The method of obtaining glycyrrhizic acid

 

(57) Abstract:

Usage: as medpreparate a wide spectrum of action. The inventive product glycyrrhizin acid (ha), which is obtained from glycerine by processing the Pharmacopoeia of glycyram (monoammonium salt of glycyrrhizic acid) of 1.5% solution of N2SO4when 98 - 102oC for 20 - 30 min and chloroform at room temperature, separated technical glycoside is dissolved in acetone, precipitated ZK-salt of the glycoside by adding an alcohol (ethanol or methanol) solution of KOH (pH 8.5 - 9.0 in), transfer gears and salt in odnoklikovoy by recrystallization from glacial acetic acid, washed with I-salt ONION, dried and converted into the desired product by treatment with 1.5% solution of N2SO4at 98 - 100oC pre-filtration at 55 - 60oC. the resulting glycoside stirred with chloroform and dried. Output 50,0 - 58% (90 - 92 (+ 2)% purity). 2 Il.

The invention relates to a method for producing triterpene glycoside - glycyrrhizic acid (GA) of the active principle of licorice root (Glycyrrhizae glabra and Gl. uralensis) of industrial raw materials of glycyram (substance by monoammonium CC salt), produced BY Cementboard".

Previously the neigh of a basic substance 75 to 80% according to HPLC (scheme 1) [1] Scheme 1 shown in Fig. 1.

Glitsiram (VFS 42-419-75) (substance) with a basic substance content of 75 to 80% according to HPLC (liquid chromatograph Du pont, Bond column ODS, the mobile phase CH3CN-H2O-AcOH, 350:650:5 (V), the detector 254 nm) was treated with cation exchange resin KU-2-8 or PSC-4P N+form in a weight ratio of 1:1 in 75% ethanol at room temperature, the solvent was evaporated in vacuum and the residue was dried to constant weight. Output technical glycoside 95% (atmospheric substance yellowish color). The content of the basic substance in the technical CC 75 to 80% according to HPLC.

The disadvantages of this method of obtaining the Ledger is the use of expensive solvent ethanol.

The cost of 1 l of ethanol at 1992 prices is 200 rubles, the cost of 1 kg of sulfuric acid 3 rubles 52 kopecks

In addition, when conducting aggregative synthesis in the experimental plant of the Institute receive technical glycoside of glycyram associated with the evaporation of the ethanol under vacuum was of little use because of the formation of a viscous syrup technical glycoside [1] which, as the drying stick to the walls and barely removed from reactors. The method allows to obtain only the technical glycoside maintained with the 0:1 (V), detector l 254 nm).

The claimed technical solution is developed cost-effective and convenient method of obtaining purified Ledger of industrial raw materials of glycyram, allowing you to get the glycoside content of the basic substance 902% Purified hyaluronic acid is a drug used in the treatment of AIDS and viral hepatitis [2, 3] and is used upon receipt of veterinary medicine "Chatrapati" [4]

According to the claimed method the substance of glycerine (VFS-42-419-75) is treated with a 1.5% solution of H2SO4when 98 102oC for 20 to 30 minutes, the reaction mixture cooled down to room temperature and treated with chloroform in a ratio of 3 to 1 (V%), the resulting gel-like precipitate of glycoside separated and dried to a water content of approximately 15% is dissolved in acetone and treated with ethanol or methanol solution of KOH (13 g/100 ml) obtained TRACELEVEL salt glycoside (sq-g) was transferred to odnoklikovoy (IC-g) by recrystallization from glacial acetic acid at a temperature of 98 100oC, dried, and treated with a 1.5% solution of sulfuric acid when heated at 55 60oC was filtered and the solution incubated at 98 100oC for 30 to 60 min, cooled to room temperature, filter the PTA. The output of the glycoside was 50.0 59.5 per cent in terms of 100% glitsiram or 66.7 79.4% in terms of 75% glitsiram (feedstock). The content of the basic substance 89 92% (2)% data HPLC (chromatograph Du pont, column reversed-phase m-Bondapak C-18, mobile phase: H2O-CH3CN-MeOH-AcOH 44:35: 20: 1 (V%), the detector l 254 nm, flow rate 1 ml/min). The water content of 4 to 8%

Thus, our proposed scheme for glycyrrhizic acid from the glycyram is a technologically consists of simple operations and can significantly reduce the cost of the process [1] by replacing expensive solvent of ethanol and cations on a 1.5% aqueous solution of sulfuric acid. The method allows to obtain a glycoside 89 92% ($E+->2)% purity with a yield of 50.0 59.5 per cent in terms of glitsiram with the content of the basic substance 100% or 66.7 79.4% in terms of glitsiram with a basic substance content of 75% (feedstock) (scheme 2). Scheme 2 shown in Fig. 2.

Distinctive features of the process:

1. The application of a 1.5% aqueous solution of sulfuric acid and chloroform instead of 75% ethanol and cation exchange resin KU-2-8 or PSC-4P N+form at the stage of obtaining technical glycoside of glycyram.

2. Entered the processing operation of the reaction mixture with chloroform, which is one glycoside through a potassium salt, that allows you to get the GC content of the basic substance 89 92% of your pre-normative-technical requirements on the substance of the code.

4. Method of waste relative to the source of raw materials, as the last stage water filters treated with chloroform for planting remaining in the solution of the glycoside, which after drying is used again at the stage of obtaining the LC-CC salt (see examples).

For best separation of the glycoside in the first stage to the acid solution was added chloroform at a ratio of 3 to 1 by volume and 1.5% sulfuric acid. The glycoside is allocated in the form of a gel, which are selected and dried to a water content of approximately 15% is transferred to 3K-salt by treatment with ethanol or methanol solution of KOH to a pH of 8.5 to 9 in the form of an acetone solution. Received 3K-salt Ledger then transferred to IK-salt by recrystallization from a BOW at 98 100oWith, ONIONS washed 2 times and dried.

The output of IC-salt 88 100% in terms of the initial glitsiram. At the last stage of INFRARED Sol again treated with a 1.5% solution of H2SO4, heated to 55 60o(Before dissolution), filtered and heated to 98 102oC, kept at this temperature for 30 to 60 min, cooled to room is stirred with chloroform to remove impurities aglycone.

The output of the GC content of the basic substance 89 92% ( 2%) was 50 59,5% in terms of raw materials with the content of the basic substance 100% or 66.7 79.4% in terms of glitsiram with a basic substance content of approximately 75% (pharmacopoeial).

From the aqueous filtrate and wash water residues glycoside was isolated by treatment with chloroform.

The obtained gel-like glycoside was dried and used in obtaining the LC-salt along with the technical glycoside (see examples).

The chloroform was separated from the water portion in a separating funnel and is also used in the synthesis (see examples).

Received glycyrrhizin acid meets the requirements of pre-normative-technical specifications for the substance of glycoside and was used to produce commercial batches comprehensive veterinary drugs (chatrapati) and pilot batches of new drugs anti-inflammatory action (globalcar and gosalyn) for advanced biological and Toxicological tests.

Example 1. In desyatimetrovoy reaction flask equipped with a mechanical stirrer, was loaded with 500 g of glycyram, 5000 ml of 1.5% solution of H2SO4was heated at probabaly with stirring in 1500 ml of chloroform.

Fallen viscous gel-like precipitate of glycoside separated, moved on a baking sheet and dried to a moisture content of approximately 15% of the Aqueous phase and the chloroform was poured into a separating funnel and separated the layers.

Dissolved received technical glycoside in 5000 ml of acetone at low heat (up to 45oC), was filtered and to the filtrate was added with stirring to 1000 ml of methanolic solution of KOH (pH 8.5). The yellow precipitate trikalinos salts of glycyrrhizic acid was filtered. Washed 2 times in 1000 ml of acetone. After drying in a stream of nitrogen received 566 g trikalinos CC salt (water content 10,67%).

In a five-liter flask with stirrer was loaded 5600 ml of glacial acetic acid and 566 g trikalinos CC salt and heated to 98oC (before dissolution), filtered hot, and left over night at room temperature for crystallization. The next day the crystals odnoklikovoy CC salt was filtered, washed 2 times in 1000 ml ONION, 2 times in 1000 ml of ether and dried in a stream of nitrogen. Received 470 g (91.7% of theory) of odnoklikovoy CC salt. []2D0= +42(c 0,02; 25% EtOH). UV25%maxEtOH(lg]2D0= +55(c 0,04; EtOH); UV,EtOmaxH(lg2% (the data is tOH) [5]

To the aqueous filtrate was added with stirring, 2000 ml of chloroform, precipitated gel-like product was separated and dried in a tray (150 g) until the water content of approximately 15%

Example 2. In desyatimetrovoy flask was loaded with 600 g of glycyram and 6000 ml of 1.5% solution of N2SO4and heated with stirring to 98oC, held at this temperature for 20 min and cooled to room temperature. To the reaction mass was added chloroform (1500 ml), precipitated viscous product was separated and dried in a tray to a moisture content of approximately 15% Aqueous and chloroform layers were separated in a separating funnel.

Received technical glycoside dissolved in 6000 ml of acetone with stirring, was filtered and to the filtrate was added ethanol solution of KOH (1300 ml) (pH 9). The residue LC-CC salt was filtered, washed 2 times in 1000 ml of acetone and dried in point of nitrogen. Got 780 g trikalinos CC salt (the water content of 10.3%).

Dissolved received WC-Sol group of companies in 7800 ml BOW when heated 98oC, filtered, and left to crystallize overnight at room temperature. The crystalline precipitate odnoklikovoy CC salt was filtered, washed 2 times in 1000 ml ONION, 2 times in 1000 ml of ether and dried in a stream of nitrogen. Paul is the thief of H2SO4and was heated to 98oC under stirring, kept at this temperature for 30 minutes, cooled to room temperature and the white precipitate was filtered Ledger. Washed the precipitate with distilled water to neutral reaction (20 l) and dried in a stream of nitrogen.

Dry acid (314 g) was mixed with 3000 ml of chloroform for 1 h, filtered, and again dried. Received 304 g (51,7%) CC in terms of 100% of glycyram or 69,0%, calculated on 75% of glycyram. So pl. 215 216oC []2D0= +60(c 0,04 MeOH). UVMEOmaxH(lg2% of the water content of 7.97%

To the aqueous filtrate was added 1500 ml of chloroform, precipitated viscous gel-like product was separated and dried (150 g).

Example 3. In desyatimetrovoy flask was loaded with 500 g of glycyram, 5000 ml of 1.5% solution of H2SO4was heated with stirring to 98oC, held for 20 min, cooled to room temperature and added to 1500 ml of chloroform (regenerated). Released viscous gel-like glycoside separated and dried in the tub until the water content of approximately 15%

665 g technical glycoside and 150 g of glycoside from the filtrate of example 2 was combined and dissolved under stirring in 6000 ml of acetone. Filtered the solution and added to the if in a stream of nitrogen. Received 765 g, trikalinos CC salt (the water content of 10.4%).

In desyatimetrovoy flask downloaded 765 g trikalinos CC salt and 7650 ml ONIONS, heated to 100oC, filtered, and left to crystallize at room temperature overnight. Crystals of odnoklikovoy CC salt was filtered, washed 2 times in 1000 ml ONION and 2 times in 1500 ml of ether. Dried in a stream of nitrogen. Received 544 g odnoklikovoy CC salt.

Were loaded into a flask 5400 ml of 1.5% solution of N2SO4and 544 g odnoklikovoy CC salt, heated to 55oWith was filtered, the filtrate was heated to 100oWith, held at a temperature of 98 100oC for 40 min and cooled to room temperature. A white precipitate Ledger was filtered, washed 3 times in 4000 ml of distilled water and dried. Got 260 g of glycyrrhizic acid, which grind in the mill and sifted through a sieve 0,7 x 0,4 mm Crushed acid was stirred with 2600 ml l3within 1 h, was filtered, washed 1000 ml fresh l3and dried in a stream of nitrogen. The output SC 245 g (50,0% in recalculation on 100% of glycyram or 66.7%, calculated on 75% of glycyram). So pl. 209 210oC; []2D0= +62(from 0.05, EtOH). The content of the basic substance 90,22% Content of N2O 7,41%

From UB>2O approximately 15% (130 g).

Example 4. In desyatimetrovoy flask was loaded with 600 g of glycyram, 6000 ml of 1.5% solution of H2SO4under stirring and heated the mixture up to 102oC. was Passed at a temperature of 98 102oC for 20 min and cooled the mixture to room temperature. Added to a mixture of 1500 ml of chloroform with stirring, the precipitated viscous gel-like glycoside was unloaded in a dish and dried to a water content of approximately 15%

785 g of dried technical glycoside was dissolved with stirring and mild heating (up to 45o(C) in 7000 ml of acetone, filtered, and added to 1500 ml of an ethanol solution of KOH (pH 9). Sediment trikalinos CC salt was filtered, washed 2 times in 1000 ml of acetone and dried in a stream of nitrogen. Received 736 g trikalinos CC salt. Were loaded into a flask 736 g trikalinos salt and 7360 ml ONION and heated while stirred to 100oWith was filtered while hot, was left to crystallize at room temperature overnight. The crystalline precipitate odnoklikovoy CC salt was filtered, washed 2 times in 1000 ml ONION, 2 times in 2000 ml of ether. Dried in a stream of nitrogen. Received 543 g (88,3%) odnoklikovoy Ledger.

Were loaded into a flask 5430 ml of 1.5% solution of H2SO4and 543 g odnoklikovoy with the temperature. A white precipitate Ledger was filtered, washed 3 times in 7000 ml of distilled water and dried in a stream of nitrogen. Received 345 g GK that grind at the mill and sifted through a sieve 0,4 x 0,4 mm

Pulverized acid was stirred 1 h with 3000 ml of chloroform, filtered, washed on the filter with 2000 ml of chloroform. Received 340 g GK (57,8%) based on 100% of glycyram or 77.1%, calculated on 75% of glycyram. So pl. 215 216oC; []2D0= +59(c 0,04; EtOH); UV,EtOmaxH(lg2% water content 4.09 to%

From the aqueous filtrate landed a gel-like product by adding 2000 ml HCl3and dried.

Weight 100 g (content of H2O approximately 15%).

Example 5. A 10-liter flask equipped with a mechanical stirrer, was loaded with 600 g of glycyram and 6,000 ml of a 1.5% aqueous solution of sulfuric acid and heated to 100oWith stirring. Withstood the reaction mass at 98 - 100oC for 20 min, cooled to room temperature and added with stirring to 2000 ml of chloroform (regenerated). Released viscous gel-like glycoside separated and moved in the tub to dry. Dried to a water content of approximately 15% Aqueous and chloroform layers were separated in a separating Cetona at low heat (up to 45oC) was filtered and to the filtrate was added 1500 ml of an ethanol solution of KOH (pH 9) with stirring. Sediment trikalinos CC salt was filtered, washed twice up to 1500 ml of acetone and dried in a stream of nitrogen. Got 780 g trikalinos CC salt (the water content of 10.7%).

A 10-liter flask was loaded 7200 ml ONION and 780 g of LC-CC salt, heated to 99oC was filtered hot and left to crystallize at room temperature overnight. Crystals of odnoklikovoy CC salt was filtered, washed 2 times in 1000 ml ONION, 2 times in 1500 ml of ether and dried in a stream of nitrogen. Received 613 g (99.7 per cent) odnoklikovoy CC salt. []2D0= +55(c 0,06; 25% EtOH). UV25%maxETOH(lg]2D0= +50(c 0,07; EtOH). UVEtOmaxH(lg2% water Content 5,26%

From the aqueous filtrate landed a gel-like product by adding 1500 ml l3and dried. Weight 130 g

Example 6. A 10-liter flask was loaded with 500 g of glycyram and 5000 ml of a 1.5% aqueous solution of sulfuric acid and heated to 100oC with stirring. Withstood the reaction mass at 98 100oC for 20 min, cooled to room temperature and added with stirring to 1500 ml of chloroform.

Contributing the cosida in 5000 ml of acetone at low heat (45oC), filtered, and added to the filtrate with stirring 1200 ml of methanolic KOH solution, the precipitate trikalinos CC salt was filtered, washed 2 times in 1000 ml of acetone, 2 times in 1000 ml of ether and dried in a stream of nitrogen. Received 747 g trikalinos CC salt (the water content of 10.8 per cent).

A 10-liter flask was loaded 7400 ml ONION and 747 g HCC-CC salt, heated to 98oC, filtered, and left to crystallize at room temperature overnight. Crystals of odnoklikovoy moth Ledger was filtered, washed 2 times in 1000 ml ONION, 2 times in 1500 ml of ether and dried in a stream of nitrogen. Received 513 g IK-CC salt (100%).

Loaded into the reaction flask 523 g IK-CC salt and 5200 ml of 1.5% solution of H2SO4and heated with stirring to 60oC was filtered, the filtrate was heated to 100oC, passed with 98 100oC for 30 min and cooled the mixture to room temperature. Sediment glycyrrhizic acid was filtered, washed with distilled water (15 l) and dried in a stream of nitrogen. Dry acid grind at the mill, sifted through it, 0,4 x 0,4 mm and stirred 1 h with 3000 ml of chloroform. Was filtered again and dried. Got 350 g GK (59,5% in recalculation on 100% of glycyram or 79.4% in terms of 75% of glycyram). So pl. 219 220oC []2is about get glycyrrhizic acid from the glycyram, includes a step for technical glycoside, wherein the source glitsiram treated with a 1.5% solution of sulfuric acid at a temperature of 98 102oC for 20 to 30 minutes, cooled to room temperature and treated with chloroform in a ratio of 3:1(volume/volume), then 3-potassium salt of glycyrrhizic acid, obtained by deposition of technical glycoside 13% ethanol or methanol solution of KOH, was transferred to a 1-potassium salt, followed by conversion of the latter into the desired product by treatment with 1.5% solution of sulfuric acid at 98 100oC for 30 to 60 minutes

 

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