40-80° C.) and pressure (0.5-2 MPa) conditions.

3. The method for synthesizing glabridin in an asymmetric gasification system according to claim 1, characterized in that: The reaction container is a pressure-resistant stainless steel reactor.