A method for synthesizing optically pure (2R,3R)-dihydroquercetin

Abstract

This invention relates to an optically pure (2) R ,3 R The synthesis method of dihydroquercetin includes the following steps: a) under inert gas protection and Lewis acid catalysis, m-phenylenedimethyl ether and oxaloyl chloride monoethyl ester react to give compound V; b) under divalent cobalt salt catalysis, the C-H bond at the ortho position of compound V is selectively activated, and then reacted with 3,4-dimethoxybenzyl alcohol to give compound IV; c) under alkaline conditions under inert gas protection, compound IV undergoes intramolecular cyclization to give compound III; d) under inert gas protection and catalysis of a rhodium complex formed in situ by a monovalent rhodium salt and a chiral phosphine ligand, compound III selectively undergoes hydrogenation reduction of the double bond to give compound II; e) under sodium bromide or sodium iodide catalysis, compound II reacts with aluminum trichloride to demethylate, and then yields optically pure (2-)-dihydroquercetin. R ,3 R The present invention synthesizes dihydroquercetin using inexpensive and readily available raw materials, with simple operation, high yield and optical purity, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of dihydroquercetin technology, specifically relating to an optically pure (2) R , 3 R Synthesis method of dihydroquercetin. Background Technology

[0002] Dihydroquercetin (DHQ), also known as taxol, is chemically named 3,5,7,3′,4′-pentahydroxydihydroflavonoid. It was first isolated from the leaves of the Douglas fir (Pterocarpus santalinus), a plant in the genus Douglas fir, by the Japanese scholar Fukui. Dihydroquercetin belongs to the flavonoid class of compounds. Its molecule contains two chiral carbon atoms and has four chiral isomers. In natural plants, it is mainly found as (2...) R , 3 R Its primary configuration is achiral, and this specific configuration endows it with unique properties. Compared to similar substances with non-chiral or other configurations, this raw material offers unique and precise biological activity and safety in pharmaceutical and health science applications. Its structural formula is shown below:

[0003] .

[0004] Dihydroquercetin (DHQ) possesses a variety of biological activities, including anti-inflammatory, free radical scavenging, antioxidant, antiviral, and antibacterial effects. It also exhibits cardiovascular protection, anti-cancer properties, liver protection, and collagen fiber formation promotion. It is widely used in pharmaceuticals, health foods, and cosmetics, and its demand continues to grow. The preparation methods for DHQ mainly include plant extraction, chemical synthesis, and biosynthesis. Currently, DHQ is primarily extracted from plants such as Douglas fir bark (US2744919A), larch (CN1844095A, CN1858046A, CN103360359A), and astragalus leaves (CN 116836144 A) using solvent extraction. However, this method has significant limitations: firstly, the DHQ content in plants is extremely low (maximum only 3%); secondly, the scarcity of raw materials and stringent growing conditions result in high production costs, and output falls far short of market demand. In 2025, Academician Chen Jian's team, through modification of key enzymes and optimization of culture conditions, achieved a de novo biosynthesis yield of DHQ using glucose as a substrate, reaching 4.2 g / L. This is the highest yield reported in the literature to date, but it is still some distance from large-scale production. Food Bioscience (2025, 64, 105912). Chemical synthesis has advantages such as inexpensive raw materials and ease of scale-up, which can meet the growing market demand for DHQ.

[0005] In the existing technology, there are three main chemical synthesis methods for dihydroquercetin: Method one uses 2,4,6-trihydroxyacetophenone and 3,4-dihydroxybenzaldehyde as raw materials, and obtains racemic dihydroquercetin (currently) through hydroxyl protection, condensation, epoxidation, and deprotection processes. Chemical manufacturing December 27-29, 1998; Chinese Journal of Medicinal Chemistry 1997, 2, 107-111; J. Med. Chem. (2009, 52, 7732-7752). This method has the advantages of inexpensive raw materials and simple operation, but the use of carcinogenic chloromethyl methyl ether (MOMCl) to protect the hydroxyl group poses a potential health hazard to operators when used in large-scale industrial production. Wang Chunde changed the method to use 3,4-dihydro-2H-pyran (DHP) to protect the hydroxyl group, while keeping the rest of the synthetic route unchanged. However, this method has poor atom economy and can only be used for the synthesis of racemic dihydroquercetin (CN102070592B). The chemical reaction process is as follows:

[0006] .

[0007] Method two is the synthesis of optically active dihydroquercetin by Sang-sup Jew et al. in 2000 using an asymmetric dihydroxylation strategy. Tetrahedron Letters (2000, 41, 7925-7928). This method uses methyl 3,4-dimethoxycinnamate as a raw material, processed by a chiral osmium tetroxide complex (AD-mix-). α An asymmetric dihydroxylation reaction catalyzed by ruthenium introduces a chiral hydroxyl group. Following ruthenium-catalyzed oxidation, deprotection, cyclization, and demethylation, optically pure (2...) is obtained. R ,3 R )-Dihydroquercetin. This method involves lengthy reaction steps and uses the highly toxic chloromethyl methyl ether (MOMCl) as a protecting group and expensive AD-mix- α Using ruthenium as a catalyst results in high costs and significant challenges for industrialization. The chemical reaction process is as follows:

[0008] .

[0009] Method three utilizes catechin, a natural extract, as a raw material. After benzyl protection of the hydroxyl group, a carbonyl group is introduced through sequential oxidation using DDQ and PCC. Finally, the benzyl group is removed by palladium-catalyzed hydrogenation to obtain optically pure dihydroquercetin (Molecules, 2007, 12, 2228-2258; Eur. J. Med. Chem. 2010, 45, 1028-1033; Synlett. 2020, 31, 1097-1101). This method has a short synthetic procedure, but the yield is low and high-purity natural catechin is difficult to obtain, making industrial-scale production challenging. The chemical reaction process is as follows:

[0010] .

[0011] In summary, among the three existing chemical synthesis methods mentioned above, only Method 2 can synthesize optically pure dihydroquercetin. However, due to the use of highly toxic reagents and the complexity of the synthetic route, mass production is difficult to achieve. Therefore, it is necessary to develop a safe, environmentally friendly, low-cost, and suitable method for large-scale industrial production of optically pure (2... R ,3 R A new approach to dihydroquercetin has become an urgent priority. Summary of the Invention

[0012] To address the problems in the prior art, this invention provides an optically pure (2 R ,3 R A method for synthesizing dihydroquercetin was developed to achieve optical purity (2...). R ,3 R Dihydroquercetin is a cheap and readily available raw material, and the operation is simple, with high yield and optical purity, making it suitable for industrial production.

[0013] The technical problem solved by this invention is achieved by the following technical solution:

[0014] The purpose of this invention is to provide an optically pure (2) R ,3 R The method for synthesizing dihydroquercetin includes the following steps:

[0015] a. Preparation of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate (compound V)

[0016] Under inert gas protection and Lewis acid catalysis, m-phenylenedimethyl ether and oxaloyl chloride monoethyl ester react to give ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl ester;

[0017] b. Preparation of ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate (compound IV)

[0018] Under the catalysis of divalent cobalt salt, the CH bond at the ortho position of 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate is selectively activated through a carbonyl-directed C-H bond activation strategy. After reacting with 3,4-dimethoxybenzyl alcohol, 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate is obtained.

[0019] c. Preparation of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one (Compound III)

[0020] Under inert gas protection and alkaline conditions, ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate undergoes intramolecular cyclization to give 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one.

[0021] d. Preparation (2) R ,3 R 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one (Compound II)

[0022] Enantioselective hydrogenation reduction of the double bond in 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one was achieved under the catalysis of a rhodium complex formed in situ from a monovalent rhodium salt and a chiral phosphine ligand, yielding an optically pure compound (2 R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one;

[0023] e. Preparation of optically pure (2 R ,3 R )-Dihydroquercetin

[0024] Under the catalysis of sodium bromide or sodium iodide, (2) R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one reacts with aluminum trichloride, and after demethylation, the target compound is obtained as optically pure (2 R ,3 R )-Dihydroquercetin.

[0025] Further, the method for preparing ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate includes: under inert gas protection, adding Lewis acid catalyst, solvent, and m-phenylenediamine sequentially to a reactor, cooling to -5~5℃, and then adding oxaloyl chloride monoethyl ester dropwise to the reactor. After the addition is complete, the reaction is carried out at -5~30℃ for 1~12 hours, with the molar ratio of m-phenylenediamine:oxaloyl chloride monoethyl ester:Lewis acid being 1.0:(1.0~1.5):(1.0~2.0). After the reaction is complete, dilute hydrochloric acid and organic solvent are added. After separation, the organic phase is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the organic phase is concentrated to obtain a yellow oily substance. The yellow oily substance is then subjected to vacuum distillation, and the fraction collected is the prepared ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate (shown in Formula V). The chemical reaction process is as follows:

[0026]

[0027] Furthermore, the Lewis acid catalyst is one or more of aluminum trichloride, tin tetrachloride, boron trifluoride diethyl ether, and ferric trichloride;

[0028] The solvent is one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0029] Furthermore, methods for preparing ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate include:

[0030] A divalent cobalt salt, oxidant, and additive were added to a reactor equipped with a condenser. Solvent A, ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl alcohol, and 3,4-dimethoxybenzyl alcohol were added under stirring at room temperature. The reaction was carried out at 60–130 °C for 10–36 hours to obtain a reaction solution containing compound IV. The molar ratio of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl alcohol to 3,4-dimethoxybenzyl alcohol to divalent cobalt salt to oxidant to additive was 1.0:(1.0) ~3.0): (0.01~0.2): (1.0~4.0): (0.01~0.2); After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a brown oily substance. Isopropyl acetate was added to the brown oily substance, the organic phase was washed with saturated sodium chloride solution, the organic phase was concentrated, and the resulting yellow residue was recrystallized with solvent B to obtain ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate (shown in Formula IV). The chemical reaction process is as follows:

[0031]

[0032] Further, the method for preparing 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one includes: under inert gas protection, dissolving ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate in organic solvent C, cooling to -5~5°C, slowly adding a alkali tetrahydrofuran solution, and then heating to 25~80°C to react for 6~24 hours to obtain a reaction mixture containing compound III. The reaction mixture consisted of ethyl acetate 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate and base in a molar ratio of 1.0:(1.0~3.0). After the reaction was complete, water and an organic solvent were added. After separation, the organic phase was washed with saturated sodium chloride solution and concentrated. The resulting yellow residue was recrystallized from solvent B to obtain 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one (as shown in Formula III). The chemical reaction process is as follows:

[0033]

[0034] Furthermore, the divalent cobalt salts used are Co(acac)2, Co(OAc)2, and Co(OAc)2. . One of 4H2O, CoF2, or CoBr2, preferably, the divalent cobalt salt is Co(acac)2 or Co(OAc)2. . 4H2O;

[0035] The oxidizing agent used is Cu(OAc)2, Cu(OAc)2 . H2O, AgOAc, Ag2CO3 or Mn(OAc)3 . 2H2O, preferably, Cu(OAc)2 is used as the oxidant. . H2O, Ag2CO3 or Mn(OAc)3 . One or more of 2H2O;

[0036] The additive is used to adjust the pH value of the reaction system. The additive is one of NaOAc, KOAc, NaOPiv, Na2CO3 or K2CO3.

[0037] Solvent A is one or more of 1,2-dichloroethane, toluene, and acetonitrile;

[0038] Solvent B is one or more of methanol, ethanol, isopropanol, 2-butanone, ethyl acetate, and n-hexane;

[0039] The alkali is one of bis(trimethylsilylaminolithium), bis(trimethylsilyl)aminosodium, or potassium tert-butoxide;

[0040] Solvent C is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and n-hexane.

[0041] Further, preparation (2) R ,3 R The method for adding 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychromene-4-one includes: sequentially adding a monovalent rhodium salt, a chiral phosphorus ligand, and solvent D to a high-pressure reactor, stirring at room temperature for 1 hour, adding 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one, purging the reaction system with hydrogen three times, and during the fourth purging, introducing hydrogen into the high-pressure reactor to increase the reaction pressure. The force was 1.0~5.0 MPa, and then the temperature was raised to 25~80℃ for 12~48 hours to obtain a reaction solution containing compound II. The molar ratio of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one: monovalent rhodium salt: chiral phosphorus ligand was 1.0:(0.0001~0.005):(0.0001~0.007). After the reaction was completed, the organic phase was concentrated to obtain (2 R ,3 R Crude product of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one (as shown in Formula II). The chemical reaction process is as follows:

[0042]

[0043] Furthermore, the monovalent rhodium salt is one of Rh(COD)₂BF₄, [Rh(COD)Cl]₂, or [Rh(NBD)₂BF₄].

[0044] Chiral phosphorus ligands employ chiral diphosphorus ligands, including ( S , S , R , R )-TangPhos、( R , S )-DuanPhos、( R , R )-Duphos, ZhaoPhos, ( R , R )-Miniphos or ( S One of )-TCFP, preferably, the chiral phosphorus ligand adopts ( S , S , R , R )-TangPhos, ZhaoPhos and ( S One of the TCFPs; its structural formula is as follows:

[0045]

[0046] Solvent D is one or more of methanol, dichloromethane, 1,2-dichloroethane, ethyl acetate, 1,4-dioxane, tetrahydrofuran, and toluene.

[0047] Furthermore, optically pure (2) R ,3 R The method for obtaining dihydroquercetin includes: sequentially adding (2) to a dry reaction vessel. R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one crude product, NaX (sodium bromide or sodium iodide) and solvent E, replace the air in the reactor with an inert gas, lower the temperature to -10~5℃, add aluminum trichloride in batches, and slowly raise the temperature to 40~120℃ and react for 6~36 hours. (2) R ,3 R The molar ratio of crude 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one to aluminum trichloride to NaX was 1.0:(4.0~10.0):(0.01~0.15). After the reaction was completed, the temperature was lowered to -10~0℃, and water was slowly added dropwise to the reaction system. The mixture was separated, the organic phase was washed with saturated sodium chloride solution, the organic phase was concentrated, and the resulting yellow residue was recrystallized with solvent F to obtain optically pure (2) R ,3 R )-Dihydroquercetin (shown in Formula I). ​​The chemical reaction process is as follows:

[0048]

[0049] Furthermore, solvent E is one or more of dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, and n-heptane;

[0050] Solvent F is one or more of methanol, ethanol, isopropanol, 2-butanone, ethyl acetate, and n-hexane.

[0051] In this invention, the inert gas is nitrogen or argon.

[0052] In this invention, the amount of solvent used in each step can be 2 to 10 times the total mass of other raw materials used in this step. The appropriate amount can be determined as needed, and this can be understood and implemented by those skilled in the art.

[0053] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0054] 1. This invention uses inexpensive m-phenylenediamine and oxaloyl chloride monoethyl ester as raw materials, and applies advanced CH bond activation and asymmetric hydrogenation strategies to rapidly and efficiently synthesize optically pure (2) R ,3 R Dihydroquercetin has advantages such as low metal catalyst usage, simple route, high optical purity and yield, and low cost.

[0055] 2. The synthetic route of this invention does not require the introduction of a protecting agent, has high atom economy, and the synthetic method is more environmentally friendly.

[0056] 3. The raw materials and reagents used in this invention do not contain highly toxic or environmentally harmful reagents, making them easier to produce industrially, which is beneficial to environmental protection and human health.

[0057] 4. In the entire synthesis method of this invention, the post-processing is very easy; only the compound shown in formula V needs to be purified by distillation, and the other two steps can be completed by recrystallization to obtain the target compound, which reduces energy consumption and the requirements for industrial equipment.

[0058] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention, it can be implemented according to the contents of the specification. Furthermore, in order to make the above contents, objectives, features and advantages of the present invention more obvious and understandable, specific embodiments of the present invention are described below. Attached Figure Description

[0059] Figure 1 For the present invention, an optically pure (2) R ,3 R A schematic diagram of the chemical reaction process for the synthesis of dihydroquercetin.

[0060] Figure 2 The optically pure (2) prepared in Example 1 R ,3 R HPLC chromatogram of dihydroquercetin on reversed-phase column.

[0061] Figure 3 This is the HPLC chromatogram of racemic dihydroquercetin.

[0062] Figure 4 The optically pure (2) prepared in Example 1 R ,3 R Normal-phase column HPLC chromatogram of dihydroquercetin.

[0063] Figure 5 The optically pure (2) prepared in Example 1 R ,3 R 1H NMR spectrum of dihydroquercetin.

[0064] Figure 6The optically pure (2) prepared in Example 1 R ,3 R 1-dihydroquercetin NMR spectrum. Detailed Implementation

[0065] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0066] In addition, unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be obtained by purchasing them from the market or prepared by existing methods. Example 1

[0067] An optically pure (2 R ,3 R The method for synthesizing dihydroquercetin includes the following steps:

[0068] Preparation of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate (V)

[0069] Under nitrogen protection, aluminum trichloride (158.92 g, 1.05 mol, 1.5 eq), dichloromethane (500.0 g), and m-phenylenediamine (96.72 g, 0.70 mol, 1.0 eq) were added sequentially to the reactor. The temperature was lowered to 0 °C, and oxaloyl chloride monoethyl ester (114.69 g, 0.84 mol, 1.2 eq) was slowly added dropwise to the reactor. After the addition was complete, the reactor was reacted at 0 °C for 10 hours. After the reaction was completed, 1M hydrochloric acid aqueous solution (300.0 g) and dichloromethane (200.0 g) were added. After separation, the organic phase was washed with saturated sodium chloride solution (300.0 g), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily substance. The yellow oily substance was subjected to vacuum distillation, and the fraction collected was the prepared ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate V (152.47 g, 0.64 mol), with a yield of 91%.

[0070] Preparation of ethyl 2-(2-((3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate (IV)

[0071] Add Co(OAc)2 to a reactor equipped with a condenser . 4H2O (4.73g, 0.019mol, 0.03eq), Mn(OAc)3 .2H₂O (227.93 g, 0.93 mol, 1.5 eq) and NaOAc (5.09 g, 0.062 mol, 0.10 eq) were added with stirring at room temperature, followed by the addition of 1,2-dichloroethane (1050.0 g), compound V (147.71 g, 0.62 mol, 1.0 eq), and 3,4-dimethoxybenzyl alcohol (208.56 g, 1.24 mol, 2.0 eq). The reaction was carried out at 100 °C for 20 hours to obtain a reaction solution containing compound IV. After the reaction was completed, the solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a brown oily substance. Isopropyl acetate (560.0 g) was added to the brown oily substance. The organic phase was washed with saturated sodium chloride solution (300.0 g), concentrated, and the resulting yellow residue was recrystallized from ethanol / n-hexane (400 g, mass ratio = 2.8:1) to give ethyl acetate IV (210.30 g, 0.52 mol), yield 84%.

[0072] Preparation of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one (III)

[0073] Under nitrogen protection, compound IV (198.17 g, 0.49 mol, 1.0 eq) was dissolved in tetrahydrofuran (200.0 g), cooled to 0 °C, and a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (540 mL, 0.54 mol, 1.10 eq, concentration: 1.0 M) was slowly added. The mixture was then heated to 30 °C and reacted for 12 hours to obtain a reaction solution containing compound III. After the reaction was complete, water (400.0 g) and isopropyl acetate (500.0 g) were added. After separation, the organic phase was washed twice with saturated sodium chloride solution (400.0 g), concentrated, and the resulting yellow residue was recrystallized from ethanol (380.0 g) to give 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one III (157.67 g, 0.44 mol), yield 90%.

[0074] Preparation (2) R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychrom-4-one (II)

[0075] Monovalent rhodium salt [Rh(COD)Cl]2 (41.42 mg, 0.084 mmol, 0.0002 eq) and chiral phosphorus ligand ( ) were added sequentially to a high-pressure reactor. S)-TCFP (55.10 mg, 0.21 mmol, 0.0005 eq) and methanol (500.0 g) were stirred at room temperature for 1 hour. Then, compound III (150.0 g, 0.42 mol, 1.0 eq) was added. The reaction system was purged with hydrogen three times. During the fourth purging, hydrogen was introduced into the high-pressure reactor to bring the reaction pressure to 3.0 MPa. The temperature was then raised to 70 °C and reacted for 30 hours to obtain a reaction solution containing compound II. After the reaction was complete, the organic phase was concentrated to obtain (2 R ,3 R Crude product II of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one.

[0076] Preparation of optically pure (2) R ,3 R )-Dihydroquercetin (I)

[0077] The crude compound II, sodium bromide (2.16 g, 0.021 mol, 0.05 eq), acetonitrile (200.0 g), and toluene (400.0 g) were added sequentially to a dry reaction vessel. Under nitrogen protection, aluminum trichloride (381.40 g, 2.52 mol, 6.0 eq) was added in seven batches. After the addition was complete, the temperature was slowly raised to 80 °C and the reaction was carried out for 20 hours. After the reaction was completed, the temperature was lowered to -10 to 0 °C, and 1M hydrochloric acid aqueous solution (300.0 g) was slowly added dropwise to the reaction system. The mixture was separated, and the organic phase was washed with saturated sodium chloride solution. The organic phase was concentrated, and the resulting yellow residue was recrystallized from 2-butanone / n-hexane (450 g, mass ratio = 3.0:1) to obtain optically pure (2... R ,3 R Dihydroquercetin I (103.45 g, 0.34 mol) yielded 81% (two steps), with an HPLC purity of 98.2%. dr = 56:1, ee = 98.0%, Specific rotation [α] D 25 = +44 (c = 1.0, acetone). Example 2

[0078] An optically pure (2 R ,3 R The method for synthesizing dihydroquercetin includes the following steps:

[0079] a. Preparation of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate (V)

[0080] Under argon protection, boron trifluoride diethyl ether (198.8 g, 1.40 mol, 2.0 eq), dichloromethane (500.0 g), and m-phenylenediamine (96.72 g, 0.70 mol, 1.0 eq) were added sequentially to the reactor. The temperature was lowered to -5 °C, and oxaloyl chloride monoethyl ester (143.37 g, 0.84 mol, 1.5 eq) was slowly added dropwise to the reactor. After the addition was complete, the reactor was reacted at -5 °C for 1 hour. After the reaction was completed, 1M hydrochloric acid aqueous solution (300.0 g) and dichloromethane (200.0 g) were added. After separation, the organic phase was washed with saturated sodium chloride solution (300.0 g), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily substance. The yellow oily substance was subjected to vacuum distillation, and the fraction collected was the prepared ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate V (150.09 g, 0.63 mol), with a yield of 90%.

[0081] b. Preparation of ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate (IV)

[0082] Co(acac)₂ (1.59 g, 0.0062 mol, 0.01 eq) and Ag₂CO₃ were added to a reactor equipped with a condenser.

[0083] (171.12 g, 0.62 mol, 1.0 eq) and NaOAc (0.5 g, 0.0062 mol, 0.01 eq) were added toluene (1050.0 g), compound V (147.71 g, 0.62 mol, 1.0 eq), and 3,4-dimethoxybenzyl alcohol (104.28 g, 0.62 mol, 1.0 eq) under stirring at room temperature. The reaction was carried out at 60 °C for 10 hours to obtain a reaction solution containing compound IV. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a brown oily substance. Isopropyl acetate (560.0 g) was added to the brown oily substance. The organic phase was washed with saturated sodium chloride solution (300.0 g), concentrated, and the resulting yellow residue was recrystallized from ethyl acetate (400 g) to give 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate IV (202.21 g, 0.50 mol), yield 83%.

[0084] c. Preparation of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one (III)

[0085] Under nitrogen protection, compound IV (198.17 g, 0.49 mol, 1.0 eq) was dissolved in 2-methyltetrahydrofuran (200.0 g), cooled to 5 °C, and a solution of potassium tert-butoxide in tetrahydrofuran (980 mL, 0.98 mol, 2.0 eq, concentration: 1.0 M) was slowly added. The mixture was then heated to 25 °C and reacted for 6 hours to obtain a reaction solution containing compound III. After the reaction was complete, water (400.0 g) and isopropyl acetate (500.0 g) were added. After separation, the organic phase was washed twice with saturated sodium chloride solution (400.0 g), concentrated, and the resulting yellow residue was recrystallized from ethanol (380.0 g) to give 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one III (150.5 g, 0.42 mol), yield 89%.

[0086] d. Preparation (2) R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychrom-4-one (II)

[0087] Rhodium monovalent salt Rh(COD)2BF4 (341.62 mg, 0.84 mmol, 0.002 eq), chiral phosphorus ligand ZhaoPhos (315.23 mg, 1.26 mmol, 0.003 eq), and 1,4-dioxane (500.0 g) were added sequentially to a high-pressure reactor. The mixture was stirred at room temperature for 1 hour. Then, compound III (150.0 g, 0.42 mol, 1.0 eq) was added. The reaction system was purged with hydrogen three times. During the fourth purging, hydrogen was introduced into the high-pressure reactor to bring the reaction pressure to 1.0 MPa. The temperature was then raised to 25°C and reacted for 12 hours to obtain a reaction solution containing compound II. After the reaction was completed, the organic phase was concentrated to obtain (2... R ,3 R Crude product II of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one.

[0088] e. Preparation of optically pure (2 R ,3 R )-Dihydroquercetin (I)

[0089] The crude compound II, sodium iodide (2.16 g, 0.021 mol, 0.05 eq), and 1,2-dichloroethane (600.0 g) were added sequentially to a dry reaction vessel. Under nitrogen protection, aluminum trichloride (381.40 g, 2.52 mol, 6.0 eq) was added in seven batches. After the addition was complete, the temperature was slowly raised to 40 °C and the reaction was carried out for 6 hours. After the reaction was completed, the temperature was lowered to -10 °C, and 1M hydrochloric acid aqueous solution (300.0 g) was slowly added dropwise to the reaction system. The mixture was separated, and the organic phase was washed with saturated sodium chloride solution. The organic phase was concentrated, and the resulting yellow residue was recrystallized from ethanol / isopropanol (450 g, mass ratio = 3.0:1) to obtain optically pure (2... R ,3 R Dihydroquercetin I (97.37 g, 0.32 mol) yielded 80% (two steps), with an HPLC purity of 97.1%. dr = 40:1, ee =99.1%, Specific rotation [α] D 25 = +43 (c = 1.0, acetone).

[0090] Figure 2 The optically pure (2) prepared in Example 1 R ,3 R The reversed-phase column HPLC chromatogram of dihydroquercetin, from... Figure 2 As can be seen from the above, the purity of the dihydroquercetin synthesized in this invention is as high as 98%.

[0091] Figure 3 This is the HPLC spectrum of racemic dihydroquercetin. Figure 4 The optically pure (2) prepared in Example 1 R ,3 R Normal-phase column HPLC chromatogram of dihydroquercetin. From Figure 3 and Figure 4 As can be seen from this, the dihydroquercetin synthesized in this invention has higher optical purity, comparable to that of natural extracts.

[0092] Figure 5 The optically pure (2) prepared in Example 1 R ,3 R 1H NMR spectrum of dihydroquercetin Figure 6 The optically pure (2) prepared in Example 1 R ,3 R Carbon NMR spectrum of dihydroquercetin, Figure 5 and Figure 6 It can be seen that the dihydroquercetin synthesized in this invention has the correct structure.

[0093] This invention is optically pure (2) R ,3R The synthesis of dihydroquercetin employs a novel synthetic route, using inexpensive m-phenylenediamine and oxaloyl chloride monoethyl ester as raw materials. The synthesis proceeds through five steps: Lewis acid-catalyzed Friedel-Crafts acylation, cobalt salt-catalyzed CH activation, intramolecular cyclization, rhodium salt-catalyzed asymmetric hydrogenation, and aluminum trichloride de-O-methylation. This yields optically pure dihydroquercetin (2-dihydroquercetin). R ,3 R (2-Dihydroquercetin). Compared with existing technologies, the synthesis method of this invention has the advantages of using less metal catalyst, no need to introduce protective agents, simple route, high optical purity and total yield, and low cost. Moreover, the raw materials and reagents used do not contain highly toxic or environmentally harmful reagents, making it easier to industrialize and environmentally friendly, and has good application prospects.

[0094] The sequence numbers of the above embodiments of the present invention are for descriptive purposes only and do not represent the superiority or inferiority of the embodiments.

[0095] The embodiments of the present invention have been described above with reference to the accompanying drawings. However, the present invention is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of the present invention without departing from the spirit and scope of the claims. All of these forms are within the protection scope of the present invention.

Claims

1. An optically pure (2 R ,3 R The method for synthesizing dihydroquercetin is characterized by, Includes the following steps: a. Preparation of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate Under inert gas protection and Lewis acid catalysis, m-phenylenedimethyl ether and oxaloyl chloride monoethyl ester react to give ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl ester; b. Preparation of ethyl 2-(2-((3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate Under the catalysis of divalent cobalt salt, the CH bond at the ortho position of 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate is selectively activated through a carbonyl-directed C-H bond activation strategy. After reacting with 3,4-dimethoxybenzyl alcohol, 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate is obtained. c. Preparation of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one Under inert gas protection and alkaline conditions, ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate undergoes intramolecular cyclization to give 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one. d. Preparation (2) R ,3 R 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one Enantioselective hydrogenation reduction of the double bond in 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one was achieved under the catalysis of a rhodium complex formed in situ from a monovalent rhodium salt and a chiral phosphine ligand, yielding an optically pure compound (2 R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one; e. Preparation of optically pure (2 R ,3 R )-Dihydroquercetin Under the catalysis of sodium bromide or sodium iodide, (2) R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one reacts with aluminum trichloride, and after demethylation, the target compound is obtained as optically pure (2 R ,3 R )-Dihydroquercetin.

2. An optically pure (2) as described in claim 1 R ,3 R The method for synthesizing dihydroquercetin is characterized by: The method for preparing ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate includes: under inert gas protection, Lewis acid catalyst, solvent and m-phenylenediamine are added sequentially to a reactor, the temperature is lowered to -5~5℃, oxaloyl chloride monoethyl ester is added dropwise to the reactor, and after the addition is complete, the reaction is carried out at -5~30℃ for 1~12 hours. The molar ratio of m-phenylenediamine:oxaloyl chloride monoethyl ester:Lewis acid is 1.0:(1.0~1.5):(1.0~2.0). After the reaction is completed, dilute hydrochloric acid and organic solvent are added. After separation, the organic phase is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the organic phase is concentrated to obtain a yellow oily substance. The yellow oily substance is subjected to vacuum distillation, and the fraction collected is the prepared ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl acetate.

3. An optically pure (2) as described in claim 2 R ,3 R The method for synthesizing dihydroquercetin is characterized by: Lewis acid catalysts are selected from one or more of aluminum trichloride, tin tetrachloride, boron trifluoride diethyl ether, and ferric trichloride; The solvent is one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and 2-methyltetrahydrofuran.

4. An optically pure (2) as described in claim 1 R ,3 R The method for synthesizing dihydroquercetin is characterized by: Methods for preparing ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate include: A divalent cobalt salt, oxidant, and additive were added to a reactor equipped with a condenser. Solvent A, ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl alcohol, and 3,4-dimethoxybenzyl alcohol were added under stirring at room temperature. The reaction was carried out at 60–130 °C for 10–36 hours to obtain a reaction solution. The molar ratio of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoethyl alcohol to 3,4-dimethoxybenzyl alcohol to divalent cobalt salt to oxidant to additive was 1.0:(1.0) ~3.0): (0.01~0.2): (1.0~4.0): (0.01~0.2); After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated to obtain a brown oily substance. Isopropyl acetate was added to the brown oily substance, the organic phase was washed with saturated sodium chloride solution, the organic phase was concentrated, and the resulting yellow residue was recrystallized with solvent B to obtain 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate.

5. An optically pure (2) as described in claim 4 R ,3 R The method for synthesizing dihydroquercetin is characterized by: The method for preparing 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one includes: under inert gas protection, dissolving ethyl acetate of 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoethyl acetate in organic solvent C, cooling to -5~5℃, slowly adding a base tetrahydrofuran solution, and then heating to 25~80℃ to react for 6~24 hours to obtain a reaction solution; The molar ratio of ethyl acetate to base was 1.0:(1.0~3.0). After the reaction was completed, water and organic solvent were added. After separation, the organic phase was washed with saturated sodium chloride solution and concentrated. The resulting yellow residue was recrystallized with solvent B to obtain 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one.

6. An optically pure (2) as described in claim 5 R ,3 R The method for synthesizing dihydroquercetin is characterized by: Divalent cobalt salts are Co(acac)2, Co(OAc)2, and Co(OAc)2. . One of 4H2O, CoF2, or CoBr2; The oxidizing agent used is Cu(OAc)2, Cu(OAc)2 . H2O, AgOAc, Ag2CO3 or Mn(OAc)3 . One or more of 2H2O; The additive is used to adjust the pH value of the reaction system. The additive is one of NaOAc, KOAc, NaOPiv, Na2CO3 or K2CO3. Solvent A may be one or more of 1,2-dichloroethane, toluene, or acetonitrile; Solvent B is one or more of methanol, ethanol, isopropanol, 2-butanone, ethyl acetate, or n-hexane; The alkali is one of bis(trimethylsilylaminolithium), bis(trimethylsilyl)aminosodium, or potassium tert-butoxide; Solvent C is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or n-hexane.

7. An optically pure (2) as described in claim 1 R ,3 R The method for synthesizing dihydroquercetin is characterized by: Preparation (2) R ,3 R The method for adding 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychromene-4-one includes: sequentially adding a monovalent rhodium salt, a chiral phosphorus ligand, and solvent D to a high-pressure reactor, stirring at room temperature for 1 hour, adding 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one, purging the reaction system with hydrogen three times, and introducing hydrogen into the high-pressure reactor during the fourth purging. The reaction pressure was set to 1.0~5.0 MPa, and then the temperature was raised to 25~80℃ for 12~48 hours to obtain a reaction solution. The molar ratio of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromene-4-one: monovalent rhodium salt: chiral phosphorus ligand was 1.0:(0.0001~0.005):(0.0001~0.007). After the reaction was completed, the organic phase was concentrated to obtain (2 R ,3 R Crude product of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one.

8. An optically pure (2) as described in claim 7 R ,3 R The method for synthesizing dihydroquercetin is characterized by: The monovalent rhodium salt is one of Rh(COD)₂BF₄, [Rh(COD)Cl]₂, or [Rh(NBD)₂BF₄]. The chiral phosphorus ligand is a chiral diphosphorus ligand, wherein the chiral diphosphorus ligand is selected from ( S , S , R , R )-TangPhos、( R , S )-DuanPhos、( R , R )-Duphos, ZhaoPhos, ( R , R )-Miniphos or ( S One of the TCFPs; Solvent D is one or more of methanol, dichloromethane, 1,2-dichloroethane, ethyl acetate, 1,4-dioxane, tetrahydrofuran, or toluene.

9. An optically pure (2) as described in claim 1 R ,3 R The method for synthesizing dihydroquercetin is characterized by: Preparation of optically pure (2) R ,3 R The method for obtaining dihydroquercetin includes: sequentially adding (2) to a dry reaction vessel. R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one crude product, NaX and solvent E, the air in the reactor was replaced with an inert gas, the temperature was lowered to -10~5℃, aluminum trichloride was added in batches, and the temperature was slowly raised to 40~120℃ for 6~36 hours. (2) R ,3 R The molar ratio of crude 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one to aluminum trichloride to NaX was 1.0:(4.0~10.0):(0.01~0.15). After the reaction was completed, the temperature was lowered to -10~0℃, and water was slowly added dropwise to the reaction system. The mixture was separated, the organic phase was washed with saturated sodium chloride solution, the organic phase was concentrated, and the resulting yellow residue was recrystallized with solvent F to obtain optically pure (2) R ,3 R )-Dihydroquercetin.

10. An optically pure (2) as described in claim 9 R ,3 R The method for synthesizing dihydroquercetin is characterized by: Solvent E is one or more of dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, or n-heptane; Solvent F is one or more of methanol, ethanol, isopropanol, 2-butanone, ethyl acetate, or n-hexane.

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