Method for betulin isolation from birch bark

FIELD: fine organic synthesis, in particular production of triterpene compounds, betulin, useful in pharmaceutical and cosmetic industry.

SUBSTANCE: betulin is isolated from birch bark by extraction with neutral organic solvents, namely dioxan aqueous solution containing 0-20 mass % of water.

EFFECT: accelerated extraction process, increased yield of target product, decreased concentration of ester contaminants, and simplified betulin purification.

1 cl, 7 ex, 1 tbl

 

The invention relates to the field of fine organic synthesis, in particular to a technology for obtaining betulin, triterpenoids With30H50About2and structural formula (1):

Betulin is contained as the main triterpene component in the bark (outer crust) common species of white birch (Betula Pendula R.) and the other in an amount of about 30 wt.% per bark. In recent years, interest in betulina has increased dramatically, as its basis synthesize promising pharmaceutical drugs with antitumor and antiviral activity [Pisha et al. Natural Medicine 1, 1995, R; Evers et.al. J. Med. Chem., 1996, v.39, p.1069]. Betulin is also used for the production of shampoos, Soaps and other perfumery products.

A known method of extraction of betulin from birch bark by liquid or supercritical extraction with carbon dioxide [US Pat 6634575 from 21.10.2003]. Its main disadvantage is the high operating pressure of more than 7 MPa, and therefore, the high cost of manufacturing the equipment.

A known method of extraction of betulin from birch bark by supercritical extraction with mixtures of carbon dioxide with different solvents (methanol, ethanol, propanol, hexanol, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, ammonia, chlorine which forms propylene carbonate, dimethylacetamide, dimethyl sulfoxide, formic acid, water, carbon disulfide, acetone, propane, toluene, hexane or pentane) [Pat WO 0110885 from 15.02.2001]. Its main disadvantage is the high operating pressure of the process - 20-70 MPa and, consequently, the high cost of manufacturing the equipment.

A known method of extraction of betulin from birch bark by boiling in a solution of isopropanol - water - alkali within a few hours [EN 2131882 from 26.03.1998]. According to a known method in the solution of the bark goes betulin and the products of hydrolysis of suberin, oxyacids10-C20. The resulting solution was filtered, diluted with water and the thus precipitated betulin and subernova oxyacids remain in alkaline solution. The main disadvantage of this method is the low solubility of the target product is betulin - in isopropanol (not more than 15 g/l) and, especially, in aqueous-alcoholic media. This requires a large consumption of reagents and, ultimately, leads to low productivity. Another disadvantage of this method lies in the necessity of regeneration isopropanol from dilute aqueous solutions.

The closest to the essence of the claimed invention is a method of extraction of betulin from birch bark by extraction with neutral (without bases) races the thieves petroleum ether - toluene [EN 2184120 from 27.06.2002]. In accordance with the known method betulin extracted with a mixture of petroleum ether and toluene at a ratio of 1:1 to 7:3 in to conventional Soxhlet extractions for 3 hours Betulin are separated from the extract by distillation of the solvents. The output of betulin - 16-20 wt.% from absolutely dry matter of birch bark, the content of the target product in a dry extract - 90-98%.

The known method has the following disadvantages:

- small yield of the target product 16-20% (based on raw materials with its content in bark 30-35%;

- low process speed is the duration of the extraction is 3 h;

a significant level of impurities esters in the target product, due to the low polarity of the used extractant.

The marked disadvantages of this method is due to its essential characteristics - the use of petroleum ether and toluene as the extracting agent. The solubility of betulin in relatively small (not more than 10-15 g/l), and this causes the low speed extraction, high consumption of extractants and low product yield at the time 3 o'clock Ester compounds in this solvent sufficiently soluble, now they are extracted, resulting allocated betulin is characterized by a relatively high content of impurities ester character.

C is any of this invention is increase the yield of the target product, the increase in the rate of extraction and the reduced content of impurities ester character in the target product.

This objective is achieved in that the extract betulin from birch bark by extraction of neutral organic solvent, which is used as solutions of dioxane - water content of the latter from zero to 20 wt.%.

The General features of the proposed method and the prototype: obtaining betulin by extraction of the bark neutral (without bases) organic solvents.

Distinctive features of the claimed invention are the use of solutions of dioxane - water as a solvent with a water content of from zero to 20 wt.%.

Named hallmark leads to the achievement of the technical result of the claimed invention. We unexpectedly found that the solubility of betulin in dioxane and the solution dioxane - water content last up to 20 vol.% very high (up to 150 g/l) and more than 10 times higher than that in isopropanol, toluene and petroleum ether.

The result of the high solubility of betulin in dioxane is a sharp increase in the rate of extraction and the yield of the target product at a given duration of extraction. Below data show that the use of dioxane allows Uwe is ICICI yield of the target product with 20 to 30.5 wt.% in the calculation of raw materials for the same duration of extraction or shorten the duration of the extraction twice, from three to one and a half hours with the same efficiency of extraction of betulin, as in the prototype. The output of betulin, i.e. the degree of extraction of birch bark for the same duration of extraction, thus increasing according to the claimed method to 93% compared with 60% in the prototype.

Dioxane and aqueous solutions is more polar and hydrophilic solvent than toluene or petroleum ether, and this leads to reduction of the proportion of extractable monopolarly ester compounds almost in 2 times, i.e. to increase the purity of the target product. Significant decrease in the proportion of extractable monopolarly ester compounds can be achieved according to the claimed invention, using a more polar solutions of dioxane - water (20%), in which the solubility of betulin also quite large (up to 40 g/l).

The method is confirmed by specific examples.

Example 1 (prototype). In the experiments used the bark of silver birch (Betula Pendula R.) with the content of extractable petroleum ether to 32.8 wt.%. The content of extractables was determined by exhaustive extraction to conventional Soxhlet extractions for 50 hours

Extraction of 100 g of birch bark with a mixture of petroleum ether - toluene (1:1) was performed to conventional Soxhlet extractions within 3 hours After removal of the solvents got to 19.7 g of the extract or of 19.7 wt.% in the calculation of raw materials. The content is of betulin in the obtained extract, determined by the method of column chromatography, accounts for 93.4%.

The ester content of impurities in the extract was determined by saponification in aqueous alcoholic alkali solution for 5 h at boiling temperature. Alcohol drove, betulin was filtered and the aqueous filtrate was acidified and extracted with diethyl ether. Output ester impurities (0.12 g, or of 0.61 wt.% in the calculation of the target product) was determined by the gravimetric method after distillation of the ether (see table).

Example 2. The experiment is carried out as in example 1, but the bark is extracted with dioxane for one and a half hours. After removal of the solvent gain of 20.3 g of extract or 20.3 wt.% in the calculation of raw materials. The content of betulin in the obtained extract was determined by the method of column chromatography is 93,8%.

The content of esters in the target product defined according to example 1 is 0.09 g or 0.33 wt.% in the calculation of the target product.

Example 3. The experiment is carried out as in example 1, but the bark 1.5 h extracted with a solution of dioxane - water with content of 0.1 wt.%. After removal of the solvent receive a 20.2 g of an extract or a 20.2 wt.% in the calculation of raw materials. The content of betulin in the obtained extract was determined by the method of column chromatography, is 93.9%.

The content of esters in the target product as determined under PR is a measure 1, is 0.09 g or 0.33 wt.% in the calculation of the target product.

Example 4. The experiment is carried out as in example 1, but the bark 3 h, extracted with a solution of dioxane - water with content of 0.1 wt.%. After distillation of the solvent to obtain 30.5 g of the extract or of 30.5 wt.% in the calculation of raw materials. The content of betulin in the obtained extract was determined by the method of column chromatography is 93,6%.

The content of esters in the target product defined according to example 1 is 0.09 g or 0.33 wt.% in the calculation of the target product.

Example 5. The experiment is carried out as in example 1, but the bark 2 h, extracted with a solution of dioxane - water content of the last 10 wt.%. After removal of the solvent gain of 25.1 g of extract 25.1 wt.% in the calculation of raw materials. The content of betulin in the obtained extract was determined by the method of column chromatography is 94,9%.

The content of esters in the target product, as dened in example 1 is 0.06 g or 0.23 wt.% in the calculation of the target product.

Example 6. The experiment is carried out as in example 1, but the bark 2 h, extracted with a solution of dioxane - water content of the last 20 wt.%. After removal of the solvent receive 21,0 g of extract, or to 21.0 wt.% in the calculation of raw materials. The content of betulin in the obtained extract was determined by the method of column chromatography, the composition is employed to 95.7%.

The content of esters in the target product, as dened in example 1 is 0.04 grams or 0.19 wt.% in the calculation of the target product.

Example 7. The experiment is carried out as in example 1, but the bark 3 h, extracted with a solution of dioxane - water content of the last 30 wt.%.

After removal of the solvent gain of 18.3 g of extract or 18.3 wt.% in the calculation of raw materials. The content of betulin in the obtained extract was determined by the method of column chromatography, is 95.9%.

The content of esters in the target product, as dened in example 1 is 0.03 g or 0.16 wt.% in the calculation of the target product.

Thus, the claimed invention allows to increase the yield of the target product, to reduce the duration of the extraction and to reduce the content of impurities ester character in the target product - betulin.

td align="center"> The placeholder
Table

The allocation of betulin from birch bark aqueous solutions of dioxane.
No. sampleThe water content in dioxane, wt.%The duration of extraction, hThe output of betulin, wt.% on barkThe content of betulin in the extract, %Content omiltemi extract, %The degree of extraction of betulin, %
1319,7for 93.40,6160
201,520,393,80,3362
30,11,520,293,90,3361
40,1330,593,60,3393
510225,194,90,2376
620221,095,70,1964
730318,395,70,1656

Isolation of betulin from birch bark by extraction of neutral organic extractants, characterized in that the extractant use solutions of dioxane - water with content of from 0 to 20 wt.%.



 

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