• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    1479512 Purification of dimeric vinca alkaloids ELI LILLY & CO 23 Oct 1974 [24 Oct 1973] 45910/74 Heading C2C A process for purifying the dimeric indole alkaloids-vincristine, des-N-methylvinblastine, and vinblastine-which comprises the following steps: (a) extracting a plant source of said alkaloids with acid; (b) raising the pH of the acidic solution from step (a) (preferably to pH = 6) and extracting the dimeric alkaloids into a waterimmiscible organic solvent, e.g. benzene; (c) optionally subjecting the extracted dimeric alkaloids from step (b) to gel exclusion chromatography preferably in a pH= 7 buffer; (d) dissolving the extracted dimeric alkaloids from step (b) or step (c) in a C 1-4 alkanol; (e) optionally separating any precipitated alkaloids from the alkanolic solution of step (d); (f) converting the alkaloids from step (d) or step (e) to the sulphate salts and isolating the precipitated alkaloid sulphate salts; (g) optionally converting the isolated sulphate salts to the corresponding free bases; (h) subjecting the alkaloid sulphate salts from step (f) or the alkaloid free bases from step (g) to high pressure chromatography over alumina; (i) collecting the chromatographic fractions containing purified separated vincristine, des-N-methyl-vinblastine and vinblastine substantially free of other dimeric vinca alkaloids and from each other.
    公开号:SU884573A3
    申请号:SU742062709
    申请日:1974-09-24
    公开日:1981-11-23
    发明作者:Юджин Джонс Вильям
    申请人:Эли Лилли Энд Компани(Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD OF OBTAINING DES-N-METHYL-WINE BLASTINE
    one
    The invention relates to an improved method for the preparation of des-M-methylvinblastin with pharmacological activity.
    A method of producing de-M-methylvinblastin is known, which consists in boiling vincristine sulfate solution in 0.01% sulfuric acid, after basifying with ammonium hydroxide) 0 is extracted with methylene chloride, the extract is evaporated to dryness, the residue is dissolved in methylene chloride, diluted ether, filtered, the filtrate is evaporated to dryness, the residue is chromatographed on alumina, eluted with benzene-chloroform 13.
    The disadvantage of this method is the use of vincristine as a raw material, Kotopafi has a high effect (2) in the treatment of cancer and requires prior isolation from natural sources.
     The purpose of the invention is to simplify the process, allowing the release of des-M-25-methylquinblastin directly from plant extracts from the plant.
    The goal is achieved by the method of obtaining des-N-methylvinblac-30
    Tin, which means that the Vinca rosea plant is extracted with an aqueous acid solution, filtered, the concentrate is concentrated under vacuum, extracted with benzene, the benzene extract is discarded, the pH of the aqueous solution is raised, the mixture is extracted with an organic solvent, the extract is evaporated under vacuum, the residue is dissolved in the lower alcohol, the alkaloids contained in it are converted to sulphates, from which bases are obtained and chromatographed on alumina under high pressure, followed by the selection of chromatographic fractions s containing the desired product. ; For extraction, an aqueous acidic solution is used at a pH of about 3.
    The extraction of the aqueous solution is preferably carried out at a pH of about 6, and benzene is used as the water-immiscible solvent. Alkaloid judgments are preferably prepared by adding a solution of sulfuric acid in ethanol to a pH of 5.3.
    N: p and me. Purification of des-N-lviyyblastina.
    权利要求:
    Claims (3)
    [1]
    270 kg of dried leaves of Qataranturs rose twice for 1 hour, using 22 volumes of water at 50 ° C, acidified to pH 3, by adding 30% (weight / volume sulfuric acid. Aqueous extracts are drained from the fibrous material, combined After the termination of the ration to one-fifth volume in vacuo, the filtrate is extracted twice with dilute volumes of benzene and the benzene extracts are discarded. Then the pH of the filtrate is increased to pH 6 by adding concentrated ammonium hydroxide. The aqueous phase at pH 6 is extracted twice with equal volumes benzene. The benzene extracts are combined and concentrated in vacuo to obtain a precipitate of 793 g of a crude alkaloid. The crude alkaloid is dissolved in 5 volumes of anhydrous ethanol. The pH of the solution is adjusted to 5.3 by adding 3% sulfuric acid in ethanol. The vinblastine crystallization mixture is stirred for 48 hours and 112 sulphate salts of the dimeric alkaloid are collected by centrifugation and drying. These SALTS are converted into the corresponding free bases by dissolving in water, adjusting the pH of the aqueous solution to 8 osredstvom 7% strength (weight / obemj ammonium hydroxide, followed by extraction with methylene chloride and kaloidov. Methylene chloride extracts are concentrated to dryness in vacuo to give 99 g of free base. The free base was chromatographed on 3400 g of alumina (lli-iV activity, 200 mg / g) using ethyl acetate-methylene chloride as water (25: 75: 0.4j). The chromatography was carried out in a stainless steel column, 2 5 cm by 7 m, at a pressure of 500-900 psi (35.1363, 27 kg / cm). The ratio of alumina to loading is approximately 250/1. The eluate is controlled at a wavelength of 280 nm and fractions separated on the basis of peaks of ultraviolet sinter rzg. Fraction containing des-M-hetilvinblastin by thin-layer chromatography eluted after aluminization of vinblastine. All des-N-methylvinblastin fractions were concentrated to dryness in vacuo to give 7.73 g. Formula 1. Invention method for the production of des-N-methylvinblastin using an organic solvent extraction step and alumina chromatography, characterized in In order to simplify the process, the Vinca rosea plant is extracted with an aqueous acid solution, filtered, the filtrate is concentrated in vacuo, extracted with benzenes, the benzene extract is discarded, the pH of the aqueous solution is raised, extracted with no eshivayuschims organic solvent with water, the extract was evaporated in vacuo, the residue was dissolved in a lower alcohol, alkaloids dissolved therein is converted into sulfates, from which the base and their chromatographed on alumina under a high pressure, followed by selection of chromatographic fractions containing the desired product.
    [2]
    2. Method POP.1, characterized in that an aqueous solution of the acid is used at extraction at a pH of about 3. 3. Method POP.1, characterized in that the extraction of the aqueous solution is carried out at a pH around biv as an organic solvent that is not miscible with water benzene. 4. The method according to claim 1, and the fact that the sulfates of alkaloids are obtained by adding a solution of sulfuric acid in ethanol to a pH of 5,
    [3]
    3. And the sites and information taken into account during the examination 1. US patent No. 3354163, cl. 260-287, 1967.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU884573A3|1981-11-23|Method of preparing des-n-methylvinblastin
    SU867313A3|1981-09-23|Method of preparing alkalods-leurosin,vincrystin,vinblastin,desacetoxyvinblastin,vindolin,catharantin,3.4-anhydrovinblastin
    Crow et al.1970|New alkaloids of Alstonia constricta
    US3799933A|1974-03-26|Method of preparing new indolic derivatives usable for synthesizing dextro-rotary vincamine
    SU657751A3|1979-04-15|Method of obtaining vincamine and/or epi-16-vincamine
    US3887565A|1975-06-03|Vincadioline
    CN108558913B|2020-06-19|Preparation method of vincristine sulfate
    CN105753820B|2018-04-06|A kind of method of purification of dehydroandrographolide succinate
    US6676976B2|2004-01-13|Process for the production of vasicine
    EP0295273A1|1988-12-21|Method of isolating vinblastine
    CN100376577C|2008-03-26|Method for preparing vindoline and Catharanthine
    SU670304A1|1979-06-30|Isocoryn production method
    Kupchan et al.1955|Zygadenus Alkaloids. VI. 1 Active Principles of Zygadenus paniculatus2
    SU495311A1|1975-12-15|Method for isolating alkaloids from greater celandine
    SU1168254A1|1985-07-23|Method of obtaining rosavine
    Kutney et al.1982|Studies on natural products from Cuban plants. Alkaloids from Tabernaemontana citrifolia
    EP1487837B1|2006-08-30|An improved process for the production of vasicine
    SU833252A1|1981-05-30|Method of obtaining flavonoids
    RU2295355C2|2007-03-20|Method for production of lappaconitine hydrobromide
    SU435825A1|1974-07-15|METHOD OF OBTAINING OLEANDRIN
    SU410791A1|1974-01-15|
    Il'inskaya et al.1967|Alkaloids ofNuphar luteum
    US3008954A|1961-11-14|Process for obtaining an koquinuclt
    Aripova et al.1982|Subhirsine—A new alkaloid from the roots ofConvolvulus subhirsutus
    SU621681A1|1978-08-30|Method of obtaining sitosterol
    同族专利:
    公开号 | 公开日
    DD115675A5|1975-10-12|
    DK138541B|1978-09-25|
    HU170134B|1977-04-28|
    NL184110C|1989-04-17|
    NL184110B|1988-11-16|
    IL45553D0|1974-11-29|
    DE2442245A1|1975-04-30|
    SU1207396A3|1986-01-23|
    DK555374A|1975-06-16|
    ZA745355B|1976-03-31|
    JPS5649919B2|1981-11-25|
    CA1030963A|1978-05-09|
    PH10811A|1977-09-07|
    CS177884B2|1977-08-31|
    ATA856974A|1977-07-15|
    FR2249090B1|1979-01-05|
    SE418185B|1981-05-11|
    AR200542A1|1974-11-15|
    BG40316A3|1986-11-14|
    GB1479512A|1977-07-13|
    IL45553A|1979-01-31|
    PL95570B1|1977-10-31|
    SE7413357L|1975-04-25|
    DK138541C|1979-02-26|
    BE819663A|1975-03-10|
    YU36610B|1984-08-31|
    NL7413724A|1975-04-28|
    YU240574A|1982-02-25|
    AU7262774A|1976-02-26|
    US3932417A|1976-01-13|
    IE39669B1|1978-12-06|
    AT342215B|1978-03-28|
    IE39669L|1975-04-24|
    FR2249090A1|1975-05-23|
    JPS5070400A|1975-06-11|
    ES431340A1|1976-11-01|
    CH606022A5|1978-10-13|
    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|
    US3225030A|1965-02-15|1965-12-21|Lilly Co Eli|Method of preparing leurosine and vincaleukoblastine|
    US3354163A|1966-12-15|1967-11-21|Eli Lillty And Company|Nu-desmethylvinblastine|
    DE2124023C3|1970-05-27|1980-07-10|Richter Gedeon Vegyeszeti Gyar R.T., Budapest|Process for the selective extraction of vinblastine, vinleurosine and vincristine or their sulfates|
    BE793336A|1972-12-05|1973-04-16|Richter Gedeon Vegyeszet|METHOD FOR INCREASING THE YIELD OF VINCRISTINE WHEN ISOLATING VINCRISTINE FROM PARTS OF THE VINCA ROSEA L.|HU178084B|1977-05-31|1982-03-28|Richter Gedeon Vegyeszet|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|
    US4749787A|1986-10-23|1988-06-07|Harbor Branch Oceanographic Institution, Inc.|Process of isolating vinblastine from the plant catharanthis roseus|
    EP2266607A3|1999-10-01|2011-04-20|Immunogen, Inc.|Immunoconjugates for treating cancer|
    CN100336817C|2005-07-12|2007-09-12|东北林业大学|Method of chromatography preparing high purity catharanthine sulphate by continuous medium pressure column|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/409,225|US3932417A|1973-10-24|1973-10-24|Dimeric indole alkaloid purification process|
    [返回顶部]