A method for synthesizing gallic acid ester by esterification reaction of gallic acid and diol

Abstract

The present invention discloses a method for synthesizing gallic acid esters by esterification of gallic acid and diols. The method uses p-toluenesulfonic acid as a catalyst, heats and refluxes the reaction in an organic solvent for 5 to 20 hours, and then post-treats the reaction solution to produce gallic acid ester compounds. The gallic acid ester compounds obtained by the present invention can be used in the field of molecular biology. The method is simple to operate, utilizes readily available and inexpensive raw materials, and is simple to purify. The resulting product is high in purity, making it suitable for large-scale production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing gallic acid ester by esterification reaction of gallic acid and diol. Background Art

[0002] Gallic acid, an important derivative of Galla chinensis, a specialty Chinese medicinal herb, has high antioxidant activity but poor lipid solubility. When the carboxyl group of gallic acid reacts with an alcohol to form an ester, its lipid solubility is increased. The three phenolic hydroxyl groups in the gallate molecule are located in the ortho position, acting as proton donors and exhibiting active reducing properties. Gallic acid esters possess excellent antioxidant properties, surpassing those of the commonly used synthetic antioxidants butylated hydroxyanisole (BHA) and 2,6-di-tert-butylated cresol (BHT). Gallic acid esters are primarily used for antioxidant effects in oils and fats, as well as in the preservation of fruits and vegetables. They also have a wide range of applications in pharmaceuticals, cosmetics, feed, photosensitive and thermosensitive materials, and are also used as antioxidants for fats and creams. Gallic acid esters possess significant free radical scavenging capacity and biological activity, making them useful as antioxidant stabilizers or anti-aging agents for biodiesel and certain materials. Following the use of propyl gallate (PG) as an antioxidant in fried foods, octyl gallate (OG) and dodecyl gallate (DG) have also been approved by the US Food and Drug Administration (FDA), the Food and Agriculture Organization of the United Nations (FAO), and the World Health Organization (WHO) as antioxidants for oils and fat-rich foods. Gallic acid esters also possess pharmacological activity, acting as inhibitors of platelet aggregation, enhancing fibrinolysis and thrombus dissolution, vasodilation, and increased coronary blood flow. They are also effective in treating cardiovascular and cerebrovascular diseases, viral diseases, bacterial infections, gastric ulcers, and viral hepatitis. Propyl gallate is marketed under the pharmaceutical name "Tongmai Ester." Consequently, the synthesis of gallic acid esters and the research on their application properties are attracting increasing attention. Dodecyl gallate is an effective platelet aggregation inhibitor and is listed in the US and British Pharmacopoeias. In addition, it has bactericidal, antibacterial and preservative effects, and is a food antioxidant approved for use by the WTO.

[0003] At present, gallic acid ester compounds can be synthesized by chemical or biochemical methods. Chemical synthesis mainly uses gallic acid and alcohol to carry out esterification reaction under reflux. The catalysts used include concentrated sulfuric acid, dry hydrogen chloride, magnetic nano solid superacid, etc., but these synthesis methods have high reaction temperature, long reaction time, low conversion rate, difficult product separation, and high cost. Biochemical methods mainly adopt enzymology and enzyme engineering. Tannase or its immobilized enzyme produced by microbial fermentation such as Aspergillus niger hydrolyzes the ester bond of gallic acid tannin for the production of gallic acid. Tannase can also catalyze the reverse reaction of hydrolysis reaction and is used for the synthesis of gallic acid esters, but the shortcomings are also obvious. The enzyme is easily inactivated by the influence of organic solvents, and the reuse rate of the enzyme is relatively low. CN10158575769A adopts microwave reactor to carry out esterification reaction, which has high equipment requirements and large production cost, and is not suitable for industrial production. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the shortcomings of the existing technology and provide a method for synthesizing gallic acid esters with simple operation, short reaction time, and high yield. The present invention uses a direct esterification method. Through in-depth and meticulous research on the required catalyst, solvent, reaction temperature, and other conditions, the present invention uses gallic acid and diol as raw materials to directly carry out an esterification reaction, obtaining the target gallic acid ester with relatively high yield and purity. After recrystallization, the yield is 90% and the purity reaches 99%. This method provides a process route for synthesizing gallic acid esters with readily available raw materials, mild reaction conditions, simple experimental operation, low experimental cost, and ease of mass production, thus facilitating the large-scale industrial production and application of gallic acid esters.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] A method for synthesizing gallic acid ester by esterification of gallic acid and diol, comprising:

[0007] Gallic acid and the diol compound represented by formula I are reacted in an organic solvent under heating reflux for 5 to 20 hours using p-toluenesulfonic acid as a catalyst. After the reaction, the reaction solution is post-treated to prepare the gallic acid ester compound represented by formula II;

[0008]

[0009] In the formula I or formula II, R is a C2-C8 methylene group, or a C2-C8 methylene group containing an oxygen atom in the carbon chain.

[0010] Furthermore, the diol compound is preferably ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, 1,5-pentanediol, diethylene glycol, triethylene glycol or tetraethylene glycol.

[0011] The molar ratio of the gallic acid to the diol compound is 1:2 to 1:12, preferably 1:10-12.

[0012] In the method, the catalyst is p-toluenesulfonic acid, which has the advantages of less reaction by-products and high yield.

[0013] The molar ratio of the gallic acid to p-toluenesulfonic acid is 1:0.05-0.5, preferably 1:0.1.

[0014] The organic solvent is one or more of 1,4-dioxane, dimethyl sulfoxide, dimethylformamide, toluene, chloroform, acetone, tetrahydrofuran, and acetonitrile, preferably 1,4-dioxane. The advantages of using 1,4-dioxane are less reaction by-products, high yield, low boiling point, and simple post-processing.

[0015] The volume usage of the organic solvent is preferably 0.5 to 2 L / mol based on the amount of gallic acid.

[0016] In the present invention, the reaction time is preferably 10 to 11 hours.

[0017] The post-treatment method of the reaction liquid is preferably as follows: after the reaction is completed, the reaction liquid is cooled to room temperature, petroleum ether is added for extraction, the upper petroleum ether phase is removed after separation, water is added to the lower organic phase, dichloromethane is added, extraction is carried out, the lower organic phase is taken and the solvent is evaporated, and pure water is used for recrystallization to obtain a white solid, which is the gallic acid ester compound represented by Formula II.

[0018] The present invention has the following beneficial effects: it uses a diol raw material to carry out the esterification reaction of gallic acid. By controlling the catalyst, the equivalent amount of the reaction raw materials, the reaction temperature, and the reaction time, the production of polymer byproducts during the reaction is suppressed, and ultimately a monoesterified gallic acid ester is obtained with high selectivity, with a product yield of 80%-90% and high purity. Furthermore, in the post-processing, the present invention innovatively uses petroleum ether as an extractant. The petroleum ether can extract impurities and excess diol equivalents in the reaction solution, leaving the organic phase containing only the target gallic acid ester. Subsequent purification is simpler and more convenient, facilitating application in large-scale production. Furthermore, the diol enriched in the petroleum ether can be recycled.

[0019] In the post-treatment methods in the prior art, the excess alcohol and the product are generally extracted into the organic phase together, and then a second extraction is performed to separate the product and the alcohol raw material. This makes the subsequent product purification more complicated and the yield is reduced. The excess alcohol raw material is also difficult to recycle. DETAILED DESCRIPTION

[0020] The technical solution of the present invention is further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.

[0021] Manufacturers and specifications of the reagents used in the following examples:

[0022]

[0023]

[0024] Example 1: Preparation of 2-hydroxyethyl gallate: Gallic acid (17 g, 0.1 mol) and ethylene glycol (62 g, 1.0 mol) were catalyzed by p-toluenesulfonic acid (1.72 g, 0.01 mol) and refluxed in 100 mL of 1,4-dioxane solution for 10 h. After TLC monitoring, the reaction was cooled to room temperature, 100 mL of petroleum ether was added, the layers were separated, the petroleum ether phase was removed, and 100 mL of petroleum ether was added, the layers were separated, the petroleum ether phase was removed, 100 mL of water was added to the remaining organic phase, 100 mL of dichloromethane was added, extraction was performed, the aqueous phase was removed, the organic phase was spin-dried, and recrystallization was performed using pure water. The mixture was filtered and dried to obtain 19.3 g of a white solid with a yield of 90%. Structural standard of the product: NMR: 1 HNMR(500MHz,DMSO-d6)δ9.27(s,2H),8.96(s,1H),6.97(s,2H),4.87(t,J=5 .3Hz,1H),4.22–4.07(m,2H),3.65(q,J=4.6Hz,2H).ESI-MSm / z:215.2[M+H] +

[0025] Example 2: Preparation of 2-diethylene glycol gallate: Gallic acid (17 g, 0.1 mol) and diethylene glycol (106 g, 1.0 mol) were refluxed in 100 mL of 1,4-dioxane solution under the catalysis of p-toluenesulfonic acid (1.72 g, 0.01 mol) for 10 h. After the reaction, the temperature was lowered and 100 mL of petroleum ether was added for extraction three times. The petroleum ether phase was removed, and the organic phase was added with water and extracted with dichloromethane. The mixture was dried and recrystallized with pure water. The mixture was dried to obtain 23.6 g of a white solid with a yield of 91%. The product structure was analyzed by nuclear magnetic resonance (NMR). 1 HNMR(500MHz,DMSO-d6)δ9.33(s,2H),8.99(s,1H),7.03(s,2H),4.63(t,J=7.1Hz,2H),4.29(t,J=7.4 Hz,1H),3.72(t,J=7.1Hz,2H),3.68–3.62(m,2H),3.56(td,J=7.2,1.2Hz,2H).ESI-MSm / z:259.2[M+H]+

[0026] Example 3: Preparation of 2-triethylene glycol gallate: Gallic acid (17 g, 0.1 mol) and triethylene glycol (150 g, 1.0 mol) were refluxed in 100 ml of 1,4-dioxane solution under the catalysis of p-toluenesulfonic acid (1.72 g, 0.01 mol) for 10 h. After the reaction, the temperature was lowered and 100 ml of petroleum ether was added and extracted three times. The petroleum ether phase was removed, and the organic phase was added with water and extracted with dichloromethane. The mixture was dried and recrystallized with pure water. The mixture was dried to obtain 27 g of a white solid with a yield of 90%. The structural standard of the product: NMR: 1 HNMR(500MHz,DMSO-d6)δ9.2(s,2H),8.96(s,1H),7.06–6.93(s,2H),4.69–4.57(t,J=7.1Hz,2H),4.30–4.18(t,J=7.5Hz,1H ),3.74–3.69(t,J=7.1Hz,2H),3.68–3.61(dtd,J=7.5,6.4,1.2Hz,4H),3.61–3.56(m,4H),3.56–3.51(td,J=7.0,0.9Hz,2H). ESI-MSm / z: 303.2[M+H] +

[0027] Example 4: Preparation of Gallic Acid-2-Tetraethylene Glycol Ester: Gallic acid (17 g, 0.1 mol) and tetraethylene glycol (194 g, 1.0 mol) were refluxed in 100 mL of 1,4-dioxane solution under the catalysis of p-toluenesulfonic acid (1.72 g, 0.01 mol) for 10 h. After the reaction, the temperature was lowered and 100 mL of petroleum ether was added for extraction three times. The petroleum ether phase was removed, and the organic phase was added with water and extracted with dichloromethane. The mixture was dried and recrystallized with pure water. The mixture was dried to obtain 30.6 g of a white solid with a yield of 90%. The structural standard of the product: NMR: 1 HNMR(500MHz,DMSO-d6)δ9.14(s,2H),8.8(s,1H),7.06-6.93(s,2H),4.69-4.57(t,J=7.1Hz,2H),4.30–4.18(t,J=7.5Hz,1H ), 3.74–3.69(t,J=7.1Hz,2H), 3.68–3.61(dtd,J=7.5,6.4,1.2Hz,6H), 3.61–3.56(m,4H), 3.56–3.51(td,J=7.0,0.9Hz,2H). ESI-MSm / z: 347[M+H] +

[0028] Example 5 Effect of reaction solvent

[0029] The reaction solvent in Example 1 was changed to tetrahydrofuran, and other reaction conditions were the same as in Example 1. The yield of the final product was 40%.

[0030] Example 6 Effect of diol equivalent

[0031] The amount of ethylene glycol in Example 1 was changed to 1.2 mol, and the other reaction conditions were the same as in Example 1. The yield of the final product was 85%.

[0032] The amount of ethylene glycol in Example 1 was changed to 0.8 mol, and the other reaction conditions were the same as in Example 1. The yield of the final product was 61%.

[0033] The amount of ethylene glycol in Example 1 was changed to 0.5 mol, and the other reaction conditions were the same as in Example 1. The yield of the final product was 42%.

[0034] It can be seen that the equivalent of ethylene glycol has a decisive influence on the yield of the product, and this equivalent must be greatly excessive.

[0035] Example 7 Effect of reaction temperature

[0036] The reaction temperature in Example 1 was changed to 80° C., and other reaction conditions were the same as in Example 1. The yield of the final product was 60%.

[0037] Example 9 Effect of reaction time

[0038] The reaction time in Example 1 was changed to 6 hours, and other reaction conditions were the same as in Example 1. The yield of the final product was 70%.

[0039] The reaction time in Example 1 was changed to 12 hours, and other reaction conditions were the same as in Example 1. The yield of the final product was 82%.

[0040] Effect of post-treatment method in Example 9

[0041] The post-treatment method of the reaction solution in Example 1 was changed to: adding water and extracting with dichloromethane. The yield of the final product was 50%.

[0042] The post-treatment method of the reaction solution in Example 1 was changed to: extraction with ethyl acetate, followed by washing with water and saturated brine, and then recrystallization with n-hexane. The final product yield was 40%.

Claims

1. A method for synthesizing gallic acid ester by esterification of gallic acid and diol, characterized in that The method is: Gallic acid and the diol compound represented by formula I are reacted in an organic solvent under heating and reflux for 5 to 20 hours using p-toluenesulfonic acid as a catalyst. After the reaction, the reaction solution is post-treated to prepare the gallic acid ester compound represented by formula II; The molar ratio of the gallic acid to the diol compound is 1:10-12; The organic solvent is 1,4-dioxane; The post-treatment method of the reaction solution is as follows: after the reaction is completed, the reaction solution is cooled to room temperature, petroleum ether is added for extraction, the upper petroleum ether phase is removed after separation, water is added to the lower organic phase, dichloromethane is added, extraction is carried out, the lower organic phase is taken and the solvent is evaporated, and pure water is used for recrystallization to obtain a white solid, which is the gallic acid ester compound represented by formula II; ， The diol compound represented by formula I is ethylene glycol, 1,3-propylene glycol, 1,4-butanediol, 1,5-pentanediol, diethylene glycol, triethylene glycol or tetraethylene glycol.

2. The method according to claim 1, wherein The molar ratio of the gallic acid to p-toluenesulfonic acid is 1:0.05-0.

5.

3. The method according to claim 2, wherein The molar ratio of the gallic acid to the p-toluenesulfonic acid is 1:0.

1.

4. The method according to claim 1, wherein The reaction time is 10 to 11 hours.

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