A silybin derivative, its preparation method and application

Abstract

The present invention relates to a silybin derivative, its preparation method and application, belonging to the field of chemical technology. In the present invention, a hydrophilic sodium sulfonate group is introduced into silybin, and silybin is sulfonated to form a new compound with good water solubility - sodium silybin sulfonate, which enhances its solubility in water, improves the pharmacokinetic characteristics of silybin from a pharmacokinetic perspective, increases its affinity and biological activity for organisms, and is formulated into an injection for clinical treatment, providing a more excellent administration route, having advantages incomparable to silybin, and having broad significance and great therapeutic value in clinical applications.

Description

Technical Field

[0001] The present invention relates to a silybin derivative, a preparation method and an application thereof, belonging to the field of chemical technology. Background Art

[0002] Silymarin is a flavonolignan compound extracted and refined from the fruits of the Compositae plant Silybum marianum. The main components are four isomers: silybin, isosilybin, silydianin, and silychristin. Among them, silybin has the highest content and the strongest hepatoprotective activity. It has good curative effects on acute and chronic hepatitis, liver cirrhosis, and liver injury caused by metabolic poisoning, and is a natural hepatoprotective drug. Modern research has found that silybin is a drug with multiple functions and targets. Its pharmacological effects are not only reflected in the most widely studied hepatoprotective effect at present, but also have a variety of pharmacological activities, such as lipid-lowering, antioxidant, anti-diabetes, myocardial protection, anti-platelet aggregation, and anti-tumor pharmacological effects. Silybin is composed of two diastereoisomers, silybin A and silybin B, in equal proportions. English name: Silybin, Chinese name: 2,3-Dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-6-(3,5,7-trihydroxy-4-oxobenzopyran-2-yl)benzodioxane, CAS No.: 22888-70-6, molecular formula: C25H22O10, molecular weight: 482.436, melting point: 164-174 °C, density: 1.527 g / cm3. Pure silybin is a kind of white crystalline powder, odorless, slightly bitter and astringent, and hygroscopic. It is soluble in acetone, ethyl acetate, methanol, ethanol, slightly soluble in chloroform, and almost insoluble in water. Its structural formula is shown in Formula (I):

[0003] Formula (I).

[0004] Related literature shows that silybin is a liver disease treatment drug with high safety and a long history of use. There have been a large number of studies on the structural modification and structure-activity relationship of silybin, but no ideal derivatives have been obtained yet. This is mainly because most derivatives start with improving solubility by changing one or more hydroxyl groups of silybin, and no synergistic groups are introduced into the flavonoid mother nucleus skeleton. Preliminary studies on the structure-activity relationship of silybin's hepatoprotective effect indicate that the presence of the flavonoid mother nucleus, benzodioxane structure, and multiple hydroxyl groups in its molecule are all beneficial to the improvement of hepatoprotective activity. The hydroxyl groups at the 3-position and 23-position hydroxymethyl are essential groups for maintaining activity, and the derivatives of these hydroxyl groups have a reducing effect on silybin's hepatoprotective effect. For natural drugs with complex structures and poor water solubility, due to low bioavailability, it is difficult to fully exert their pharmacological activities, which greatly limits their use. The sulfonate group (-SO3Na) is a strongly hydrophilic group. Introducing a hydrophilic group into the molecule of a poorly soluble compound can greatly increase its water solubility, which is an effective method to improve its bioavailability and efficacy. There have been successful examples such as preparing tanshinone IIA sulfonate injection from the cardiovascular treatment drug tanshinone IIA. Although silybin has pharmacological activities such as scavenging free radicals, anti-lipid peroxidation, protecting liver cell membranes, promoting the synthesis of DNA and structural proteins in damaged hepatocytes, and anti-fibrosis, and has good curative effects on acute and chronic hepatitis, metabolic toxic liver injury, and cirrhosis, due to silybin being insoluble in water and having extremely poor solubility in water, its bioavailability is low, greatly reducing the clinical efficacy. Currently, the hepatoprotective drugs mainly containing silybin are all oral capsules and tablets. There are individual literatures that use silybin and solubilizers to make injections, or make freeze-dried powder injections after salifying silybin with meglumine. However, even so, due to unstable absorption, the bioavailability is still poor, and it is difficult to exert its pharmacological activities. Currently, no injection mainly containing silybin has been approved for marketing and clinical treatment use. Summary of the Invention

[0005] The object of the present invention is to propose a derivative of silybin, its preparation method and application in view of the defects existing in the prior art, introducing a hydrophilic group into the molecule of a poorly soluble compound, greatly increasing its water solubility, and improving its bioavailability and efficacy.

[0006] The present invention solves the technical problems through the following technical solutions: First, a derivative of silybin is proposed. The silybin derivative is silybin sulfonate or silybin derivative sulfonate, and the general formula is as follows:

[0007]

[0008] Formula (II)

[0009] In the formula, R1-R5 can be at least one of hydrogen, alkyl, alkanoyl, phenyl, and benzoyl. The silybin derivative of the present invention, sodium silybin sulfonate, is a newly synthesized compound for the first time. Chemical name: Sodium 2,3-dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-6-(3,5,7-trihydroxy-4-oxo-2H-chromen-2-yl)-1,4-benzodioxane-8-sulfonate. Molecular formula: C25H21NaO13S, molecular weight: 584.49, melting point: 173-176 °C, soluble in water and methanol, soluble in ethanol, slightly soluble in isopropanol, it is a kind of off-white crystalline powder, odorless, slightly bitter and astringent taste, and hygroscopic. The structure of the product was confirmed by mass spectrometry, nuclear magnetic resonance, infrared spectroscopy, and ultraviolet spectroscopy: The chemical structural formula (III) of sodium silybin sulfonate:

[0010] Formula (III).

[0011] Silybin is a compound with alternating benzene rings and heterocycles. The chemical structural formula (I) shows that there are 3 benzene rings and 2 heterocycles, and there are 5 hydroxyl groups. According to their positions, they can be divided into phenolic hydroxyl groups, secondary hydroxyl groups, and primary hydroxyl groups. Secondary hydroxyl groups and primary hydroxyl groups have strong reactivity, and phenolic hydroxyl groups make silybin show weak acidity in aqueous solution. Silybin is easily oxidized, relatively stable under acidic conditions, but strong alkali or heating will destroy its structure and become unstable. The structure of silybin is complex, and there are many parts where chemical reactions are likely to occur. It is quite difficult to carry out sulfonation reaction to prepare the target product sulfonate. Especially, both the 6th and 8th positions of the benzene ring of the flavonoid nucleus of silybin have strong reactivity, and the reactivity of the 8th position is slightly greater than that of the 6th position. The target product is obtained by sulfonation reaction at the 8th position of the benzene ring of the flavonoid nucleus. Silybin is only soluble in acetone, ethyl acetate, methanol, ethanol, etc., and has poor solubility in most organic solvents, which increases the difficulty of carrying out sulfonation reaction. It is extremely important to select suitable solvents and sulfonating agents and explore reaction conditions, etc.

[0012] For the above reasons, the present invention further provides a preparation method of the above-mentioned sodium silybin sulfonate and sodium silybin derivative sulfonate. According to the characteristics of the reactivity of the 8th position of the benzene ring of the flavonoid nucleus of silybin, a suitable sulfonating reagent and a special sulfonation technology process are selected, the reaction conditions are controlled, and sulfonation reaction is selectively carried out at the 8th position of the benzene ring of the flavonoid nucleus to generate an 8-silybin sulfonic acid intermediate, which is salted with a saturated sodium chloride aqueous solution and purified by a water-soluble lower alcohol organic solvent, and vacuum or freeze-dried to obtain 8-sodium silybin sulfonate. The reaction equation is as follows:

[0013]

[0014] The specific method includes the following steps,

[0015] Step 1: Extract silybin. The silybum marianum fruits are pressed to remove oil, pre - degreased with n - hexane, and then silymarin is extracted using ethanol or ethyl acetate as the extraction solvent. The silymarin is dissolved by heating with absolute ethanol, decolorized with activated carbon, and the filtrate is allowed to stand to precipitate white crystals, which are recrystallized with ethyl acetate - methanol to obtain silybin;

[0016] Step 2: Prepare the 8 - silybin sulfonic acid intermediate. A sulfonation reaction is carried out at the 8 - position of the benzene ring of the silybin flavonoid nucleus to generate a reaction mixture containing the 8 - silybin sulfonic acid intermediate;

[0017] Step 3: Salt formation and purification. After quenching the reaction mixture containing the silybin sulfonic acid intermediate with saturated sodium chloride aqueous solution, the acetonitrile or dioxane solvent is separated, and most of the acetonitrile or dioxane solvent is removed by concentration under reduced pressure. Then, saturated sodium chloride aqueous solution is added for salt formation. After salt formation, the crude solid is recrystallized multiple times with isopropanol or other water - soluble lower - alcohol organic solvents. After purification to meet the quality purity requirements of the injection, 8 - silybin sodium sulfonate is obtained by vacuum or freeze - drying.

[0018] The present invention further provides three sulfonation reaction methods,

[0019] The first method: In the second step, the sulfonation reaction is carried out in a solvent such as acetonitrile or dioxane with a weight of 5 - 50 times that of silybin. Add 0.5 - 5 times the molar amount of silybin of sulfamic acid, 0.5 - 5 times the molar amount of silybin of sodium bisulfate monohydrate, 0.5 - 5 times the molar amount of silybin of concentrated sulfuric acid, and 0.5 - 5% by weight of silybin of 18 - crown - 6 phase - transfer catalyst. After stirring and mixing at room temperature, add silybin and continue to stir evenly, then raise the temperature to 30 - 80 °C and stir for 3 hours. The reaction process is monitored by TLC until the raw materials disappear and then the reaction is stopped to obtain the 8 - silybin sulfonic acid intermediate.

[0020] The second method: In the second step, the sulfonation reaction is carried out in a solvent such as acetonitrile or dioxane with a weight of 5 - 50 times that of silybin. Add 0.5 - 5 times the molar amount of silybin of phosphorus pentoxide, and while stirring, add dropwise 0.5 - 5 times the molar amount of silybin of concentrated sulfuric acid. After stirring at room temperature for 30 minutes, slowly add silybin, continue to stir the reaction solution, and react at 30 - 80 °C for 3 hours. The reaction process is monitored by TLC until the raw materials disappear and then the reaction is stopped to obtain the 8 - silybin sulfonic acid intermediate.

[0021] In the third method, in the second step, the sulfonation reaction is carried out by adding 0.5 - 5 times the molar amount of sodium sulfate, 0.5 - 5 times the molar amount of concentrated sulfuric acid, and 0.5 - 5 times the molar amount of acetic anhydride to a solvent such as acetonitrile or dioxane which is 5 - 50 times the weight of silybin. After stirring and mixing at room temperature, silybin is added and stirred evenly, and then stirred and reacted at 30 - 80 °C for about 3 hours. The reaction process is monitored by TLC until the raw materials disappear, and then the reaction is stopped to obtain the 8 - silybin sulfonic acid intermediate.

[0022] Through a large number of experimental explorations and screenings, the present invention obtains the selection of each reagent in the sulfonation reaction:

[0023] Common sulfonating agents include concentrated sulfuric acid, fuming sulfuric acid, chlorosulfonic acid, sulfur trioxide, sulfur trioxide pyridine complex, and sulfamic acid, etc. At present, the most widely used and mature process in industry is sulfonation with concentrated sulfuric acid and fuming sulfuric acid, but more waste acid is generated and the post - treatment cost is high; sulfur trioxide and chlorosulfonic acid are chemically active. When used in sulfonation reactions, they have less dosage, good sulfonation effect, and less waste acid, but the reaction is difficult to control and there are more side reactions. Sulfamic acid (NH 2 SO 3 H) is a non - volatile, odorless and non - toxic solid strong acid, appearing as white crystals. It is chemically stable in a dry environment, can be stored for a long time, and is convenient for transportation.

[0024] Select one of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran, pyridine, dioxane, and acetonitrile as the solvent. The sulfonating agents include the combination of concentrated sulfuric acid with acetic anhydride and sodium sulfate, the combination of anhydrous phosphorus pentoxide with concentrated sulfuric acid, and the combination of sulfamic acid with concentrated sulfuric acid and sodium bisulfate. It is found that these 3 sulfonating agents have strong selectivity for the sulfonation reaction of silybin, and 8 - sodium silybin sulfonate with high yield and purity can be obtained.

[0025] Dimethylformamide and dimethyl sulfoxide are not easily removed of residual solvents, and tetrahydrofuran and pyridine are highly toxic. The solvent is preferably acetonitrile or dioxane, and the sulfonating agent is preferably sulfamic acid. Sulfamic acid has many advantages as a sulfonating agent, such as high reaction selectivity, high purity of the product generated, and less generation of three wastes in the reaction process. Sulfamic acid has relatively mild chemical properties, similar to the sulfur trioxide tertiary amine complex. Its sulfonation mechanism may be that sulfamic acid releases sulfur trioxide through a certain transformation, and then the sulfur trioxide molecule acts on the reactant for sulfonation reaction. However, the sulfonation reaction activity of sulfamic acid is weak, and it is a heterogeneous solid-liquid reaction, which requires vigorous stirring and has disadvantages such as low conversion rate of reactants. The present invention discovers for the first time that adding a phase transfer catalyst can accelerate the reaction rate and make the reaction more complete. The phase transfer catalyst includes but is not limited to one or several of azacrown-15-crown-5, 15-crown-5, 18-crown-6, 4-carboxybenzo-15-crown-5, and azacrown-18-crown-6. Adding sodium bisulfate can enhance the activity of sulfamic acid and improve the product yield.

[0026] In the third step of the above preparation method, the water-soluble organic solvent is lower alcohols or acetone; the lower alcohols are methanol, ethanol, propanol or isopropanol.

[0027] The present invention further provides the application of silybin derivatives, including the application in the preparation of pharmaceutical preparations for treating liver diseases.

[0028] The dosage form of the preparation is an injection or an oral preparation, and the oral preparation is a capsule, a tablet, a granule or an oral solution.

[0029] The preparation method of sodium silybin sulfonate provided by the present invention and the technical ideas such as preparing a sulfonate salt with good water solubility are also equally applicable to flavonolignan compounds (chemical structure general formula IV) contained in silybum marianum such as isosilybin, silybinin, and silychristin,

[0030]

[0031] Formula (IV)

[0032] Preparing them into sulfonate derivatives with good water solubility, and the reaction equation is as follows:

[0033]

[0034] In the present invention, a hydrophilic sodium sulfonate group is introduced into silybin, and silybin is sulfonated to prepare sodium silybin sulfonate with good water solubility. Only by sulfonating silybin to prepare a sodium sulfonate salt with good water solubility, its bioavailability is greatly improved, and the effective group and the parent nucleus structure of silybin with pharmacological activity are not changed. Its solubility in water is enhanced, the pharmacokinetic characteristics of silybin are improved from the perspective of pharmacokinetics, its affinity and biological activity for organisms are increased, and it is made into an injection for clinical treatment. It can also be made into oral preparations such as capsules, tablets, granules, and oral solutions. Its pharmacological effects and therapeutic effects on liver diseases and the like will be significantly better than those of natural silybin. Its beneficial effect is to provide a more excellent administration route, with advantages that silybin cannot match, and it will have broad significance and great therapeutic value in clinical applications. Description of the Drawings

[0035] Figure 1 It is the MS spectrum of sodium silybin sulfonate.

[0036] Figure 2 It is the 1H NMR spectrum of sodium silybin sulfonate.

[0037] Figure 3 It is the 13C NMR spectrum of sodium silybin sulfonate.

[0038] Figure 4 It is the IR (KBr) spectrum of sodium silybin sulfonate.

[0039] Figure 5 It is the UV spectrum of sodium silybin sulfonate. Detailed Embodiments

[0040] Example 1

[0041] In this example, sodium 8-silybin sulfonate was prepared according to the following method: In a reaction flask, 80 g of sulfamic acid, 60 g of sodium bisulfate monohydrate, 1000 ml of acetonitrile solvent, 80 ml of concentrated sulfuric acid, and 5 g of 18-crown-6 phase transfer catalyst were added. After stirring at room temperature for 30 minutes, 200 g of silybin was slowly added and stirred evenly. Then the temperature was raised to 50 - 60 °C and stirred for about 3 hours. The reaction process was monitored by TLC until the raw materials disappeared and then the reaction was stopped.

[0042] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by reduced pressure concentration. Then saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 162 g of refined sodium 8-silybin sulfonate was obtained, with a yield of 81%.

[0043] Example 2

[0044] Sodium silybin-8-sulfonate was prepared according to the following method in this example: In a reaction flask, 100 g of sulfamic acid, 40 g of sodium bisulfate monohydrate, 1000 ml of acetonitrile solvent, 50 ml of concentrated sulfuric acid, and 5 g of 18-crown-6 phase transfer catalyst were added. After stirring at room temperature for 30 minutes, 200 g of silybin was slowly added and stirred evenly. The temperature was raised to 60 - 70 °C and stirred for about 3 hours. The reaction process was monitored by TLC and the reaction was stopped after the raw materials disappeared.

[0045] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 168 g of refined sodium silybin-8-sulfonate was obtained, with a yield of 84%.

[0046] Example 3

[0047] Sodium silybin-8-sulfonate was prepared according to the following method in this example: In a reaction flask, 100 g of sulfamic acid, 60 g of sodium bisulfate monohydrate, 1000 ml of acetonitrile solvent, 30 ml of concentrated sulfuric acid were added. After stirring at room temperature for 30 minutes, 200 g of silybin was slowly added and stirred evenly. The temperature was raised to 70 - 80 °C and stirred for about 3 hours. The reaction process was monitored by TLC and the reaction was stopped after the raw materials disappeared.

[0048] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 158 g of refined sodium silybin-8-sulfonate was obtained, with a yield of 79%.

[0049] Example 4

[0050] Sodium silybin-8-sulfonate was prepared according to the following method in this example: In a reaction flask, 100 g of sulfamic acid, 50 g of sodium bisulfate monohydrate, 1000 ml of dioxane solvent, 60 ml of concentrated sulfuric acid, and 5 g of 18-crown-6 phase transfer catalyst were added. After stirring at room temperature for 30 minutes, 200 g of silybin was slowly added and stirred evenly. The temperature was raised to 70 - 80 °C and stirred for about 2 hours. The reaction process was monitored by TLC and the reaction was stopped after the raw materials disappeared.

[0051] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the dioxane solvent was separated, and most of the dioxane solvent was removed by concentration under reduced pressure. Then, saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 160 g of refined sodium silybin-8-sulfonate was obtained, with a yield of 80%.

[0052] Example 5

[0053] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 60 g of sulfamic acid, 80 g of sodium bisulfate monohydrate, 1000 ml of dioxane solvent, 70 ml of concentrated sulfuric acid, and 5 g of 18-crown-6 phase transfer catalyst were added. After stirring at room temperature for 30 minutes, 200 g of silybin was slowly added and stirred evenly. The temperature was raised to 60 - 70 °C and stirred for about 2 hours. The reaction process was monitored by TLC until the raw materials disappeared and then the reaction was stopped.

[0054] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the dioxane solvent was separated, and most of the dioxane solvent was removed by concentration under reduced pressure. Then, saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 156 g of refined sodium silybin-8-sulfonate was obtained, with a yield of 78%.

[0055] Example 6

[0056] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 60 g of phosphorus pentoxide and 1000 ml of acetonitrile solvent were added. 30 ml of concentrated sulfuric acid was added dropwise with stirring. After stirring at room temperature for 30 minutes, 100 g of silybin was slowly added, and the reaction solution was continuously stirred and reacted at 40 - 50 °C for about 3 hours. The reaction process was monitored by TLC until the raw materials disappeared and then the reaction was stopped.

[0057] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 73 g of refined sodium silybin disulfonate was obtained, with a yield of 73%.

[0058] Example 7

[0059] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 50 g of phosphorus pentoxide and 1000 ml of acetonitrile solvent were added. 50 ml of concentrated sulfuric acid was added dropwise with stirring. After stirring at room temperature for 30 minutes, 100 g of silybin was slowly added, and the reaction solution was continuously stirred and reacted at 40 - 50 °C for about 3 hours. The reaction process was monitored by TLC until the raw materials disappeared and then the reaction was stopped.

[0060] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 75 g of refined sodium silybin disulfonate was obtained, with a yield of 75%.

[0061] Example 8

[0062] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 1000 ml of acetonitrile solvent, 60 g of anhydrous sodium sulfate, 15 ml of concentrated sulfuric acid, and 50 ml of acetic anhydride were added. After stirring at room temperature for 30 minutes, 100 g of silybin was slowly added and stirred evenly. The temperature was raised to 40 - 50 °C and stirred for about 3 hours. The reaction process was monitored by TLC until the raw materials disappeared and then the reaction was stopped.

[0063] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching. The acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 60 g of refined sodium silybin-8-sulfonate was obtained, with a yield of 60%.

[0064] Example 9

[0065] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 30 g of sulfamic acid, 20 g of sodium bisulfate monohydrate, 400 ml of acetonitrile solvent, and 50 g of silybin were added. After stirring at room temperature for 30 minutes, 20 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. The temperature was raised to 60 - 65 °C and stirred for about 3 hours. The reaction process was monitored by TLC until the raw materials disappeared and then the reaction was stopped.

[0066] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching. The acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 36 g of refined sodium silybin-8-sulfonate was obtained, with a yield of 72%.

[0067] Example 10

[0068] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 25 g of sulfamic acid, 300 ml of acetonitrile solvent, and 50 g of silybin were added. After stirring at room temperature for 30 minutes, 25 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. The temperature was raised to 40 - 50 °C and stirred for about 3 hours. The reaction process was monitored by TLC until the raw materials disappeared and then the reaction was stopped.

[0069] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching. The acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 30 g of refined sodium silybin-8-sulfonate was obtained, with a yield of 60%.

[0070] Example 11

[0071] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 20 g of sulfamic acid, 20 g of sodium bisulfate monohydrate, 300 ml of dioxane solvent, and 50 g of silybin were added. After stirring at room temperature for 30 minutes, 20 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. Then the temperature was raised to 60 - 70 °C and stirred for about 3 hours. The reaction process was monitored by TLC until the raw materials disappeared and then the reaction was stopped. After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the dioxane solvent was separated out, and most of the dioxane solvent was removed by reduced pressure concentration. Then saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 35 g of refined sodium silybin-8-sulfonate was obtained with a yield of 70%.

[0072] Example 12

[0073] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 30 g of sulfamic acid, 1 g of 18-crown-6 phase transfer catalyst, 300 ml of dioxane solvent, and 50 g of silybin were added. After stirring at room temperature for 30 minutes, 20 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. Then the temperature was raised to 50 - 60 °C and stirred for about 3 hours. The reaction process was monitored by TLC until the raw materials disappeared and then the reaction was stopped.

[0074] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the dioxane solvent was separated out, and most of the dioxane solvent was removed by reduced pressure concentration. Then saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 32 g of refined sodium silybin-8-sulfonate was obtained with a yield of 64%.

[0075] Example 13

[0076] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 30 g of sulfamic acid, 20 g of sodium bisulfate monohydrate, 1 g of 18-crown-6 phase transfer catalyst, 500 ml of tetrahydrofuran solvent, and 50 g of silybin were added. After stirring at room temperature for 30 minutes, 20 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. Then the temperature was raised to 50 - 60 °C and stirred for about 3 hours. The reaction process was monitored by TLC until the raw materials disappeared and then the reaction was stopped.

[0077] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the tetrahydrofuran solvent was separated out, and most of the tetrahydrofuran solvent was removed by reduced pressure concentration. Then saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 38 g of refined sodium silybin-8-sulfonate was obtained with a yield of 76%.

[0078] Example 14

[0079] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 45 g of sulfur trioxide pyridine complex, 1 g of 18-crown-6 phase transfer catalyst, 500 ml of pyridine solvent, and 50 g of silybin were added. After stirring at room temperature for 30 minutes, 10 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. Then the temperature was raised to 70 - 80 °C and stirred for about 3 hours. The reaction process was monitored by TLC and the reaction was stopped after the raw materials disappeared.

[0080] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the pyridine solvent was separated, and most of the pyridine solvent was removed by concentration under reduced pressure. Then saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 30 g of refined sodium silybin-8-sulfonate was obtained, with a yield of 60%.

[0081] Example 15

[0082] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 30 g of sulfamic acid, 20 g of sodium bisulfate monohydrate, 1 g of 18-crown-6 phase transfer catalyst, 200 ml of dimethylformamide solvent, and 50 g of silybin were added. After stirring at room temperature for 30 minutes, 20 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. Then the temperature was raised to 70 - 80 °C and stirred for about 3 hours. The reaction process was monitored by TLC and the reaction was stopped after the raw materials disappeared.

[0083] Example 16

[0084] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the dimethylformamide solvent was separated, and most of the dimethylformamide solvent was removed by concentration under reduced pressure. Then saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 41 g of refined sodium silybin-8-sulfonate was obtained, with a yield of 82%.

[0085] In this example, sodium silybin-8-sulfonate was prepared according to the following method: In a reaction flask, 10 g of silybin and 70 ml of acetonitrile solvent were added. After stirring at room temperature for 10 minutes, a solution prepared by dissolving 10 ml of chlorosulfonic acid in 30 ml of acetonitrile solvent was slowly added dropwise. After the addition, the reaction was continued to stir at room temperature for about 2 hours. The reaction process was monitored by TLC and the reaction was stopped after the raw materials disappeared.

[0086] After the reaction was completed, saturated sodium chloride aqueous solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then saturated sodium chloride aqueous solution was added for salting out. The crude solid was recrystallized several times with isopropanol, and after purification and drying, 7.5 g of refined sodium silybin-8-sulfonate was obtained, with a yield of 75%.

[0087] The obtained product was passed through mass spectrometry ( Figure 1), nuclear magnetic resonance ( Figure 2 and Figure 3 ), infrared spectroscopy ( Figure 4 ), ultraviolet spectroscopy ( Figure 5 Characteristic peaks appear at wavelengths of 203 nm and 286 nm) for structure confirmation: the chemical structural formula of silybin sodium sulfonate (III). According to the solubility determination method in the Chinese Pharmacopoeia, at room temperature, 650 mg of silybin sodium sulfonate can be dissolved in every 1 ml of purified water, which is easily soluble in water.

[0088] In addition to the above embodiments, the present invention may also have other embodiments. All technical solutions formed by equivalent substitution or equivalent transformation fall within the protection scope required by the present invention.

Claims

1. A silybin derivative, characterized in that: The silybin derivative is silybin sulfonic acid sodium salt, and the chemical structural formula of the silybin sulfonic acid sodium salt is as follows: Formula (III).

2. The method for preparing the silybin derivative according to claim 1, characterized in that: The following steps are included: The first step is to extract silybin. After squeezing and defatting the milk thistle fruit, silymarin is extracted, silymarin is dissolved, filtered and decolorized, and white crystals are precipitated from the filtrate and then recrystallized to obtain silybin. The second step is to prepare an 8-silybin sulfonic acid intermediate, and to carry out a sulfonation reaction at the 8-position of the benzene ring of the silybin flavonoid mother nucleus to generate a reaction mixture containing the 8-silybin sulfonic acid intermediate; the sulfonation reaction is to add 0.5-5 times of aminosulfonic acid, 0.5-5 times of sodium bisulfate monohydrate, 0.5-5 times of concentrated sulfuric acid, and 0.5-5% of 18-crown ether-6 phase transfer catalyst by weight of silybin in an acetonitrile or dioxane solvent of 5-50 times the weight of silybin, stir and mix at room temperature, add silybin, continue to stir evenly, raise the temperature to 30-80°C, and stir and react for 3 hours, and the reaction process is tracked and detected by TLC until the raw material disappears and then the reaction is stopped to obtain the 8-silybin sulfonic acid intermediate; or in an acetonitrile or dioxane solvent of 5-50 times the weight of silybin , add 0.5-5 times of phosphorus pentoxide based on the molar amount of silybin, add 0.5-5 times of concentrated sulfuric acid based on the molar amount of silybin dropwise under stirring, stir at room temperature for 30 minutes, slowly add silybin, continue to stir the reaction solution, react at 30-80°C for 3 hours, and stop the reaction after the reaction is tracked and detected by TLC until the raw material disappears to obtain 8-silybin sulfonic acid intermediate; or add 0.5-5 times of sodium sulfate, 0.5-5 times of concentrated sulfuric acid, and 0.5-5 times of acetic anhydride based on the molar amount of silybin in acetonitrile or dioxane solvent 5-50 times the weight of silybin, stir and mix at room temperature, add silybin and continue to stir evenly, stir and react at 30-80°C for about 3 hours, and stop the reaction after the reaction is tracked and detected by TLC until the raw material disappears to obtain 8-silybin sulfonic acid intermediate; The third step is salt formation and refining and purification. After adding saturated sodium chloride aqueous solution to the reaction mixture containing the silybin sulfonic acid intermediate for quenching, the acetonitrile or dioxane solvent is separated, and most of the acetonitrile or dioxane solvent is removed by concentration under reduced pressure, and then saturated sodium chloride aqueous solution is added to form salt. After salt formation, the solid crude product is recrystallized multiple times with a water-soluble organic solvent, and after refining and purification to meet the quality purity requirements of the injection, 8-silybin sulfonate sodium is obtained by vacuum drying or freeze drying.

3. The method for preparing the silybin derivative according to claim 2, characterized in that: In the third step, the water-soluble organic solvent is lower alcohols or acetone; the lower alcohols are methanol, ethanol, or propanol.

4. The method for preparing the silybin derivative according to claim 3, characterized in that: The propanol is isopropanol.

5. Use of the silybin derivative according to claim 1 in the preparation of a pharmaceutical preparation for treating liver diseases.

6. The use of the silibinin derivative according to claim 5 in the preparation of a pharmaceutical preparation for treating liver disease, characterized in that: The dosage form of the preparation is an injection or an oral preparation, and the oral preparation is a capsule, a tablet, a granule or an oral solution.

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