JPS60178898A - Novel reduction-modified compound of glycyrrhizin and preparation thereof - Google Patents

Abstract

NEW MATERIAL:A compound (salt) expressed by formula I . EXAMPLE:11beta-Hydroglycyrrhizin sodium salt. USE:An anti-inflammatory agent, antiallergic agent and antiulcer agent. PREPARATION:For example, glycyrrhizin expressed by formula II (R is H, NH4, Na or K) is dissolved in tetrahydrofuran, and sodium hydroxide solution of sodium boron hydride is added to the resultant solution and heated or sodium hydroxide solution of glycyrrhizin ammonium salt or sodium salt is reacted with sodium hydroxide solution of sodium boron hydride under heating to give the compound expressed by formula I .

Description

Detailed Description of the Invention The present invention provides 11β-hydroglycyrrhizin, which is a novel reduction modification compound of glycyrrhizin, and 1], 13(1).
8)-Dienglycyrrhizin (heteroannuular dienglycyrrhizin), their alkali salts, and their production methods.

Glycyrrhizin (saponin), an active ingredient in licorice, has already received high praise in the clinical field as an anti-inflammatory, anti-allergy, and anti-ulcer agent. Furthermore, succinic acid derivatives of glycyrrhetinic acid, which is an aglycone of glycyrrhizin, have been recognized as antiulcer agents.

However, glycyrrhizin has a long-term effect, especially when administered orally.
There is a side effect of pseudoaldosteronism. This is because glycyrrhetinic acid, an aglycone, is produced when glycyrrhizin deices, and this is the hepatic steroid-metabolizing enzyme -Δ
It inhibits the activity of 4-5β-reductase, and aldosterone metabolism is stagnated.

Therefore, its enhancement causes symptoms such as abnormal electrolyte metabolism, hypertension, hypokalemia, and edema.

The inventors of this application, Shibata et al., first searched for a compound that could prevent such side effects of glinalretinoic acid and enhance its pharmacological effects, and used a new method to reductively modify crilyrretinoic acid. -3β,30-diol" was found to sufficiently achieve this purpose, and the results were published in JP-A-56-139416 and JP-A-5
'? -73 (1 (Publication No. 10 and JP-A-58-'/2
It was announced in Publication No. 542, etc.

Recently, glycyrrhizin has been recognized to be effective against chronic hepatitis diseases in addition to its anti-inflammatory effects as mentioned above, and its importance as a liver drug is rapidly increasing. still,
It has been found that its natural saponin form, that is, glycyrrhizin, which is conjugated with two molecules of glucuronic acid, has a better action on the liver than glycyrrhetinic acid, which is an acricon.

Here, the two applicants have previously developed “diol”
As a result of repeated research in search of glycyrrhizin-related compounds that do not cause pseudohyperaldosteronism, have the same saponin structure as glycyrrhizin, and exhibit superior pharmacological effects, we have developed glycyrrhizin using a unique method. Several compounds were discovered by reduction modification.

The purpose of the present invention is to eliminate such side effects such as pseudoaldosteronism that are often found in glycyrrhizin or glinarretinate preparations, and to enhance the effect of the original drug. The object of the present invention is to provide a drug based on reduced glycyrrhizin.

(1) 11β-hydroglycyrrhizin (It) 11.13 (18)-dienglycyrrhizin having the structural formula shown in claims 1 and 2 of the present application are all unknown in the literature based on this research result. It is a new compound.

Next, the formula of the aglycon of the new banknote compound of ZwL mentioned above is shown.

(A) 11β-Hutolog (B) 11.13 (+8
) -linalretinoic acid dienglycyrrhetinic acid The above (A) is obtained by reduction of glycyrrhetinic acid,
(B) is derived from (A), but has been isolated as a trace component from the licorice extract, and these are known compounds that have anti-aldosterone and anti-inflammatory effects. this(
A) and (B) Both compounds are thought to exist in licorice as they are, i.e. in the form of aglycones, in small amounts or perhaps in large part as saponin forms of (N, (11)) obtained by reducing the glycyrrhizin. However, these salt saponins have not yet been extracted from licorice.If they were to be used as glycyrrhizin drugs without the side effects mentioned above [I]
2. Trying to synthesize [mouth] from (A) and (B) would require extremely difficult, complex, and expensive techniques, even if it were possible.

There is no possibility of industrial production to meet mass demand.

According to the method according to the present invention, glycyrrhizin, which is a large component in licorice, is used as a raw material, and easily available and relatively inexpensive auxiliary materials are used, and a safe and simple technique is used to achieve high yields. This innovative method is expected to realize the industrial production of ideal glycyrrhizin drugs.

Next, the manufacturing process using this method will be illustrated.

The above steps will be explained in detail below.

First, a method for producing 11β-hydroglycyrrhizine trisodium salt and tripotassium salt will be described.

The solvent and reducing agent differ depending on the target alkali salt and the raw material glycyrrhizin or its salt used. In the method for producing the trisodium salt, when glycyrrhizin is used, tetrahydrofuran is used as a solvent. When using glycyrrhizin ammonium salt, only N sodium hydroxide solution is sufficient. Sodium borohydride is the most suitable reducing agent.

When the raw material is glycyrrhizin, sodium borohydride is dissolved in an aqueous tetrahydrofuran solution containing a sodium hydroxide solution, and when the raw material is an ammonium salt, sodium borohydride is simply dissolved in a sodium hydroxide solution. Heat to reflux on a water bath at 80° C. or higher to the boiling point of the solvent.

When the raw material is glycyrrhizin, a tetrahydrofuran solution of glycyrrhizin is added dropwise, and when the raw material is an ammonium salt, a sodium hydroxide solution of glycyrrhizin ammonium salt is added dropwise, and a heating reaction is performed for 24 hours. When acetone and dilute hydrochloric acid are added to the reaction solution to decompose excess alkali and reducing agent, and the liquid property is adjusted to pu9-10, glycyrrhizin is reduced.

It becomes the trisodium salt of 11β-hydroglycyrrhizin.

Concentrate the reaction solution and add a mixture of methanol and acetone to produce a white precipitate. Filter the precipitate.

'When recrystallized with 15% ethanol, the target product 11β
- Obtaining a white crystalline powder of hydroglycyrrhizin trisodium salt.

Second, regarding the method for producing 11β-hydroglycyrrhizine tripotassium salt, the reaction is carried out under exactly the same conditions as in the case of the above-mentioned trisodium salt.

For example, when using Glinaritin monoammonium salt, dissolve potassium borohydride in a potassium hydroxide solution, heat it on a water bath to 80°C or higher, and dissolve Glinaritin ammonium salt in the potassium hydroxide solution. The mixture was added dropwise and reacted with heating for 24 hours, and one reaction solution was treated in the same manner as for the above trisodium salt to obtain a white crystalline powder of 11β-hydroglycyrrhizin tripotassium salt.

Thirdly, 11β according to claim 5
- Regarding the manufacturing method of hydroglycyrrhizin, 11β-hydroglycyrrhizin trialkali salt obtained by the above-mentioned manufacturing method is dissolved in water, and strongly acidic cation exchange resin 2
For example, DOWEX 50W.

When a sulfonic acid type resin such as Amberlite IN-1208 is added and stirred at room temperature, free 11β-hydroglycyrrhizin is produced. When the resin is separated from the reaction solution and freeze-dried, white 11β-hydroglycyrrhizin is obtained in high yield.

Fourthly, 11°13 as stated in claim 2.
(18)-Dienglycyrrhizin can be obtained very easily using 11β-hydroglycyrrhizine trisodium salt or tripotassium salt obtained by the above-mentioned production method as a raw material.

That is, when an alkali salt is dissolved in an appropriate amount of water, its pH is adjusted to pH 7 to 8 with dilute hydrochloric acid, and then heated, the alkali salt of 11.13 (18)-dienglycyrrhizin is completely quantitatively converted. Add dilute hydrochloric acid to the reaction solution to adjust the liquid to p.
i (adjusted to 2-3, extracted with n-butanol and distilled off the solvent to obtain a white crystalline powder.

To obtain this soluble alkali salt of dienglycyrrhizin, a metal solution of dienglycyrrhizin is prepared,
The corresponding amount is 0. After adding IN alkali hydroxide solution and heating, acetone is added to the concentrated solution distilled under reduced pressure to obtain mono-, di-, or tri-alkali salts, respectively.

Hereinafter, two examples will be given of the method for producing 11β-hydroglycyrrhizin and its alkali salt, 1 and 11.13 (1B)-dienglycyrrhizin, and its salt.

Example 1 Method for producing 11β-hydroglycyrrhizin trisodium salt: (1) Water 5 (1 ml, tetrahydrofuran 100 ml.
Dissolve 7.56 g (0.2 mol) of sodium borohydride in 50 ml of N sodium hydroxide solution and place on a water bath for 80 min.
Reflux at °C. Next, 100ml of tetrahydrofuran
It was melted. Glycyrrhizin 8.23 g (0,0
1 mol) was added dropwise and reacted under reflux for 24 hours. Return the reaction solution to room temperature.

After adding 50 ml of acetone and stirring, adjust the pH to 9 to 10 with dilute hydrochloric acid.

After filtering the solution, the filtrate is concentrated to 100 ml.

Add acetone 70 (] ml. methanol 3 (lt) to the concentrate.
When 1 ml of the mixture is added, white crystals precipitate.

The precipitate is collected by filtration and dried to obtain 3 to 14 g of crude crystals 1.

200 ml of 75% ethanol is added to the crude crystals, and the mixture is refluxed to remove insoluble matter by filtration while hot. When the filtrate is cooled, crystals precipitate out. The crystals are filtered and dried to obtain 7.6 g of 11β-hydroglinaritin trisodium salt, which is the desired product. Yield 85%.

(2) 100m1 of water. N sodium hydroxide solution 100m
Dissolve 15.1 g of sodium borohydride in 8
Heat to 0°C. Then, 16.8 g of glycyrrhizin ammonium salt dissolved in 300 n+l of water and 100 ml of O, IN 1-lium hydroxide solution was added dropwise and reacted for 24 hours. The reaction solution was returned to room temperature, 100 ml of acetone was added thereto, stirred, and then adjusted to p (19-10) with dilute hydrochloric acid.

After filtering this solution, the solvent is distilled off to a volume of 200ml, and a mixed solution of 1.4β acetone and 0.61ml methanol is added.

The precipitated white precipitate was filtered and dried as crude crystals.
Obtain 8g.

When the crude crystals are recrystallized from 75% ethanol, the target product 11β-hydroglycyrrhizine trisodium salt 1 is obtained.
5. :(g is obtained. Yield 86%.

Example 11 Method for producing 11β-hydroglycyrrhizine tripotassium salt: Dissolve 23.5 g of potassium borohydride in 100 ml of water and 1 (10 ml) of N potassium hydroxide solution and heat to 80°C.

Then, 16.8 g of glycyrrhizin ammonium salt dissolved in 1 ml of 3 flf of water and 100 ml of 0.1N potassium hydroxide solution was added dropwise, and the mixture was allowed to react for 24 hours.

Thereafter, the same procedure as in (2) of Example I is carried out to obtain 16 g of 11β-hydroglycyrrhizine tripotassium salt, which is the desired product. Yield 85%.

Example M Method for producing 11β-hydroglycyrrhizin: 30 g of 11β-hydroglycyrrhizin trisodium salt was added to 500 ml of water.
Dissolve and add 1 strongly acidic ion exchange resin (Da'7 I7, 2.50W-X2.H type) 1801Il+.

After stirring at room temperature for 15 minutes and separating the resin, the solution is freeze-dried to obtain the target product 11β-hydroglycyrrhizin 2.
Obtain 6g. Yield 93.6%.

Example 1 ■ 11, 13 (1B)-Production method of dienglycyrrhizin and disodium salt: 5 g of ++111β-hydroglycyrrhizin trisodium salt was dissolved in 100 ml of water, and diluted with dilute hydrochloric acid to dissolve p117-8.
Adjust to.

This solution is heated at 100° C. for 6 hours. Thereafter, the pH was adjusted to 2 to 3 with dilute hydrochloric acid, and extracted twice with 100 ml of n-buknol. The extract is washed with water and dehydrated with anhydrous sodium sulfate. When the dehydrating agent is separated and the solvent is distilled off, the desired product is obtained.11.
4.2 g of 13 (18)-dienglycyrrhizin are obtained. Yield 92.7%.

+211L 13 (18)-dienglycyrrhizin 3
．． Add 2g to 40ml of methanol and dissolve. 0 for this
．． Add 80 ml of IN sodium hydroxide solution and reflux on a water bath for 1 hour. The reaction solution was concentrated under reduced pressure to a syrup state, and 200 ml of acetone was added to form a white precipitate. Collect the crystals by filtration and dry them to obtain the desired product, 11.13 (18)
- 3.2 g of diengrinaritin disodium salt are obtained.

Yield 95%.

The physical properties of the reduction-modified compounds (1) and (II) of clinalritin obtained in the above examples are as follows.

(+)11β-Hydroglycyrrhizin Melting point: 206-210° (decomposition) [α]D = I H (cm-'): 1050 (C-011)
, 1080 (C-0-C)164+1 (C=C
), 1"/10 (COOII) 2950 (CI
+, ), 3450 (0-H) PMR: CMR: Mass: to) IL 13 (18)-dienglycyrrhizin melting point: 180-189° (decomposition) (α) D,: -41,47 (methanol) Uv: λm
ax 243.25L260nm (methanol) I
R (cm-'): 1040 (C-OH), 1
080 (C-0-C).

1640 (C=C-C=C).

1720 (COOII), 2930 (CI)
.

340 (+ (0-11) P M R (Me0!1-d Buddha) δppm (1'M
S ); 6.35 (dd, Ill, vinyl, H,
J = 16Hz) 5.59 (d, IH, vinyl, H, J = 1.21(z)CM R(DMSO-
66) δppm (TMS) ; ], 78.9 (s
, C-30) 88.5 (d, c-3) Mass: The results of measuring L Ll 5o for one drug (alkaline salt) are as follows.

The results of the acute toxicity test (LD&〇) according to Van der Waerden's method are as follows.

11β-Hutroglinaritin trisodium salt = 12
60-1397mg/kg +1.13 (+8)-dienglycyrrhizin disodium salt: 333-. ') 58 mg/kg (ICR mouse 8 week old male: 36-38 g, intravenous injection) Both have low toxicity.

Procedural amendment April 12, 1980 Director of the Patent Office Mr. Kazuo Wakasugi1, Indication of the case 1988 Patent side No. 0348332, Title of invention Novel reduction-modified compound of glycyrrhizin and its manufacturing process 3, Person making amendment Relationship with Patent Applicant Address 3-2-7 Yotsuya, Shinjuku-ku, Tokyo Name of Seiyaku Honpo Limited Partnership Company Minofagen Pharmaceutical Honpo Tsunomyatokuma Representative Utsunomiya Kyuma 4, Agent ◎271 Address 20-3 Konemoto, Matsudo City, Chiba Prefecture 6.? , The number of inventions increases due to iIIi 7, Subject of amendment Description 8, Contents of amendment as attached. Formula 11: 11β-hydroglycyrrhizin and its pharmaceutically acceptable salt.

(2) Formula: 11.13 (18)-dienglycyrrhizin and its pharmaceutically acceptable salt.

(3) Heat a tetrahydrofuran solution of glycyrrhizin and a sodium hydroxide solution of sodium borohydride, or heat a sodium hydroxide solution of glycyrrhizin ammonium salt or sodium salt and a sodium hydroxide solution of sodium borohydride. The method for producing trisodium salt of 11β-hydroglycyrrhizin according to claim 1, which comprises:

(4) Heat a tetrahydrofuran solution of glycyrrhizin and a potassium hydroxide solution of potassium borohydride, or heat a potassium hydroxide solution of glycyrrhizin ammonium salt or potassium salt and a potassium hydroxide solution of potassium borohydride. A method for producing a tripotassium salt of 11β-hydroglycyrrhizin according to claim 1, which comprises:

(The first claim is characterized in that the alkaline salt of 5111β-hydroglycyrrhizin is dissolved in water, a strongly acidic cation exchange resin is added thereto, the mixture is stirred at room temperature, the resin is separated, and the solution is freeze-dried. The method for producing 11β-hydroglycyrrhizin as described in 1.

(The aqueous solution of the alkaline salt of 6111β-hydroglycyrrhizin is adjusted to pH 7 to 8 with mineral acid and heated, and then the pn is adjusted to 2 to 3. 11.13 Method for producing (1B)-dienglycyrrhizin.

(7111,13(18)-dienglycyrrhizin is dissolved in methanol, a corresponding amount of an alkali agent is added, and acetone is added to the reaction solution to precipitate the target product. 11.13 (1) described in Section 2
8) - Method for producing mono-, di-, and trial-alkali salts of dienglycyrrhizin.

3. Detailed Description of the Invention The present invention provides 11β-hydroglycyrrhizin, which is a novel reduction modification compound of glycyrrhizin, and 11.13 (18
)-dienglycyrrhizin (heteroannuular dienglycyrrhizin), their alkali salts, and their production methods.

Glycyrrhizin (saponin), an active ingredient in licorice, has already received high praise in the clinical field as an anti-inflammatory, anti-allergy, and anti-ulcer agent. Furthermore, the succinic acid derivative of glycyrrhetinic acid, which is an aglycone of glycyrrhizin, has been recognized as an antiulcer agent.

However, glycyrrhizin has a long-term effect, especially when administered orally.
There is a side effect of pseudoaldosteronism. This is because glycyrrhetinic acid, which is an aglycone, is produced by the ice melting of glycyrrhizin, and this is a steroid metabolizing enzyme in the liver.
It inhibits the activity of 4-5β-reductase, and aldosterone metabolism is stagnated.

Therefore, its enhancement causes symptoms such as abnormal electrolyte metabolism, hypertension, hypokalemia, and edema.

The inventors of the present application, Shuga et al., first searched for a compound that can prevent such side effects of glycyrrhetinic acid and enhance its pharmacological action, and conducted reduction modification of glycyrrhetinic acid using a new method and produced "osyan-12-ene- 3β,30-diol" was found to sufficiently achieve this purpose, and the results were published in JP-A-56-139416 and JP-A-57-
The invention was published in JP-A No. 73000 and Japanese Patent Application Laid-Open No. 72542-1983.

Recently, glycyrrhizin has been recognized to be effective against chronic hepatitis diseases in addition to its anti-inflammatory effects as mentioned above, and its importance as a liver drug is rapidly increasing. still,
It has been found that its natural saponin form, that is, glycyrrhizin, which is conjugated with two molecules of glucuronic acid, has a better effect on the liver than the aglycone glycyrrhetinic acid.

Here, the applicant et al. has previously developed “diol”.
As a result of various research in search of glycyrrhizin related compounds that do not cause pseudohyperaldosteronism, have the same saponin structure as glycyrrhizin, and have superior pharmacological effects, we have developed a unique glycyrrhizin. Several compounds were discovered by reductive modification using the method.

The purpose of the present invention is to eliminate such side effects such as pseudoaldosteronism that are often found in glycyrrhizin or glycyrrhetinic acid preparations, and to enhance the effect of the original drug. The object of the present invention is to provide a reduced glycyrrhizin-based drug.

(1) 11β-hydroglycyrrhizin (II) IL 13 (18)-dienglycyrrhizin, which has the structural formula shown in claims 1 and 2 of the present application, is a new novel unknown in the literature based on the results of this research. It is a compound.

Next, the formulas of the aglycones of the above two new compounds are shown.

(A) 11β-Hutolog (B) IL 13 (1B
) -Rycyrrhetinic acid Dienglycyrrhetinic acid The above (A) is obtained by reduction of glycyrrhetinic acid,
(B) is derived from (A), but has been isolated as a trace component from the licorice extract, and these are known compounds that have anti-aldosterone and anti-inflammatory effects. this(
Both compounds A) and (B) are thought to exist in licorice as they are, i.e. in the form of aglycones, in small amounts or perhaps in large part as saponins (1) and (II) obtained by reducing the glycyrrhizin. It will be done. However, these have not been extracted from licorice as saponins until now. If a glycyrrhizin drug (1
), [■) from (A) and (B) would require extremely difficult, complex and expensive techniques, even if possible.

There is no possibility of industrial production to meet mass demand.

According to the method according to the present invention, glycyrrhizin, which is a large component in licorice, is used as a raw material, and easily available and relatively inexpensive auxiliary materials are used, and safe and simple techniques are used to achieve high yields. Is this innovative method ideal? ``It is hoped that industrial production of J-chiruritin drugs will be realized.

Next, the manufacturing process using this method will be illustrated.

The above steps will be explained in detail below.

First, a method for producing 11β-hydroglycyrrhizine trisodium salt and tripotassium salt will be described.

The solvent and reducing agent differ depending on the desired alkali salt, the raw material glycyrrhizin or its salt. In the method for producing the trisodium salt, when glycyrrhizin is used, tetrahydrofuran is used as a solvent. When using glycyrrhizin ammonium salt, only N sodium hydroxide solution is sufficient. Sodium borohydride is the most suitable reducing agent.

When the raw material is glycyrrhizin, sodium borohydride is dissolved in an aqueous tetrahydrofuran solution containing a sodium hydroxide solution, and when the raw material is an ammonium salt, sodium borohydride is simply dissolved in a sodium hydroxide solution. In either case, the mixture is heated to reflux on a water bath at 80° C. or higher to the boiling point of the solvent.

When the raw material is glycyrrhizin, a tetrahydrofuran solution of glycyrrhizin is added dropwise, and when the raw material is an ammonium salt, a sodium hydroxide solution of glycyrrhizin ammonium salt is added dropwise, and a heating reaction is performed for 24 hours. When acetone and dilute hydrochloric acid are added to the reaction solution to decompose excess alkali and reducing agent, and the pH is adjusted to 9 to 10, glycyrrhizin is reduced.

It becomes the trisodium salt of 11β-hydroglycyrrhizin.

Concentrate the reaction solution and add a mixture of methanol and acetone to produce a white precipitate. Filter the precipitate.

When recrystallized with 75% ethanol, the target product 11β-
A white crystalline powder of hydroglycyrrhizin trisodium salt is obtained.

Second, regarding the method for producing 11β-hydroglycyrrhizine tripotassium salt, the reaction is carried out under exactly the same conditions as in the case of the above-mentioned trisodium salt.

For example, when using glycyrrhizin monoammonium salt, dissolve potassium borohydride in a potassium hydroxide solution, heat it on a water bath to 80°C or higher, and dropwise add a solution that dissolves glycyrrhizin ammonium salt in the potassium hydroxide solution.
After a heating reaction for 4 hours, one reaction solution is treated in the same manner as for the above trisodium salt to obtain a white crystalline powder of 11β-hydroglycyrrhizin tripotassium salt. - Thirdly, 11β according to claim 5
- Regarding the manufacturing method of hydroglycyrrhizin, 11β-hydroglycyrrhizin trialkali salt obtained by the above-mentioned manufacturing method is dissolved in water, and a strongly acidic cation exchange resin 1
For example, DOWEX 50-.

When a sulfonic acid type resin such as Amberlite 111-120B is added and stirred at room temperature, free 11β-hydroglycyrrhizin is produced. When the resin is separated from the reaction solution and freeze-dried, white 11β-hydroglycyrrhizin is obtained in high yield.

Fourthly, 11°13 as stated in claim 2.
(18)-Dienglycyrrhizin can be obtained very easily using 11β-hydroglycyrrhizine trisodium salt or tripotassium salt obtained by the above-mentioned production method as a raw material.

That is, when an alkali salt is dissolved in an appropriate amount of water, its pH is adjusted to pH 7 to 8 with dilute hydrochloric acid, and then heated, the alkali salt of 11.13-(18)-dienglycyrrhizin is completely quantitatively converted. Add dilute hydrochloric acid to the reaction solution to adjust the liquid to p.
112-3, extracted with n-butanol and distilled off the solvent to obtain a white crystalline powder.

To obtain this soluble alkali salt of dienglycyrrhizin, a metal solution of dienglycyrrhizin is prepared,
The corresponding amount is 0. After adding IN alkali hydroxide solution and heating, acetone is added to the concentrated solution distilled under reduced pressure to obtain mono-, di-, or tri-alkali salts, respectively.

Hereinafter, two examples will be given of methods for producing 11β-hydroglycyrrhizin and its alkali salts, 2 and 11.13 (1B)-dienglycyrrhizin, and its salts.

Example ■ Preparation of 11β-hydroglycyrrhizin trisodium salt: fl) 50 ml of water. Tetrahydrofuran 100ml1.
7.56 g (0.2 mol) of sodium borohydride is dissolved in 50 ml of N sodium hydroxide solution and refluxed at 80° C. on a water bath. Then, 8.23 g (0.01 mol) of glycyrrhizin dissolved in 100 ml of tetrahydrofuran was added dropwise and reacted under reflux for 24 hours. Return the reaction solution to room temperature.

After adding 50 ml of acetone and stirring, adjust the pH to 9 to 10 with dilute hydrochloric acid.

After filtering the solution, the filtrate is concentrated to 100 ml.

Add 700ml of acetone to the concentrate. Methanol 300Ill
When the mixture of I is added, white crystals precipitate.

The precipitate is filtered and dried to obtain 13 to 14 g of crude crystals.

Add 200 ml of 75% ethanol to the crude crystals and reflux to remove insoluble materials while hot. When the filtrate is cooled, crystals precipitate out.

The crystals are filtered and dried to obtain 7.6 g of 11β-hydroglycyrrhizine trisodium salt, which is the desired product. Yield 85
%.

(2) 100m1 of water. N sodium hydroxide solution 100m
Dissolve 15.1 g of sodium borohydride in 1 and 80
Heat to ℃. Then 300m of water 1.0. 16.8 g of glycyrrhizin ammonium salt dissolved in 100 ml of IN sodium hydroxide solution was added dropwise and reacted for 24 hours. The reaction solution was returned to room temperature, 100 ml of acetone was added thereto and stirred, and then the pH was adjusted to 9 to 10 with dilute hydrochloric acid.

After filtering this solution, the solvent was distilled off to a volume of 200 ml, and a mixed solution of 1.41 N of acetone and 0.6 N of methanol was added.

The precipitated white precipitate was filtered and dried as crude crystals.
Obtain 111 g.

When the crude crystals are recrystallized from 75% ethanol, the target product 11β-hydroglycyrrhizine trisodium salt 15 is obtained.
．． Obtain 3g. Yield 86%.

Example (1) Preparation of 11β-hydroglycyrrhizin tripotassium salt: 23.5 g of potassium borohydride is dissolved in 100 ml of water and 100 mL of N potassium hydroxide solution and heated to 80°C.

Then 300m of water 1.0. IN potassium hydroxide solution 1
Glycyrrhizin ammonium salt dissolved in 00ml 1
6.8 g was added dropwise and allowed to react for 24 hours.

Thereafter, the same procedure as in Example I (2) is carried out to obtain 16 g of 11β-hydroglycyrrhizine tripotassium salt, which is the desired product. Yield 85%.

Example ■ Process for producing 11β-hydroglycyrrhizin: 30 g of 11β-hydroglycyrrhizin trisodium salt and 500 g of water...1
1 strongly acidic ion exchange resin (Dowex 50)
W-X2. +1 type) Add 180m1.

After stirring at room temperature for 15 minutes and separating the resin, the solution is freeze-dried to obtain the target product 11β-hydroglycyrrhizin 2.
Obtain 6g. Yield 93.6%.

Example ■ Process for producing IL 13 (1B)-dienglycyrrhizin and disodium salt: (5 g of 1111β-hydroglycyrrhizin trisodium salt is dissolved in 100 ml of water, and the pH is adjusted to 7 to 8 with dilute hydrochloric acid.

This solution is heated at 100° C. for 6 hours. Thereafter, the pH was adjusted to 112 to 3 with dilute hydrochloric acid and extracted twice with 100 ml of n-butanol. The extract is washed with water and dehydrated with anhydrous sodium sulfate. When the dehydrating agent is separated and the solvent is distilled off, the desired product 11
．． 13 (1B)-4.2 g of dienglycyrrhizin is obtained. Yield 92.7%.

(2111,13(18)-dienglycyrrhizin 3.
Add 2g to 40ml of methanol and dissolve. 0 for this.
Add 80 ml of IN sodium hydroxide solution and reflux on a water bath for 1 hour. The reaction solution was concentrated under reduced pressure to a syrup state, and 200 ml of acetone was added to form a white precipitate. The crystals are collected by filtration and dried to obtain the target IL 13 (18)
- 3.2 g of dienglycyrrhizine disodium salt are obtained.

Yield 95%.

The physical properties of the reduction-modified glycyrrhizin compounds (1) and (II) obtained in the above examples are as follows.

(1) 11β-Hydroglycyrrhizin Melting point: 206-210° (decomposition) [α]p: I R (cm-1): 1050 (C-0!()
, 1080 (C-0-C) 1640 (, C=C)
, 1710 (COOH) 2950 (CH3) ,
3450 (0-H) PMR: CMR: Mass: (It) 11.13 (18)-Diene glycyrrhizin Melting point: 180-189° (Decomposition) [α) o Knee 41.47 (Methanol) U ■: λl
1lax 243,251,260nm (methanol) IR (cm”): 1040 (C-OH)
, 1080 (C-0-C).

1640 (C-C-C=C).

1720 (COOH), 2930 (CHB)
.

3400 (0-H) PMR(MeOH-d4) δpprm (TM
S) i6.35 (DD, IH, vinyl, H,
J = 16Hz) 5.59 (d, LH, vinyl, H, J = 12Hz) CM R (DMSO-66
) δppm (TMS) 1178.9 (s,
C-30) 170.2 (s) 169.9 (s) (c'-6, c#-6 or vice versa)
135.1 (s) 134.4 (s) (c-13, c-18 or vice versa)
126.3 (d) 127.8 (d) (c-11, c-12 or vice versa)
104.6 (cl) 103.5 (d) (c'-1, c''-2 or vice versa)
88.5 (d, c-3) Mass: The results of measuring LD for one drug (alkaline salt) are as follows.

, Acute toxicity test according to Van der Waerden method (LD,.

) results are as follows.

11β-hydroglycyrrhizin trisodium salt: 12
60 to 1397 ■/kg 11,13 (18)-Dienglycyrrhizin disodium salt: 333 to 358 nw/kg (ICR mouse 8 weeks old male: 36 to 38 g, intravenous injection) Both have low toxicity.

Claims (4)

[Claims] (1) Formula: 11β-hydroglythitritin and its pharmaceutically acceptable salt. (2) Formula: 11.13 (18)-dienglycyrrhizin and its pharmaceutically acceptable salt. (3) Heat a tetrahydrofuran solution of glycyrrhizin and a sodium hydroxide solution of sodium borohydride, or heat a sodium hydroxide solution of glycyrrhizin ammonium salt or sodium salt and a sodium hydroxide solution of sodium borohydride. The method for producing trisodium salt of 11β-hydroglycyrrhizin according to claim 1, which comprises: (4) Heat a tetrahydrofuran solution of glycyrrhizin and a potassium hydroxide solution of potassium borohydride, or heat a potassium hydroxide solution of glycyrrhizin ammonium salt or potassium salt and a potassium hydroxide solution of potassium borohydride. A method for producing a tripotassium salt of 11β-hydroglycyrrhizin according to claim 1, which comprises: Fi+ 11β-Hydroglycyrrhizin alkaline salt is dissolved in water, a strongly acidic cation exchange resin is added thereto, stirred at room temperature, the resin is separated, and the solution is freeze-dried. The method for producing 11β-hydroglycyrrhizin as described in 1. (Claim 2) characterized in that an aqueous solution of an alkaline salt of 6111β-hydroglinaritin is adjusted to a pH of 7 to 8 with a mineral acid, heated, and then adjusted to a pH of 2 to 3. 11.13 Method for producing (18)-dienglycyrrhizin. 11 and 13 according to claim 2, characterized in that acetone is added to precipitate the target product.
(18) - Method for producing mono-, di-, and trial-alkali salts of dienglycyrrhizin.