阅读说明：本技术 氯喹甘草酸盐或羟基氯喹甘草酸盐、制备方法、应用 (Chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate, and preparation method and application thereof ) 是由 王振元 张嘉恒 马彩玉 于 2020-05-13 设计创作，主要内容包括：本发明公开了一种氯喹甘草酸盐或羟基氯喹甘草酸盐、制备方法、应用,所述氯喹甘草酸盐或羟基氯喹甘草酸盐满足如下通式所示结构：A·B,其中,A为甘草酸阴离子,B为氯喹阳离子或羟基氯喹阳离子。通过将氯喹、羟基氯喹与甘草酸进行成盐拼合形成新的化合物,氯喹甘草酸盐和羟基氯喹甘草酸盐可有效解决甘草酸单体水溶性差,影响功效发挥的问题。在提高了甘草酸水溶性的基础上,有效拓宽并提高了氯喹、羟基氯喹和甘草酸在医药领域的应用,强化二者共同具有的抗病毒、抗炎等功效。(The invention discloses chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate, a preparation method and application thereof, wherein the chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate satisfies the following structure shown by the general formula: a and B, wherein A is glycyrrhizic acid anion, and B is chloroquine cation or hydroxychloroquine cation. The chloroquine, the hydroxychloroquine and the glycyrrhizic acid are salified and spliced to form a new compound, and the chloroquine glycyrrhetate and the hydroxychloroquine glycyrrhetate can effectively solve the problem that the glycyrrhizic acid monomer is poor in water solubility and affects the efficacy. On the basis of improving the water solubility of glycyrrhizic acid, the application of chloroquine, hydroxychloroquine and glycyrrhizic acid in the field of medicine is effectively widened and improved, and the antiviral, anti-inflammatory and other effects of the chloroquine, hydroxychloroquine and glycyrrhizic acid are enhanced.)

1. The chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate is characterized in that the chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate satisfies the following structure shown in the general formula:

A·B

wherein A is glycyrrhizic acid anion, B is chloroquine cation or hydroxychloroquine cation.

2. A method for preparing chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate of claim 1, wherein the method comprises the following steps:

under inert atmosphere, adding a glycyrrhizic acid solution into a chloroquine solution, reacting and crystallizing to obtain chloroquine glycyrrhetate; or

Under inert atmosphere, adding the glycyrrhizic acid solution into hydroxychloroquine solution, reacting and crystallizing to obtain hydroxychloroquine glycyrrhetate; or

Under inert atmosphere, adding the glycyrrhizic acid salt solution into chloroquine salt solution for ion exchange reaction, filtering to remove inorganic salt, and crystallizing the solution to obtain chloroquine glycyrrhizic acid salt; or

Adding the glycyrrhizic acid salt solution into hydroxychloroquine salt solution under inert atmosphere for ion exchange reaction, filtering to remove inorganic salt, and crystallizing to obtain hydroxychloroquine glycyrrhizic acid salt.

3. The method for preparing chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate of claim 2, wherein the chloroquine salt solution comprises: one or more of chloroquine hydrochloride solution, chloroquine phosphate solution, chloroquine nitrate solution and chloroquine sulfate solution;

the hydroxychloroquine salt solution comprises: one or more of hydroxychloroquine hydrochloride solution, phosphate hydroxychloroquine solution, nitrate hydroxychloroquine solution and sulfate hydroxychloroquine solution;

the glycyrrhetate solution comprises: one or more of sodium glycyrrhizinate solution, potassium glycyrrhizinate solution, magnesium glycyrrhizinate solution, and calcium glycyrrhizinate solution.

4. The method for preparing chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate of claim 2, wherein the reaction temperature is 40-85 ℃, and the reaction time is 8-24 hours.

5. The method for producing chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate according to claim 2, wherein the ratio of the amount of chloroquine in the chloroquine solution to the amount of glycyrrhizic acid in the glycyrrhizic acid solution is 1: 1-2; the ratio of the quantity of hydroxychloroquine in the hydroxychloroquine solution to the quantity of glycyrrhizic acid in the glycyrrhizic acid solution is 1: 1-2; the ratio of the amount of chloroquine salt substances in the chloroquine salt solution to the amount of glycyrrhetate substances in the glycyrrhizinate solution is 1: 1-2; the ratio of the quantity of hydroxychloroquine salt substances in the hydroxychloroquine salt solution to the quantity of glycyrrhetate substances in the glycyrrhizinate solution is 1: 1-2.

6. The method for preparing chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate according to claim 2, wherein the solvent in the chloroquine solution is one or more of methanol, ethanol and isopropanol; the solvent in the glycyrrhizic acid solution is one or more of methanol, ethanol and isopropanol; the solvent in the hydroxychloroquine solution is one or more of methanol, ethanol and isopropanol; the solvent in the chloroquine salt solution is one or more of methanol, ethanol and isopropanol; the solvent in the glycyrrhizinate solution is one or more of methanol, ethanol and isopropanol; the solvent in the hydroxychloroquine salt solution is one or more of methanol, ethanol and isopropanol.

7. The chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate of claim 2, wherein the inert atmosphere gas is argon or nitrogen.

8. The method for preparing chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate of claim 2, wherein the crystallization treatment comprises:

and concentrating the solution obtained by the reaction to saturation, performing freeze crystallization, performing suction filtration and washing, performing recrystallization, and drying to obtain chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate.

9. The method for preparing chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate of claim 8, wherein the temperature of freezing and crystallizing is 2-8 ℃, and the temperature of drying is 40-60 ℃.

10. Use of chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate of claim 1 in anti-inflammatory, antiviral and antitumor drugs.

Technical Field

The invention relates to the field of medicinal compounds, in particular to chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate, and a preparation method and application thereof.

Background

Licorice is often used in two major areas, food addition and drug synthesis. Glycyrrhizic acid is an effective component extracted from licorice root and accounts for about 4-5% of the dry weight of licorice root. Glycyrrhizic acid is widely used as a medicine in clinical application, has good anti-inflammatory and antiviral effects (inhibiting the infection of novel coronavirus and oncogenic virus such as hepatitis virus, EB virus and HIV), and is also frequently used as a medicine research for anticancer treatment. In the prior art, the glycyrrhetinic acid monomer has poor water solubility and influences the performance of the efficacy.

Accordingly, the prior art is yet to be improved and developed.

Disclosure of Invention

The technical problem to be solved by the invention is to provide chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate, a preparation method and application aiming at solving the problem that the glycyrrhizic acid monomer in the prior art has poor water solubility and influences the efficacy.

The technical scheme adopted by the invention for solving the technical problem is as follows:

a chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate, wherein the chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate satisfies the following general formula:

A·B

wherein A is glycyrrhizic acid anion, B is chloroquine cation or hydroxychloroquine cation.

A preparation method of chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate comprises the following steps:

under inert atmosphere, adding a glycyrrhizic acid solution into a chloroquine solution, reacting and crystallizing to obtain chloroquine glycyrrhetate; or

Under inert atmosphere, adding the glycyrrhizic acid solution into hydroxychloroquine solution, reacting and crystallizing to obtain hydroxychloroquine glycyrrhetate; or

Under inert atmosphere, adding the glycyrrhizic acid salt solution into chloroquine salt solution for ion exchange reaction, filtering to remove inorganic salt, and crystallizing the solution to obtain chloroquine glycyrrhizic acid salt; or

Adding the glycyrrhizic acid salt solution into hydroxychloroquine salt solution under inert atmosphere for ion exchange reaction, filtering to remove inorganic salt, and crystallizing to obtain hydroxychloroquine glycyrrhizic acid salt.

The preparation method of chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate, wherein the chloroquine salt solution comprises the following steps: one or more of chloroquine hydrochloride solution, chloroquine phosphate solution, chloroquine nitrate solution and chloroquine sulfate solution;

the hydroxychloroquine salt solution comprises: one or more of hydroxychloroquine hydrochloride solution, phosphate hydroxychloroquine solution, nitrate hydroxychloroquine solution and sulfate hydroxychloroquine solution;

the glycyrrhetate solution comprises: one or more of sodium glycyrrhizinate solution, potassium glycyrrhizinate solution, magnesium glycyrrhizinate solution, and calcium glycyrrhizinate solution.

The preparation method of chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate is characterized in that the reaction temperature is 40-85 ℃, and the reaction time is 8-24 hours.

The preparation method of the chloroquine glycyrrhetate or the hydroxychloroquine glycyrrhetate is characterized in that the ratio of the amount of chloroquine substances in the chloroquine solution to the amount of glycyrrhizic acid substances in the glycyrrhizic acid solution is 1: 1-2; the ratio of the quantity of hydroxychloroquine in the hydroxychloroquine solution to the quantity of glycyrrhizic acid in the glycyrrhizic acid solution is 1: 1-2; the ratio of the amount of chloroquine salt substances in the chloroquine salt solution to the amount of glycyrrhetate substances in the glycyrrhizinate solution is 1: 1-2; the ratio of the quantity of hydroxychloroquine salt substances in the hydroxychloroquine salt solution to the quantity of glycyrrhetate substances in the glycyrrhizinate solution is 1: 1-2.

The preparation method of chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate is characterized in that a solvent in the chloroquine solution is one or more of methanol, ethanol and isopropanol; the solvent in the glycyrrhizic acid solution is one or more of methanol, ethanol and isopropanol; the solvent in the hydroxychloroquine solution is one or more of methanol, ethanol and isopropanol; the solvent in the chloroquine salt solution is one or more of methanol, ethanol and isopropanol; the solvent in the glycyrrhizinate solution is one or more of methanol, ethanol and isopropanol; the solvent in the hydroxychloroquine salt solution is one or more of methanol, ethanol and isopropanol.

The preparation method of the chloroquine glycyrrhetate or the hydroxychloroquine glycyrrhetate, wherein the gas in the inert atmosphere is argon or nitrogen.

The preparation method of chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate, wherein the crystallization treatment comprises the following steps:

and concentrating the solution obtained by the reaction to saturation, performing freeze crystallization, performing suction filtration and washing, performing recrystallization, and drying to obtain chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate.

The preparation method of chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate is characterized in that the freezing and crystallizing temperature is 2-8 ℃, and the drying temperature is 40-60 ℃.

An application of the chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate in preparing the medicines for treating inflammation, viral diseases and tumor is disclosed.

Has the advantages that: the chloroquine cation and the hydroxychloroquine cation are respectively salified and spliced with the glycyrrhizic acid anion to form a new compound, and the chloroquine glycyrrhetate and the hydroxychloroquine glycyrrhetate can effectively solve the problems that the glycyrrhizic acid monomer is poor in water solubility and influences the efficacy. On the basis of improving the water solubility of glycyrrhizic acid, the application of chloroquine, hydroxychloroquine and glycyrrhizic acid in the field of medicine is effectively widened and improved, and the antiviral, anti-inflammatory and other effects of the chloroquine, hydroxychloroquine and glycyrrhizic acid are enhanced.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention clearer and clearer, the present invention is further described in detail below with reference to examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The invention provides some embodiments of chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate.

The chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate satisfies the following structure shown by the general formula:

A·B

wherein A is glycyrrhizic acid anion, B is chloroquine cation or hydroxychloroquine cation.

Specifically, the structural formula of glycyrrhizic acid is:

glycyrrhizic acid has three carboxyl units in the molecule, so the chemical property of glycyrrhizic acid is shown to be stronger acidity, wherein, except that the carboxyl at the aglycone position is not easy to be dissociated, the other two carboxyl are more active, and are easy to be dissociated into protons, and the protons react with alkalies to form salts, such as sodium glycyrrhetate, potassium glycyrrhetate and the like. That is, the glycyrrhizic acid anion A may be a monovalent ion, a divalent ion or a trivalent ion (without excluding that the carboxyl group at the aglycon position is also dissociated). Since one carboxyl unit is not easily dissociated, the glycyrrhizic acid anion a is preferably a monovalent ion or a divalent ion. More preferably, chloroquine also forms a divalent ion, and thus a stronger ionic bond can be formed when a divalent ion is used.

The structural formula of the monovalent glycyrrhizic acid anion is as follows:

or

The structural formula of the divalent glycyrrhizic acid anion is as follows:

the structural formula of chloroquine is as follows:

the chloroquine has three amines in the molecule, so the chemical property of the chloroquine is shown to be stronger alkalinity, wherein the amines on the quinoline are not easy to form ammonium, and the other two amines are more active and easy to form ammonium, and react with acids to form salts, such as chloroquine hydrochloride, chloroquine phosphate, chloroquine nitrate, chloroquine sulfate and the like. That is, the chloroquine cation may be a monovalent ion or a divalent ion. Preferably, the chloroquine cation B is a divalent ion, and since glycyrrhizic acid can also form a divalent ion, a stronger ionic bond can be formed when a divalent ion is used.

The structure of the monovalent chloroquine cation is as follows:

or

The structural formula of the divalent chloroquine cation is as follows:

the structural formula of hydroxychloroquine is as follows:

the hydroxychloroquine cation includes monovalent hydroxychloroquine cations and divalent hydroxychloroquine cations, as with the chloroquine cation.

It is to be noted that, as can be seen from the elemental analysis of chloroquine glycyrrhetate (see the first embodiment for details), if the ratio of the number of glycyrrhetate anions to the number of chloroquine cations in the chloroquine glycyrrhetate is 1:1, and if the ratio is not 1:1, for example, assuming that the ratio of the number of glycyrrhetate anions to the number of chloroquine cations in the chloroquine glycyrrhetate is 1:1.2, the measured values of the respective elements obtained may greatly deviate from the theoretical values. That is, monovalent glycyrrhetate anion is combined with monovalent chloroquine cation, and divalent glycyrrhetate anion is combined with divalent chloroquine cation, so that the ratio of the number of glycyrrhetate anion to the number of chloroquine cation is 1:1. From the viewpoint of product structure, the ratio of the number of glycyrrhizic acid anions to the number of chloroquine cations in the chloroquine glycyrrhetate is 1:1, so that when the chloroquine glycyrrhetate is prepared, the chloroquine glycyrrhetate is generated by reaction of the glycyrrhizic acid solution and the chloroquine solution or the glycyrrhizic acid salt solution and the chloroquine salt solution, but not by physical mixture of glycyrrhizic acid and chloroquine, because the ratio of the glycyrrhizic acid anions to the chloroquine cations in the final product is 1:1 no matter what the ratio of glycyrrhizic acid to chloroquine in the raw materials is, that is, the glycyrrhizic acid and the chloroquine in the product exist in the form of anions and are not simply physically mixed, because if the ratio of the number of each substance is simply physically mixed, the ratio of each raw material is related to the ratio of each raw material, and the ratio of each raw material is changed, the ratio of each substance in the obtained physical mixed product can be changed correspondingly.

Similarly, the ratio of the number of glycyrrhetinic acid anions to the number of hydroxychloroquine cations in hydroxychloroquine glycyrrhetate is 1:1.

The glycyrrhizic acid chloroquine salt provided by the invention takes glycyrrhizic acid as an anion precursor and chloroquine as a cation precursor, through ionization reaction, two free active protons in the glycyrrhizic acid can be combined with electron-rich tertiary amine nitrogen and secondary amine nitrogen in the side chain of a chloroquine molecule to form chloroquine cations with two positive charges, the glycyrrhizic acid is converted into glycyrrhizic acid anions with two negative charges, and the anions and the cations are mutually attracted through ionic bonds, so that the chloroquine glycyrrhetate is formed. Or, the glycyrrhetate is used as an anion precursor, the chloroquine salt is used as a cation precursor, and the chloroquine glycyrrhetate is formed through ion exchange reaction. The reaction and generation process of the hydroxychloroquine glycyrrhetate is the same as that of the chloroquine glycyrrhetate. The molecular structures and the anion and cation sites of the chloroquine glycyrrhetate and the hydroxychloroquine glycyrrhetate are shown as the following structural formulas:

the pharmacological actions of glycyrrhizic acid are as follows:

glycyrrhizic acid is the most important active component in liquorice, and the content is about 10 percent. As a medicine, has anti-inflammatory and antiviral effects; as a sweetener, it is widely used in various foods. Glycyrrhizic acid has wide application in life, including food flavor, cosmetics, tobacco roll, medical medicine, etc.

1. Anti-inflammatory and antiviral effects of glycyrrhizic acid

Glycyrrhizic acid has antiinflammatory, antiviral, and antiallergic effects. It can effectively inhibit capillary permeability, resist histamine, and reduce cell response to external stimulus. Glycyrrhizic acid can inhibit simple scar and herpes virus, varicella, herpes zoster virus, hepatitis B virus, etc. by interfering its inducing activity. Experimental study on mice shows that glycyrrhizic acid can effectively treat subcutaneous granulomatous inflammation. Can also effectively inhibit staphylococcus aureus, bacillus subtilis and the like.

The neurosurgical expert of the medical college of Stanford university and the expert of the Chinese medicine college of hong Kong university jointly issue papers in 2 months of 2020, and prove that glycyrrhizic acid can be combined with angiotensin converting enzyme 2(ACE2), and the glycyrrhizic acid preparation has potential value for preventing infection of the novel COVID-19 coronavirus. Research shows that glycyrrhizic acid has definite direct antiviral effect, can regulate immunity and play an antiviral role, and has a definite anti-inflammatory mechanism. During SARS, many documents report that glycyrrhizic acid preparation has been used as effective medicine for SARS.

2. Antitumor effect of glycyrrhizic acid

Glycyrrhizic acid can be decomposed into glycyrrhetinic acid, and experiments show that glycyrrhetinic acid monoglucuronide has an inhibiting effect on mouse skin cancer and lung cancer induced by various reasons. In vitro human tumor cell experiment shows that GL, 18 alpha-glycyrrhetinic acid and 18 beta-glycyrrhetinic acid all have the function of inhibiting the growth of tumor cells.

3. Glycyrrhizic acid has the function of reducing blood fat:

the chloroquine and glycyrrhizic acid have wide application in medicine and life fields, and have the effects of treating inflammation, resisting tumor and resisting virus. In order to widen the application of the compound in the field of medicine and reduce side effects. Therefore, further improvements to the prior art are needed.

Animal experiment models prove that the glycyrrhizic acid has obvious inhibition effect on the increase of blood fat of rabbits by intragastric administration. It also has effect in inhibiting cholesterol increase of domestic pigeon on high fat diet.

Pharmacological action of chloroquine (hydroxychloroquine):

chloroquine (chloroquine) is a clinically common medicine with antiviral, antibacterial and inflammation treatment functions. And can be used for treating rheumatic arthritis, pulmonary fascioliasis, etc., and has certain effect on treating AIDS and tumor. Hydroxychloroquine (Hydroxychloroquine) is a 4-aminoquinoline derivative antimalarial, has similar action and mechanism to chloroquine, but has half the toxicity of chloroquine.

Pharmacological actions of chloroquine and hydroxychloroquine:

1. effect of chloroquine and hydroxychloroquine in treating malaria:

the chloroquine (hydroxychloroquine) has wide application in the medical field and has obvious effect on treating malaria. By chloroquine action, nucleus of plasmodium is disintegrated, vacuole appears in cytoplasm, and plasmodium pigment is gathered into lumps. While chloroquine (hydroxychloroquine) does not directly kill the malaria parasite, it interferes with its reproduction. Chloroquine (hydroxychloroquine) has strong binding force with nucleoprotein, and forms a compound with DNA, thereby preventing the replication of DNA and the transcription of RNA. Chloroquine (hydroxychloroquine) also inhibits the incorporation of phosphate into plasmodium DNA and RNA, interfering with plasmodium reproduction due to reduced nucleic acid synthesis. The concentration amount of chloroquine is related to the pH value in the food bubble, the pH value in the food is acidic (the optimal pH value for decomposing hemoglobin is 4), the concentration of the basic drug chloroquine can be caused, the concentration of the drug consumes hydrogen ions in the food bubble, so the pH value in the food bubble is further increased, the hemoglobin protease for digesting the hemoglobin is lost, the ingested hemoglobin can not be digested by plasmodium, the aminase necessary for the growth and development of the plasmodium is deficient, and ribonucleic acid is disintegrated, thereby the effect of treating malaria is achieved. Both chloroquine and hydroxychloroquine have the effects of quick response, high curative effect and the like in the aspect of treating malaria.

2. The antiviral effect of chloroquine and hydroxychloroquine:

the antiviral pharmacological action of chloroquine (hydroxychloroquine) is mainly achieved by several mechanisms: 1) by changing the pH value of endocytosis, the compound has obvious inhibiting effect on virus infection of erosion cells by endocytosis, such as Borna disease virus, avian leucosis virus, Zika virus and the like. 2) Viral replication is affected by inhibiting viral gene expression, such as chloroquine, which can change glycosylation pattern of HIV virus gp120 envelope, thereby inhibiting HIV virus replication in CD4+ T cells; 3) interfere with infection and replication of the virus by affecting the autophagy response. Animal experiments show that chloroquine (hydroxychloroquine) can effectively inhibit autophagy phenomena induced by avian influenza H5N1 virus and Zika virus, thereby inhibiting the replication of the viruses.

In addition, research of multiple scientific research institutions at home and abroad shows that chloroquine can effectively inhibit the in vitro replication of SARS coronavirus and COVID-19 novel coronavirus.

3. Chloroquine and hydroxychloroquine have an inhibitory effect on immunity:

the large dose of chloroquine (hydroxychloroquine) can inhibit immune response, and is occasionally used for immune function disorder diseases such as rheumatoid arthritis, systemic lupus erythematosus and the like. Chloroquine (hydroxychloroquine) has effects of regulating immunity and metabolism, resisting microorganism, and resisting tumor. The intervention of chloroquine (hydroxychloroquine) on the immune system is mainly shown in the following steps: 1) inhibiting acidification of lysosome and inhibiting proteolysis. 2) Reducing macrophage induced cell factor expression and the like to inhibit the immune system. 3) Relieving skin rash and protecting sunlight. Chloroquine (hydroxychloroquine) may ameliorate the cutaneous lesions of lupus erythematosus by reducing the absorption of ultraviolet light and modulating the absorption of ultraviolet light by abnormal tissues of the body.

4. The difference between hydroxychloroquine and chloroquine is:

hydroxychloroquine (Hydroxychloroquine) is a 4-aminoquinoline derivative antimalarial, and has similar action and mechanism to chloroquine, but has half of the toxicity of chloroquine. In addition, hydroxychloroquine also has antithrombotic effect, and hydroxychloroquine has anticoagulation effect in vitro, and can inhibit platelet aggregation, produce depolymerization effect on adenosine diphosphate induced aggregation, and prevent increase of blood plasma viscosity.

The chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate provided by the invention forms a new compound by salifying and splicing chloroquine, hydroxychloroquine and glycyrrhizic acid, and the chloroquine glycyrrhetate and the hydroxychloroquine glycyrrhetate can effectively solve the problems that the glycyrrhizic acid monomer is poor in water solubility and the effect is influenced. The chloroquine or hydroxychloroquine cation and the glycyrrhizic acid anion are mutually attracted to form an ionic compound through strong electrostatic interaction, so that the stable existence of the structure can be kept in vivo; and the water solubility of the chloroquine glycyrrhetate and the hydroxychloroquine glycyrrhetate is more than 10 times of that of the glycyrrhizic acid monomer, so that the chloroquine glycyrrhetate and the hydroxychloroquine glycyrrhetate can be easily absorbed by a human body. In addition, only the proton (two free active protons in glycyrrhizic acid) position is shifted by 0.1 angstrom after salification, and the skeleton of the neutral precursor and the structure of the main functional group are not changed, so that the main effects of chloroquine, hydroxychloroquine and glycyrrhizic acid are still maintained. On the basis of improving the water solubility of glycyrrhizic acid, the application of chloroquine, hydroxychloroquine and glycyrrhizic acid in the field of medicine is effectively widened and improved, and the antiviral, anti-inflammatory and other effects of the chloroquine, hydroxychloroquine and glycyrrhizic acid are enhanced.

Based on the above embodiments of chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate, the present invention also provides a preferred embodiment of a method for preparing chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate:

the preparation method of chloroquine glycyrrhetate or hydroxychloroquine glycyrrhetate provided by the embodiment of the invention comprises two preparation methods:

the first method is as follows:

and under the inert atmosphere, adding the glycyrrhizic acid solution into the chloroquine solution, reacting and crystallizing to obtain chloroquine glycyrrhetate.

The second method is as follows:

adding the glycyrrhizinate solution into chloroquine salt solution in inert atmosphere for ion exchange reaction, filtering to remove inorganic salt, and crystallizing to obtain chloroquine glycyrrhizinate.

The preparation method of hydroxychloroquine glycyrrhetate comprises two methods:

the first method is as follows:

and under the inert atmosphere, adding the glycyrrhizic acid solution into the hydroxychloroquine solution, reacting and crystallizing to obtain hydroxychloroquine glycyrrhetate.

The second method is as follows:

adding the glycyrrhizic acid salt solution into hydroxychloroquine salt solution under inert atmosphere for ion exchange reaction, filtering to remove inorganic salt, and crystallizing to obtain hydroxychloroquine glycyrrhizic acid salt.

The inorganic salt is related to the added raw materials (i.e., glycyrrhizic acid salt solution, chloroquine salt solution, hydroxychloroquine salt solution), for example, a sodium glycyrrhizinate solution and a chloroquine hydrochloride solution are subjected to an ion exchange reaction to generate chloroquine glycyrrhizinate and sodium chloride, i.e., an inorganic salt.

In the invention, chloroquine glycyrrhetate and hydroxychloroquine glycyrrhetate respectively adopt chloroquine (salt) and hydroxychloroquine (salt) as cation precursors and glycyrrhizic acid (salt) as anion precursors, and proper organic solvent is added according to a certain substance quantity ratio (molar ratio) to prepare the chloroquine glycyrrhetate and the hydroxychloroquine glycyrrhetate. And carrying out post-treatment on the prepared chloroquine glycyrrhetate and hydroxychloroquine glycyrrhetate, and purifying by concentrating, filtering, washing and other operations to finally obtain the purer chloroquine glycyrrhetate and the purer hydroxychloroquine glycyrrhetate.

In one implementation of the embodiment of the invention, the temperature of the reaction is 40-85 ℃, and the time of the reaction is 8-24 hours.

In one implementation manner of the embodiment of the present invention, the chloroquine salt solution includes: one or more of chloroquine hydrochloride solution, chloroquine phosphate solution, chloroquine nitrate solution and chloroquine sulfate solution;

the hydroxychloroquine salt solution comprises: one or more of hydroxychloroquine hydrochloride solution, phosphate hydroxychloroquine solution, nitrate hydroxychloroquine solution and sulfate hydroxychloroquine solution;

the glycyrrhetate solution comprises: one or more of sodium glycyrrhizinate solution, potassium glycyrrhizinate solution, magnesium glycyrrhizinate solution, and calcium glycyrrhizinate solution.

In one implementation of the embodiments of the present invention, the ratio of the amount of chloroquine substance in the chloroquine solution to the amount of glycyrrhizic acid substance in the glycyrrhizic acid solution is 1: 1-2; the ratio of the quantity of hydroxychloroquine in the hydroxychloroquine solution to the quantity of glycyrrhizic acid in the glycyrrhizic acid solution is 1: 1-2; the ratio of the amount of chloroquine salt substances in the chloroquine salt solution to the amount of glycyrrhetate substances in the glycyrrhizinate solution is 1: 1-2; the ratio of the quantity of hydroxychloroquine salt substances in the hydroxychloroquine salt solution to the quantity of glycyrrhetate substances in the glycyrrhizinate solution is 1: 1-2.

In one implementation of the embodiment of the invention, the gas of the inert atmosphere is argon or nitrogen.

In one implementation manner of the embodiment of the present invention, the solvent in the hydroxychloroquine solution is one or more of methanol, ethanol, and isopropanol; the solvent in the glycyrrhizic acid solution is one or more of methanol, ethanol and isopropanol; the solvent in the hydroxychloroquine solution is one or more of methanol, ethanol and isopropanol.

In one implementation manner of the embodiment of the present invention, the crystallization process includes:

concentrating the solution obtained by reacting the chloroquine solution with the glycyrrhizic acid solution to saturation, performing freeze crystallization, performing suction filtration and washing, performing recrystallization, and drying to obtain chloroquine glycyrrhetate; or

Concentrating the solution obtained by the reaction of the hydroxychloroquine solution and the glycyrrhizic acid solution to saturation, carrying out freeze crystallization, carrying out suction filtration washing, carrying out recrystallization, and drying to obtain hydroxychloroquine glycyrrhetate; or

Concentrating the solution obtained by reacting the chloroquine salt solution with the glycyrrhetate solution to saturation, freezing and crystallizing, filtering, washing, recrystallizing and drying to obtain chloroquine glycyrrhetate; or

And (3) concentrating the solution obtained by reacting the hydroxychloroquine salt solution with the glycyrrhetate solution to saturation, freezing and crystallizing, filtering and washing, recrystallizing and drying to obtain hydroxychloroquine glycyrrhetate.

In one implementation of the embodiment of the present invention, the temperature of the freezing crystallization is 2-8 ℃, and the temperature of the drying is 40-60 ℃.