Gamma-schizadrin synthesis method

FIELD: chemistry.

SUBSTANCE: Chinese magnolia is extracted with liquefied carbon dioxide. The obtained CO2 extract undergoes chromatographic separation on aluminium oxide and eluated with hexane. After eluation the obtained hexane fractions are frozen and recrystallised from the chloroform-hexane mixture in ratio of 1:10-3:10.

EFFECT: high output of product.

1 ex

 

The invention relates to chemical-pharmaceutical industry, in particular the production of medicines in the form of substances and individual biologically active compounds.

Schisandra chinensis is widely known in traditional and folk medicine, medicinal plant, toning activity which is due to the presence of Lignano. One of the main representatives of these compounds is gamma-schizandrin [1].

In the absence in our country the state standard sample of gamma-schizandrin is still an open question regarding the standardization of raw materials and products, including dietary supplements schisandra chinensis. Thus, standardization of fruits and seeds of schisandra spend only

external features, microscopy and numerical indicators [2, 3], and the analysis of the drug "Schisandra seed tincture" - on essential oil content, the amount of fatty and essential oils [4].

The presence of gamma-schizandrin will allow you to develop a state standard sample of gamma-schizandrin, which, in turn, will give the opportunity to offer methods of analysis of fruits and seeds of schisandra chinensis, drugs and biologically active additives based on them, which will meet the current requirements of objective standards.

A method of obtaining the Amma-schizandrin by extraction of the leaves and stems of schisandra chinensis liquefied carbon dioxide at supercritical pressure 20-27 MPa and a temperature of 40-60°C [5]. After static extraction (10-15 min) was followed by a dynamic extraction of liquefied carbon dioxide. The samples were dissolved in 2 ml of acetonitrile (first column) and methanol (second column), was filtered through a cartridge filled with silica gel and stationary phase With18, and conducted the analysis by high performance liquid chromatography (reversed phase). Conditions of the first analytical column (UV diode detector and Refractometer HP 1090 (Hewlett-Packard), column EU 250×4 mm, stationary phase Nucleosil 100 5 µm18; and guard column 8×4 mm I.D., Nucleosil 100 5 µm18- the temperature of 18-20°C, the analytical wavelength 254 nm; gradient A: CH3CN-H2O: 5 min 50:50 isocratic, gradient, 30 min, 60:40, gradient 20 min 70:30, 15 min, 70:30 isocratic; gradient: Meon-H2O: 1 min 70:30, 34 min gradient 95:5, 5 min 95:5 isocratic. The second analytical column was carried out using a liquid chromatograph PV 4100 (Philips), the detector in the ultraviolet and visible part of the spectrum PV 4110 and a multichannel detector Pye Unicam PV 4021 and consistently column Tessek-CGC SGX C18, 10 μm, 30×3 mm I.D. and column Merck-Lichrospher 100 RP 18, 5 µm, 250×4 mm I.D. chromatograph Conditions were as follows: temperature is about 25°C, analytical wavelength 254 nm; mobile phase acetonitrile-water 40:60 to 70:30, 60 min gradient, consistently 70:30, 30 min, isocr the political elution.

However, the disadvantage of this method is the low yield of gamma-schizandrin, which is 0,082% of air-dried raw materials and 0.017% of stems and leaves, respectively, as well as a multi-stage process.

This method is used as a prototype of the invention.

The aim of the invention is to increase the yield of gamma-schizandrin, possessing antioxidant activity of the fruits of schisandra chinensis.

This goal is achieved by the fact that after elution of hexane fraction and raids!! precrystallization from a mixture of chloroform-hexane in the ratio of 1:10-3:10.

The inventive method of obtaining gamma-schizandrin is as follows: initially, the raw material of Chinese Magnolia extracted with liquefied carbon dioxide. Received CO2the extract is subjected to chromatographic separation on alumina and elute with hexane.

This leads to the obtaining unit fractions (12-21), enriched gamma-schizandrin. The selection of gamma-schizandrin carried out by freezing one stripped off the hexane fractions and subsequent crystallization of the precipitate. Purification of the target substance carry out further by recrystallization from a mixture of chloroform-hexane.

During the experiment used physico-chemical analysis methods, such as adsorption liquid column chromatography thin layer chromatography (chromatographic plates "Sorbfil PTSH-P-a-UV), and the combination of extraction methods and recrystallization.

To analyze the structure selected lignana were used thin-layer chromatography and spectroscopic methods (UV-spectroscopy, spectrophotometer "Specord-40"; NMR-spectroscopy), allowing to identify the target connection as γ-schisandrin.

Was conducted pharmacological study of gamma-schizandrin in outbred mice, which for 6 days daily intramuscularly injected carbon tetrachloride at a dose of 2.0 g/kg On the background of toxic hepatitis in a group of animals treated with gamma-schizandrin at a dose of 25 mg/kg intraperitoneally, on the seventh day with the introduction of sodium thiopental intraperitoneally in the form of a suspension, the duration thiopental sleep was 131,83 min, which is 2.4 times lower than that in the control group (313,50 min).

Conducted by the applicant search on scientific, technical and patent information sources [6-10] and selected from the list of analogues prototype [5] allows to identify distinctive features in the claimed technical solution. Therefore, the inventive method of obtaining satisfies the criteria of the invention of "novelty."

The inventive method is illustrated by the following example.

Example 1. 250 g dried fruit of schisandra chinensis is extracted with liquid carbon dioxide at supercritical Yes the relocation 135-340 bar and a temperature of 40-80°C. The feed rate of the extractive agent about 250 ml/min, get the oil from the fruits of schisandra chinensis. The obtained oil (50 g) is mixed with is 224.4 g of aluminum oxide (II, neutral, Brockmann), dried. The obtained dry powder (CO2-extract+aluminum oxide) is applied to the layer of aluminum oxide formed in hexane (column height 20 cm, diameter 5.5 cm), and elute with hexane. The absence of impurities in the resulting connection is monitored by thin layer chromatography.

Of fractions (12-21), enriched gamma-schizandrin, the selection of gamma-schizandrin was carried out by freezing (-8-10°C) one stripped off the hexane fractions and subsequent crystallization of the precipitate. Purification of a target substance carried further by recrystallization from a mixture of chloroform-hexane in the ratio of 1:10-3:10.

To analyze the structure selected lignana were used thin-layer chromatography and spectroscopic methods to identify the target connection as γ-schisandrin.

The yield of the desired product as individual gamma-schizandrin - is 1.0 g or 0,40% by weight of air-dry raw material. Physicochemical and spectral characteristics of gamma-schizandrin following.

Gamma-schizandrin, prismatic crystals, white, With23H28About6, TPL 117-120°C, λmax(lambda) in EtOH: 220, 254 and 280 nm. Range of H'-NMR(CDCl 3) δ: 6,55 (s, 1H, H-4), of 6.49 (s, 1H, H-51), 5,95 (s, 2H, och2O), 3,90 (s, 3H, OCH3), 3,88 (s, 3H, och3), 3,82 (s, 3H, och3), 3,55 (s, 3H, och3), to 2.54 (m, 2H, H-7), 2,22 (DD, 9,1 t, 13,2 Hz, 2H, H-71), of 0.97 (d, 7.0 Hz, CH3-9), to 0.73 (d, 7.0 Hz, CH3-91).

Thus, the use of the claimed method of producing gamma-schizandrin provides the following benefits:

1) use in the claimed method as eluent hexane allows 4 and 23 times to increase the yield of the target product - gamma-schizandrin - from the fruit of schisandra chinensis compared to the prototype;

2) gamma-schizandrin, obtained by the claimed method from the seeds of schisandra chinensis has a pronounced antioxidant activity (duration thiopental sleep in animals is reduced by 2.4 times compared with the control group).

SOURCES of INFORMATION

1. Kurkin V.A. Pharmacognosy: a Textbook for students of pharmaceutical universities / Vasorin. - 2nd ed., revised and enlarged extra - Samara: Etching; Samara state medical University, 2007. - 1239 S.

2. State Pharmacopoeia of the USSR. - Tenth edition. - M.: Medicine, 1986. - 1078 S.

3. State Pharmacopoeia of the USSR. Eleventh edition (Issue 1). - M.: Medicine, 1989. - Vol.2. - 399 S.

4. FS 42-1822-90. Tincture of the seeds of the Magnolia State. inspection for quality control of medicines, products and honey. equipment. Pharmacopoeial Committee. - Instead of FS 42-1822-2; With an introd. 28.09.90 to 30.06.95. - M, - 5 C.

5. Bartlova, M. Liquid chromatographic analysis of supercritical carbon dioxide extracts of Schizandra chinensis / M. Bartlova, Opletal L., V. Chobot, H. Sovova // J. of Chromatography B.2002. - No.770. - P.283-289.

6. Kochetkov H.K. Chemical study of Chinese Magnolia vine / Nccadv, Ajaxonly, Oscill // J. of General chemistry, 1961. - t. - s-3460.

7. Ikeya, Y. The constituents of Schizandra chinensis Baill. I. Isolation and structure determination of five new lignans, gomisin a, b, C, F and G, and the absolute structure of schizandrin / Y.Ikeya, H.Taguchi, I.Yosioka, H.Kobayashi // Chem. Pharm. Bull. (Tokyo). - 1979. - Vol.27, No.6. - P.1383-1394.

8. Ikeya, Y. The constituents of Schizandra chinensis Baill. X. The structures of γ-Schizandrin and Four New Lignans, (-) Gomisins L1and L2(±)-Gomisin M1and (+) Gomisin M2/ Y.Ikeya, H.Taguchi, I.Yosioka // Chem. Pharm. Bull. (Tokyo). - 1982. - Vol. 30, No.6. - P.132-139.

9. Slanina, L. Lignans in the seeds and fruits of Schizandra chinensis cultured in Europe / L.Slanina, E.Taborska, L.Lojkova // Planta Med. - 1997. - Vol.63, No.3. - P.277-280.

10. Kim, Y. Effect of plant matrix and fluid ethanol concentration on supercritical fluid extraction efficiency of schizandrin derivatives / Y.Kim, Y.H.Choi, Y.W.Chin, Y.P.Jang, Y.C.Kim, J.Y.Kim, S.N.Joung, M.J.Noh, K.P.Yoo // J.Chromatogr. Sci. 1999. - Vol.63, No.3. - P.277-280.

The method of obtaining gamma-schizandrin from raw materials of Chinese Magnolia vine, including extraction of liquefied carbon dioxide and elution with an organic solvent, characterized in that the CO2the extract is subjected to chromatographic separation on alumina and elute with hexane, after elution of hexane fraction obtained raids!! and recrystallized from a mixture of chloroform-g is Xan in the ratio of 1:10-3:10.



 

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