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  • 优先权
    • 专利摘要:
    Tumor inhibiting alkaloids are recovered from Vinca Rosea L. by a method which comprises extracting the dried leaves with a solvent selected from the group consisting of an alkanol having 1 to 5 carbon atoms, a mixture of an alkanol having 1 to 5 carbon atoms and a dilute, aqueous solution, benzene and benzene homologs; subsequently purifying the alkaloid extract obtained by a phase-change method between immiscible solvents, precipitating the main amount of dimeric alkaloids in form of their sulphuric acid addition salts, isolating leurosine, vincistine, vinblastine, desacetoxy-vinblastine, N-desmethyl-vinblastine and desacetyl-vinblastine from the salt mixture obtained, and then completing the separation and isolation of the remaining alkaloids by separation and isolation by adjusting the pH-value of the mother liquor, after precipitation and removal of the salt mixture, to 5.5 to 10, extracting the solution with a water-immiscible organic solvent and separating vindoline, catharantine, 3',4' -anhydrovinblastine and leurosine from the extract by chromatography, extracting vindoline in the pH-range of 2.5 to 3.5 and catharantine 3',4'-anhydrovinblastine and leurosine in the pH-range of 5 to 6 with benzene or a benzene homologue, from the mother liquor obtained when isolating the salt mixture, and separating a mixture of leurosine and 3',4'-anhydrovinblastine by crystallization, epoxidizing this mixture with an oxygen source, or separating the mixture into its components by chromatography, and subsequently epoxidizing the 3',4'-anhydrovinblastine component to leurosine, and isolating catharantine remaining from the mother liquor obtained when separating the crystalline mixture, or separating the extract containing catharantine, 3',4'-anhydrovinblastine and leurosine into its components by chromatography.
    公开号:SU867313A3
    申请号:SU782621102
    申请日:1978-05-30
    公开日:1981-09-23
    发明作者:Йованович Карола；Фекете Дьердь；Дежери Эстер；Данчи Лайош；Леринч Чаба；Сарвади Бела；Добо Дьердь；Сантаи Чаба；Сабо Лайош
    申请人:Рихтер Гедеон Ведьесети Дьяр Р.Т. (Инопредприятие)；
    IPC主号:
    专利说明:

    blastin and leurozin, which are subjected to chromatographic separation or from this mixture by crystallization, the mixture of lilirosin and 3, 4-anhydrovinblastin is separated and subjected to epoxidation after separation of 3, 4 - anhydro vinblastine, and then from the crystalline product obtained after separation of the mother liquor are quarantine. Distinctive features of the method are the use of a mixture of methanol with a dilute aqueous solution of acid and benzene or its homolog for extraction, extraction of the aqueous phase at pH 8.5-9 with benzene or its homolog, treatment of the residue after evaporation of the solvent with an alcoholic solution of sulfuric acid, extraction of the crude solution after separation of sulfuric salts of leurozin, vincristine, vinblastine, deacetoxivinblastine, N-desmethylvinblastine, deacetylvinblastine at pH 5.5-10 with benzene or its homologue, followed by chromatograph p aphic secretion from vindolin extract, atarentin, h, 4 - anhydrovinblastine and leurozine, or extraction of the stock solution with benzene or its homolog at pH 2.53, 5 vindolin, at pH 5 b-caratrantin, h, 4 -anhydrovinblastin and rosin lei, which subjected to chromatographic separation or from this mixture by crystallization the mixture of leurozin and 3, 4 - anhydrovinblastine is separated and subjected to epoxidation of it or 3, 4 - anhydrovinblastin after isolation, and from the crystalline product obtained after separation of the mother liquor, quarantine This method can be used to obtain about 0.4-0.5 g of leurozin, 0.4 g of quarantine and 0.8 g of vindolin from 1 kg of dried leaves. Preferably, a 2–3% aqueous solution of sulfuric or tartaric acid with benzene or toluene is used. If biphasic was used for extraction, it also contained binder. with benzene or its homologs, the mixture, after the end of extraction, the organic phase is separated, shaken with a dilute aqueous acid solution (to transfer all alkaloids into the aqueous acidic phase) and the aqueous acidic phase is combined with the previously obtained water-alcohol phase. If, however, the benzene phase is not used in the extraction from the crushed, dried leaves, it is advisable to subject the aqueous-alcoholic extract to extraction with organic solvents, preferably benzene, in order to purify it from chlorophyll and other organic coloring agents. Epoxidation should be carried out using organic hydroperoxides, lianpHMep, cumyl or tert-butyl hydroperoxide, alkali metal hypohalites or oxygen, preferably oxygen. If air oxygen is used as an epoxidizing agent, the reaction in any organic solvent always proceeds selectively to form leurozin. The most preferred solvents are tetrahydrofuran and dimethylformamide. Example. 1 kg of crushed dried leaves of Vinca rosea L. are impregnated with a mixture of 1 l of methanol and 0.25 l of a 2% aqueous solution of sulfuric acid, after which 5 l of toluene are added and stirred for 1.5 hours. After separating the liquid phase, the extraction is repeated another three times portions of toluene, 5 l each. The toluene phases are combined and from the combined phase the extraction is carried out three times with a 2% aqueous solution of sulfuric acid in 5 l portions (or until the last aqueous acidic extract no longer contains alkaloids. The aqueous acidic phases are combined and for removal of chlorophyll and other colored impurities from them is shaken twice with benzene in 1 l portions, the pH of the separated aqueous phase is then adjusted with a concentrated aqueous solution of ammonium hydroxide to 8.5-9 and the aqueous phase is subjected to this pH value of extraction b nzol (four portions and 1 l each). The benzene phases are combined, dried with anhydrous sodium sulfate, filtered and evaporated to dryness. From the resulting mixture of about 10 g of alkaloids bases, the sulfate salts of diindole ulcaloids (vincristine, leurozine, vg iblastine, deacetoxivinblastine, N- dezmetilvinblastina and dezacetilvinblastina) are precipitated in a known manner using an ethanolic solution of sulfuric acid to obtain 0.73 g of a mixture of sulphate salts, from which individual diindiol alkaloids can be isolated by known methods their 0.18 g leurozina. The first stock solution obtained after filtering the above mixture of salts (about 100 ml) is diluted with 1.5 liters of water and its pH is set to 2.7-3.0. The acidic solution is subjected to extraction with benzene (five times in 1 l portions). The separated aqueous phase is left for further processing (mother liquor 11). The benzene phases are combined, dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The residue after evaporation is dissolved in 12 ml of benzene, clarified by adding 0.5 g of activated carbon to the solution, and 25 g of alumina (degree of activity) is filtered through a layer. This layer is then washed
    150-200 ml of benzene until vindolin is completely removed. The washings were combined with the filtrate and evaporated. The residue after evaporation is dissolved in ml of diethyl ether and the solution is left until crystals precipitate out of it. The precipitated crystals are filtered, washing with twice 1 ml of diethyl ether and dried is obtained; 0.8 g of vindolin is obtained; mp 167168 ° C; W -28,5 ° (, in chloroform).
    The mother liquor obtained at the above treatment was brought to pH 5.5 with a dilute aqueous solution of C1MMONIUM hydroxide and then extracted with benzene (3g of liter in 1 l increments). The course of the extraction is controlled by thin layer chromatography. The pH of the extractable solution before the addition of the next portion of benzene is set equal to 5.5. The benzene extracts are combined and evaporated, and the residue after evaporation is recrystallized from methanol. The resulting crystals are filtered off and the methanol mother liquor is left for further processing. The crystalline product obtained in an amount of 0.35 is a mixture of deirosin and 3, 4 - aigidrovinblastin in a 1: 1 ratio.
    The resulting mixture of leurosine and 3, J - anhydrovinblastin is dissolved in 30 ml of dimethylformamide and passed. through the solution of air for 15 minutes. The solution is left standing for 16-20 hours, after which it is adjusted to pH 8.5 and subjected to extraction with benzene. The benzene extract is evaporated to dryness to obtain 0.25 g of leurozin; m.p. 202-204С +79.4, in chloroform.
    The methanolic solution obtained by crystallization of a mixture of leurosine and 3, 4-anhydrovinblastin is evaporated to dryness. The residue is dissolved in 12 ml of benzene and the solution is subjected to chromatography on a column filled with 100 g of alumina (degree of activity III). Elution was performed with benzene, 50 ml fractions were collected. The content of the quarantine in the fractions is controlled by thin layer chromatography. The majority of the quarantine is contained in the fourth fraction. The fractions containing quarantine are combined and evaporated to dryness. The residue after evaporation is dissolved in a 1.25% ethanolic solution of sulfuric acid (pH 4.55, 0) and the solution is left overnight during crystallization. The precipitated crystals are filtered, washed with 1-2 ml of ethanol and dried, to obtain 0.41 g of quarantine, - + 58 ° (in 96% ethanol).
    Example2. 1kg of crushed dried leaves of Vinca rosea L. are treated in the same way as in Example 1. After separation of the mixture of ultraviolet salts of dimeric alkaloids, approximately 100 ml of the stock solution is diluted with 1.5 liters of water and adjusted to pH of an aqueous solution ammonium hydroxide; n equal to 8.5-9. Extraction is carried out from the alkalized solution with benzene (four times in 1 l portions). The benzene phases are combined, dried over anhydrous sodium lofate, filtered and evaporated to dryness. The residue after evaporation is dissolved in 55 ml of benzene and the resulting solution is subjected to chromatographic separation on a column filled with 450 g of alumina (activity level I1). First, elution was carried out with 2 l of benol, and then 4.5 l of a mixture of benzene and chloroform in a ratio of 3: 2. Collect fractions of the eluate in 200 ml. The content of alkaloids in individual fractions is controlled by thin layer chromatography. The first four fractions do not contain alkaloids. Quarantine is in fractions 5–9, vindolin is contained in fractions 21–26, vindolin in fractions 27 and 28 and 3–4 an. Hydrininblastin is contained in fractions 27 and lerosin in fractions 2934. The fractions containing oline and the same alkaloid are combined and evaporated to dryness, the following products are obtained: 0.57 g of quarantine (from fractions 5–9), from which 0.52 g of quarantine sulfate can be obtained. 0.145 g of 3, 4-anhydrovinblastin (from fractions 27 and 28 after recrystallization from methanol), so pl. 212214 С; td.li + 64.2 ° (, 5, in chloroform); 0.125 g of leurosine (from fraction 29-34, after recrystallization from methanol); 0.78 vindolin (from methanol stock solution obtained after separation of 3.4 anhydrovinblastin and from fractions 2126, after recrystallization from diethyl ether).
    Froze 0.145 g H, 4 anhydrovinblastin is dissolved in 20 ml of dimethylformamide. A weak stream of gaseous oxygen is passed through the solution for 10 minutes, after which the reaction mixture is left for 16-20 hours at room temperature. Then the pH of the mixture was adjusted to 8.5 using a concentrated aqueous solution of ammonium hydroxide and extraction was performed with benzene (three times in 25 ml portions). The benzene extracts are combined, dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The residue is recrystallized from 1 ml of methanol, to obtain 0.11 g of leurozin (75% of theoretical yield).
    权利要求:
    Claims (1)
    [1]
    1 .. Patent of Hungary 160967, cl. C 07 d 57/02, 1970 (prototype).
    类似技术:
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    同族专利:
    公开号 | 公开日
    IT7824055D0|1978-05-31|
    CA1094552A|1981-01-27|
    FR2393002B1|1983-05-20|
    YU129378A|1983-10-31|
    IL54761D0|1978-07-31|
    IT1096605B|1985-08-26|
    FR2393002A1|1978-12-29|
    JPS5439100A|1979-03-24|
    DK239178A|1978-12-01|
    IL54761A|1981-09-13|
    BE867670A|1978-09-18|
    DD136139A5|1979-06-20|
    AT364469B|1981-10-27|
    ATA391578A|1981-03-15|
    HU178084B|1982-03-28|
    AU3664978A|1979-12-06|
    CH640861A5|1984-01-31|
    AU515713B2|1981-04-16|
    DK146765C|1984-06-04|
    NL7805881A|1978-12-04|
    SE7805900L|1978-12-01|
    DE2823461A1|1978-12-14|
    DK146765B|1983-12-27|
    GB1602633A|1981-11-11|
    US4172077A|1979-10-23|
    SE437829B|1985-03-18|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3097137A|1960-05-19|1963-07-09|Canadian Patents Dev|Vincaleukoblastine|
    US3205220A|1961-10-26|1965-09-07|Lilly Co Eli|Leurosidine and leurocristine and their production|
    US3392173A|1964-03-09|1968-07-09|Lilly Co Eli|Novel acyl derivatives of desacetyl-vincaleukoblastine and processes for their preparation|
    US3352868A|1964-04-01|1967-11-14|Lilly Co Eli|Dihydrovinblastine|
    US3370057A|1964-04-27|1968-02-20|Lilly Co Eli|Leurosine|
    US3225030A|1965-02-15|1965-12-21|Lilly Co Eli|Method of preparing leurosine and vincaleukoblastine|
    US3422112A|1968-01-22|1969-01-14|Lilly Co Eli|Indolyl vindolines|
    AT313485B|1971-09-17|1974-02-25|Richter Gedeon Vegyeszet|Process for the selective extraction of vinblastine, vinleurosine and vinchristine or their salts|
    US3932417A|1973-10-24|1976-01-13|Eli Lilly And Company|Dimeric indole alkaloid purification process|FR2296418B1|1974-12-30|1978-07-21|Anvar|
    FR2544318B1|1983-04-14|1985-08-16|Fabre Sa Pierre|PROCESS FOR THE PREPARATION OF VINDOLINE AND CATHARANTHINE|
    US4778885A|1986-09-18|1988-10-18|Allelix Inc.|Production of alkaloid dimers using ferric ion|
    US4749787A|1986-10-23|1988-06-07|Harbor Branch Oceanographic Institution, Inc.|Process of isolating vinblastine from the plant catharanthis roseus|
    US4831133A|1987-05-01|1989-05-16|Allelix, Inc.|Extraction of alkaloids of Catharanthus roseus tissue|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU77RI638A|HU178084B|1977-05-31|1977-05-31|New process for the extraction of native vindoline,catharantine,3',4'-anhydrovinblastine,leurosine and,if desired,of other diinodle alkaloids from vinca rosea l.drogue|
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