Tocopherol derivatives, methods for producing tocopherol derivatives, and use

Abstract

This invention provides tocopherol derivatives that are produced under mild reaction conditions, are easy to operate, yield high yields, have high synthesis efficiency, and are economical and environmentally friendly, as well as methods for producing and using the same. [Solution] The following compound tocopherol derivatives with the structure shown below are provided. [Formula 1] JPEG2026097739000020.jpg60160

Description

Technical Field

[0001] The present invention relates to novel chemicals and methods for their production, and more particularly, to tocopherol derivatives, their catalytic synthesis method, and their use.

Background Art

[0002] Tocopherol and theanine have been widely noticed in the industry due to their antioxidant functions. If these can be combined, products with effects beyond expectations can be obtained.

[0003] However, based on the reaction conditions of phenolic acids and acids in existing similar technologies, it was expected to condense theanine and tocopherol in tetrahydrofuran to obtain the synthetic product. However, in the reaction process, it was found that this method not only has strict reaction conditions, but also has poor yield and purity.

[0004] Based on the reaction conditions of phenolic acids and acids in other existing similar technologies, it was expected to condense the carboxylate chloride of theanine and tocopherol to obtain the synthetic product. However, in the reaction process, it was similarly found that there are problems of strict reaction conditions and poor yield and purity.

[0005] Therefore, there is an urgent need to develop synthetic products based on tocopherol and theanine, as well as a synthetic method with high efficiency and energy saving that reduces the problems of insecurity and toxicity in the production process.

Summary of the Invention

Problems to be Solved by the Invention

[0006] The present invention aims to provide tocopherol derivatives, which are synthetic products based on tocopherol and theanine, and solves the shortcomings of conventional phenolic acid reactions, such as low economic efficiency, strict reaction conditions, and complex operation, thereby providing a novel method for producing tocopherol derivatives. This method has mild reaction conditions, is easy to operate, has high yield, high synthesis efficiency, is economically and environmentally friendly, and has good applicability. [Means for solving the problem]

[0007] Specifically, the present invention provides tocopherol derivatives. Tocopherol derivatives are characterized by being compounds represented by the following structure. [ka]

[0008] The above R' is most preferably hydrogen. Based on considerations of product stability, applications, and diversification, this can be achieved by substituting one hydrogen in NH2 with an acetyl group.

[0009] The aforementioned tocopherol derivative can be used as an antioxidant additive in cosmetics, food health products, pet supplies, and the like.

[0010] The present invention also provides a method for producing the above-mentioned tocopherol derivative. This production method is characterized by the following: Theanine and tocopherol are esterified using a catalyst and a co-catalyst to obtain a tocopherol derivative. The catalyst described above is selected from compounds shown in the following structure. [ka]

[0011] The specific reaction equation is shown below. [ka]

[0012] The most preferred catalyst may be selected from the following several compounds.

Chemical formula

[0013] Taking the catalyst cat.1 as an example, the activation mechanism of the reaction can be explained as follows.

Chemical formula

[0014] Furthermore, the method for producing a tocopherol derivative provided by the present invention is characterized in that the molar amount of the above-mentioned catalyst added is 0.2 to 0.5% of the total molar amount of the reactants, preferably 0.2 to 0.4%, and most preferably 0.2 to 0.3%.

[0015] Furthermore, the method for producing a tocopherol derivative provided by the present invention is characterized in that the molar ratio of the above-mentioned theanine to the above-mentioned tocopherol is 1 to 1.5:1, preferably 1.2 to 1.5:1, and most preferably 1.4 to 1.5:1.

[0016] Furthermore, the method for producing a tocopherol derivative provided by the present invention is characterized in that the cocatalyst is sodium phosphate. It has the effect of activating the catalyst.

[0017] Furthermore, the method for producing a tocopherol derivative provided by the present invention is characterized in that the molar ratio of the above-mentioned cocatalyst to the above-mentioned theanine is 0.1 to 0.5:1, preferably 0.1 to 0.3:1, and most preferably 0.1 to 0.2:1.

[0018] Furthermore, the method for producing a tocopherol derivative provided by the present invention is characterized in that after mixing theanine, tocopherol, a promoter and a catalyst, the mixture is stirred at room temperature for 4 to 6 hours for reaction, and the product is purified by post-treatment.

[0019] Furthermore, the method for producing a tocopherol derivative provided by the present invention is characterized in that the reaction is carried out in a solvent. The above solvent is one or more selected from halogenated alkanes (e.g., dichloromethane, chloroform, etc.), ethers (e.g., tetrahydrofuran, dioxane, tert-butyl methyl ether, diethyl ether, etc.), nitriles (e.g., acetonitrile, etc.), amides (e.g., N,N-dimethylformamide, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.).

[0020] Furthermore, the method for producing a tocopherol derivative provided by the present invention is characterized in that molecular sieves of 0.1 to 1% of the total weight of the raw materials can also be added. Preferably, it is 0.1 to 0.5%, and most preferably 0.1 to 0.3%.

[0021] Furthermore, the method for producing a tocopherol derivative provided by the present invention is characterized in that the above catalyst and promoter are used to catalyze the esterification reaction.

[0022] The present invention also provides the use of the above tocopherol derivative as an antioxidant.

Advantages of the Invention

[0023] The tocopherol derivative, which is a synthetic product based on tocopherol and theanine of the present invention, solves the defects of the conventional phenolic acid reaction, such as low economic efficiency, strict reaction conditions, and complex operation. The present invention also provides a method for producing a completely new tocopherol derivative. This method has mild reaction conditions, simple operation, high yield, high synthesis efficiency, is economical and environmentally friendly, and has good application potential.

Brief Description of the Drawings

[0024] [Figure 1] Hydrogen spectrum diagram of the tocopherol derivative of Example 1. [Figure 2] Reference curve for the DPPH free radical scavenging activity of ascorbic acid (VC). [Figure 3] The scavenging effect of the test sample on DPPH free radicals. [Figure 4] The scavenging effect on ·OH in the test sample. [Modes for carrying out the invention]

[0025] Theanine, tocopherol, sodium phosphate, catalyst, and co-catalyst are mixed and reacted by stirring at room temperature for 4 hours, and the product is purified by post-treatment.

[0026] The product structure is as follows: [ka] Based on the demand for derivative products, it is also possible to produce a product in which R' is an acetyl group by reacting the product with an acetylating reagent (e.g., acetyl chloride).

[0027] Here, the catalyst has the structure described below. [ka] R and R1 are the same or different alkyl or aryl groups, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, 2-methyl-butyl, etc.; aryl groups are linear or branched alkyl groups with 10 or fewer carbon atoms, for example: phenyl, benzyl, paratoluyl, orthotoluyl, metatoluyl, xylyl, paramethoxyphenyl, parachlorophenyl, metamethoxyphenyl, metachlorophenyl, orthomethoxyphenyl, orthochlorophenyl, etc.

[0028] The catalyst is preferably selected from cat.1, cat.2, and cat.3. [ka]

[0029] The co-catalyst is sodium phosphate.

[0030] The solvent for the reaction is one or more solvents selected from the following: halogenated alkanes (e.g., dichloromethane, chloroform, etc.), ethers (e.g., tetrahydrofuran, dioxane, tert-butylmethyl ether, diethyl ether, etc.), nitriles (e.g., acetonitrile, etc.), amides (e.g., N,N-dimethylformamide, etc.), and sulfoxides (e.g., dimethyl sulfoxide, etc.).

[0031] The molar amount of catalyst added is selected from a range of 0.2 to 0.5% of the total molar amount of reactants, or from a range of 2 to 10% of the total weight.

[0032] The molar ratio of theanine to tocopherol is selected from within the range of 1 to 1.5:1.

[0033] The molar ratio of sodium phosphate to theanine is selected from within the range of 0.1 to 0.5:1.

[0034] A further 0.1-1% of molecular sieves can be added to the total weight of the raw materials.

[0035] The sources of the raw materials used in this embodiment are as follows: [Table 1]

[0036] Preferred embodiments are shown below.

[0037] Example 1: Preparation of tocopherol theanine ester using catalyst cat.1 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), cat.1 (0.373 g), sodium phosphate (0.53 g), and the solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, 40 mL of water was added, and after stirring for 3 minutes, the organic phase was separated and dried to obtain 5.9 g of high-purity tocopherol-theanine ester (purity 97.6%). The yield was 88%. (Math 1) 1 H NMR (400 MHz, Chloroform-d) δ 6.77 (t, J = 4.1 Hz, 1H), 3.92 ~ 3.81 (m, 1H), 3.41 (dd, J = 7.3, 6.6 Hz, 1H), 3.26 ~ 3.16 (m, 2H), 2.78 (dd, J = 7.8, 5.0 Hz, 1H), 2.72 (dd, J = 7.8, 5.0 Hz, 1H), 2.38 ~ 2.25 (m, 2H), 2.19 ~ 2.04 (m, 7H), 2.04 ~ 1.90 (m, 1H), 1.75 (dd, J = 7.8, 5.0Hz, 1H), 1.73 - 1.19 (m, 25H), 1.13 (t, J = 6.4 Hz, 3H), 0.85 (dd, J = 6.8, 4.3 Hz, 9H), 0.79 (d, J = 6.7 Hz, 3H). LC-MS: 587.75[M+H] +

[0038] Example 2: Preparation of tocopherol theanine ester using catalyst cat.2 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), cat.2 (0.363 g), sodium phosphate (0.53 g), and the solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, 40 mL of water was added, and after stirring for 3 minutes, the organic phase was separated and dried to obtain 5.2 g of high-purity tocopherol-theanine ester (purity 94.3%). The yield was 75%.

[0039] Example 3: Preparation of tocopherol theanine ester using catalyst cat.3 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), cat.3 (0.353 g), sodium phosphate (0.53 g), and the solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, 40 mL of water was added, and after stirring for 3 minutes, the organic phase was separated and dried to obtain 6.2 g of high-purity tocopherol-theanine ester (purity 99.1%). The yield was 92%.

[0040] Example 4: Preparation of tocopherol theanine ester using catalyst cat.3 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), cat.3 (0.353 g), sodium phosphate (0.53 g), and tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, and 40 mL of saturated sodium bicarbonate solution was added. After stirring for 3 minutes, the organic phase was separated and dried to obtain 6.4 g of high-purity tocopherol-theanine ester (purity 99.3%). The yield was 94%.

[0041] Example 5: Preparation of tocopherol theanine ester using catalyst cat.3 (optimal conditions) In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), cat.3 (0.353 g), sodium phosphate (0.53 g), molecular sieve (0.2 g), and solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, and 40 mL of saturated sodium bicarbonate solution was added. After stirring for 3 minutes, the organic phase was separated, and another 40 mL of saturated sodium chloride solution was added. After drying, 6.9 g of high-purity tocopherol-theanine ester (purity 99.7%) was obtained. The yield was 98%.

[0042] Comparative Example 1 5 g of theanine, 3.9 g of tocopherol, and 100 mL of tetrahydrofuran solvent were added to a 250 mL three-necked flask and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, and 40 mL of saturated sodium bicarbonate solution was added. After stirring for 3 minutes, the organic phase was separated, and almost no product was detected by chromatographic analysis.

[0043] Comparative Example 2 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), cat.3 (0.35 g), and the solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, and almost no product was detected by chromatographic analysis.

[0044] Comparative Example 3 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), cat.4 (0.35 g), and the solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, and 40 mL of saturated sodium bicarbonate solution was added. After stirring for 3 minutes, the organic phase was separated, and almost no product was detected by chromatographic analysis. Cat.4 has the following structure. [ka]

[0045] Comparative Example 4 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), cat.5 (0.35 g), and the solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, and 40 mL of saturated sodium bicarbonate solution was added. After stirring for 3 minutes, the organic phase was separated, and almost no product was detected by chromatographic analysis. Cat.5 has the following structure. [ka]

[0046] Comparative Example 5 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), boric acid (0.3 g), oxalic acid (0.3 g), and the solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, and 40 mL of saturated sodium bicarbonate solution was added. After stirring for 3 minutes, the organic phase was separated, and almost no product was detected by chromatographic analysis.

[0047] Experimental Example 6 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), sodium phosphate (0.1 g), cat.3 (0.35 g), and the solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, 40 mL of water was added, and after stirring for 3 minutes, the organic phase was separated and dried to obtain 4.1 g of high-purity tocopherol-theanine ester (purity 98.4%).

[0048] Experimental Example 7 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), sodium phosphate (0.9 g), cat.3 (0.35 g), and the solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, 40 mL of water was added, and after stirring for 3 minutes, the organic phase was separated and dried to obtain 4.3 g of high-purity tocopherol-theanine ester (purity 98.1%).

[0049] Experimental Example 8 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), sodium phosphate (0.5 g), cat.3 (0.35 g), and solvent ethanol (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, 40 mL of water was added, and after stirring for 3 minutes, the organic phase was separated and dried to obtain 2.8 g (91.1% purity) of high-purity tocopherol-theanine ester.

[0050] Experimental Example 9 In a 250 mL three-necked flask, theanine (5 g), tocopherol (3.9 g), PBS (0.5 g), cat.3 (0.35 g), and the solvent tetrahydrofuran (100 mL) were added and mixed and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, 40 mL of water was added, and after stirring for 3 minutes, the organic phase was separated and dried to obtain 3.3 g of high-purity tocopherol-theanine ester (purity 89.6%).

[0051] Experimental Example 10. Antioxidant Effect Test of Tocopherol Theanine Ester (The test sample is a high-purity product of tocopherol theanine ester synthesized in Example 1)

[0052] 1. DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging ability test 1.1 Experimental Principle The DPPH radical scavenging activity evaluation method is a method for measuring antioxidant activity in vitro. DPPH is a stable large free radical in organic solvents, exhibiting a purple color in methanol or ethanol and having maximum light absorption at a wavelength of 517 nm. The DPPH colorimetric method is based on the observation that radical scavengers provide electrons to the lone pairs of electrons of DPPH, causing the purple color of DPPH itself in organic solvents to change to yellow at a wavelength of 517 nm, and that the change in absorbance exhibits a linear relationship with the free radical scavenging ability. In other words, the stronger the scavenging ability of the radical scavengers, the lower the absorbance.

[0053] 1.2 Experimental Reagents DPPH (Sigma), PBS (Gibco), anhydrous ethanol (National Pharmaceutical Reagent), petroleum ether (National Pharmaceutical Reagent), vitamin C (CNW), anhydrous ethanol (National Pharmaceutical Reagent). Main equipment: multimode microplate reader (Tecan, Spark), micro-shaker (Kylin-Bell, TS-92).

[0054] 1.3 Test Method 1.3.1 Creation of a reference curve for DPPH free radical scavenging capability of the system reference Ascorbic acid (VC) was used as the system reference and diluted with PBS to five different concentrations of 12.5, 25, 50, 100, and 200 μg / mL. Measurements and calculations were performed according to the test method in 1.3.2 to create a reference curve with the concentration of the reference product on the x-axis and the DPPH free radical scavenging rate on the y-axis. 1.3.2 In vitro DPPH free radical scavenging test Prepare the test sample into a test solution of the appropriate concentration, and then prepare and mix the reaction system according to the amount of each reagent added as shown in Table 2 below. Five replicates and one blank control are set up for each concentration. [Table 2] Place the reaction system at room temperature and allow it to react for 30 minutes in a light-shielded environment. After the reaction is complete, measure the absorbance OD value at 517 nm and calculate the scavenging rate of the test sample against DPPH free radicals according to the following formula. The scavenging rate of DPPH free radicals in the test sample = [(C1-C2)-(T1-T2)] / (C1-C2)×100% During the ceremony: C1 - Blank, showing the absorbance value of a system having DPPPH. This shows the absorbance value of a C2-blank system that does not have DPPH. T1-The absorbance values ​​of the sample group with DPPH are shown. The absorbance values ​​shown are for the T2-test sample group and systems without DPPH.

[0055] 1.4 Results of the in vitro DPPH free radical scavenging test 1.4.1 The DPPH free radical scavenging reference curve for the system reference is shown in Table 3 and Figure 2 below. [Table 3] 1.4.2 The results of the in vitro DPPH free radical scavenging test of the test samples are shown in Table 4 and Figure 3 below. [Table 4]

[0056] 1.5. Conclusion The test samples were able to improve the scavenging rate of DPPH free radicals at concentrations of 0.02% to 4%, showing a statistically significant difference compared to the control group (p<0.001), and possessing antioxidant capacity.

[0057] 2. OH ​​radical scavenging ability test 2.1 Experimental Principle When the antioxidant function of living organisms declines or cells are damaged, excessive free radicals are generated. Among various reactive oxygen species and free radicals, hydroxyl free radicals (·OH) have the strongest reaction activity (10 7 ~10 10 M -1 S -1 ), the greatest damage to living organisms. The Fenton reaction generates hydroxyl free radicals: H2O2 + Fe 2+ =·OH+H2O+Fe 3+ The ·OH generated by the reaction reacts with salicylic acid to produce a product with a special absorption at 520 nm. When a test sample with ·OH scavenging ability is added to the reaction system, the amount of ·OH generated decreases. This reduces the amount of colored compound produced accordingly. The degree of change in absorbance is related to the degree of ·OH scavenging; that is, the stronger the scavenging ability of the ·OH scavenger, the lower the absorbance.

[0058] 2.2 Test Method The test sample is prepared in a test solution of the appropriate concentration, various reagents are added according to the test method in Table 5 below, and measurements are taken. Then, the absorbance value is measured at 520 nm, and the elimination rate of the test sample is calculated according to the formula below. Five different concentrations of the test sample are set, and measurements are repeated five times at each concentration. Elimination rate of ·OH in the test sample = [(AC)-(BD)] / (AC) × 100% [Table 5]

[0059] 2.3. Results of in vitro OH elimination test of test samples [Table 6]

[0060] 2.4. Experimental conclusions: The test samples were able to improve the elimination rate of ·OH at concentrations of 0.02% to 4%, showing a statistically significant difference compared to the control group (p<0.001), and possessing antioxidant capacity. [Industrial applicability]

[0061] The tocopherol derivative compounds of the present invention can be used as antioxidants in cosmetics, food health products, pet supplies, and the like. The method of the present invention has mild reaction conditions, is easy to operate, yields high yields, has high synthesis efficiency, is economical and environmentally friendly, and has good applicability.

Claims

1. A tocopherol derivative characterized by being a compound with the following structure. 【Chemistry 1】

2. A method for producing a tocopherol derivative according to claim 1, Through the action of a catalyst and co-catalyst, theanine and tocopherol are esterified to obtain a tocopherol derivative. A method for producing the catalyst, characterized in that the catalyst is selected from compounds represented by the following structure. 【Chemistry 2】 [R and R1 are the same or different alkyl or aryl groups.] The alkyl group is selected from linear or branched alkyl groups having 10 or fewer carbon atoms. The aryl group is selected from phenyl, benzyl, p-toluyl, ortho-toluyl, meta-toluyl, xylyl, p-methoxyphenyl, p-chlorophenyl, meta-methoxyphenyl, meta-chlorophenyl, ortho-methoxyphenyl, and ortho-chlorophenyl groups.

3. The manufacturing method according to claim 2, characterized in that the molar amount of the catalyst added is 0.2 to 0.5% of the total molar amount of the reactants.

4. The manufacturing method according to claim 2, characterized in that the molar ratio of theanine to tocopherol is 1 to 1.5:

1.

5. The manufacturing method according to claim 2, characterized in that the co-catalyst is sodium phosphate.

6. The manufacturing method according to claim 2, characterized in that the molar ratio of the co-catalyst to theanine is 0.1 to 0.5:

1.

7. The manufacturing method according to claim 2, characterized in that theanine, tocopherol, a co-catalyst and a catalyst are mixed, the mixture is stirred at room temperature for 4 to 6 hours to allow the reaction to proceed, and the product is purified by post-treatment.

8. The manufacturing method according to claim 7, characterized by further adding a molecular sieve.

9. Use of the tocopherol derivative described in claim 1 as an antioxidant and the tocopherol derivative produced by the manufacturing method described in any one of claims 2 to 8.

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