Silybin derivative, and preparation method and application thereof

Abstract

The invention relates to a silybin derivative as well as a preparation method and application thereof, and belongs to the technical field of chemistry. According to the invention, a hydrophilic sodium sulfonate group is introduced into the silibinin, and the silibinin is sulfonated to prepare a novel compound, namely the silibinin sodium sulfonate with good water solubility, so that the solubility of the silibinin sodium sulfonate in water is enhanced, the pharmacokinetic characteristics of the silibinin are improved from the pharmacokinetic aspect, the affinity and biological activity of the silibinin to organisms are improved, and the application prospect of the silibinin sodium sulfonate is widened. The silybin can be prepared into an injection for clinical treatment, provides a more excellent administration route, has the superiority incomparable with that of silybin, and has wide significance and huge treatment value in clinical application.

Description

Technical Field

[0001] The invention relates to a silybin derivative, a preparation method and application thereof, and belongs to the technical field of chemistry. Background Art

[0002] Silymarin is a flavonolignan compound extracted and refined from the fruit of the Asteraceae plant, Silybum marianum. Its main components are four isomers: silybin, isosilybin, silybinin, and silybintin. Among them, silybin has the highest content and the strongest liver protection activity. It has a good therapeutic effect on acute and chronic hepatitis, cirrhosis, and metabolic poisoning liver damage, and is a natural liver protection 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 liver protection effect, but also have multiple pharmacological activities, such as lowering blood lipids, anti-oxidation, preventing diabetes, protecting the myocardium, anti-platelet aggregation and anti-tumor pharmacological effects. Silybin is composed of two diastereoisomers, silybin A and silybin B, mixed in equal proportions. Its English name is Silybin, its Chinese name is 2,3-dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-6-(3,5,7-trihydroxy-4-oxobenzopyran-2-yl)benzodioxane, CAS number: 22888-70-6, molecular formula: C25H22O10, molecular weight: 482.436, melting point: 164-174°C, density: 1.527g / cm3. Silybin pure product is off-white crystalline powder, odorless, slightly bitter, 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): Formula (I).

[0003] Relevant literature shows that silybin is a highly safe liver disease treatment drug with a long history of use. A large number of studies have been conducted on the structural modification and structure-activity relationship of silybin, but there is still no ideal derivative. This is mainly because most derivatives start with changing one or more hydroxyl groups of silybin to improve solubility, and no synergistic groups are introduced on the flavonoid core skeleton. Preliminary structure-activity relationship studies on the hepatoprotective effect of silybin show that the presence of the flavonoid core, benzodioxane structure and multiple hydroxyl groups in its molecule are all conducive to improving the hepatoprotective activity. The 3-hydroxyl group and the 23-hydroxymethyl group are necessary groups to maintain activity, and the derivatives of these hydroxyl groups have a reduced hepatoprotective effect of silybin. Natural medicines with complex structures and poor water solubility are difficult to fully exert their pharmacological activity due to their low bioavailability, which greatly limits their use. Sodium sulfonate group (-SO3Na) is a strong hydrophilic group. Introducing hydrophilic groups into the molecules of poorly soluble compounds can greatly increase their water solubility, which is an effective method to improve their bioavailability and efficacy. There have been successful examples such as the preparation of cardiovascular therapeutic drug Tanshinone IIA into Tanshinone IIA sodium sulfonate injection. Although silybin has pharmacological activities such as scavenging free radicals, resisting lipid peroxidation, protecting liver cell membranes, promoting damaged liver cells to synthesize DNA and structural proteins, and resisting fibrosis, it has good efficacy in acute and chronic hepatitis, metabolic toxic liver damage and cirrhosis. However, since silybin is insoluble in water and has extremely poor solubility in water, its bioavailability is low, which greatly reduces its clinical efficacy. At present, liver protection drugs with silybin as the main drug are capsules and tablets for oral administration. Some literatures use silybin and a solubilizer to make an injection, or salify silybin with meglumine to make a lyophilized powder injection. However, even so, due to unstable absorption, the bioavailability is still poor, and it is difficult to exert its pharmacological activity. Currently, no injection with silybin as the main active ingredient has been approved for marketing for clinical treatment. Summary of the invention

[0004] The purpose of the present invention is to address the defects of the prior art and to provide a silybin derivative, a preparation method and an application thereof, so as to introduce a hydrophilic group into the molecule of a poorly soluble compound, thereby greatly increasing its water solubility, and improving its bioavailability and therapeutic effect.

[0005] The present invention solves the technical problem through the following technical solutions: First, a silibinin derivative is proposed, wherein the silibinin derivative is silibinin sulfonic acid sodium salt or silibinin derivative sulfonic acid sodium salt, and the general formula is as follows:

[0006] Formula (II) Wherein 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 new compound synthesized for the first time, with a chemical name: sodium 2,3-dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-hydroxymethyl-6-(3,5,7-trihydroxy-4-oxobenzopyran-2-yl)benzodioxane-8-sulfonate. Molecular formula: C25H21NaO13S, molecular weight: 584.49, melting point: 173-176°C, easily soluble in water, methanol, soluble in ethanol, slightly soluble in isopropanol, off-white crystalline powder, odorless, slightly bitter, and hygroscopic. The product was structurally confirmed by mass spectrometry, nuclear magnetic resonance, infrared spectroscopy, and ultraviolet spectroscopy: Chemical structure of sodium silybin sulfonate (III): Formula (III).

[0007] Silybin is a compound with alternating benzene rings and heterocycles. Its chemical structure (I) shows that it has 3 benzene rings and 2 heterocycles, and 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. Phenolic hydroxyl groups make silybin exhibit weak acidity in aqueous solution. Silybin is easily oxidized and relatively stable under acidic conditions, but strong alkali or heating will destroy its structure and become unstable. Silybin has a complex structure and many sites that are prone to chemical reactions. It is relatively difficult to sulfonate it to prepare the target product sulfonate, especially the 6th and 8th positions of the benzene ring of the flavonoid mother nucleus of silybin have strong reactivity, among which the reactivity of the 8th position is slightly greater than that of the 6th position. The target product is sulfonated at the 8th position of the benzene ring of the flavonoid mother nucleus. Silybin is only soluble in acetone, ethyl acetate, methanol, ethanol, etc., and its solubility in most organic solvents is relatively poor, which increases the difficulty of sulfonation reaction. It is extremely important to select suitable solvents and sulfonating agents and explore reaction conditions.

[0008] Based on the above reasons, the present invention further provides a method for preparing the above-mentioned sodium silybin sulfonate and sodium silybin derivative sulfonate. According to the characteristics of the reaction activity of the 8-position of the benzene ring of the silybin flavonoid nucleus, a suitable sulfonation reagent and a special sulfonation technology are selected, the reaction conditions are controlled, and the sulfonation reaction is selectively carried out at the 8-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, refined and purified with a water-soluble lower alcohol organic solvent, and vacuum or freeze-dried to obtain 8-silybin sulfonate sodium. The reaction equation is as follows:

[0009] The specific method includes the following steps: The first step is to extract silybin. The milk thistle fruit is squeezed to remove oil, and then pre-degreased with n-hexane, and ethanol or ethyl acetate is used as an extraction solvent to extract silybin. Silybin is heated and dissolved with anhydrous ethanol, and activated carbon is used for decolorization. The filtrate is left to stand to precipitate white crystals, and silybin is obtained by recrystallization with ethyl acetate-methanol; 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 third step is salt formation and refining and purification. After adding a 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. Then, a saturated sodium chloride aqueous solution is added to form salt. After salt formation, the solid crude product is recrystallized multiple times with isopropanol or other water-soluble lower alcohol organic solvents. 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.

[0010] The present invention further provides three sulfonation reaction methods, The first method is that in the second step, the sulfonation reaction is carried out in a solvent such as acetonitrile or dioxane with a molar amount of 5-50 times the weight of silybin, 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 the weight of silybin 18-crown ether-6 phase transfer catalyst are added, based on the molar amount of silybin, and after stirring and mixing at room temperature, silybin is added and continued to be stirred evenly, and then the temperature is raised to 30-80°C and stirred for reaction for 3 hours. The reaction process is tracked and detected by TLC until the raw material disappears and then the reaction is stopped to obtain 8-silybin sulfonic acid intermediate.

[0011] The second method is that in the second step, the sulfonation reaction is carried out in a solvent such as acetonitrile or dioxane with a molar amount of 5-50 times the weight of silybin, 0.5-5 times of phosphorus pentoxide based on the molar amount of silybin is added, and 0.5-5 times of concentrated sulfuric acid based on the molar amount of silybin is added dropwise under stirring. After stirring at room temperature for 30 minutes, silybin is slowly added, and the reaction solution is continuously stirred and reacted at 30-80°C for 3 hours. The reaction process is tracked and detected by TLC until the raw material disappears and then the reaction is stopped to obtain 8-silybin sulfonic acid intermediate.

[0012] The third method is that in the second step, the sulfonation reaction is carried out by adding 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 to a solvent such as acetonitrile or dioxane with a molar amount of 5-50 times of the weight of silybin, stirring and mixing at room temperature, adding silybin and continuing to stir evenly, stirring and reacting at 30-80° C. for about 3 hours, tracking and detecting the reaction process by TLC until the raw material disappears and then stopping the reaction to obtain 8-silybin sulfonic acid intermediate.

[0013] The present invention obtains the selection of each reagent in the sulfonation reaction through a large number of experimental explorations and screenings: Commonly used sulfonating agents include concentrated sulfuric acid, oleum, chlorosulfonic acid, sulfur trioxide, sulfur trioxide pyridine complex and aminosulfonic acid. At present, the most widely used and mature process in industry is concentrated sulfuric acid and oleum sulfonation, but it produces a lot of waste acid and has high post-processing costs; sulfur trioxide and chlorosulfonic acid are chemically active. When used in sulfonation reactions, they use less, have good sulfonation effects, and produce less waste acid, but the reaction is difficult to control and has more side reactions. Aminosulfonic acid (NH2SO3H) is a non-volatile, odorless, non-toxic solid strong acid with a white crystal appearance. It has stable chemical properties in a dry environment, can be stored for a long time, and is easy to transport.

[0014] One of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran, pyridine, dioxane and acetonitrile was selected as the solvent. The sulfonating agents were concentrated sulfuric acid in combination with acetic anhydride and sodium sulfate, anhydrous phosphorus pentoxide in combination with concentrated sulfuric acid, and aminosulfonic acid in combination with concentrated sulfuric acid and sodium bisulfate. It was found that these three sulfonating agents had strong selectivity for sulfonation of silybin, and all of them could obtain 8-silybin sodium sulfonate with high yield and purity.

[0015] Dimethylformamide and dimethyl sulfoxide are not easy to remove residual solvents, and tetrahydrofuran and pyridine are highly toxic. The solvent is preferably acetonitrile or dioxane, and the sulfonating agent is preferably aminosulfonic acid. Aminosulfonic acid has many advantages as a sulfonating agent, high reaction selectivity, high purity of the generated product, and less production of three wastes during the reaction process. The chemical properties of aminosulfonic acid are relatively mild, similar to sulfur trioxide tertiary amine complexes, and its sulfonation mechanism may be that aminosulfonic acid releases sulfur trioxide through a certain conversion, and the sulfur trioxide molecules then act on the reactants for sulfonation reaction. However, the sulfonation reaction activity of aminosulfonic acid is weak, and it is a heterogeneous solid-liquid reaction, which requires vigorous stirring and has the disadvantages of low reactant conversion rate. The present invention first discovered that adding a phase transfer catalyst can accelerate the reaction rate and make the reaction more sufficient. The phase transfer catalyst includes but is not limited to one or more of aza-15-crown ether-5, 15-crown ether-5, 18-crown ether-6, 4-carbonic acid benzo-15-crown ether-5, and aza-18-crown ether-6. Adding sodium bisulfate can enhance the activity of aminosulfonic acid and increase the product yield.

[0016] 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.

[0017] The present invention further provides applications of silybin derivatives, including applications in the preparation of pharmaceutical preparations for treating liver diseases.

[0018] The dosage form of the preparation is injection or oral preparation, and the oral preparation is capsule, tablet, granule, oral solution.

[0019] The preparation method of sodium silybin sulfonate and the technical ideas for preparing sodium sulfonate with good water solubility provided by the present invention are also applicable to flavonolignan compounds (chemical structural formula IV) contained in milk thistle such as isosilybin, silybinin and silybin.

[0020] Formula (IV) It is prepared into a sodium sulfonate derivative with good water solubility, and the reaction equation is as follows:

[0021] The present invention introduces a hydrophilic sodium sulfonate group into silybin, sulfonates silybin to prepare sodium silybin sulfonate with good water solubility, and only performs a sulfonation reaction on silybin to prepare sodium sulfonate with good water solubility, thereby greatly improving its bioavailability, and does not change the effective group and the mother nucleus structure of silybin with pharmacological activity, thereby enhancing its solubility in water, improving the pharmacokinetic characteristics of silybin from the perspective of pharmacokinetics, improving its affinity and biological activity for organisms, and preparing an injection for clinical treatment. Sodium silybin sulfonate can also be prepared into capsules, tablets, granules, oral solutions and other oral preparations, and its pharmacological effects and therapeutic effects on liver diseases will be significantly better than natural silybin. Its beneficial effect is to provide a more excellent administration route, and has the incomparable superiority of silybin, and will have a wide range of significance and great therapeutic value in clinical application. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the MS spectrum of silybin sodium sulfonate.

[0023] Figure 2 This is the 1H NMR spectrum of sodium silybin sulfonate.

[0024] Figure 3 This is the 13C NMR spectrum of sodium silybin sulfonate.

[0025] Figure 4 This is the IR (KBr) spectrum of sodium silybin sulfonate.

[0026] Figure 5 This is the UV spectrum of sodium silybin sulfonate. DETAILED DESCRIPTION

[0027] Example 1 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 80 g of aminosulfonic acid, 60 g of sodium bisulfate monohydrate, 1000 ml of acetonitrile solvent, 80 ml of concentrated sulfuric acid, and 5 g of 18-crown ether-6 phase transfer catalyst were added to a reaction bottle, and stirred at room temperature for 30 minutes, and then 200 g of silybin was slowly added and stirred evenly, and the temperature was raised to 50-60° C. and stirred for about 3 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0028] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol several times, and then dried after purification to obtain 162 g of refined 8-silybin sodium sulfonate, with a yield of 81%.

[0029] Example 2 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 100 g of aminosulfonic acid, 40 g of sodium bisulfate monohydrate, 1000 ml of acetonitrile solvent, 50 ml of concentrated sulfuric acid, and 5 g of 18-crown ether-6 phase transfer catalyst were added to a reaction bottle, and stirred at room temperature for 30 minutes, and then 200 g of silybin was slowly added and stirred evenly, and the temperature was raised to 60-70° C. and stirred for about 3 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0030] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol several times, refined and purified, and then dried to obtain 168 g of refined 8-silybin sodium sulfonate, with a yield of 84%.

[0031] Example 3 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 100 g of aminosulfonic acid, 60 g of sodium bisulfate monohydrate, 1000 ml of acetonitrile solvent, and 30 ml of concentrated sulfuric acid were added to a reaction bottle. 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 tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0032] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol several times, and then dried after purification to obtain 158 g of refined 8-silybin sodium sulfonate, with a yield of 79%.

[0033] Example 4 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 100 g of aminosulfonic acid, 50 g of sodium bisulfate monohydrate, 1000 ml of dioxane solvent, 60 ml of concentrated sulfuric acid, and 5 g of 18-crown ether-6 phase transfer catalyst were added to a reaction bottle, and stirred at room temperature for 30 minutes, and then 200 g of silybin was slowly added and stirred evenly, and the temperature was raised to 70-80° C. and stirred for about 2 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0034] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the dioxane solvent was separated, and most of the dioxane solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol for multiple times, and then dried after purification to obtain 160 g of refined 8-silybin sodium sulfonate, with a yield of 80%.

[0035] Example 5 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 60 g of aminosulfonic acid, 80 g of sodium bisulfate monohydrate, 1000 ml of dioxane solvent, 70 ml of concentrated sulfuric acid, and 5 g of 18-crown ether-6 phase transfer catalyst were added to a reaction bottle, and stirred at room temperature for 30 minutes, and then 200 g of silybin was slowly added and stirred evenly, and the temperature was raised to 60-70° C. and stirred for about 2 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0036] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the dioxane solvent was separated, and most of the dioxane solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol several times, refined and purified, and then dried to obtain 156 g of refined 8-silybin sodium sulfonate, with a yield of 78%.

[0037] Example 6 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 60 g of phosphorus pentoxide and 1000 ml of acetonitrile solvent were added to a reaction bottle, and 30 ml of concentrated sulfuric acid was added dropwise under stirring. After stirring at room temperature for 30 minutes, 100 g of silybin was slowly added, and the reaction solution was continued to be stirred and reacted at 40-50° C. for about 3 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and then the reaction was stopped.

[0038] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized several times with isopropanol, refined and purified, and then dried to obtain 73 g of refined 8-silibinin sodium bissulfonate, with a yield of 73%.

[0039] Example 7 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 50 g of phosphorus pentoxide and 1000 ml of acetonitrile solvent were added to a reaction flask, and 50 ml of concentrated sulfuric acid was added dropwise under stirring. After stirring at room temperature for 30 minutes, 100 g of silybin was slowly added, and the reaction solution was continued to be stirred and reacted at 40-50° C. for about 3 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and then the reaction was stopped.

[0040] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure, and then a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized several times with isopropanol, and after purification, it was dried to obtain 75 g of refined 8-silibinin sodium disulfonate, with a yield of 75%.

[0041] Example 8 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 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 to a reaction bottle, and stirred at room temperature for 30 minutes, and then 100 g of silybin was slowly added and stirred evenly, and the temperature was raised to 40-50° C. and stirred for about 3 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0042] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure, and then a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol for multiple times, and then dried after purification to obtain 60 g of refined 8-silybin sodium sulfonate, with a yield of 60%.

[0043] Example 9 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 30 g of aminosulfonic acid, 20 g of sodium bisulfate monohydrate, 400 ml of acetonitrile solvent, and 50 g of silybin were added to a reaction bottle, and stirred at room temperature for 30 minutes, and then 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 tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0044] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized several times with isopropanol, refined and purified, and then dried to obtain 36 g of refined 8-silybin sodium sulfonate, with a yield of 72%.

[0045] Example 10 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 25 g of aminosulfonic acid, 300 ml of acetonitrile solvent, and 50 g of silybin were added to a reaction bottle, and stirred at room temperature for 30 minutes, and then 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 tracked and detected by TLC until the starting material disappeared and the reaction was stopped.

[0046] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure, and then a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol for multiple times, and then dried after purification to obtain 30 g of refined 8-silybin sodium sulfonate, with a yield of 60%.

[0047] Embodiment 11 In this embodiment, 8-silybin sodium sulfonate was prepared according to the following method: 20g of aminosulfonic acid, 20g of sodium bisulfate monohydrate, 300ml of dioxane solvent, and 50g of silybin were added to a reaction bottle, stirred at room temperature for 30 minutes, and then 20ml of concentrated sulfuric acid was slowly added dropwise, stirred evenly, and the temperature was raised to 60-70°C and stirred for about 3 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and then the reaction was stopped. After the reaction was completed, a 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, and then a saturated sodium chloride aqueous solution was added for salt formation. The crude solid was recrystallized several times with isopropanol, and after purification, it was dried to obtain 35g of refined 8-silybin sodium sulfonate, with a yield of 70%.

[0048] Example 12 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 30 g of aminosulfonic acid, 1 g of 18-crown ether-6 phase transfer catalyst, 300 ml of dioxane solvent, and 50 g of silybin were added to a reaction bottle, and stirred at room temperature for 30 minutes, and then 20 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. The temperature was raised to 50-60° C. and stirred for about 3 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0049] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the dioxane solvent was separated, and most of the dioxane solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol several times, refined and purified, and then dried to obtain 32 g of refined 8-silybin sodium sulfonate, with a yield of 64%.

[0050] Embodiment 13 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 30 g of aminosulfonic acid, 20 g of sodium bisulfate monohydrate, 1 g of 18-crown ether-6 phase transfer catalyst, 500 ml of tetrahydrofuran solvent, and 50 g of silybin were added to a reaction bottle, and stirred at room temperature for 30 minutes, and then 20 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. The temperature was raised to 50-60° C. and stirred for about 3 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0051] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the tetrahydrofuran solvent was separated, and most of the tetrahydrofuran solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol for multiple times, and then dried after purification to obtain 38 g of refined 8-silybin sodium sulfonate, with a yield of 76%.

[0052] Embodiment 14 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 45 g of sulfur trioxide pyridine complex, 1 g of 18-crown ether-6 phase transfer catalyst, 500 ml of pyridine solvent, and 50 g of silybin were added to a reaction bottle, and stirred at room temperature for 30 minutes, and then 10 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. The temperature was raised to 70-80° C. and stirred for about 3 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0053] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the pyridine solvent was separated, and most of the pyridine solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized several times with isopropanol, refined and purified, and then dried to obtain 30 g of refined 8-silybin sodium sulfonate, with a yield of 60%.

[0054] Embodiment 15 In this example, 8-silybin sodium sulfonate was prepared according to the following method: 30 g of aminosulfonic acid, 20 g of sodium bisulfate monohydrate, 1 g of 18-crown ether-6 phase transfer catalyst, 200 ml of dimethylformamide solvent, and 50 g of silybin were added to a reaction bottle, and stirred at room temperature for 30 minutes, and then 20 ml of concentrated sulfuric acid was slowly added dropwise and stirred evenly. The temperature was raised to 70-80° C. and stirred for about 3 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and the reaction was stopped.

[0055] Example 16 After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the dimethylformamide solvent was separated, and most of the dimethylformamide solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol for multiple times, and then dried after purification to obtain 41 g of refined 8-silybin sodium sulfonate, with a yield of 82%.

[0056] In this example, 8-silybin sodium sulfonate was prepared according to the following method: 10 g of silybin and 70 ml of acetonitrile solvent were added to a reaction bottle, and 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 was complete, the reaction was continued to stir at room temperature for about 2 hours. The reaction process was tracked and detected by TLC until the raw material disappeared and then the reaction was stopped.

[0057] After the reaction was completed, a saturated aqueous sodium chloride solution was added for quenching, the acetonitrile solvent was separated, and most of the acetonitrile solvent was removed by concentration under reduced pressure. Then, a saturated aqueous sodium chloride solution was added for salt formation. The crude solid was recrystallized from isopropanol for multiple times, and then dried after purification to obtain 7.5 g of refined 8-silybin sodium sulfonate, with a yield of 75%.

[0058] The obtained product was analyzed by mass spectrometry ( Figure 1 )、NMR( Figure 2 and Figure 3 )、IR spectrum( Figure 4 )、UV spectrum( Figure 5 The structure was confirmed by the following method: chemical structure of sodium silybin sulfonate (III). According to the solubility determination method of the Chinese Pharmacopoeia, 650 mg of sodium silybin sulfonate can be dissolved in 1 ml of purified water at room temperature, which is easily soluble in water.

[0059] In addition to the above implementations, the present invention may also have other implementations. Any technical solution formed by equivalent replacement or equivalent transformation falls within the protection scope required by the present invention.

Claims

1. A silybin derivative, characterized in that: The silibinin derivative is silibinin sulfonic acid sodium salt or silibinin derivative sulfonic acid sodium salt, and the general formula is as follows: Formula (II), wherein R1-R5 are at least one of hydrogen, alkyl, alkanoyl, phenyl, and benzoyl.

2. The silybin derivative according to claim 1, characterized in that: The chemical structure of silybin sulfonic acid sodium salt is as follows: Formula (III).

3. The method for preparing the silybin derivative according to claim 1 or 2, characterized in that: The method comprises subjecting silybin to a sulfonation reaction to generate silybin sulfonic acid, and then subjecting the silybin to a salt-forming reaction in a saturated sodium chloride aqueous solution, separating and treating the crude silybin sodium sulfonate to obtain the crude product, and then subjecting the crude product to recrystallization and purification using a water-soluble organic solvent, and finally subjecting the product to vacuum drying or freeze drying to obtain the finished product.

4. The method for preparing the silybin derivative according to claim 3, 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 third step is salt formation and refining and purification. A saturated sodium chloride aqueous solution is added to the reaction mixture containing the silybin sulfonic acid intermediate for quenching, and then the solvents such as acetonitrile or dioxane are separated. The solvents such as acetonitrile or dioxane are removed by vacuum concentration to remove most of the solvents, and then a 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. After refining and purification to meet the quality purity requirements of the injection, 8-silybin sodium sulfonate is obtained by vacuum drying or freeze drying.

5. The method for preparing the silybin derivative according to claim 4, characterized in that: In the second step, the sulfonation reaction is carried out in a solvent such as acetonitrile or dioxane with a molar amount of 5-50 times the weight of silybin, 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 the weight of silybin 18-crown ether-6 phase transfer catalyst are added, and after stirring and mixing at room temperature, silybin is added and continued to be stirred evenly, and then the temperature is raised to 30-80°C and stirred for reaction for 3 hours. The reaction process is tracked and detected by TLC until the raw material disappears and then the reaction is stopped to obtain 8-silybin sulfonic acid intermediate.

6. The method for preparing the silybin derivative according to claim 4, characterized in that: In the second step, the sulfonation reaction is carried out by adding 0.5-5 times the molar amount of silybin to a solvent such as acetonitrile or dioxane in an amount of 5-50 times the weight of silybin, adding 0.5-5 times the molar amount of silybin to phosphorus pentoxide, and adding 0.5-5 times the molar amount of silybin to concentrated sulfuric acid dropwise under stirring. After stirring at room temperature for 30 minutes, silybin is slowly added, and the reaction solution is continuously stirred and reacted at 30-80° C. for 3 hours. The reaction process is tracked and detected by TLC until the raw material disappears and then the reaction is stopped to obtain 8-silybin sulfonic acid intermediate.

7. The method for preparing the silybin derivative according to claim 4, characterized in that: In the second step, the sulfonation reaction is carried out by adding 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 to a solvent such as acetonitrile or dioxane with a molar amount of 5-50 times of the weight of silybin, stirring and mixing at room temperature, adding silybin and continuing to stir evenly, stirring and reacting at 30-80° C. for about 3 hours, tracking and detecting the reaction process by TLC until the raw material disappears and then stopping the reaction to obtain 8-silybin sulfonic acid intermediate.

8. The method for preparing the silybin derivative according to claim 4, characterized in that: In the third step, the water-soluble organic solvent is lower alcohols or acetone; the lower alcohols are methanol, ethanol, propanol or isopropanol.

9. Use of the silybin derivative according to claim 1 or 2, including use in the preparation of a pharmaceutical preparation for treating liver disease.

10. The use of the silybin derivative according to claim 9, 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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