CN113173896A

CN113173896A - Ferulic acid derivative with antioxidant activity and preparation method thereof

Info

Publication number: CN113173896A
Application number: CN202110402623.1A
Authority: CN
Inventors: 张洪胜
Original assignee: Individual
Current assignee: Individual
Priority date: 2021-04-14
Filing date: 2021-04-14
Publication date: 2021-07-27

Abstract

The invention provides a ferulic acid derivative with antioxidant activity and a preparation method thereof, wherein the ferulic acid derivative comprises the following steps: andrographolide is dissolved in an organic solvent, ferulic acid is added, ferulic acid derivatives with a novel structure are formed through esterification, the new compounds have a good clearance rate on DPPH free radicals, the highest clearance rate reaches 94.22 percent and is higher than that of vitamin C (90.48 percent) under the same concentration, and the ferulic acid derivatives have the potential and significance for preparing new anti-oxidation active drugs. The preparation method provided by the invention is simple, the raw materials are easy to obtain, the yield is high, the operation condition is mild, the ferulic acid derivative can be conveniently prepared, and the preparation method is suitable for industrial production.

Description

Ferulic acid derivative with antioxidant activity and preparation method thereof

Technical Field

The invention belongs to the technical field of chemical drug synthesis, and relates to a ferulic acid derivative with antioxidant activity and a preparation method thereof.

Background

Ferulic acid has strong antioxidant activity, because ferulic acid has strong scavenging effect on hydrogen peroxide, superoxide radical, hydroxyl radical and peroxynitrite radical, on the other hand, ferulic acid can inhibit enzyme generating free radical and promote the generation of antioxidant enzyme. Researches show that the ferulic acid derivative also has better antioxidant activity, for example, Zhang Qiang and the like (research on antioxidant activity of ferulic acid Poria cocos polysaccharide, modern food science and technology, (27)9, 2011) combines ferulic acid with Poria cocos to synthesize the ferulic acid Poria cocos polysaccharide compound.

Disclosure of Invention

One object of the present invention is to provide an antioxidant ferulic acid derivative having the molecular structure of formula (I):

another object of the present invention is to provide a method for preparing ferulic acid derivatives with antioxidant activity, comprising the following steps:

(1) dissolving andrographolide in an anhydrous organic solvent A, slowly adding oxalyl chloride at the temperature of-10-0 ℃, adding 2-3 drops of DMF (N, N-dimethylformamide), raising the temperature to react for 2-5 h, and removing redundant oxalyl chloride to obtain a compound 1 after the reaction is finished;

(2) dissolving the compound 1 in an organic solvent B, adding ferulic acid, stirring at room temperature for reaction for 4-8 h, and displaying no progress of the reaction by thin-layer chromatography. Adding sodium bicarbonate solution into the reaction solution, extracting with dichloromethane or ethyl acetate, washing the organic phase with saturated saline solution and 5% hydrochloric acid solution in sequence, drying, concentrating, and eluting and purifying the crude product with silica gel column to obtain andrographolide derivatives.

In the preparation method, in the step (1), the organic solvent A is one, two, three or more of dichloromethane, diethyl ether, tetrahydrofuran, benzene and toluene;

the mass/volume ratio of the andrographolide to the organic solvent A is 1: 3-5 g/mL;

the feeding molar ratio of the andrographolide to the oxalyl chloride is 1: 3-7;

the reaction temperature is 40-80 ℃.

In the preparation method, in the step (2), the dosage of the ferulic acid is 50-70% of the dosage of the compound 1;

the solvent B is chloroform, acetone, dioxane, a mixed solvent of chloroform and acetone in a volume ratio of 1:1 or a mixed solvent of chloroform and dioxane in a volume ratio of 1: 1;

the filler of the chromatographic column in the silica gel column chromatography is 100-400 meshes of silica gel; the mass ratio of the crude product sample to the silica gel is 1: 20-50; adopting a wet method for sample loading, and dissolving the crude product sample in a low-polarity solvent selected from ether, petroleum ether or n-hexane to obtain a loaded sample;

the eluent is a mixed solution of n-hexane and ethyl acetate, and the volume ratio of the n-hexane to the ethyl acetate is 5: 1-10: 1.

Compared with the prior art, the invention has the beneficial effects that:

the ferulic acid derivative provided by the invention has a better clearance rate on DPPH free radicals, the highest clearance rate reaches 94.22 percent and is higher than that of vitamin C (90.48 percent) under the same concentration, which indicates that the ferulic acid derivative has the potential and significance for preparing novel anti-oxidation active medicaments. The preparation method provided by the invention is simple, good in repeatability, good in stability, easy in obtaining of raw materials, high in yield, mild in operation condition, capable of conveniently preparing the andrographolide derivative and suitable for industrial production.

Drawings

FIG. 1: nuclear magnetic resonance hydrogen spectrum of the antioxidant active ferulic acid derivative of example 1.

Detailed Description

The present invention will be described in further detail with reference to specific embodiments for the purpose of making the objects, technical solutions and advantages of the present invention more apparent, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples.

Example 1

(1) Adding 20g of andrographolide into 60mL of anhydrous dichloromethane, refluxing and dissolving for 30min, slowly adding 21.7g of oxalyl chloride at the temperature of-10-0 ℃, stirring for 30min, adding 2-3 drops of DMF (N, N-dimethylformamide), raising the temperature to 40 ℃, reacting for 2h, and removing excessive oxalyl chloride by rotary evaporation to obtain a compound 1 after the reaction is finished.

(2) Dissolving 15g of the compound 1 in 100mL of chloroform, adding 7.5g of ferulic acid, stirring at room temperature for reaction for 4h, wherein thin-layer chromatography shows that the reaction does not progress, adding a sodium bicarbonate solution into a reaction solution, extracting with dichloromethane (3X 0.5L), washing an organic phase with a saturated saline solution and a 5% hydrochloric acid solution in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product; dissolving the crude product with low-polarity ether, stirring the crude product with 100-400-mesh silica gel to obtain a sample, wherein the mass ratio of the crude product to the silica gel is 1:20, separating and purifying the sample on the silica gel column, eluting impurities with an eluant consisting of n-hexane and ethyl acetate according to the volume ratio of 5:1, collecting the eluant, and concentrating to obtain the andrographolide derivative.

Experimental example 2 antioxidant Activity test of the derivative of the present invention

DPPH is a very stable nitrogen-centered radical that traps ("scavenges") other radicals, has a strong absorption at 520nm, and its alcohol solution is purple in color. When a radical scavenger is added to the DPPH solution, it enables the pairing of single electrons, thereby enabling A_520nmThe value is reduced, the solution becomes light in color and yellow or light yellow, the change degree of the solution and the free radical scavenging degree are in a linear relation, so the method can be used for expressing the scavenging rate, and the higher the scavenging rate is, the stronger the scavenging capacity of the substance is.

Preparation of DPPH solution: accurately weighing 20mg of DPPH, dissolving with absolute ethyl alcohol, and metering the volume to a 500mL brown volumetric flask to obtain 0.004 percent DPPH solution, and storing in dark for later use.

Preparation of sample and reference solution: the derivative derivatives of example 1 were precisely weighed, dissolved in water, to a volume of 10mL, diluted, and dispensed into 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7mg/mL solutions, to prepare four sample solutions. In the same manner, vitamin C sample solution (control group 1), andrographolide sample solution (control group 2), ferulic acid sample solution (control group 3), and a physical mixture of andrographolide and ferulic acid (control group 4) were prepared.

The determination method comprises the following steps: adding 1mL of sample or reference solution (0.00-5.00 mg/mL) into 1mL of DPPH alcoholic solution, mixing uniformly, reacting in dark, measuring absorbance at 520nm, repeating the above experiment for 3 times, and averaging

Wherein A is_oIs the light absorption value of 1mL of DPPH alcoholic solution plus 1mL of water; a. the_iIs the light absorption value of 1mL of DPPH alcoholic solution plus 1mL of sample solution;A_jthe absorbance was measured after mixing 1mL of the sample solution with 1mL of ultrapure water.

TABLE 1 assay of DPPH radical scavenging Activity of derivatives of the invention

Test results show that compared with a control group, the derivative of the invention has obvious antioxidant activity, and the DPPH free radical clearance rate reaches 94.22% under the same concentration, which indicates that the compound prepared by the invention has good antioxidant activity; in the other three control groups, except vitamin C, the antioxidant activity of the physical mixture group of andrographolide and asafetida is the lowest, which indicates that the two antioxidants cannot obtain obvious antioxidant performance by simple physical mixing, and the two compounds need to be combined through chemical bonds to improve the antioxidant performance of the substances in a synergistic manner, so that the usage amount of the antioxidants is reduced.

Claims

1. An antioxidative ferulic acid derivative, which has a molecular structure represented by formula (I):

。

2. a preparation method of ferulic acid derivatives with antioxidant activity is characterized by comprising the following steps:

(1) dissolving andrographolide in an anhydrous organic solvent A, slowly adding oxalyl chloride at the temperature of-10-0 ℃, adding 2-3 drops of DMF (N, N-dimethylformamide), raising the temperature to react for 2-5 h, and removing the oxalyl chloride after the reaction is finished;

(2) and (2) dissolving the product obtained in the step (1) in an organic solvent B, adding ferulic acid, stirring at room temperature for reaction for 4-8 h, and displaying no progress of the reaction by thin-layer chromatography. Adding sodium bicarbonate solution into the reaction solution, extracting with dichloromethane or ethyl acetate, washing the organic phase with saturated saline solution and 5% hydrochloric acid solution in sequence, drying, concentrating, and purifying the crude product by silica gel column chromatography to obtain andrographolide derivatives;

in the step (1), the organic A is dichloromethane, diethyl ether, tetrahydrofuran, benzene and toluene;

the reaction temperature is 40-80 ℃.

In the step (2), the dosage of the ferulic acid is 50-70% of the dosage of the compound 1;

3. The method of claim 2, comprising the steps of:

(1) adding 20g of andrographolide into 60mL of anhydrous dichloromethane, refluxing and dissolving for 30min, slowly adding 21.7g of oxalyl chloride at the temperature of-10-0 ℃, stirring for 30min, adding 2-3 drops of DMF (N, N-dimethylformamide), raising the temperature to 40 ℃, reacting for 2h, and removing the redundant oxalyl chloride by rotary evaporation after the reaction is finished.

4. The use of the derivative of claim in an antioxidant agent.