CN114634412A - A kind of high-purity gentisic acid and application thereof - Google Patents

Abstract

。本申请还公开了上述高纯度龙胆酸在制备抗病毒剂、抗菌剂、止痛剂或抗氧化赋形剂中的应用。本申请的高纯度龙胆酸通过特定的制备方法制得，高纯度龙胆酸的收率可达18~22%，适于大规模工业生产。The present application discloses a high-purity gentisic acid with a purity of ≥99.50%, comprising: gentisic acid, salicylic acid and impurity A, wherein the structural formula of the impurity A is:

. The application also discloses the application of the above-mentioned high-purity gentisic acid in the preparation of antiviral agents, antibacterial agents, pain relievers or antioxidant excipients. The high-purity gentisic acid of the present application is prepared by a specific preparation method, and the yield of the high-purity gentisic acid can reach 18-22%, which is suitable for large-scale industrial production.

Description

A kind of high-purity gentisic acid and application thereof

technical field

The present application relates to the field of medicine and chemical industry. Specifically, the present application relates to a high-purity gentisic acid and applications thereof.

Background technique

Gentianic acid, chemical name 2,5-dihydroxybenzoic acid, also known as 5-hydroxysalicylic acid, is a secondary product of salicylic acid after renal metabolism, and is commonly used clinically as an antiviral, antibacterial and analgesic agent (sodium salt). Gentianic acid is a hydroquinone compound that is prone to oxidation reaction and is also used as an antioxidant excipient in the pharmaceutical industry. Gentianic acid has been used as a pharmaceutical excipient in foreign countries.

In the prior art, benzoic acid is used as a raw material to synthesize products through steps such as chlorination and hydrolysis, but there are five main products synthesized by this method, and the products are difficult to separate and purify, resulting in a final yield of only about 5%, which is difficult to achieve. Industrial production.

In the current process, gentisic acid is mainly prepared by the Kerber-Schmidt reaction of hydroquinone, but the product obtained by this method contains a large amount of isomers 2,4-dihydroxybenzoic acid and 2,6-dihydroxybenzene. Formic acid not only has a low product purity, but also has a darker color. It is a yellow powder crystal. It needs to be recrystallized and purified for many times to obtain a white gentisic acid product that meets the specifications. The yield is low and the cost is high.

Patent CN100363322C discloses a method for producing hydroxybenzoic acid compounds, the method comprises preparing alkali metal salts of phenolic compounds from phenolic compounds, the alkali metal salts are reacted with carbon dioxide, wherein the bases of phenolic compounds are prepared from phenolic compounds The metal salt comprises the steps of: a) reacting the alkali metal alkoxide with an excess of the phenolic compound in excess of the alkali metal alkoxide to form the phenolic compound alkali metal salt; and b) while performing a), The alcohol formed is distilled from the reaction. The method does not employ aprotic polar organic solvents.

Patent CN1684935A discloses a preparation method of hydroxybenzoic acids, which is to make the phenols and alkali metal compounds carry out dehydration reaction to obtain alkali metal salts of phenols, and then react the alkali metal salts of phenols with carbon dioxide to prepare hydroxybenzenes In the formic acid method, the alkali metal compound and the phenols in excess relative to the alkali metal compound are subjected to a dehydration reaction at a temperature of 160°C or higher. The method of the invention does not use aprotic polar organic solvent, and has simple process and low cost.

Patent CN102766042A discloses a method for preparing high-purity gentisic acid. Glacial acetic acid; in the presence of cuprous chloride, add liquid caustic soda, heat up, and react to obtain hydroxysalicylic acid; cool to room temperature, remove cuprous chloride by filtration, and adjust pH to 2; filter out hydroxysalicylic acid The mixture is added to the water, the pH value is adjusted to 6.9~7.1, and the high-purity gentisate sodium salt is obtained by cooling and crystallization; the obtained gentisate sodium salt is added to the water, and the pH value is adjusted to 2. In the presence of activated carbon and oxalic acid Under the conditions of temperature, the temperature is raised to reflux; filtered, and the filtrate is cooled and crystallized to obtain gentisic acid.

The purity of the gentisic acid product obtained by each method of the prior art is relatively poor, and the yield is relatively low.

SUMMARY OF THE INVENTION

In order to overcome the defects of the prior art, the present application, based on the prior art, screened catalysts and alkalis, conducted optimization studies on reaction temperature, etc. The salt-forming, dissociation, decolorization and crystallization process are adopted, and finally a qualified high-purity gentisic acid is obtained.

The specific technical solutions of this application are as follows:

1. a high-purity gentisic acid, is characterized in that, its purity >=99.50%, it comprises: gentisic acid, salicylic acid and impurity A, wherein, described impurity A has the structure shown in formula (I):

Formula (I);

Preferably, in the high-purity gentisic acid, the mass percentage of the salicylic acid≤0.1%, and the mass percentage of the impurity A≤0.1%;

Preferably, the high-purity gentisic acid further comprises impurity B, wherein the impurity B has the structure shown in formula (II):

formula (II);

Preferably, in the high-purity gentisic acid, the mass percentage of the impurity B is less than or equal to 0.1%.

2. high-purity gentisic acid according to item 1, is characterized in that, it is prepared by the method comprising the following steps:

Feeding reaction: 5-bromosalicylic acid is added to inorganic alkali solution for reaction;

Acidification: add concentrated hydrochloric acid to adjust pH, separate out solid, filter;

Extraction: add extractant 1 to the filtrate obtained in the acidification step, extract, and flocculates appear after standing;

Filtration: Filtration and liquid separation to obtain organic phase 1 and water phase, add extractant 2 to the water phase, extract, filter and separate liquids to obtain organic phase 2, combine organic phase 2 and organic phase 1 to obtain organic phase 3. ;

Crystallization: Concentrate the organic phase 3, separate out the solid, and add the organic solvent 1 to obtain the gentisic acid crude product;

Salt formation: adding the crude gentisic acid product into the organic solvent II, and adding the solution of the organic solvent II containing an organic base dropwise to obtain a wet product of the organic base salt of gentisic acid;

Free: add the wet product of gentisic acid organic base salt into water, add concentrated hydrochloric acid dropwise to adjust pH, and filter to obtain the wet product of gentisic acid refined product;

Decolorization and crystallization: add the wet product of gentisic acid refined product and decolorizing agent into water, and filter to obtain gentisic acid crystals;

Filtration and drying: the gentisic acid crystals are rinsed with water, then washed with an organic solvent, and dried to obtain high-purity gentisic acid.

3. high-purity gentisic acid according to item 2, is characterized in that, in the feed intake reaction step, under the condition that copper catalyst exists, 5-bromosalicylic acid is added to the inorganic base solution, stirs, and the temperature rises to make 5- Bromosalicylic acid reacts with the inorganic base solution, then cools down and adds water;

Preferably, the inorganic alkali solution is an aqueous solution of sodium hydroxide or an aqueous solution of potassium hydroxide, preferably an aqueous solution of potassium hydroxide;

Preferably, the concentration of the inorganic alkali solution is 4-8 mol/L, more preferably 5-6 mol/L;

Preferably, the ratio of the amount of material of the inorganic base to 5-bromosalicylic acid is 4~7:1, more preferably 5~6:1;

Preferably, the temperature rises to 90-114°C, more preferably 105-114°C;

Preferably, the temperature rises to make the 5-bromosalicylic acid react with the inorganic base solution, the content of the 5-bromosalicylic acid in the HPLC is controlled to be less than 1.5%, and the reaction time is 20～48h, more preferably 20～30h;

Preferably, the temperature is lowered to 20-30°C;

Preferably, in the presence of copper catalyst and oxalic acid, 5-bromosalicylic acid is added to the inorganic base solution; more preferably, the ratio of the amount of the oxalic acid to the amount of 5-bromosalicylic acid is 0.05 to 0.15: 1;

Preferably, the copper catalyst is copper sulfate pentahydrate or cuprous oxide, more preferably copper sulfate pentahydrate; 0.15:1; preferably, the ratio of the amount of the cuprous oxide to the amount of 5-bromosalicylic acid is 0.025 to 0.075:1.

Preferably, the ratio of the amount of water to 5-bromosalicylic acid is 40 to 70:1, more preferably 50 to 60:1.

4. The high-purity gentisic acid according to item 2 or 3, characterized in that, in the acidifying step, pH is adjusted to 2.3～2.5;

Preferably, the pH is adjusted by adding concentrated hydrochloric acid at 20-30°C.

5. The high-purity gentisic acid according to any one of items 2 to 4, characterized in that, in the extraction step, the extraction agent—is selected from the group consisting of methylene chloride, ethyl acetate, isopropyl acetate, toluene and any one or more of methyl tert-butyl ether;

Preferably, the extractant one is methyl tert-butyl ether;

Preferably, in the extraction step, an extraction agent 1 and an extraction aid are added to the filtrate obtained in the acidification step, and the extraction aid is preferably sodium chloride;

Preferably, the mass ratio of the methyl tertiary butyl ether and 5-bromosalicylic acid is 4～6:1, preferably 5～5.5:1;

Preferably, the mass ratio of described sodium chloride and 5-bromosalicylic acid is 1.0～1.5:1;

Preferably, in the filtering step, the extractant two is selected from any one or two or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene and methyl tert-butyl ether;

Preferably, the mass ratio of the extractant two and 5-bromosalicylic acid is 4～6:1, preferably 5～5.5:1;

Preferably, a filter aid is added to the funnel, filtered and liquid-separated to obtain an organic phase I and an aqueous phase; more preferably, the filter aid is diatomaceous earth.

6. according to the high-purity gentisic acid described in any one of items 2～5, it is characterized in that, in the crystallization step, concentrating organic phase three, separate out solid, add organic solvent one, stir, filter and filter cake. Dry to obtain crude gentisic acid;

Preferably, the organic solvent is one or more selected from n-heptane, acetone, ethyl acetate, petroleum ether and chloroform;

Preferably, the organic phase is concentrated to precipitate a large amount of solid;

Preferably, the organic phase III is concentrated under reduced pressure under the condition of 40~60°C, more preferably under the condition of 40~50°C;

Preferably, the mass ratio of described organic solvent one to 5-bromosalicylic acid is 4～5.5:1, preferably 4.5～5:1;

Preferably, the stirring time is 1～2h;

Preferably, filter at 20~30°C;

Preferably, the filter cake is vacuum-dried at 40 to 50° C. for 2 to 4 hours to obtain crude gentisic acid.

7. according to the high-purity gentisic acid described in any one of items 2～6, it is characterized in that, in the salification step, the gentisic acid crude product is added in organic solvent two, stirs, drips the organic solvent that contains organic base. The solution of solvent two is cooled and filtered to obtain the wet product of gentisic acid organic alkali salt;

Preferably, under the condition of 10～35 ℃, the solution of organic solvent two containing organic base is added dropwise;

Preferably, the organic base is diethylamine;

Preferably, the ratio of the amount of the organic base to the amount of 5-bromosalicylic acid is 0.75 to 0.85:1;

Preferably, the mass ratio of described organic solvent two and gentisic acid crude product is 8.6～10:1, preferably 9～9.8:1;

Preferably, the organic solvent is one or more selected from acetone, isopropanol and tetrahydrofuran;

Preferably, the temperature is lowered to 2-8°C.

8. The high-purity gentisic acid according to any one of items 2 to 7, characterized in that, in the free step, the gentisic acid organic base salt wet product is added to water, stirred, and concentrated hydrochloric acid is added dropwise to adjust pH, Cool down and filter to get the wet product of gentisic acid refined product;

Preferably, concentrated hydrochloric acid is added dropwise to adjust pH at 20-30°C;

Preferably, the pH is adjusted to 1~2;

Preferably, the mass ratio of described water and gentisic acid organic alkali salt wet product is 4～6:1;

Preferably, the temperature is lowered to 0-10°C.

9. according to the high-purity gentisic acid described in any one of items 2～8, it is characterized in that, in decolorization and crystallization step, the gentisic acid refined product wet product and decolorizing agent are added in water, stir, heat up, filter. and cooling the filtrate to obtain gentisic acid crystals;

Preferably, the wet product of the gentisic acid refined product, the depigmenting agent and the oxalic acid are added to the water;

Preferably, the decolorizing agent is selected from one or more of activated carbon, alumina and clay;

Preferably, the temperature is maintained for 0.5-6h, preferably 0.5-4h, more preferably 0.5-1.5h;

Preferably, the temperature rises to 65-75°C;

Preferably, the mass ratio of the activated carbon to the gentisic acid refined wet product is 0.05 to 0.1:1;

Preferably, the mass ratio of described oxalic acid and gentisic acid refined wet product is 0.01～0.03:1;

Preferably, the mass ratio of described water and gentisic acid refined product wet product is 4～6:1;

Preferably, filtering and cooling the filtrate to 0-10° C. to obtain gentisic acid crystals.

10. The high-purity gentisic acid according to any one of items 2 to 9, characterized in that, in the filtration and drying steps, the drying conditions are: 40 to 55° C., and vacuum-dried for 10 to 15 h.

11. The application of the high-purity gentisic acid according to any one of items 1 to 10 in the preparation of an antiviral agent, an antibacterial agent, an analgesic agent or an antioxidant vehicle.

effect of invention

The purity of the high-purity gentisic acid of the present application is controlled to be above 99.5%, and various organic impurities can be controlled to be below 0.1%, which can be used as pharmaceutical excipients, and the high-purity gentisic acid of the present application is prepared by a specific preparation method. , the yield of high-purity gentisic acid can reach 18-22%, which is suitable for large-scale industrial production.

Detailed ways

Exemplary embodiments of the present application are described below, including various details of the embodiments of the present application to facilitate understanding and should be considered as exemplary only. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the present application. Also, descriptions of well-known functions, structures, and reagents are omitted from the following description for clarity and conciseness.

The application provides a high-purity gentisic acid, which is characterized in that its purity is greater than or equal to 99.5%, and it comprises: gentisic acid, salicylic acid and impurity A. Wherein, the impurity A has the structure shown in formula (I):

Formula (I).

In a specific embodiment, in the high-purity gentisic acid, the mass percentage of the salicylic acid is less than or equal to 0.1%, such as 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07% %, 0.08%, 0.09%, 0.1%, etc., the mass percentage of the impurity A ≤ 0.1%, such as 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, etc.

In a specific embodiment, the high-purity gentisic acid comprises: gentisic acid, salicylic acid, impurity A and impurity B, wherein the impurity B has the structure shown in formula (II):

Formula (II).

In a specific embodiment, in the high-purity gentisic acid, the mass percentage of the impurity B is ≤ 0.1%, such as 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07% , 0.08%, 0.09%, 0.1%, etc.

In a specific embodiment, the high-purity gentisic acid comprises: gentisic acid, salicylic acid and impurity A, and does not contain impurity B.

In a specific embodiment, the high-purity gentisic acid comprises impurity C (2,3-dihydroxybenzoic acid), and in the high-purity gentisic acid, the mass percentage of the 2,3-dihydroxybenzoic acid is ≤0.1%, for example, it can be 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, etc.

The "gentisic acid" in this application has its English name: Gentisic Acid, its chemical name: 2,5-dihydroxybenzoic acid, its Chemical Abstracts (CAS) number: 490-79-9, and its other name: DHB , 5-hydroxysalicylic acid, molecular formula: C ₇ H ₆ O ₄ , molecular weight: 154.12; it is white to light yellow powder, easily soluble in methanol, soluble in acetonitrile, slightly soluble in water, melting point is 207 ~210℃. The use of gentisic acid is a pharmaceutical excipient, and it is used as a free radical quencher in preparations to reduce the radiation self-decomposition effect of radionuclides on prodrugs.

In a specific embodiment, the high-purity gentisic acid of the present application is prepared by a method comprising the following steps:

(1) feed intake reaction: 5-bromosalicylic acid is added to inorganic base, and the catalyst solution reacts;

(2) acidification: add concentrated hydrochloric acid to adjust pH, separate out solid, filter;

(3) extraction: add extractant one to the filtrate obtained in the acidification step, extract, and flocculent appears after standing;

(4) filter: filter, separate liquid, obtain organic phase one and water phase, add extractant two to water phase, extract, filter, separate liquid again, obtain organic phase two, combine organic phase two with organic phase one to obtain organic phase three;

(5) crystallization: concentrate organic phase three, separate out solid, add organic solvent one, obtain gentisic acid crude product;

(6) salify: the gentisic acid crude product is added in the organic solvent two, the solution of the organic solvent two containing the organic base is added dropwise, and the gentisic acid organic base salt wet product is obtained;

(7) dissociation: adding the wet product of gentisic acid organic base salt to water, adding concentrated hydrochloric acid dropwise to adjust pH, and filtering to obtain the wet product of gentisic acid refined product;

(8) decolorization and crystallization: add the gentisic acid refined product wet product and decolorizing agent into the crystallization solvent water, and filter to obtain the gentisic acid refined product;

(9) Filtration and drying: the gentisic acid refined product is rinsed with water, then washed with an organic solvent, and dried to obtain high-purity gentisic acid.

"5-Bromosalicylic acid" in this application, its English name is: 5-Bromosalicylic acid, other chemical names are: 5-bromo-2-hydroxybenzoic acid, and the Chemical Abstracts (CAS) number is: 89-55- 4. The molecular formula is: C ₇ H ₅ BrO ₃ , the molecular weight is: 217.02; the content of C ₇ H ₅ BrO ₃ is not less than 98.0% based on anhydrous; it is a white or off-white crystalline powder.

In a specific embodiment, in the feeding reaction step, in the presence of a copper catalyst, 5-bromosalicylic acid is added to the inorganic alkali solution, stirred, and the temperature is raised to make the 5-bromosalicylic acid react with the inorganic alkali solution, and then Cool and add water.

In a specific embodiment, in the feeding reaction step, the inorganic alkali solution is an aqueous solution of sodium hydroxide or an aqueous solution of potassium hydroxide, preferably an aqueous solution of potassium hydroxide; the concentration of the inorganic alkali solution is 4～8mol /L, such as 4mol/L, 4.5mol/L, 5mol/L, 5.5mol/L, 6mol/L, 6.5mol/L, 7mol/L, 7.5mol/L, 8mol/L, etc., inorganic alkali solution The lower the concentration, the slower the reaction. Considering the cost and ease of operation, the inorganic alkali solution of 5~6 mol/L is preferred.

In a specific embodiment, in the feeding reaction step, the ratio of the amount of material of the inorganic base to 5-bromosalicylic acid, that is, the ratio of the molar amount is 4～7:1, such as 4:1, 4.5:1, 5:1, 5.3:1, 5.5:1, 6:1, 6.5:1, 7:1, etc., preferably 5 to 6:1.

In a specific embodiment, in the feeding reaction step, the temperature is raised to 0-114°C, such as 90°C, 100°C, 101°C, 102°C, 103°C, 104°C, 105°C, 106°C , 107°C, 108°C, 109°C, 110°C, 111°C, 112°C, 113°C, 114°C, etc., preferably up to 105-114°C. 114°C is the boiling point of the reaction system, which cannot be raised to a higher temperature. The temperature is controlled within this range, the reaction time is short, and the raw materials are completely converted.

In a specific embodiment, in the feeding reaction step, the temperature rises to make 5-bromosalicylic acid react with the inorganic base solution, and the content of 5-bromosalicylic acid is controlled in HPLC to be less than 1.5%, and the reaction time is 20 ~ 48h, for example It can be 20h, 22h, 24h, 26h, 28h, 30h, 32h, 34h, 36h, 38h, 40h, 42h, 44h, 46h, 48h, etc., preferably 20~30h. When the reaction time is controlled within this range, the reaction is complete and there are few impurities.

In a specific embodiment, in the feeding reaction step, the method for controlling the content of 5-bromosalicylic acid in HPLC comprises the following steps:

5-Bromosalicylic acid positioning solution: take an appropriate amount of 5-bromosalicylic acid reference substance, add solvent to dissolve and dilute to make a solution containing about 6 μg per 1mL, and shake well;

Test solution: take an appropriate amount of the reaction solution, dilute it 400 times with a solvent (for example, take 0.025mL to dilute to 10mL), shake well, filter, and get the filtrate;

Chromatographic conditions: use octadecylsilane-bonded silica gel (Thermo Acclaim 120 ÅC18, 4.6mm×250mm, 5μm, or a chromatographic column with equivalent performance) as filler; 0.05% phosphoric acid aqueous solution as mobile phase A, acetonitrile as mobile phase Phase B; trapping column: Welch Ghost-Buster ColumnII 4.0×50mm or other suitable trapping column; the flow rate is 1.0mL per minute, and linear gradient elution is performed; the column temperature is 40°C; the detection wavelength is 220nm; the injection volume is 10 μL;

Determination method: Precisely measure the test solution and inject it into a liquid chromatograph, and record the chromatogram;

In the chromatogram of the limit test solution, calculated by the area normalization method, the peak area of 5-bromosalicylic acid should not be greater than 1.5% of the total peak area.

In a specific embodiment, in the feeding reaction step, the temperature is lowered to 20-30°C, such as 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C , 28℃, 29℃, 30℃, etc.

In a specific embodiment, in the feeding reaction step, in the presence of copper catalyst and oxalic acid, 5-bromosalicylic acid is added to the inorganic base solution. Oxalic acid is used as an antioxidant and is easily removed by water.

In a specific embodiment, in the feeding reaction step, the ratio of the amount of oxalic acid and the amount of 5-bromosalicylic acid, that is, the ratio of the molar amount is 0.05~0.15:1, such as 0.05:1, 0.06:1 , 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, etc. The oxalic acid content is controlled within the above range, and the product yield is high.

In a specific embodiment, in the feeding reaction step, the copper catalyst is copper sulfate pentahydrate or cuprous oxide. Since copper sulfate is soluble in water, post-processing is convenient, and the reaction can be made more thorough, so the most preferred Copper sulfate pentahydrate.

In a specific embodiment, in the feeding reaction step, the copper catalyst is copper sulfate pentahydrate, and the ratio of the substance amount of the copper sulfate pentahydrate and 5-bromosalicylic acid, that is, the ratio of the molar amount is 0.05 ~0.15:1, such as 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15: 1 and so on. The content of copper sulfate pentahydrate is controlled within the above range, the reaction time is shorter, the conversion rate is higher, and the copper sulfate pentahydrate is completely dissolved.

In a specific embodiment, in the feeding reaction step, the copper catalyst is cuprous oxide, and the ratio of the substance amount of the cuprous oxide to 5-bromosalicylic acid, that is, the molar ratio is 0.025～0.075 :1, such as 0.025:1, 0.03:1, 0.035:1, 0.04:1, 0.045:1, 0.05:1, 0.055:1, 0.06:1, 0.065:1, 0.07:1, 0.075:1, etc. .

In a specific embodiment, in the feeding reaction step, the ratio of the amount of the water to the substance of 5-bromosalicylic acid, that is, the molar ratio is 40 to 70:1, such as 40:1, 41.2 :1, 42:1, 44:1, 46:1, 48:1, 50:1, 52:1, 54:1, 54.9:1, 55:1, 56:1, 58:1, 60:1 , 62:1, 64:1, 66:1, 68:1, 68.6:1, 70:1, etc., preferably 50 to 60:1.

In a specific embodiment, in the acidification step, the pH is adjusted to 2.3-2.5, for example, it can be 2.3, 2.35, 2.4, 2.45, 2.5 and the like. By controlling the pH within this range, salicylic acid can be effectively removed, and the yield is higher, and the subsequent extraction of methyl tert-butyl ether has the least pigment impurities, and the product has a lighter color.

In a specific embodiment, in the acidification step, concentrated hydrochloric acid is added at 20-30°C to adjust pH, for example, at 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C Concentrated hydrochloric acid was added to adjust pH under the conditions of ℃, 28℃, 29℃, 30℃, etc.

In a specific embodiment, in the extraction step, the extractant is selected from any one or two or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene and methyl tert-butyl ether; Preference is given to methyl tert-butyl ether.

In a specific embodiment, in the extraction step, the mass ratio of the methyl tert-butyl ether to 5-bromosalicylic acid is 4 to 6:1, such as 4:1, 4.1:1, 4.2: 1, 4.3:1, 4.4:1, 4.44:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 5:1, 5.1:1, 5.18:1, 5.2:1, 5.3:1, 5.4:1, 5.5:1, 5.6:1, 5.7:1, 5.8:1, 5.92:1, 6:1, etc., preferably 5~5.5:1.

In a specific embodiment, in the extraction step, the mass ratio of the sodium chloride to 5-bromosalicylic acid is 1.0 to 1.5:1, such as 1.0:1, 1.1:1, 1.2:1, 1.3 :1, 1.4:1, 1.5:1, etc.

In a specific embodiment, in the filtration step, the extractant two is selected from any one or two or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene and methyl tert-butyl ether.

In a specific embodiment, in the filtration step, the mass ratio of the extractant two to 5-bromosalicylic acid is 4 to 6:1, such as 4:1, 4.1:1, 4.2:1, 4.3 :1, 4.4:1, 4.44:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 5:1, 5.1:1, 5.18:1, 5.2:1, 5.3:1 , 5.4:1, 5.5:1, 5.6:1, 5.7:1, 5.8:1, 5.92:1, 6:1, etc., preferably 5~5.5:1.

In a specific embodiment, in the filtration step, diatomaceous earth is added to the Buchner funnel, filtered and separated to obtain an organic phase 1 and an aqueous phase.

In a specific embodiment, in the crystallization step, the organic phase 3 is concentrated, the solid is precipitated, the organic solvent 1 is added, stirred, filtered and the filter cake is dried to obtain a crude gentisic acid; the organic solvent 1 is selected from n-heptane One or more of alkane, acetone, ethyl acetate, petroleum ether and dichloromethane.

In a specific embodiment, in the crystallization step, under the condition of 40~60°C, for example, it can be 40°C, 42°C, 44°C, 46°C, 48°C, 50°C, 52°C, 54°C, 56°C , 58°C, 60°C, etc., preferably at 40-50°C, the organic phase is concentrated under reduced pressure until a large amount of solids are precipitated. When the temperature is controlled within this range, the product purity is high and the concentration time is shorter.

In a specific embodiment, in the crystallization step, the mass ratio of the organic solvent one to 5-bromosalicylic acid is 4 to 5.5:1, such as 4:1, 4.08:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 5:1, 5.1:1, 5.2:1, 5.3:1, 5.44: 1, 5.5:1, etc., preferably 4.5~5:1.

In a specific embodiment, in the crystallization step, the stirring time is 1~2h, such as 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h , 1.9h, 2h, etc.; filter at 20~30°C, for example, it can be 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C °C, etc.

In a specific embodiment, in the crystallization step, the filter cake is vacuum-dried at 40 to 50 ° C for 2 to 4 h to obtain crude gentisic acid, for example, at 40 ° C, 41 ° C, 42 ° C, 43 ° C , 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C under vacuum drying conditions for 2h, 2.2h, 2.4h, 2.6h, 2.8h, 3h, 3.2h, 3.4h, 3.6h, 3.8h, 4h, etc.

Solvent crystallization method alone cannot be effectively purified, and gentisic acid has a carboxylic acid structure, so the present application develops a salt-forming step and a free step.

In a specific embodiment, in the salification step, the crude gentisic acid is added to the organic solvent two, stirred, and the solution of the organic solvent two containing the organic base is added dropwise, and the temperature is lowered and filtered to obtain the gentisic acid organic base to form a salt. Wet goods.

In a specific embodiment, in the salt forming step, under the condition of 10°C to 35°C, for example, it can be 10°C, 12°C, 14°C, 15°C, 18°C, 20°C, 22°C, 25°C, 27°C , 30 ℃, 32 ℃, 34 ℃, 35 ℃ and other conditions, dropwise add the solution of organic solvent two containing organic base. When the temperature is controlled within the above-mentioned range, it is not easy to explode when the crystals are precipitated by subsequent cooling, and the impurities are less.

In a specific embodiment, in the salt-forming step, the organic base is diethylamine, and the organic solvent is one or more selected from acetone, isopropanol and tetrahydrofuran.

In a specific embodiment, in the salt-forming step, the ratio of the amount of the organic base to the substance of 5-bromosalicylic acid, that is, the ratio of the molar amount is 0.75-0.85:1, for example, it can be 0.75:1, 0.76:1, 0.77:1, 0.78:1, 0.79:1, 0.8:1, 0.81:1, 0.82:1, 0.83:1, 0.84:1, 0.85:1, etc., preferably 0.75 to 0.81:1. Controlling the content of the organic base within the above range can result in sufficient salt formation and less impurities.

In a specific embodiment, in the salt-forming step, the mass ratio of the organic solvent two and the gentisic acid crude product is 8.6 to 10:1, such as 8.6:1, 8.7:1, 8.8:1, 8.9: 1, 9:1, 9.1:1, 9.2:1, 9.3:1, 9.4:1, 9.42:1, 9.5:1, 9.6:1, 9.7:1, 9.8:1, 9.9:1, 10:1, etc. , preferably 9~9.8:1. Controlling the acetone within the above range can make the yield higher and the gentisic acid crude product dissolve more completely.

In a specific embodiment, in the salt forming step, the temperature is lowered to 2-8°C, for example, 2°C, 2.5°C, 3°C, 3.5°C, 4°C, 4.5°C, 5°C, 5.5°C , 6℃, 6.5℃, 7℃, 7.5℃, 8℃, etc. When the temperature is controlled within the above range, higher purity and yield can be obtained.

In a specific embodiment, in the salt-forming step, after the dropwise addition of the solution of the organic solvent 2 containing the organic base is completed, the temperature is kept for 0.3-0.8h, and then the temperature is lowered, for example, the temperature can be kept for 0.3h, 0.4h, 0.5h, 0.6h , 0.7h, 0.8h, etc.

In a specific embodiment, in the salt forming step, the cooling gradient is 15-25°C/h, for example, 15°C/h, 17°C/h, 19°C/h, 20°C/h, 22°C /h, 23°C/h, 25°C/h, etc.

In a specific embodiment, in the salt-forming step, the temperature is kept for 0.3-0.8h after cooling, and filtered, for example, the temperature can be kept for 0.3h, 0.4h, 0.5h, 0.6h, 0.7h, 0.8h, and the like.

In a specific embodiment, in the dissociation step, the wet product of organic base salt of gentisic acid is added to water, stirred, and concentrated hydrochloric acid is added dropwise to adjust pH, cooled, and filtered to obtain the wet product of gentisic acid refined product.

In a specific embodiment, in the dissociation step, concentrated hydrochloric acid is added dropwise at 20~30°C to adjust pH, for example, at 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, Concentrated hydrochloric acid was added dropwise at 27°C, 28°C, 29°C, and 30°C to adjust pH.

In a specific embodiment, in the free step, the pH is adjusted to 1~2, for example, it can be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, etc. When pH is controlled within this range, the gentisic acid can be freed more completely and the product yield can be higher.

In a specific embodiment, in the free step, the mass ratio of the water to the wet product of the organic base salt of gentisic acid is 4 to 6:1, such as 4:1, 4.2:1, 4.4:1, 4.6 :1, 4.8:1, 5:1, 5.2:1, 5.4:1, 5.6:1, 5.8:1, 6:1, etc. Controlling the water within the above range can completely dissolve the wet product of the organic base salt of gentisic acid and have a higher product yield.

In a specific embodiment, in the dissociation step, the temperature is lowered to 0-10°C, for example, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, etc., the cooling gradient is 15~25°C/h, such as 15°C/h, 17°C/h, 19°C/h, 20°C/h, 22°C/h, 23℃/h, 25℃/h, etc.

In a specific embodiment, in the dissociation step, the temperature can be kept for 0.3-0.8h after cooling, and filtered, for example, the temperature can be kept for 0.3h, 0.4h, 0.5h, 0.6h, 0.7h, 0.8h and the like.

In a specific embodiment, in the decolorization and crystallization step, the wet product of the gentisic acid refined product and the decolorizing agent are added into water, stirred, heated, filtered and the filtrate is cooled to obtain gentisic acid crystals; the decolorizing agent is not limited to One or more of activated carbon, alumina and clay.

In a specific embodiment, in the decolorization and crystallization step, the wet product of gentisic acid refined product, decolorizer and oxalic acid are added to water, and oxalic acid acts as an antioxidant.

In a specific embodiment, in the step of decolorization and crystallization, the temperature is maintained for 0.5~6h, for example, it can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.2h, 1.5h, 2h, 2.5h h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, etc., preferably 0.5~1.5h. Controlling the holding time within this range can completely dissolve the wet product of the gentisic acid refined product, and further control the impurity B content.

In a specific embodiment, in the decolorization and crystallization step, the temperature is raised to 65-75°C, such as 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C °C, 73 °C, 74 °C, 75 °C, etc. Controlling the temperature within this range can completely dissolve the gentisic acid refined wet product and improve the purity of the final product.

In a specific embodiment, in the decolorization and crystallization steps, the mass ratio of the activated carbon to the gentisic acid refined wet product is 0.05 to 0.1:1, such as 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, etc. Controlling the mass ratio of activated carbon to the wet product of gentisic acid refined products within this range can improve the pigment removal efficiency.

In a specific embodiment, in the decolorization and crystallization steps, the mass ratio of the oxalic acid to the wet product of the gentisic acid refined product is 0.01 to 0.03:1, such as 0.01:1, 0.015:1, 0.02:1, 0.025:1, 0.03:1, etc.

In a specific embodiment, in the decolorization and crystallization steps, the mass ratio of the water to the wet product of the gentisic acid refined product is 4 to 6:1, such as 4:1, 4.2:1, 4.4:1, 4.6:1, 4.8:1, 5:1, 5.2:1, 5.4:1, 5.6:1, 5.8:1, 6:1, etc. Controlling the mass ratio of water to the wet product of the gentisic acid refined product within this range can make the wet product of the refined gentisic acid product and further improve the product yield.

In a specific embodiment, in the decolorization and crystallization step, filtering and cooling the filtrate to 0-10°C, for example, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C ℃, 8 ℃, 9 ℃, 10 ℃, etc., keep the temperature for 0.3~0.8h, such as 0.3h, 0.4h, 0.5h, 0.6h, 0.7h, 0.8h, etc., to obtain gentisic acid crystals.

In a specific embodiment, in the filtration and drying steps, the drying conditions are: vacuum drying at 40-55°C for 10-15h, for example, at 40°C, 42°C, 44°C, 46°C, 48°C, 50°C 10h, 11h, 12h, 13h, 14h, 15h, etc. under vacuum drying conditions at ℃, 52℃, 54℃, 55℃, etc.

In a specific embodiment, the stirring in this application is all carried out under nitrogen protection.

In a specific embodiment, the water is purified water.

The application also provides an application of the high-purity gentisic acid described in any one of the above in the preparation of an antiviral agent, an antibacterial agent, an analgesic agent or an antioxidant excipient.

Example

This application generally and/or specifically describes the materials and test methods used in the test. In the following examples, the materials or instruments used without the manufacturer's indication are conventional materials that can be purchased from the market. or instrument.

Example 1

Feeding reaction: add 5.0mol/L NaOH solution to the reaction kettle, add 50g of 5-bromosalicylic acid, 0.5g of cuprous iodide, and 0.5g of oxalic acid; under nitrogen protection, start stirring; heat up to 100~120℃ for 24h, Sampling control HPLC (5-bromosalicylic acid)≤1.5%; cool down to 20~30℃, add water;

Acidification: control the temperature to 20~30℃, add concentrated hydrochloric acid to adjust the pH of the reaction solution to (2.4), there is solid precipitation, filter;

Extraction: add 50 g of sodium chloride and 250 g of methyl tert-butyl ether to the filtrate, stir and extract, and flocs appear after standing;

Filtration: 5 g of diatomaceous earth was added to the Buchner funnel, filtered and separated to obtain the first organic phase and the aqueous phase; 125 g of methyl tert-butyl ether was added to the aqueous phase, filtered and separated to obtain the second organic phase. 2 and organic phase 1 are combined to obtain organic phase 3;

Crystallization: Concentrate the organic phase under reduced pressure at 40~50°C until a large amount of solids are precipitated, add 360 g of n-heptane; stir for 1~2 hours, filter at room temperature at 20~30°C; vacuum dry the filter cake at 40~50°C for 2~4 hours, and obtain a Crude cholic acid 16g;

Salt formation: Add 250 g of acetone to the reaction kettle, add crude gentisic acid, start stirring under nitrogen protection; control the temperature to 10-35 °C, add 36 g of acetone solution containing 13.15 g of diethylamine dropwise, and keep the temperature for 0.5 h after the dropwise addition is completed. ; Turn off the heating, lower the temperature (15~25°C/h) to 2~8°C, keep the temperature for 0.5h, and filter to obtain about 25g of gentisic acid diethylamine salt wet product;

Free: add 200g of water to the reaction kettle, add the wet product of gentisic acid diethylamine salt; under nitrogen protection, start stirring, control the temperature to 20~30℃, and add concentrated hydrochloric acid dropwise to adjust the pH; cool down to 0~10℃, keep the temperature for 0.5h , filtered to obtain the wet product of gentisic acid refined products;

Decolorization and crystallization: add 250 g of water to the reaction kettle, add the wet product of gentisic acid refined product, add 0.2 g of activated carbon, and add 0.1 g of oxalic acid; under the protection of nitrogen, start stirring, heat up to 65~75 °C, keep the temperature for 0.5~1 h, while the Hot filtration; the filtrate is cooled to 0~10℃ and kept for 0.5h;

Filtration and drying: rinse with water, then wash the filter cake with 22 g of n-heptane, and dry the filter cake under vacuum at 40~55°C for 12 hours to obtain 11 g of high-purity gentisic acid.

Example 2

Feeding reaction: add 5.0mol/L NaOH solution to the reaction kettle, add 200g of 5-bromosalicylic acid, 1.8g of cuprous chloride, and 2g of oxalic acid; under nitrogen protection, turn on stirring; heat up to 100~120℃ for 24h reaction, take samples In-control HPLC (5-bromosalicylic acid)≤1.5%; cool down to room temperature (20~30℃), add water;

Acidification: control the temperature to 20~30℃, add concentrated hydrochloric acid to adjust the pH of the reaction solution to 2.4, there is solid precipitation, and filter;

Extraction: add 200 g of sodium chloride and 1000 g of methyl tert-butyl ether to the filtrate, stir and extract, and flocs appear after standing;

Filtration: add 50 g of diatomaceous earth to the Buchner funnel, filter, and separate the liquids to obtain an organic phase 1 and an aqueous phase; add 500 g of methyl tert-butyl ether to the aqueous phase, filter, and separate liquids to obtain an organic phase 2. 2 and organic phase 1 are combined to obtain organic phase 3;

Crystallization: Concentrate the organic phase under reduced pressure at 40~50 °C until a large amount of solids are precipitated, add 500 g of n-heptane; stir for 1~2 h, filter at room temperature at 20~30 °C; vacuum dry the filter cake at 40~50 °C for 2~4 h, get the dragon Crude cholic acid 68g;

Salt formation: add 450 g of acetone to the reaction kettle, add crude gentisic acid, under nitrogen protection, start stirring; control the temperature to 10-35 °C, add 150 g of acetone solution of 52.60 g of diethylamine dropwise, and keep the temperature for 0.5 h after the dropwise addition; Turn off the heating, lower the temperature (15~25℃/h) to 2~8℃, keep the temperature for 0.5h, and filter to obtain 96g of gentisic acid diethylamine salt wet product;

Free: add water to the reaction kettle, add the wet product of gentisic acid diethylamine salt; under nitrogen protection, start stirring, control the temperature to 20~30°C, and add concentrated hydrochloric acid dropwise to adjust the pH; Filter to get the wet product of gentisic acid refined product;

Decolorization and crystallization: add 1000 g of water to the reaction kettle, add the wet product of gentisic acid refined product, add 1 g of activated carbon, and add 0.5 g of oxalic acid; under nitrogen protection, start stirring, heat up to 65~75 °C, keep the temperature for 0.5~1 h, and keep it hot. Filtration; the filtrate was cooled to 0~10℃ and kept for 0.5h;

Filtration and drying: rinse with water, then wash the filter cake with 200 g of n-heptane, and vacuum dry the filter cake at 40-55 °C for 12.0 h to obtain 48 g of high-purity gentisic acid.

Example 3

Feeding reaction: add 5.0mol/L KOH solution to the reaction kettle, add 500 g of 5-bromosalicylic acid, 5.0 g of copper sulfate pentahydrate, and 5 g of oxalic acid; under nitrogen protection, start stirring; heat up to 100~120 ° C for 24 hours, and take samples In-control HPLC (5-bromosalicylic acid)≤1.5%; cool down to room temperature (20~30℃), add water;

Acidification: control the temperature to 20~30℃, add concentrated hydrochloric acid to adjust the pH of the reaction solution to 2.4, there is solid precipitation, and filter;

Extraction: Add 500 g of sodium chloride and 250 g of methyl tert-butyl ether to the filtrate, stir and extract, and flocs appear after standing;

Filtration: add 50 g of diatomaceous earth to the Buchner funnel, filter, and separate the liquids to obtain an organic phase 1 and an aqueous phase; add 125 g of methyl tert-butyl ether to the aqueous phase, filter, and separate liquids to obtain an organic phase 2. 2 and organic phase 1 are combined to obtain organic phase 3;

Crystallization: Concentrate the organic phase under reduced pressure at 40~50°C until a large amount of solid is precipitated, add 250 g of n-heptane; stir for 1~2 hours, filter at room temperature at 20~30°C; vacuum dry the filter cake at 40~50°C for 2~4 hours to obtain gentian Crude acid 160g;

Salt formation: add 1200 g of acetone to the reaction kettle, add crude gentisic acid, under nitrogen protection, start stirring; control the temperature to 10-35 °C, add 280 g of acetone solution of 131.50 g of diethylamine dropwise, and keep the temperature for 0.5 h after the dropwise addition; Turn off the heating, cool down (15~25℃/h) to 2~8℃, keep the temperature for 0.5h, and filter to obtain the wet product of gentisic acid diethylamine salt;

Free: add 2000g of water to the reaction kettle, add the wet product of gentisic acid diethylamine salt; under nitrogen protection, start stirring, control the temperature to 20~30℃, add concentrated hydrochloric acid dropwise to adjust the pH; cool down to 0~10℃, keep the temperature for 0.5h , filtered to obtain the wet product of gentisic acid refined products;

Decolorization and crystallization: add 2000g of water to the reaction kettle, add the wet product of gentisic acid refined product, add 3g of activated carbon, and add 1.5g of oxalic acid; under nitrogen protection, start stirring, heat up to 65~75℃, keep warm for 0.5~1h, and keep hot Filtration; the filtrate was cooled to 0~10℃ and kept for 0.5h;

Filtration and drying: rinse with water, then wash the filter cake with 400 g of n-heptane, and dry the filter cake under vacuum at 40~55°C for 12 hours to obtain 110 g of high-purity gentisic acid.

Example 4

The difference between this example and Example 3 is that, in the acidification step, the pH of the reaction solution is adjusted to 2.3.

Example 5

The difference between this example and Example 3 is that, in the acidification step, the pH of the reaction solution is adjusted to 2.5.

Example 6

The difference between this example and Example 3 is that in the acidification step, the pH of the reaction solution is adjusted to 2.1.

Example 7

The difference between this example and Example 3 is that in the acidification step, the pH of the reaction solution is adjusted to 2.7.

Example 8

The difference between this example and Example 3 is that in the salt-forming step, the ratio of the amount of diethylamine to 5-bromosalicylic acid is 0.75:1.

Example 9

The difference between this example and Example 3 is that in the salt-forming step, the ratio of the amount of diethylamine to 5-bromosalicylic acid is 0.81:1.

Example 10

The difference between this example and Example 3 is that in the salt-forming step, the ratio of the amount of diethylamine to 5-bromosalicylic acid is 0.7:1.

Example 11

The difference between this example and Example 3 is that in the salt-forming step, the ratio of the amount of diethylamine to 5-bromosalicylic acid is 0.85:1.

Example 12

The difference between this example and Example 3 lies in that, in the decolorization and crystallization steps, the temperature is heated for 6 hours, and then filtered while hot.

The raw materials, reagents, reaction conditions and test results of the obtained samples of each embodiment are listed in Table 1 below.

Table 1

The above are only preferred embodiments of the present application, and are not intended to limit the present application in other forms. Any person skilled in the art may use the technical content disclosed above to make changes or modifications to the equivalents of equivalent changes. Example. However, any simple modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present application without departing from the content of the technical solutions of the present application still fall within the protection scope of the technical solutions of the present application.

Claims (15)

1. A high-purity gentisic acid is characterized in that the purity is more than or equal to 99.50%, and comprises: gentisic acid, salicylic acid and impurity A, wherein the impurity A has a structure shown in formula (I):

formula (I).

2. The high purity gentisic acid as claimed in claim 1, wherein the salicylic acid is present in an amount of 0.1% by mass or less and the impurity a is present in an amount of 0.1% by mass or less.

3. The high purity gentisic acid of claim 1, further comprising impurity B, wherein the impurity B has a structure represented by formula (II):

formula (II).

4. The high-purity gentisic acid as claimed in claim 3, wherein the impurity B is present in the high-purity gentisic acid in an amount of 0.1% by mass or less.

5. The high purity gentisic acid according to any one of claims 1 to 4, characterized in that it is prepared by a method comprising the steps of:

feeding and reacting: adding 5-bromosalicylic acid into an inorganic alkali solution for reaction;

acidifying: adding concentrated hydrochloric acid to adjust pH, separating out solid, and filtering;

and (3) extraction: adding an extracting agent I into the filtrate obtained in the acidification step, extracting, and standing to obtain floccules;

and (3) filtering: filtering and separating the solution to obtain an organic phase I and a water phase, adding an extracting agent II into the water phase, extracting, filtering and separating the solution to obtain an organic phase II, and combining the organic phase II and the organic phase I to obtain an organic phase III;

and (3) crystallization: concentrating the organic phase III, separating out solids, and adding the organic solvent I to obtain a crude gentisic acid product;

salifying: adding the crude gentisic acid into a second organic solvent, and dropwise adding a solution of the second organic solvent containing organic base to obtain a wet gentisic acid organic base salt;

dissociating: adding the wet gentisic acid organic base salt into water, dropwise adding concentrated hydrochloric acid to adjust the pH value, and filtering to obtain a refined gentisic acid wet product;

decoloring and crystallizing: adding refined wet gentisic acid and a decolorant into water, and filtering to obtain gentisic acid crystals;

and (3) filtering and drying: and leaching the gentisic acid crystal with water, then cleaning with an organic solvent I, and drying to obtain the high-purity gentisic acid.

6. The high-purity gentisic acid as claimed in claim 5, wherein in the acidification step, the pH is adjusted to 2.3 to 2.5.

7. The highly pure gentisic acid as claimed in claim 5, wherein in the extraction step, the extractant one is selected from any one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene and methyl t-butyl ether.

8. The highly pure gentisic acid as claimed in claim 5, wherein in the filtration step, the second extractant is selected from any one or more of dichloromethane, ethyl acetate, isopropyl acetate, toluene and methyl t-butyl ether.

9. The high-purity gentisic acid as claimed in claim 5, wherein in the crystallization step, the organic solvent one is one or more selected from n-heptane, acetone, ethyl acetate, petroleum ether and chloroform.

10. The high-purity gentisic acid as claimed in claim 5, wherein the mass ratio of the organic base to 5-bromosalicylic acid is 0.75-0.85: 1.

11. The high purity gentisic acid of claim 5 wherein the organic base is diethylamine.

12. The high purity gentisic acid as claimed in claim 5, wherein in the salt formation step, the organic solvent II is one or more selected from acetone, isopropanol and tetrahydrofuran.

13. The high-purity gentisic acid as claimed in claim 5, wherein in the decoloring and crystallizing steps, the gentisic acid refined product wet product and the decoloring agent are added into water, stirred, heated, filtered and the filtrate is cooled to obtain gentisic acid crystals.

14. The high-purity gentisic acid as claimed in claim 13, wherein in the decoloring and crystallizing steps, the temperature is raised and then maintained for 0.5-6 h.

15. Use of high purity gentisic acid as claimed in any one of claims 1 to 14 in the manufacture of an antiviral, antibacterial, analgesic or antioxidant excipient.