Tocopherol derivatives, method for producing tocopherol derivatives and use thereof

Abstract

The present invention provides a tocopherol derivative which requires mild reaction conditions, is easy to operate, has a high yield and high synthesis efficiency, and is economical and environmentally friendly, as well as a method for producing the same and its use. The present invention provides a compound tocopherol derivative represented by the following structure: [Formula 1] JPEG0007799365000020.jpg60160

Description

[Technical Field]

[0001] The present invention relates to novel chemical products and methods for their preparation, and in particular to tocopherol derivatives and their catalytic synthesis methods and uses. [Background technology]

[0002] Tocopherol and theanine have attracted widespread attention in the industry due to their antioxidant properties, and combining them could result in products with effects that exceed expectations.

[0003] However, based on the reaction conditions of phenolic acid and acid in existing similar technology, it was expected that the synthesis product would be obtained by condensing theanine and tocopherol in tetrahydrofuran. However, during the reaction process, it was discovered that this method not only required harsh reaction conditions, but also had poor yield and purity.

[0004] Based on the reaction conditions of phenolic acid and acid in other similar existing technologies, it was expected that the carboxylic acid chloride of theanine and tocopherol would be condensed to obtain the synthesized product. However, it was discovered that the reaction conditions were similarly harsh during the reaction process, and the yield and purity were also poor.

[0005] Therefore, there is an urgent need to develop synthetic products based on tocopherol and theanine, as well as synthetic methods for producing such products with high efficiency and energy saving, while reducing the unsafe and toxic harmful issues during the production process. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention aims to provide a tocopherol derivative, which is a synthetic product based on tocopherol and theanine, by overcoming the drawbacks of the conventional phenolic acid reaction, such as low economic efficiency, harsh reaction conditions, and complicated procedures, and by providing a novel method for producing a tocopherol derivative, which has mild reaction conditions, simple procedures, high yields, high synthetic efficiency, is economical and environmentally friendly, and has good applicability. [Means for solving the problem]

[0007] Specifically, the present invention provides a tocopherol derivative, which is characterized by being a compound represented by the following structure: [ka]

[0008] The most preferred R' is hydrogen, which can be achieved by substituting one hydrogen atom in NH2 with an acetyl group, taking into consideration the stability, application and versatility of the product.

[0009] The tocopherol derivatives can be used as antioxidant additives in cosmetics, food and health products, pet supplies, etc.

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

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

[0012] The most preferred catalysts may be selected from several compounds: [ka] The reaction mechanism of the catalyst in the preparation of the tocopherol derivative is as follows: The acidic hydrogen in the cationic portion of the catalyst acts as a hydrogen bond donor to activate the carbonyl group of theanine, and the negative oxygen ions in the anionic portion of the catalyst act as hydrogen bond acceptors to activate the phenolic hydroxyl group on the tocopherol, thereby promoting the esterification reaction.

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

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

[0015] Furthermore, the method for producing a tocopherol derivative provided by the present invention is characterized in that the molar ratio of theanine to 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 co-catalyst is sodium phosphate, which 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 promoter to the 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 theanine, tocopherol, a co-catalyst, and a catalyst are mixed, and then the mixture is stirred at room temperature for 4 to 6 hours to react, 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 solvent is at least one 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.), and 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 can be added in an amount of 0.1 to 1% of the total weight of the raw materials, preferably 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 co-catalyst are used to catalyze the esterification reaction.

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

[0023] The tocopherol derivatives synthesized from tocopherol and theanine of the present invention overcome the drawbacks of the conventional phenolic acid reaction, such as low economic efficiency, harsh reaction conditions, and complicated procedures. The present invention also provides a novel method for producing tocopherol derivatives, which has mild reaction conditions, simple procedures, high yields, high synthetic efficiency, is economical, environmentally friendly, and has good applicability. [Brief explanation of the drawings]

[0024] [Figure 1] 1 is a hydrogen spectrum of the tocopherol derivative of Example 1. [Figure 2] Reference curve for the DPPH free radical scavenging activity of ascorbic acid (VC). [Figure 3] DPPH free radical scavenging activity of test samples. [Figure 4] Scavenging activity of the test sample against ·OH. DETAILED DESCRIPTION OF THE INVENTION

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

[0026] The product structure is as follows: [ka] Depending on the demand for derivative products, the product can also be reacted with an acetylating reagent (eg, acetyl chloride) to achieve a product in which R' is an acetyl group.

[0027] Here, the catalyst has the structure shown below. [ka] R and R1 are the same or different alkyl groups or aryl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and 2-methylbutyl groups; aryl groups are straight-chain or branched alkyl groups having 10 or less carbon atoms, such as phenyl, benzyl, para-toluyl, ortho-toluyl, meta-toluyl, xylyl, para-methoxyphenyl, para-chlorophenyl, meta-methoxyphenyl, meta-chlorophenyl, ortho-methoxyphenyl, and ortho-chlorophenyl groups.

[0028] Preferably, the catalyst is selected from cat.1, cat.2 and cat.3. [ka]

[0029] The promoter is sodium phosphate.

[0030] The reaction solvent is at least one 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.), and sulfoxides (e.g., dimethyl sulfoxide, etc.).

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

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

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

[0034] Molecular sieves can be further added in an amount of 0.1 to 1% of the total weight of the raw materials.

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

[0036] The following is a preferred embodiment.

[0037] Example 1: Preparation of tocopherol theanine esters with catalyst cat. 1 Theanine (5 g), tocopherol (3.9 g), cat. 1 (0.373 g), sodium phosphate (0.53 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask 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 highly purified tocopherol theanine ester (97.6% purity). The yield was 88%. (Number 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 esters with catalyst cat. 2 Theanine (5 g), tocopherol (3.9 g), cat. 2 (0.363 g), sodium phosphate (0.53 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask 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 esters with catalyst cat. 3 Theanine (5 g), tocopherol (3.9 g), cat. 3 (0.353 g), sodium phosphate (0.53 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask 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 (99.1% purity). The yield was 92%.

[0040] Example 4: Preparation of tocopherol theanine esters with catalyst cat. 3 Theanine (5 g), tocopherol (3.9 g), cat. 3 (0.353 g), sodium phosphate (0.53 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask 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 highly purified tocopherol theanine ester (99.3% purity). The yield was 94%.

[0041] Example 5: Preparation of tocopherol theanine esters using catalyst cat. 3 (optimal conditions) Theanine (5 g), tocopherol (3.9 g), cat. 3 (0.353 g), sodium phosphate (0.53 g), molecular sieves (0.2 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask 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 highly purified tocopherol theanine ester (purity 99.7%) was obtained. The yield was 98%.

[0042] Comparative Example 1 Theanine (5 g), tocopherol (3.9 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask 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 chromatographic analysis showed almost no product.

[0043] Comparative Example 2 Theanine (5 g), tocopherol (3.9 g), cat. 3 (0.35 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, and chromatographic analysis revealed almost no product.

[0044] Comparative Example 3 Theanine (5 g), tocopherol (3.9 g), cat. 4 (0.35 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask 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 chromatographic analysis revealed almost no product. Cat.4 has the following structure: [ka]

[0045] Comparative Example 4 Theanine (5 g), tocopherol (3.9 g), cat. 5 (0.35 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask 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 chromatographic analysis showed almost no product. cat.5 has the following structure: [ka]

[0046] Comparative Example 5 Theanine (5 g), tocopherol (3.9 g), boric acid (0.3 g), oxalic acid (0.3 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask 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 chromatographic analysis showed almost no product.

[0047] Experimental Example 6 Theanine (5 g), tocopherol (3.9 g), sodium phosphate (0.1 g), cat. 3 (0.35 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, 40 mL of water was added, and the mixture was stirred 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 Theanine (5 g), tocopherol (3.9 g), sodium phosphate (0.9 g), cat. 3 (0.35 g), and tetrahydrofuran (100 mL) were added to a 250 mL three-neck flask and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, 40 mL of water was added, and the mixture was stirred 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 Theanine (5 g), tocopherol (3.9 g), sodium phosphate (0.5 g), cat. 3 (0.35 g), and ethanol (100 mL) were added to a 250 mL three-neck flask and stirred at room temperature for 4 hours. Solid impurities were removed by filtration, 40 mL of water was added, and the mixture was stirred for 3 minutes. The organic phase was separated and dried to obtain 2.8 g of high-purity tocopherol theanine ester (purity 91.1%).

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

[0051] Experimental Example 10: Antioxidant effect test of tocopherol theanine ester (the test sample is the high-purity 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 assay is a method for measuring antioxidant activity in vitro. DPPH is a large free radical that is stable in organic solvents. It exhibits a purple color in methanol or ethanol and has a maximum optical absorbance at 517 nm. The DPPH colorimetric assay is based on the fact that radical scavengers donate electrons to the lone electron pair of DPPH, causing the purple color of DPPH in organic solvent to change to yellow at 517 nm. The change in absorbance also exhibits a linear relationship with the free radical scavenging ability of the radical scavenger. In other words, the stronger the scavenging ability of the radical scavenger, the lower the absorbance.

[0053] 1.2 Experimental Reagents DPPH (Sigma), PBS (Gibco), absolute ethanol (Kokuyo Reagents), petroleum ether (Kokuyo Reagents), vitamin C (CNW), absolute ethanol (Kokuyo Reagents). Major equipment: multi-mode microplate reader (Tecan, Spark), microshaker (Kylin-Bell, TS-92).

[0054] 1.3 Test Method 1.3.1 Creation of a standard curve for the DPPH free radical scavenging capacity of the system reference Ascorbic acid (VC) is used as the system reference, and diluted with PBS to five concentrations of 12.5, 25, 50, 100, and 200 μg / mL. Measurements and calculations are performed according to the test method in 1.3.2, and a standard curve is created 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 corresponding concentration, and prepare and mix the reaction system according to the amount of each reagent added in Table 2. Set up five replicates for each concentration and one blank control. [Table 2] The reaction system is placed at room temperature and reacted in a dark environment for 30 minutes. After the reaction is completed, the absorbance OD value is measured at 517 nm, and the scavenging rate of the test sample against DPPH free radicals is calculated according to the following formula: DPPH free radical scavenging rate of the test sample = [(C1-C2)-(T1-T2)] / (C1-C2) x 100% During the ceremony: C1 - Blank, showing the absorbance value of the system with DPPPH. C2 - Blank, showing the absorbance value of the system without DPPH. T1 - the test sample group, showing the absorbance values ​​of the system with DPPH. T2 - shows the absorbance values ​​of the test sample group, the system without DPPH.

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

[0056] 1.5. Conclusion The test sample can improve the scavenging rate of DPPH free radicals at concentrations of 0.02% to 4%, and has a statistically significant difference (p<0.001) compared to the control group, demonstrating its antioxidant capacity.

[0057] 2. OH ​​radical scavenging ability test 2.1 Experimental principle When the antioxidant function of the body is reduced or cells are damaged, excessive free radicals are generated. Among various reactive oxygen free radicals, the hydroxyl free radical (·OH) has the strongest reaction activity (10 7 ~10 10 M -1 S -1 ), which is the most damaging to living organisms. It generates hydroxyl free radicals using the Fenton reaction: H2O2 + Fe 2+ = OH + HO + Fe 3+ The ·OH generated by the reaction reacts with salicylic acid to produce a product with a specific absorption at 520 nm. When a test sample with ·OH scavenging ability is added to the reaction system, the ·OH generated decreases, which correspondingly reduces the amount of colored compounds produced. The degree of absorbance change is related to the degree of ·OH scavenging; that is, the stronger the scavenging ability of the ·OH scavenger, the smaller the absorbance.

[0058] 2.2 Test Method The test sample is prepared into a test solution of the appropriate concentration, and various reagents are added according to the test method in Table 5 below to perform measurements, and then the absorbance value is measured at 520 nm and the elimination rate of the test sample is calculated according to the following formula: The test sample is prepared into five concentration levels, and the measurement is repeated five times at each concentration. Scavenging rate of test sample against OH = [(AC)-(BD)] / (AC) × 100% [Table 5]

[0059] 2.3. In vitro OH elimination test results for test samples [Table 6]

[0060] 2.4. Experimental Conclusions: The test sample was able to improve the scavenging rate of ·OH at concentrations of 0.02% to 4%, and had statistically significant differences (p<0.001) compared with the control group, demonstrating its antioxidant capacity. [Industrial Applicability]

[0061] The tocopherol derivative compound of the present invention can be used as an antioxidant additive in cosmetics, food and health products, pet supplies, etc. The method of the present invention has mild reaction conditions, simple operation, high yield, high synthetic efficiency, is economical and environmentally friendly, and has good applicability.

Claims

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

2. A method for producing the tocopherol derivative according to claim 1, comprising the steps of: Theanine and tocopherol are esterified by the action of a catalyst and a co-catalyst to obtain a tocopherol derivative; The method of claim 1, wherein the catalyst is selected from compounds having the following structure: 【Chemistry 2】 [R and R1 are the same or different alkyl groups or aryl groups, The alkyl group is selected from linear or branched alkyl groups having 10 or less carbon atoms; The aryl group is selected from a phenyl group, a benzyl group, a para-toluyl group, an ortho-toluyl group, a meta-toluyl group, a xylyl group, a para-methoxyphenyl group, a para-chlorophenyl group, a meta-methoxyphenyl group, a meta-chlorophenyl group, an ortho-methoxyphenyl group, and an ortho-chlorophenyl group.

3. The method of claim 2, wherein the molar amount of the catalyst added is 0.2-0.5% of the total molar amount of the reactants.

4. The method according to claim 2, wherein the molar ratio of theanine to tocopherol is 1 to 1.5:

1.

5. The method according to claim 2, wherein the promoter is sodium phosphate.

6. The method according to claim 2, wherein the molar ratio of the promoter to the theanine is 0.1 to 0.5:

1.

7. 3. The method of claim 2, wherein theanine, tocopherol, co-catalyst and catalyst are mixed together, and then the mixture is stirred at room temperature for 4 to 6 hours to react, and the product is purified by post-treatment.

8. 8. The method according to claim 7, further comprising adding a molecular sieve.

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

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