A method for preparing (-)EGCG by photocatalytic debenzylation reaction
Through photocatalytic debenzylation reaction and microwave-assisted esterification reaction, the problems of complicated synthesis steps and high cost of (-)EGCG were solved, and efficient and environmentally friendly (-)EGCG synthesis was achieved.
Patent Information
- Application Number
- CN202410879685.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-07-02
- Publication Date
- 2025-09-30
- Estimated Expiration
- 2044-07-02
AI Technical Summary
The synthesis of (-)EGCG in the prior art is complicated, costly, and environmentally unfriendly. In particular, the esterification reaction uses acyl chloride and precious metal palladium catalyst, which leads to environmental pollution and metal residues.
A photocatalytic debenzylation reaction was adopted, in which Lewis acid and organic amine ligand were used for debenzylation reaction under inert atmosphere and light source irradiation, and esterification reaction was carried out under microwave assistance, using perfluoromethanesulfonate zinc catalyst, avoiding acyl chloride and precious metal palladium catalyst.
The method achieves efficient synthesis of (-)EGCG, simplifies the operation process, reduces costs, is environmentally friendly, and meets the requirements of green and sustainable development.
Smart Images
Figure CN118702664B_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing (-)EGCG through a photocatalytic debenzylation reaction. Background Art
[0002] Epigallocatechin gallate ((-)-EGCG) protects against free radical DNA damage, radiation and UV rays, prevents lipid peroxidation, reduces serum levels of low-density lipoprotein cholesterol, ultra-low-density lipoprotein cholesterol, and triglycerides, interferes with signaling pathways necessary for cancer cell survival, inhibits dietary carcinogens, and works with other enzymes and antioxidants in the intestines, liver, and lungs to block the activity of certain carcinogens. It scavenges free radicals, protects against the effects of pollution, sun exposure, and smoking, and prevents skin aging and wrinkling. (-)-EGCG plays an important role in cancer prevention and cardiovascular disease. It can also be used as a reversal agent for multidrug resistance in tumors, improving cancer cell sensitivity to chemotherapy and reducing cardiotoxicity.
[0003] (-)EGCG can be extracted from tea leaves, but the extraction process to obtain pure (-)EGCG is complicated, and it is difficult to separate the active ingredients and retain the natural flavor of tea leaves. In addition, the content of (-)EGCG in tea leaves is related to factors such as the origin, picking period, and age of the tea leaves. Therefore, the chemical synthesis of (-)-EGCG and its derivatives has gradually received research and attention. (-)-EGCG can be synthesized by acid-catalyzed Friedel-Crafts alkylation, Sharpless asymmetric dihydroxylation, protection of the o-dihydroxy group, S N 2. Preparation by nucleophilic substitution ring closure, Dess-Martin oxidation, L-Selectride asymmetric reduction, esterification and debenzylation reaction. Among them, the esterification reaction requires the raw material carboxylic acid 1 to be converted into an acyl chloride in advance, and then esterified with the benzyl-protected polyphenol hydroxyl compound 2 to synthesize the intermediate ester compound 3. This not only makes the synthesis steps cumbersome and the operation complicated, but also the use of acyl chloride is environmentally unfriendly and does not meet the requirements of green and sustainable development. The debenzylation reaction needs to be carried out under the catalysis of precious metal palladium in a hydrogen atmosphere, which not only makes the production cost higher, but also makes it difficult to completely remove the precious metal palladium catalyst, resulting in metal residues in the product. Summary of the Invention
[0004] The technical problem to be solved by the present invention is to overcome the deficiencies and defects mentioned in the above background technology and provide a method for preparing (-)EGCG by photocatalytic debenzylation reaction.
[0005] In order to solve the above technical problems, the technical solution proposed by the present invention is:
[0006] A method for preparing (-)EGCG by photocatalytic debenzylation reaction comprises the following steps:
[0007] Under an inert protective atmosphere and light source, compound 3 undergoes a debenzylation reaction under the action of Lewis acid and organic amine ligand, and then acidifies to obtain (-)EGCG;
[0008] Among them, the structural formulas of compound 3 and (-)EGCG are as follows:
[0009]
[0010] The light source is green light, blue light or white light.
[0011] As a further improvement, the following steps are also included:
[0012] In an inert protective atmosphere and with the assistance of microwaves, the raw material carboxylic acid 1 and the benzyl-protected polyphenolic hydroxy compound 2 were subjected to an esterification reaction in the presence of a catalyst, zinc perfluoromethanesulfonate, to obtain compound 3.
[0013] The structural formulas of the raw material carboxylic acid 1 and the benzyl-protected polyphenol hydroxy compound 2 are as follows:
[0014]
[0015] Preferably, the light source is white light.
[0016] As a further improvement, the Lewis acid includes one or any combination of AlCl3, AlBr3, AlI3, Al2O3, ZnCl2, ZnBr2, ZnI2, TiCl2, FeCl3, FeBr3, BCl3, BBr3, NiCl2, NiBr2, NiI2, Ni(OTf)2, CoCl2 or Cp*Co(CO)I2.
[0017] Preferably, the Lewis acid is AlI3.
[0018] As a further improvement, the organic amine ligand includes one or any combination of N-methylaniline, N,N-dimethylaniline, N,N,N′,N′-tetramethyl-p-phenylenediamine, N-methyldiphenylamine, N-isopropylaniline, N-ethyl-N-methylaniline, triphenylamine, N,N-dimethyl-p-toluidine, triethylamine, diisopropylamine, diisopropylethylamine or N,N′-dimethylethylenediamine.
[0019] Preferably, the organic amine ligand is N-ethyl-N-methylaniline or N-methylaniline.
[0020] As a further improvement, the reaction solvent of the debenzylation reaction is selected from the following solvents or solvent combinations: THF, 1,4-dioxane, chloroform, acetonitrile, acetone, ethanol, isopropanol, methanol, tert-butanol, DMF, DMSO, ether, toluene, methanol / dichloromethane, methanol / THF, methanol / 1,4-dioxane, DMF / 1,4-dioxane, DMF / THF, ethanol / dichloromethane, ethanol / THF, ethanol / 1,4-dioxane, methanol / dichloromethane / 1,4-dioxane.
[0021] Preferably, the reaction solvent of the debenzylation reaction is N-ethyl-N-methylaniline.
[0022] As a further improvement, the temperature of the debenzylation reaction is -30 to 50°C, and the temperature of the esterification reaction is 20 to 110°C.
[0023] Compared with the prior art, the present invention has the following beneficial effects:
[0024] The present invention efficiently synthesizes an intermediate ester compound 3 by directly esterifying a carboxylic acid 1 and a benzyl-protected polyphenol hydroxy compound 2 using perfluoromethanesulfonate zinc catalyzed under microwave assistance, without the need for prior preparation of an acyl chloride.
[0025] The present invention promotes the debenzylation reaction of compound 3 by Lewis acid under photocatalysis to prepare (-)EGCG with high yield, avoiding the use of palladium noble metal catalysts.
[0026] The present invention develops a new synthetic route for the natural product (-)EGCG, which can make up for the series deficiencies of the existing acyl chloride esterification and palladium-catalyzed debenzylation reaction systems and has the advantages of low cost, simple operation, mild reaction conditions and environmental friendliness. DETAILED DESCRIPTION
[0027] To facilitate understanding of the present invention, the present invention will be described more comprehensively and meticulously below in conjunction with preferred embodiments, but the protection scope of the present invention is not limited to the following specific embodiments.
[0028] Unless otherwise defined, all technical terms used hereinafter have the same meanings as those generally understood by those skilled in the art. The technical terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention.
[0029] 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.
[0030] The method for preparing (-)EGCG by photocatalytic debenzylation reaction of the present invention has the following synthesis path:
[0031]
[0032] Under an inert protective atmosphere and irradiation with a light source, compound 3 undergoes a debenzylation reaction under the action of a Lewis acid and an organic amine ligand.
[0033] After the reaction is complete, some phenolic hydroxyl groups exist in the form of salts, which are completely released by acidification. In some embodiments, after the reaction is complete, the reaction mixture is acidified, the pH is adjusted to 1-2, stirred for 5-12 hours, and concentrated to obtain crude (-)EGCG. Pure (-)EGCG is obtained by silica gel column chromatography.
[0034] Compound 3 has the following structural characteristics: it contains three benzene rings, two of which have three adjacent OBn groups. Ensuring that all benzyl groups are removed simultaneously is challenging. The present invention utilizes specific lighting and controlled reaction conditions (such as Lewis acid, organic amine, temperature, and solvent) to obtain (-)-EGCG in high yield.
[0035] The light source is green, blue, or white light. Different wavelengths of light significantly affect the yield of the debenzylation reaction. White light has the highest yield, while blue and green light have lower yields, and red light has a very low yield. Without a light source, the reaction yield is low.
[0036] A Lewis acid is used as a catalyst to catalyze the debenzylation reaction. In some embodiments, the Lewis acid is selected from the group consisting of AlCl₃, AlBr₃, AlI₃, Al₂O₃, ZnCl₂, ZnBr₂, ZnI₂, TiCl₂, FeCl₃, FeBr₃, BCl₃, BBr₃, NiCl₂, NiBr₂, NiI₂, Ni(OTf)₂, CoCl₂, and Cp*Co(CO)I₂. AlI₃ is preferred, as it offers the highest yield, followed by AlCl₃, ZnI₂, and Cp*Co(CO)I₂, which offer relatively high yields. The molar ratio of the Lewis acid to compound 3 is 2 to 6:1, preferably 4 to 6:1.
[0037] Organic amine ligands can enhance the catalytic activity of Lewis acids. In some embodiments, the organic amine ligand is selected from the group consisting of: N-methylaniline, N,N-dimethylaniline, N,N,N′,N′-tetramethyl-p-phenylenediamine, N-methyldiphenylamine, N-isopropylaniline, N-ethyl-N-methylaniline, triphenylamine, N,N-dimethyl-p-toluidine, triethylamine, diisopropylamine, diisopropylethylamine, and N,N′-dimethylethylenediamine. N-ethyl-N-methylaniline and N-methylaniline are preferred, as they offer the highest yields, followed by N,N-dimethylaniline. The molar ratio of the organic amine ligand to compound 3 is 2.4 to 8:1, preferably 5 to 6:1.
[0038] In some embodiments, the debenzylation reaction solvent is selected from the following solvents: THF, 1,4-dioxane, chloroform, acetonitrile, acetone, ethanol, isopropanol, methanol, tert-butanol, DMF, DMSO, diethyl ether, toluene, methanol / dichloromethane, methanol / THF, methanol / 1,4-dioxane, DMF / 1,4-dioxane, DMF / THF, ethanol / dichloromethane, ethanol / THF, ethanol / 1,4-dioxane, methanol / dichloromethane / 1,4-dioxane. N-ethyl-N-methylaniline is preferred due to its highest yield.
[0039] In some embodiments, the temperature of the debenzylation reaction is controlled at -30 to 50° C., preferably 0 to 10° C., at which the yield is higher. The debenzylation reaction time is 5 to 10 hours.
[0040] The synthesis path of compound 3 in the present invention is as follows:
[0041]
[0042] Under an inert atmosphere and with microwave assistance, a carboxylic acid 1 and a benzyl-protected polyphenolic hydroxy compound 2 undergo an esterification reaction in the presence of zinc perfluoromethanesulfonate. After completion, the reaction is extracted and the organic phase is dried by spin drying to yield crude compound 3. Microwaves promote collisional mixing of the reactants and catalyst in solution, thereby accelerating the esterification reaction. Without microwave assistance, the yield is lower (based on Example 1, the yield is only approximately 40%). The present invention does not require a specific microwave wavelength.
[0043] In some embodiments, the molar ratio of the carboxylic acid 1 to the benzyl-protected polyphenolic hydroxy compound 2 in the esterification reaction is 1.2 to 1.0: 1. The molar amount of zinc perfluoromethanesulfonate added is 2 to 20% of the benzyl-protected polyphenolic hydroxy compound 2.
[0044] In some embodiments, the esterification reaction solvent is selected from the group consisting of THF, chloroform, dichloromethane, acetonitrile, acetone, ethanol, isopropanol, methanol, tert-butanol, DMF, diethyl ether, and toluene.
[0045] In some embodiments, the temperature of the esterification reaction is 20-110° C., preferably 70-90° C. The time of the esterification reaction is 6-35 hours.
[0046] The present invention uses carboxylic acid 1 and benzyl-protected polyphenol hydroxyl compound 2 as raw materials, zinc perfluoromethanesulfonate as a catalyst, and performs an esterification reaction under microwave assistance to efficiently synthesize compound 3; under light irradiation and Lewis acid catalysis, (-)-EGCG is prepared at low cost and efficiently through a debenzylation reaction of compound 3.
[0047] Example 1 Esterification reaction
[0048] To a 250 mL three-necked flask, the raw material carboxylic acid 1 (0.4845 g, 1.1 mmol), the benzyl-protected polyphenol hydroxy compound 2 (0.7549 g, 1.0 mmol), zinc perfluoromethanesulfonate (0.0364 g, 0.1 mmol), and THF (20 mL) were added. Under nitrogen protection, the reaction was carried out at 85°C in a microwave oven for 15 h. After the reaction, saturated brine and ethyl acetate were added, and the organic phase was extracted. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 6 / 1) to obtain the intermediate ester compound 3 (0.8846 g, 75%).
[0049] The structural formula of target product 3 is as follows:
[0050]
[0051] The target product is a white solid with a yield of 75% (mol).
[0052] 1 H NMR (400MHz, CDCl3): δ7.42-7.18(m,42H),6.73(s,2H),6.37(t,J=16Hz,2H),5.66(s,1H),5.05-5.01( m,9H),4.96(d,J=4Hz,2H),4.90(s,2H),4.80(d,J=12Hz,2H),4.66(d,J=12Hz,2H),3.14-3.04(m,2H).
[0053] Example 2 Debenzylation reaction
[0054] Compound 3 (0.5887 g, 0.5 mmol), AlI (0.9784 g, 2.4 mmol), N-ethyl-N-methylaniline (0.3784 g, 2.8 mmol), CHCl (30 mL), and methanol (30 mL) were added to a 250 mL three-necked flask. The mixture was reacted under nitrogen protection in an ice bath (approximately 0-10°C) and irradiated with a 50W white light source for 8 h. After completion of the reaction, dilute hydrochloric acid (1.0 M) was added to adjust the pH to approximately 1. The mixture was stirred overnight, and the reaction mixture was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / methanol, 2 / 1) to obtain (-)EGCG (0.1856 g, 81%).
[0055] The target product (-)EGCG structural formula is as follows:
[0056]
[0057] The target product is a white solid with a yield of 81% (mol).
[0058] 1 H NMR (400MHz, CDCl3): δ6.97 (s, 2H), 6.61 (s, 2H), 5.98 (d, J = 4Hz, 2H), 5.38 (s, 1H), 4.98 (s, 1H), 4.42 (s, 8H), 2.99-2.84 (m, 2H).
[0059] The above Example 2 was used as the standard reaction conditions to conduct the following comparative experiment, in which the debenzylation reaction of compound 3 was carried out under different conditions to synthesize (-)EGCG. The differences from the standard reaction conditions are listed in the table below.
[0060]
[0061]
[0062] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any form. Therefore, any simple modifications, equivalent variations, and modifications to the above embodiments that do not depart from the technical solution of the present invention and are based on the technical essence of the present invention shall fall within the scope of protection of the technical solution of the present invention.
Claims
1. A method for preparing (-)EGCG by photocatalytic debenzylation reaction, characterized in that: The following steps are included: Under an inert protective atmosphere and light source, compound 3 undergoes a debenzylation reaction under the action of Lewis acid and organic amine ligand, and then acidifies to obtain (-)EGCG; Among them, the structural formulas of compound 3 and (-)EGCG are as follows: The light source is green light, blue light or white light.
2. The method for preparing (-)EGCG by photocatalytic debenzylation reaction according to claim 1, characterized in that: The following steps are also included: In an inert protective atmosphere and with the assistance of microwaves, the raw material carboxylic acid 1 and the benzyl-protected polyphenolic hydroxy compound 2 were subjected to an esterification reaction in the presence of a catalyst, zinc perfluoromethanesulfonate, to obtain compound 3. The structural formulas of the raw material carboxylic acid 1 and the benzyl-protected polyphenol hydroxy compound 2 are as follows:
3. The method for preparing (-)EGCG by photocatalytic debenzylation reaction according to claim 1, characterized in that: The light source is white light.
4. The method for preparing (-)EGCG by photocatalytic debenzylation reaction according to claim 1, characterized in that: The Lewis acid includes one or any combination of AlCl3, AlBr3, AlI3, Al2O3, ZnCl2, ZnBr2, ZnI2, TiCl2, FeCl3, FeBr3, BCl3, BBr3, NiCl2, NiBr2, NiI2, Ni(OTf)2, CoCl2 or Cp*Co(CO)I2.
5. The method for preparing (-)EGCG by photocatalytic debenzylation reaction according to claim 4, characterized in that: The Lewis acid is AlI3.
6. The method for preparing (-)EGCG by photocatalytic debenzylation reaction according to claim 1 or 4, characterized in that: The organic amine ligand includes one or any combination of N-methylaniline, N,N-dimethylaniline, N,N,N′,N′-tetramethyl-p-phenylenediamine, N-methyldiphenylamine, N-isopropylaniline, N-ethyl-N-methylaniline, triphenylamine, N,N-dimethyl-p-toluidine, triethylamine, diisopropylamine, diisopropylethylamine or N,N′-dimethylethylenediamine.
7. The method for preparing (-)EGCG by photocatalytic debenzylation reaction according to claim 6, characterized in that: The organic amine ligand is N-ethyl-N-methylaniline or N-methylaniline.
8. The method for preparing (-)EGCG by photocatalytic debenzylation reaction according to claim 1 or 4, characterized in that: The reaction solvent of the debenzylation reaction is selected from the following solvents or solvent combinations: THF, 1,4-dioxane, chloroform, acetonitrile, acetone, ethanol, isopropanol, methanol, tert-butanol, DMF, DMSO, ether, toluene, methanol / dichloromethane, methanol / THF, methanol / 1,4-dioxane, DMF / 1,4-dioxane, DMF / THF, ethanol / dichloromethane, ethanol / THF, ethanol / 1,4-dioxane, methanol / dichloromethane / 1,4-dioxane.
9. The method for preparing (-)EGCG by photocatalytic debenzylation reaction according to claim 8, characterized in that: The reaction solvent of the debenzylation reaction is N-ethyl-N-methylaniline.
10. The method for preparing (-)EGCG by photocatalytic debenzylation reaction according to claim 2, characterized in that: The temperature of the debenzylation reaction is -30 to 50°C, and the temperature of the esterification reaction is 20 to 110°C.