Synthetic method of optically pure (2R, 3R)-dihydroquercetin

Abstract

The invention relates to a synthetic method of optically pure (2R, 3R)-dihydroquercetin, which comprises the following steps of: a, reacting m-dimethoxybenzene with ethyl oxalyl chloride under the protection of inert gas and catalysis of Lewis acid to obtain a compound V; b, under the catalysis of divalent cobalt salt, selectively activating the ortho-position C-H bond of the compound V, and reacting with 3, 4-dimethoxybenzyl alcohol to obtain a compound IV; c, carrying out intramolecular cyclization on the compound IV under the alkaline condition of inert gas protection to obtain a compound III; d, under protection of inert gas and catalysis of a rhodium complex formed by monovalent rhodium salt and a chiral phosphine ligand in situ, hydrogenation reduction of double bonds is correspondingly and selectively realized by the compound III, and a compound II is obtained; e, under the catalysis of sodium bromide or sodium iodide, the compound II reacts with aluminum trichloride for demethylation, and optically pure (2R, 3R)-dihydroquercetin is obtained.The synthetic raw materials are low in price and easy to obtain, operation is easy, the yield and optical purity are high, and the method is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of dihydroquercetin, and specifically relates to an optically pure (2 R , 3 R )-dihydroquercetin synthesis method. Background Art

[0002] Dihydroquercetin (DHQ), also known as Taxodium indica, Taxodium indica or Taxodium truncatum, is chemically named 3,5,7,3′,4′-pentahydroxydihydroflavone. It was first extracted and isolated from the leaves of the Douglas fir plant by Japanese scholar Fukui. Dihydroquercetin belongs to the flavonoids. Its molecule has two chiral carbon atoms and four chiral isomers. It is mainly found in natural plants as (2 R , 3 R ) configuration, and its specific configuration gives it unique properties. Compared with similar substances with achiral or other configurations, this raw material can bring unique and precise biological activity and safety in applications in the fields of medicine and health sciences. Its structural formula is shown below:

[0003] Dihydroquercetin exhibits multiple biological activities, including anti-inflammatory, free radical scavenging, antioxidant, antiviral, and antibacterial properties. It also exhibits cardiovascular, anti-cancer, and hepatoprotective properties, as well as promoting collagen fibrillogenesis. It is widely used in pharmaceuticals, health foods, cosmetics, and other fields, and its demand continues to grow. Methods for preparing dihydroquercetin primarily 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) via solvent extraction. However, this method has significant limitations: Firstly, the DHQ content in plants is extremely low (maximum 3%); secondly, the scarcity of the raw materials and the demanding growing conditions result in high production costs, and the yield falls far short of market demand. In 2025, Academician Chen Jian's team, through the modification of key enzymes and optimization of culture conditions, increased the yield of de novo biosynthesis of DHQ to 4.2 g / L using glucose as a substrate. This is the highest yield reported in the literature, but it is still some distance away from large-scale production ( Food Bioscience , 2025, 64, 105912). Chemical synthesis has the advantages of cheap raw materials and easy scale-up, which can meet the growing market demand for DHQ.

[0004] In the prior art, there are three main chemical synthesis methods for dihydroquercetin: Method 1 is to use 2,4,6-trihydroxyacetophenone and 3,4-dihydroxybenzaldehyde as raw materials, and obtain racemic dihydroquercetin (now Chemical Industry, 1998, 12, 27-29; Chinese Journal of Medicinal Chemistry Zhi, 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 quantities in industrial production. Wang Chunde instead used 3,4-dihydro-2H-pyran (DHP) to protect the hydroxyl group, while retaining the rest of the synthetic route. However, this method has poor atom economy and can only be used to synthesize racemic dihydroquercetin (CN102070592B). The chemical reaction process is as follows:

[0005] The second method is that in 2000, Sang-sup Jew et al. used asymmetric dihydroxylation strategy to synthesize optically active dihydroquercetin ( Tetrahedron Letters , 2000, 41, 7925-7928). This method uses methyl 3,4-dimethoxycinnamate as raw material and chiral osmate complex (AD-mix- α ) catalyzed asymmetric dihydroxylation reaction to introduce chiral hydroxyl groups. Then, through ruthenium-catalyzed oxidation, deprotection, cyclization and demethylation, optically pure (2 R ,3 R )-dihydroquercetin. This method has lengthy reaction steps and uses highly toxic chloromethyl methyl ether (MOMCl) as a protecting group and expensive AD-mix- α The use of ruthenium as a catalyst is costly and difficult to industrialize. The chemical reaction process is as follows:

[0006] Method three uses natural extract catechin as a raw material. After benzyl protection of the hydroxyl group, DDQ and PCC are used to introduce a carbonyl group through oxidation, and finally the benzyl group is removed by palladium-carbon catalytic hydrogenation to produce 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 synthesis process, but the yield is low and high-purity natural product catechin is difficult to obtain, making it difficult to scale up industrial production. The chemical reaction process is as follows:

[0007] In summary, among the three existing chemical synthesis methods mentioned above, only method 2 can synthesize optically pure dihydroquercetin, but it is difficult to achieve mass production due to the use of highly toxic reagents and the complexity of the synthesis route. Therefore, it is necessary to develop a safe, environmentally friendly, low-cost and suitable for large-scale industrial production of optically pure (2 R ,3 R )-Dihydroquercetin new methods have become a top priority. Summary of the Invention

[0008] In order to solve the problems in the prior art, the present invention provides an optically pure (2 R ,3 R )-dihydroquercetin synthesis method, to achieve the synthesis of optical purity (2 R ,3 R The raw materials of )-dihydroquercetin are cheap and easily available, the operation is simple, the yield and optical purity are high, and it is suitable for the purpose of industrial production.

[0009] The present invention solves the technical problem by adopting the following technical solutions: The present invention aims to provide an optically pure (2 R ,3 R )-dihydroquercetin synthesis method, comprising the following steps: a. Preparation of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate (Compound V): Under inert gas protection and Lewis acid catalysis, m-phenylenedimethyl ether and ethyl oxalyl chloride react to obtain ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate; b. Preparation of ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate (Compound IV): Under the catalysis of divalent cobalt salt, the C-H bond of the ortho position of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate was selectively activated through a carbonyl-directed carbon-hydrogen bond activation strategy. The resulting product was reacted with 3,4-dimethoxybenzyl alcohol to obtain ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate; c. Preparation of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one (Compound III): Under inert gas protection and alkaline conditions, ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate undergoes intramolecular ring closure to obtain 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one; d. Preparation (2 R ,3 R)-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one (Compound II) Under the catalysis of a rhodium complex formed in situ by a monovalent rhodium salt and a chiral phosphine ligand, the enantioselective hydrogenation reduction of the double bond in 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one was achieved to give 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 chloride and demethylates to obtain the target compound (2 R ,3 R )-Dihydroquercetin.

[0010] Furthermore, a method for preparing ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate includes: under inert gas protection, sequentially adding a Lewis acid catalyst, a solvent, and m-phenylenedimethyl ether to a reactor, cooling the reactor to -5-5°C, dropwise adding ethyl oxalyl chloride to the reactor, and reacting at -5-30°C for 1-12 hours after the addition is complete. The molar ratio of m-phenylenedimethyl ether: ethyl oxalyl chloride: Lewis acid is 1.0:(1.0-1.5):(1.0-2.0). After the reaction, dilute hydrochloric acid and an organic solvent are added. After separation, the organic phase is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The yellow oil is subjected to reduced pressure distillation, and the fractions are collected to obtain ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate (shown in Formula V). The chemical reaction process is as follows:

[0011] Furthermore, the Lewis acid catalyst is one or more of aluminum trichloride, tin tetrachloride, boron trifluoride etherate and ferric chloride; The solvent is one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0012] Furthermore, the method for preparing ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate comprises: A divalent cobalt salt, an oxidant, and an additive are added to a reactor equipped with a condenser. Under stirring at room temperature, solvent A, ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate, and 3,4-dimethoxybenzyl alcohol are added, and the mixture is reacted at a temperature of 60 to 130° C. for 10 to 36 hours to obtain a reaction solution containing compound IV. The molar ratio of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate: 3,4-dimethoxybenzyl alcohol: divalent cobalt salt: oxidant: additive is 1.0: (1.0 ~3.0): (0.01~0.2): (1.0~4.0): (0.01~0.2); After the reaction is completed, cool to room temperature, filter the reaction solution, and concentrate the filtrate to obtain a brown oil. Isopropyl acetate is added to the brown oil, and the organic phase is washed with a saturated sodium chloride solution. The organic phase is concentrated, and the resulting yellow residue is recrystallized from solvent B to obtain ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate (shown in Formula IV). The chemical reaction process is as follows:

[0013] Furthermore, a method for preparing 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one comprises: dissolving ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate in an organic solvent C under inert gas protection, cooling to -5 to 5°C, slowly adding a tetrahydrofuran solution of an alkali, and then heating to 25 to 80°C for reaction for 6 to 24 hours to obtain a reaction product containing compound III. The reaction mixture is prepared by adding ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate to the base in a molar ratio of 1.0:(1.0-3.0). After the reaction is completed, water and an organic solvent are added. After separation, the organic phase is washed with a saturated sodium chloride solution and concentrated. The resulting yellow residue is recrystallized from solvent B to obtain 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one (shown in Formula III). The chemical reaction process is as follows:

[0014] Furthermore, the divalent cobalt salts are Co(acac)2, Co(OAc)2, Co(OAc)2 . 4H2O, CoF2 or CoBr2, preferably, the divalent cobalt salt is Co(acac)2 or Co(OAc)2 . 4H2O; The oxidant used was Cu(OAc)2, Cu(OAc)2 . H2O, AgOAc, Ag2CO3 or Mn(OAc)3 .2H2O, preferably, the oxidant is Cu(OAc)2 . H2O, Ag2CO3 or Mn(OAc)3 . One or more of 2H2O; The additive is used to adjust the pH value of the reaction system, and the additive is one of NaOAc, KOAc, NaOPiv, Na2CO3 or K2CO3; Solvent A is one or more of 1,2-dichloroethane, toluene, and acetonitrile; Solvent B is one or more of methanol, ethanol, isopropanol, 2-butanone, ethyl acetate, and n-hexane; The base is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium tert-butoxide; Solvent C is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene and n-hexane.

[0015] Further, the preparation (2 R ,3 R The method comprises the following steps of: sequentially adding a monovalent rhodium salt, a chiral phosphorus ligand, and a solvent D into a high-pressure reactor, stirring at room temperature for 1 hour, adding 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one, replacing the reaction system with hydrogen three times, introducing hydrogen into the high-pressure reactor for the fourth replacement, and raising the reaction pressure to 100%. The pressure is 1.0~5.0Mpa, and then the temperature is raised to 25~80℃ for reaction for 12~48 hours to obtain a reaction solution containing compound II, wherein the molar ratio of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one: monovalent rhodium salt: chiral phosphorus ligand is 1.0:(0.0001~0.005):(0.0001~0.007); after the reaction is completed, the organic phase is concentrated to obtain (2 R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one crude product (shown in Formula II). The chemical reaction process is as follows:

[0016] Furthermore, the monovalent rhodium salt is one of Rh(COD)2BF4, [Rh(COD)Cl]2, and [Rh(NBD)2BF4]; Chiral phosphorus ligands are chiral diphosphorus ligands, including ( S , S , R , R )-TangPhos, ( R ,S )-DuanPhos, ( R , R )-Duphos、ZhaoPhos、( R , R )-Miniphos or ( S )-TCFP, preferably, the chiral phosphorus ligand is ( S , S , R , R )-TangPhos, ZhaoPhos and ( S )-TCFP; its structural formula is as follows:

[0017] Solvent D is one or more of methanol, dichloromethane, 1,2-dichloroethane, ethyl acetate, 1,4-dioxane, tetrahydrofuran and toluene.

[0018] Furthermore, optically pure (2 R ,3 R )-dihydroquercetin method comprises: adding (2 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 reaction kettle with inert gas, lower the temperature to -10~5℃, add aluminum chloride in batches, 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: aluminum chloride: NaX is 1.0: (4.0~10.0): (0.01~0.15); after the reaction, the temperature is lowered to -10~0°C, water is slowly added dropwise to the reaction system, the liquid is separated, the organic phase is washed with saturated sodium chloride solution, the organic phase is concentrated, and the resulting yellow residue is recrystallized from solvent F to obtain optically pure (2 R ,3 R )-dihydroquercetin (shown in Formula I). ​​The chemical reaction process is as follows:

[0019] Furthermore, the solvent E is one or more of dichloromethane, 1,2-dichloroethane, acetonitrile, toluene and n-heptane; Solvent F is one or more of methanol, ethanol, isopropanol, 2-butanone, ethyl acetate, and n-hexane.

[0020] In the present invention, the inert gas is nitrogen or argon.

[0021] In the present invention, the amount of solvent used in each step can be 2 to 10 times the total amount of other raw materials used in the step. The appropriate amount can be determined as needed, which can be understood and implemented by ordinary technicians in this field.

[0022] Compared with the prior art, the beneficial technical effects of the present invention are: 1. The present invention uses cheap m-phenylenedimethyl ether and ethyl oxalyl chloride as raw materials, and applies advanced CH bond activation strategy and asymmetric hydrogenation strategy to quickly and efficiently synthesize optically pure (2 R ,3 R )-dihydroquercetin, which has the advantages of less use of metal catalysts, simple route, high optical purity and yield, and low cost; 2. The synthetic route of the present invention does not require the introduction of protective agents, has high atom economy, and is a greener synthetic method; 3. The raw materials and reagents used in the present invention do not contain highly toxic or environmentally harmful reagents, making it easier to industrialize and more environmentally friendly, and beneficial to human health. 4. In the entire synthesis method of the present invention, post-processing is very easy; only the compound represented by Formula V needs to be purified by distillation, and the target compound can be obtained by recrystallization in the other two steps, which reduces energy consumption and the requirements for industrial equipment; The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention, it can be implemented in accordance with the contents of the specification. In order to make the above contents of the present invention and its objectives, features and advantages more obvious and easy to understand, the specific implementation methods of the present invention are specifically listed below. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The present invention is an optically pure (2 R ,3 R )-Schematic diagram of the chemical reaction process for the synthesis of dihydroquercetin.

[0024] Figure 2 The optically pure (2 R ,3 R )-dihydroquercetin reversed-phase column HPLC spectrum.

[0025] Figure 3 HPLC spectrum of racemic dihydroquercetin.

[0026] Figure 4 The optically pure (2 R ,3 R )-Dihydroquercetin normal phase column HPLC spectrum.

[0027] Figure 5 The optically pure (2 R ,3 R )-dihydroquercetin H NMR spectrum.

[0028] Figure 6 The optically pure (2 R ,3 R )-dihydroquercetin. DETAILED DESCRIPTION

[0029] The technical solutions of the present invention are further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely exemplary illustrations and explanations 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 encompassed within the scope of protection that the present invention is intended to protect.

[0030] In addition, unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0031] Example 1

[0032] An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, comprising the following steps: Preparation of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate (V) Under nitrogen protection, aluminum chloride (158.92 g, 1.05 mol, 1.5 eq), dichloromethane (500.0 g), and m-phenylenedimethyl ether (96.72 g, 0.70 mol, 1.0 eq) were added to the reactor in sequence. The temperature was lowered to 0°C, and ethyl oxalyl chloride (114.69 g, 0.84 mol, 1.2 eq) was slowly added dropwise to the reactor. After the addition was complete, the reaction was allowed to proceed at 0°C for 10 hours. After the reaction, 1M aqueous hydrochloric acid 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 over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The yellow oil was distilled under reduced pressure, and the fractions were collected to obtain ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate V (152.47 g, 0.64 mol) with a yield of 91%.

[0033] Preparation of ethyl 2-(2-((3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate (IV) Add Co(OAc)2 to the 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 to 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 mixture was reacted at 100°C for 20 hours to obtain a reaction solution containing compound IV. After the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a brown oil. Isopropyl acetate (560.0 g) was added to the brown oil, and the organic phase was washed with a saturated sodium chloride solution (300.0 g). The organic phase was concentrated, and the resulting yellow residue was recrystallized from ethanol / n-hexane (400 g, mass ratio = 2.8:1) to obtain ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate IV (210.30 g, 0.52 mol) in a yield of 84%.

[0034] Preparation of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one (III) Under nitrogen, compound IV (198.17 g, 0.49 mol, 1.0 eq) was dissolved in tetrahydrofuran (200.0 g). The temperature was lowered to 0°C, and a solution of lithium bistrimethylsilylamide in tetrahydrofuran (540 mL, 0.54 mol, 1.10 eq, 1.0 M) was slowly added. The reaction mixture was then heated to 30°C and allowed to react for 12 hours to yield a reaction solution containing compound III. After the reaction, 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) and concentrated. The resulting yellow residue was recrystallized from ethanol (380.0 g) to yield 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one III (157.67 g, 0.44 mol) in a 90% yield.

[0035] Preparation (2 R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one (II) Monovalent rhodium salt [Rh(COD)Cl]2 (41.42 mg, 0.084 mmol, 0.0002 eq), chiral phosphorus ligand ( S)-TCFP (55.10 mg, 0.21 mmol, 0.0005 eq) and methanol (500.0 g) were stirred at room temperature for 1 hour, and compound III (150.0 g, 0.42 mol, 1.0 eq) was added. The reaction system was replaced with hydrogen three times. During the fourth replacement, hydrogen was introduced into the autoclave to make the reaction pressure 3.0 MPa. The temperature was then raised to 70 ° C and the reaction was carried out for 30 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 )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one crude product II.

[0036] Preparation of optically pure (2 R ,3 R )-Dihydroquercetin (I) 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 to a dry reactor in sequence. Aluminum chloride (381.40 g, 2.52 mol, 6.0 eq) was added in 7 batches under nitrogen protection. After the addition, the temperature was slowly raised to 80°C and the reaction was continued for 20 hours. After the reaction was completed, the temperature was lowered to -10~0°C, and a 1M aqueous hydrochloric acid solution (300.0 g) was slowly added dropwise to the reaction system. The liquids were separated, and the organic phase was washed with a 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) yield 81% (two steps), HPLC purity 98.2%, dr = 56:1, ee = 98.0%, specific rotation [α] D 25 = +44 (c = 1.0, acetone).

[0037] Example 2

[0038] An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, comprising the following steps: a. Preparation of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate (V) Under argon protection, boron trifluoride etherate (198.8 g, 1.40 mol, 2.0 eq), dichloromethane (500.0 g), and m-phenylenedimethyl ether (96.72 g, 0.70 mol, 1.0 eq) were added to the reactor in sequence. The temperature was lowered to -5°C, and ethyl oxalyl chloride (143.37 g, 0.84 mol, 1.5 eq) was slowly added dropwise to the reactor. After the addition was complete, the reaction was allowed to proceed at -5°C for 1 hour. After the reaction, 1M aqueous hydrochloric acid 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 over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The yellow oil was distilled under reduced pressure, and the fractions were collected to obtain ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate V (150.09 g, 0.63 mol) with a yield of 90%.

[0039] b. Preparation of ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate (IV) To a reactor equipped with a condenser, Co(acac)2 (1.59 g, 0.0062 mol, 0.01 eq), Ag2CO3 (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) were added with stirring at room temperature. The mixture was reacted at 60°C for 10 hours to obtain a reaction solution containing compound IV. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate concentrated to obtain a brown oil. Isopropyl acetate (560.0 g) was added to the brown oil, and the organic phase was washed with saturated sodium chloride solution (300.0 g). The organic phase was concentrated, and the resulting yellow residue was recrystallized from ethyl acetate (400 g) to give ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate IV (202.21 g, 0.50 mol) in a yield of 83%.

[0040] c. Preparation of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one (III) Under nitrogen, compound IV (198.17 g, 0.49 mol, 1.0 eq) was dissolved in 2-methyltetrahydrofuran (200.0 g). The temperature was lowered to 5°C, and a solution of potassium tert-butoxide in tetrahydrofuran (980 mL, 0.98 mol, 2.0 eq, 1.0 M) was slowly added. The temperature was then raised to 25°C and allowed to react for 6 hours, yielding a reaction solution containing compound III. After completion of the reaction, 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) and concentrated. The resulting yellow residue was recrystallized from ethanol (380.0 g) to yield 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one III (150.5 g, 0.42 mol) in an 89% yield.

[0041] d. Preparation (2 R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one (II) Monovalent rhodium 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 to the autoclave in sequence and stirred at room temperature for 1 hour. After compound III (150.0 g, 0.42 mol, 1.0 eq) was added, the reaction system was replaced with hydrogen three times. During the fourth replacement, hydrogen was introduced into the autoclave to make the reaction pressure 1.0 MPa. The temperature was then raised to 25°C and the reaction was carried out 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 )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one crude product II.

[0042] e. Preparation of optically pure (2 R ,3 R )-Dihydroquercetin (I) The crude compound II, sodium iodide (2.16 g, 0.021 mol, 0.05 eq), and 1,2-dichloroethane (600.0 g) were added to a dry reactor in sequence. Aluminum chloride (381.40 g, 2.52 mol, 6.0 eq) was added in 7 batches under nitrogen protection. After the addition, the temperature was slowly raised to 40°C and the reaction was continued for 6 hours. After the reaction was completed, the temperature was lowered to -10°C, and a 1M aqueous hydrochloric acid solution (300.0 g) was slowly added dropwise to the reaction system. The liquids were separated, and the organic phase was washed with a 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) yield 80% (two steps), HPLC purity 97.1%, dr = 40:1, ee = 99.1%, specific rotation [α] D 25 = +43 (c = 1.0, acetone).

[0043] Figure 2 The optically pure (2 R ,3 R )-dihydroquercetin reverse phase column HPLC spectrum, from Figure 2 It can be seen that the purity of the dihydroquercetin synthesized by the present invention is as high as 98%; Figure 3 is the HPLC spectrum of racemic-dihydroquercetin, Figure 4 The optically pure (2 R ,3 R )-Dihydroquercetin normal phase column HPLC spectrum. Figure 3 and Figure 4 It can be seen that the optical purity of the dihydroquercetin synthesized by the present invention is higher and is comparable to that of the natural extract.

[0044] Figure 5 The optically pure (2 R ,3 R )-dihydroquercetin H NMR spectrum, Figure 6 The optically pure (2 R ,3 R )-dihydroquercetin NMR carbon spectrum, Figure 5 and Figure 6 It can be seen that the dihydroquercetin synthesized by the present invention has a correct structure.

[0045] The present invention is optically pure (2 R ,3 R)-dihydroquercetin is synthesized by a novel synthetic route, using cheap m-phenylenedimethyl ether and ethyl oxalyl chloride as raw materials, and sequentially undergoing a Lewis acid-catalyzed Friedel-Crafts acylation reaction, a divalent cobalt salt-catalyzed CH activation reaction, an intramolecular cyclization reaction, a monovalent rhodium salt-catalyzed asymmetric hydrogenation reaction, and an aluminum chloride de-O-methylation reaction, to obtain optically pure (2 R ,3 R )-dihydroquercetin. Compared with existing technologies, the synthesis method of the present invention has the advantages of using less metal catalyst, not requiring the introduction of protective agents, a simple route, high optical purity and total yield, and low cost. In addition, the raw materials and reagents used do not contain highly toxic or environmentally harmful reagents, making it easier to industrialize and environmentally friendly, and having good application prospects.

[0046] The serial numbers of the above embodiments of the present invention are for description only and do not represent the advantages or disadvantages of the embodiments.

[0047] The embodiments of the present invention are described above in conjunction with the accompanying drawings, but the present invention is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are merely illustrative and not restrictive. Under the guidance of the present invention, ordinary technicians in this field can also make many forms without departing from the scope of protection of the present invention and the claims, all of which are protected by the present invention.

Claims

1. An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, characterized in that, The following steps are involved: a. Preparation of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate Under the protection of inert gas and catalyzed by Lewis acid, m-phenylenedimethyl ether and monoethyl oxalyl chloride react to obtain ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate; b. Preparation of ethyl 2-(2-((3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate Under the catalysis of divalent cobalt salt, the C-H bond of the ortho position of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate was selectively activated through a carbonyl-directed carbon-hydrogen bond activation strategy. After reaction with 3,4-dimethoxybenzyl alcohol, ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate was 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-oxoacetate undergoes intramolecular ring closure to give 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one; d. Preparation (2 R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one Under the catalysis of a rhodium complex formed in situ by a monovalent rhodium salt and a chiral phosphine ligand, the enantioselective hydrogenation reduction of the double bond in 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one was achieved to give 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 chloride and demethylates to obtain the target compound (2 R ,3 R )-Dihydroquercetin.

2. An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, characterized in that: The method for preparing ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate comprises: under the protection of an inert gas, sequentially adding a Lewis acid catalyst, a solvent, and m-phenylenedimethyl ether into a reactor, cooling the temperature to -5-5°C, dropwise adding ethyl oxalyl chloride into the reactor, and reacting at -5-30°C for 1-12 hours after the dropwise addition is complete, wherein the molar ratio of m-phenylenedimethyl ether: ethyl oxalyl chloride: Lewis acid is 1.0:(1.0-1.5):(1.0-2.0); after the reaction is completed, adding dilute hydrochloric acid and an organic solvent, separating the liquids, washing the organic phase with a saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtering, and concentrating the organic phase to obtain a yellow oily substance, subjecting the yellow oily substance to reduced pressure distillation, and collecting the fractions to obtain the prepared ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate.

3. An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, characterized in that: The Lewis acid catalyst is one or more of aluminum chloride, tin tetrachloride, boron trifluoride etherate and ferric chloride; The solvent is one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, and 2-methyltetrahydrofuran.

4. An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, characterized in that: The method for preparing ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate comprises: A divalent cobalt salt, an oxidant, and an additive are added to a reactor equipped with a condensing device. Under stirring at room temperature, solvent A, ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate, and 3,4-dimethoxybenzyl alcohol are added, and the mixture is reacted at a temperature of 60 to 130° C. for 10 to 36 hours to obtain a reaction solution, wherein the molar ratio of ethyl 2-(2,4-dimethoxyphenyl)-2-oxoacetate: 3,4-dimethoxybenzyl alcohol: divalent cobalt salt: oxidant: additive is 1.0: (1.0 ~3.0): (0.01~0.2): (1.0~4.0): (0.01~0.2); After the reaction is completed, the reaction solution is cooled to room temperature, the reaction solution is filtered, and the filtrate is concentrated to obtain a brown oil. Isopropyl acetate is added to the brown oil, the organic phase is washed with a saturated sodium chloride solution, and the organic phase is concentrated. The obtained yellow residue is recrystallized from solvent B to obtain ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate.

5. An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, characterized in that: The method for preparing 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one comprises: dissolving ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate in an organic solvent C under inert gas protection, cooling the mixture to -5°C to 5°C, slowly adding a tetrahydrofuran solution of an alkali, and then heating the mixture to 25°C to 80°C for reaction for 6 to 24 hours to obtain a reaction solution; The molar ratio of ethyl 2-((2-(3,4-dimethoxybenzyl)oxy)-4,6-dimethoxyphenyl)-2-oxoacetate:base is 1.0:(1.0-3.0). After the reaction, water and an organic solvent are added. After separation, the organic phase is washed with a saturated sodium chloride solution and concentrated. The resulting yellow residue is recrystallized from solvent B to obtain 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one.

6. An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, characterized in that: Cobalt salts include Co(acac)2, Co(OAc)2, Co(OAc)2 . One of 4H2O, CoF2 or CoBr2; The oxidant used was 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, and the additive is one of NaOAc, KOAc, NaOPiv, Na2CO3 or K2CO3; Solvent A is 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 base is one of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium tert-butoxide; Solvent C is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene or n-hexane.

7. An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, characterized in that: Preparation (2 R ,3 R The method for preparing 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one comprises: sequentially adding a monovalent rhodium salt, a chiral phosphorus ligand, and a solvent D into a high-pressure reactor, stirring at room temperature for 1 hour, adding 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one, and replacing the reaction system with hydrogen three times, and introducing hydrogen into the high-pressure reactor during the fourth replacement. The reaction pressure is set to 1.0-5.0 MPa, and then the temperature is raised to 25-80°C for reaction for 12-48 hours to obtain a reaction solution, wherein the molar ratio of 2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-chromen-4-one: monovalent rhodium salt: chiral phosphorus ligand is 1.0:(0.0001-0.005):(0.0001-0.007); after the reaction is completed, the organic phase is concentrated to obtain (2 R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one crude product.

8. An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, characterized in that: The monovalent rhodium salt is one of Rh(COD)2BF4, [Rh(COD)Cl]2 or [Rh(NBD)2BF4]; Chiral phosphorus ligands are chiral diphosphorus ligands, including ( 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 R ,3 R )-dihydroquercetin synthesis method, characterized in that: Preparation of optically pure (2 R ,3 R )-dihydroquercetin method comprises: adding (2 R ,3 R )-2-(3,4-dimethoxyphenyl)-3-hydroxy-5,7-dimethoxychroman-4-one crude product, NaX and solvent E, replace the air in the reactor with inert gas, reduce the temperature to -10~5℃, add aluminum chloride in batches, 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: aluminum chloride: NaX is 1.0: (4.0~10.0): (0.01~0.15); after the reaction, the temperature is lowered to -10~0°C, water is slowly added dropwise to the reaction system, the liquid is separated, the organic phase is washed with saturated sodium chloride solution, the organic phase is concentrated, and the resulting yellow residue is recrystallized from solvent F to obtain optically pure (2 R ,3 R )-Dihydroquercetin.

10. An optically pure (2 R ,3 R )-dihydroquercetin synthesis method, characterized in that: 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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