The method of receiving sanguinarine

 

(57) Abstract:

Makley cordate and(or) makley small-fruited extracted with a hydrophobic solvent in the presence of an alkaline agent. Spend the deposition of bisulfate target alkaloids transferring them to the base and re-presidenial of bisulfate of the hydrophobic organic solvent. When this extraction is performed with ethyl acetate or dichloromethane sequential processing of multiple servings of raw materials one volume of the extractant on the counterflow principle. When cleaning as the alkaline agent is used an aqueous solution of ammonia as a solvent is chloroform. Side alkaloids optionally separated by filtration, extraction of the organic phase with water. The invention allows to simplify the process, reduce the consumption norms of raw materials and energy costs. table 1.

The invention relates to chemical-pharmaceutical industry, namely, the method of production of drugs of plant origin. Mainly can be used to obtain drug "Sangviritrin" possessing antimicrobial and anticholinesterase activity. "Sangviritrin" is a mixture of acidic bisulfate benzo[c]phenanthridinium alkaloi the different plant sources, for example Sanguinaria canadian (Sanguinaria canadensis). The essence of the first group of methods consists in the deposition of sanguinarine and chelerythrine in the form of a mixture of the chloride from the aqueous solution of their citrates concentrated solution of sodium chloride. During this operation, prior to obtaining citrate alkaloids vary, but the General is the use of polar extractant (water-methanol) on the head stage technology.

Thus, in the patent /1/ describes a method for chlorides sanguinarine and chelerythrine from Sanguinaria canadensis extraction of the roots of plants of water with methanol, acidified with citric and hydrochloric acids, precipitation of alkaloids salts of zinc, followed by dissolving the precipitate in a solution of citric acid, filtering the solution and the deposition amount of chlorides target alkaloids sodium chloride.

Also described is a method of obtaining the amount of chlorides sanguinarine and chelerythrine root Sanguinaria canadensis /2/ water extraction with methanol with the addition of caustic soda, the processing of the extract methylene chloride, extraction of alkaloids from the organic phase with an aqueous solution of citric acid and precipitation of chlorides target alkaloids from aqueous their citrates sodium chloride.

Described talinolol with the addition of hydroxide ammonium, cooling, filtering, drying the intermediate product, by dissolving the latter in hydrochloric acid and drying.

In another group of methods uses a hydrophobic solvent with the addition of an alkaline reagent.

In the patent /4/ described method to produce these alkaloids extraction of plant raw materials containing benzo[C]phenanthridinium alkaloids, with the addition of an aqueous solution of an alkaline reagent with a pH of 8.5 and an organic solvent type, methylene chloride, by treatment of the organic phase with an aqueous solution of the acid. Salts of the target compounds precipitate.

A similar method is proposed in patent /5/. It consists in extracting the crushed plant materials treated with hydroxide ammonium, dichloroethane, filtration, subsequent processing of the extract diluted sulfuric acid, separating drawn bisulfate alkaloids and recrystallization from acidified alcohol.

Pilot-regulations /6/ on the production of sanguinarine final stage of recrystallization was replaced by a cleaning product by re-translating bisulfate alkaloids in the Foundation, and then again in bisulfate.

The known is in an alkaline environment with a gradual elimination of the third volume of the extract from the extractor for carrying out the subsequent stages of treatment with sulfuric acid /7/. Waste organic phase is returned to the extractor, and water-acid - processing of a new portion of the extract. The disadvantage is the continuous decrease of the content of alkaloids in the organic extracts that hinders the precipitation of salts alkaloids of the extracts at the final stage of extraction. Furthermore, the method is unsuitable for the extraction of raw materials with a low content of the target alkaloids.

A method of obtaining the amount of salts of sanguinarine and chelerythrine from the grass of makley, consisting in the extraction crushed and treated with an aqueous solution of alkali raw materials with ethyl acetate or other esters of acetic acid followed by treatment of the organic phase with aqueous solutions of sulfuric or hydrochloric acid /8/. Cleaning technical product carried out by filtration of the aqueous solution, followed by treatment in an alkaline aqueous filtrate with ethyl acetate and processing of the organic phase with an aqueous solution of the same acid.

The disadvantage of this method is incomplete purification of the target amount of alkaloids from undesirable impurities. Compared with the methods /6, 9/ in the way /8/ cleanup phase technical product excluded filtering the organic phase after separation s nonpolar organic solvents. These impurities can contaminate the target product and must be removed.

The disadvantage of the first group of methods is the contamination of the product with mineral admixtures, citrates, impurities other benzo[c]phenanthridine alkaloids, if the goal is to retrieve only the salts of sanguinarine and chelerythrine. The second drawback is the use of head-stage toxic solvent is methanol.

Another group of methods of obtaining sanguinarine free from the first drawback, but in the case of use for the extraction of chlorinated hydrocarbons the second drawback is saved. For each method is marked private and disadvantages.

We previously proposed a method of obtaining sanguinarine using on the head stage non-toxic solvent that meets the requirements of ecology /9/. According to this method, the crushed grass of makley extracted with aqueous aliphatic alcohol, for example ethanol, in the presence of hydroxide ammonium, remove the alcohol in vacuo, treated with an aqueous phase of a hydrophobic solvent, such as dichloroethane, chloroform, methylene chloride, toluene, ethyl acetate, treated with the secondary extract Rabaul the 5/.

This method satisfies the requirements of ecology and provides obtaining the target product necessary qualitative and quantitative composition. However, the option /4-8/ may not be completely abandoned, as it can be used by companies with good sealing equipment.

The present invention is the optimization of the technological process allows to simplify it and reduce the rates of consumption of raw materials, electricity and other energy costs per unit of finished product, and to ensure the quality of the finished product. As a prototype elected way /8/.

Thus, the method of obtaining technical sanguinarine according to the prototype is the following: the extraction of the crushed material, treated with aqueous ammonia, ethyl acetate, filtering, processing of the extract diluted sulfuric acid, the separation of the precipitated sludge technical amount bisulfate of sanguinarine and chelerythrine, washing with acetone, drying and grinding of the finished product.

The disadvantage of the latter method is the selection of technical sanguinarine of the organic extract with a low concentration of alkaloids, the necessity to the technology process, because sulfuric acid is processed organic extract and each exhaust extract evaporated in vacuo separately, and inadequate cleaning product.

The use of chloroform on the stage of purification of technical product preferably ethyl acetate, as it is much better dissolve the alkaloids in the form of pseudomonotone after alkaline treatment of an aqueous solution of a technical product. This enables you to filter the organic solution with minimal losses. In the case of ethyl acetate is incomplete dissolution of pseudomonotone alkaloids that when you want to clean the filter leads to losses. If we exclude filtering with the aim of preserving the exit /8/, the product is not purified.

This object is achieved in that the crushed and dried grass of makley small-fruited or cordate, soaked in an aqueous ammonia solution, extracted with a hydrophobic organic solvent. The extract is filtered and served on the new batch of raw materials in the same sequence in which they were received. The missing volumes of extractant in subsequent boots after the first, and so obuslovlennogo D. ). In the last extract from the previous load, serves as an extractant for further loading, add fresh solvent. Alkalinization of conduct as necessary, so that the initial pH of the extractant was about 9. On fresh raw materials serves aqueous solution of ammonia, the amount of which decreases with increasing pH of the first extract. Enriched so organic extracts washed with water until neutral, treated with diluted sulfuric acid, technical product further purified according to the method /9/.

Comparative physico-chemical characteristics of sanguinarine obtained by the claimed method and method /9/ of materials with the same content of the target product, show that the inventive method provides for obtaining the target product that meets the requirements of normative and technical documentation on the product. The prototype of the product is less clear. The outputs of the drug in all three methods are close.

Compliance with the proposed method the criterion of "inventive" is caused by the obviousness of the possibility to use the same volume of solvent for the extraction of several servings of raw materials without reducing the extracting ability of the reagent.

The content of the target alkaloids in the technical product is 87-97%, which after purification rises to 96.5-99%, respectively. The moisture in the obtained samples is 3.7-4.9 percent. In General, all indicators of quality substance sanguiliano obtained by the proposed method meets the requirements of FS 42-2444-86.

The following are specific examples of implementation of the proposed method.

Example 1.

1 download. Crushed herb of makley content of sanguinarine 1,01% in the amount of 30.0 g, pre-moistened with 15 ml of 10% aqueous ammonia solution, extracted with 300 ml ethyl acetate (1:10) for 3 hours. Get 230 ml of the first extract from first boot with a pH of 8. The second extraction is carried out by pouring the raw material is the same extractant in the first volume of the extract from the first load (230 ml) with addition of 7.5 ml of 10% water is narrow with a pH of 8. The third and fourth extraction carried out similarly to the second. Get in 230 ml of the third and fourth extracts from first boot with a pH of 8.

2 download. Crushed herb of makley the same sample in the amount of 30.0 g, pre-moistened with 15 ml of 10% aqueous ammonia solution, fill in 230 ml of the first extract and 70 ml of the second extract from first boot (1:10). Extracted 3 hours. Get 230 ml of the first extract from two downloads, pH 8. The second extraction is carried out by pouring raw materials 170 ml (240 ml - 70 ml) the second extract and 60 ml of the third extract from first boot mixed with 7.5 ml of 10% aqueous ammonia solution. The extraction was carried out for 2 hours. Get 220 ml of the third extract from two downloads, pH 9. The fourth extraction is carried out by pouring the raw material 170 ml of the fourth extract from the first load and 50 ml of pure ethyl acetate, with the addition of 7.5 ml of 10% aqueous ammonia solution. The extraction time is 2 hours. Get 240 ml of the fourth extract from two downloads, pH 9.

Subsequent reboots carried out similarly to the second. The process set out in tabular form (see end of description)

Each extract from five downloads washed with water to pH 7 wash water, then treated with 10% aqueous solution of sulfuric acid, since chetvertok is of the reaction mixture is left for 30-40 minutes to coagulate the precipitate, then the precipitate is filtered off. Sulfuric acid the filtrate is again treated with the organic phase, as in the first case. After separation of the portions of the sediment volume of the sulfuric acid filtrate is brought to the original, adding the missing amount of 10% sulfuric acid and consistently spend twice the processing of III, II and I-th extract. The combined precipitates washed with ethyl acetate, then with acetone until the pH of the filtrate 5 on universal indicator paper, dried and milled. The output product from the mass of raw materials 0,98%. The content of alkaloids 96,84%. Cleaning technical product performed as described in /9/.

Technical sangviritrin (20 g) dissolved in water (300 ml) at a temperature of 90-95oC, cooled to room temperature, filtered, alkalinized by hydroxide of ammonia (25 ml, 25%), extracted with a hydrophobic solvent, chloroform (CH ml), filtered organic phase from the dark-colored impurities alkaloid nature, the organic phase is washed with water (I ml) to remove ammonia and alkaloids zwitterionic character, and then precipitated sangviritrin treatment with 5% solution of sulfuric acid (150 ml). The precipitation is filtered on a Buchner funnel under vacuum, washed with acetone (835 ml) and sushi% and the content of sanguinarine in drug 98,95%.

Comparative experiments obtaining technical sanguinarine different ways and content of sanguinarine in raw materials is 1.01%. It was found that the content of sanguinarine technical product ranges from 87,41% to 99,54% depending on the extractant.

Example 2.

The extraction of raw materials were carried out as described in example 1, except that as a solvent used dichloroethane. As the alkaline agent in the wetting of fresh raw materials using 10% ammonia solution and subsequent extraction, when the alkaline agent is paid extractant, using 25% ammonia solution. The number of downloads in a continuous loop 5, the number of extraction in each load 4. The output product from the mass of raw material is 1.01%. The content of total alkaloids 97,67%. Cleaning technical product were carried out as described in example 1.

Example 3.

The extraction of raw materials were carried out as described in example 1, except that the number of extraction in each load 3, number of downloads in a continuous loop 3, the first extraction 3 hours, the second and third extraction for 2 hours. Output technical sanguinarine from the mass of raw materials 0,88%. The alkaloid content in the technical is straccia raw materials, shown in examples 1-3, confirms that there is an exhaustive extraction in all five weekly cycle. The content of sanguinarine in the meal on the analytical data (extractant-ethyl acetate):

1 download - 0,024; 2 download - 0,022; 3 download - 0,023; 4 download - 0,033; 5 download - 0,022%

The advantages of the proposed method of obtaining sanguinarine is as follows.

1. Reduction of expenses provisions of the extractant on the head stage per unit of finished product is approximately 4-5 times in a continuous loop of 5 downloads.

2. Reducing the time and amount of sulfuric acid per unit of finished product, as the acidic treatment with organic extracts is carried out only once at the end of a continuous cycle of multiple downloads.

3. Reducing the complexity and intensity of the process as waste organic phase evaporated in vacuum at the end of just a continuous cycle of multiple downloads.

4. Reduction standards for emissions of toxic substances per unit of finished product.

5. The production efficiency when working with raw materials of low quality (the content of sanguinarine about 0.6%). The ability to get the product from nestand the ptx2">

2. Application 0379623, EPO, MKI5C 07 D 491/14.

3. U.S. patent 5133981, US 546-41.

4. U.S. patent 4813533, US 546-41.

5. RF patent 571268, A 61 K 35/78, "Method of obtaining sanguinarine".

6. B. N. Zakharov, N. I. Chibisov, H. A. Aslanov. Medicinal substances from plants and methods for their production. Ed.FAN Uz.SSR, Tashkent, 1980, S. 136-138.

7. RF application 93057354/14, A 61 K 35/78 "Method of obtaining sanguinarine from makley".

8. RF patent 2051687, A 61 K 35/78 "Method of production of sanguinarine and chelerythrine".

9. RF application 95117356, A 61 K 35/78 "Method of obtaining sanguinarine". A positive decision on granting a patent from 28.08.96.

The method of receiving sanguinarine from the aerial parts of makley small (Macleaya microcarpa) and makley cordate (Macleaya cordata), including solid-phase extraction of the crushed material a hydrophobic solvent in the presence of an alkaline agent, the deposition of bisulfate target alkaloids, treatment of a mixture of salts of alkaloids processing filtered and modelchange aqueous solution with an organic solvent followed by treatment of the organic phase with an aqueous solution of sulfuric acid, separating the precipitate by filtration and wash it with acetone, characterized in that the extraction of the ethyl is the Gent on the counterflow principle with the formation of extracts, enriched alkaloids, when cleaning as the alkaline agent is used an aqueous solution of ammonia as a solvent is chloroform, side alkaloids before processing the organic phase with a solution of sulfuric acid addition is separated by filtration of a solution of an organic solvent and extraction of the organic phase with water.

 

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