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WO2006012824A1 - Method for producing dimethylaminoarglabine hydrochloride - Google Patents

Method for producing dimethylaminoarglabine hydrochloride Download PDF

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Publication number
WO2006012824A1
WO2006012824A1 PCT/DE2005/001175 DE2005001175W WO2006012824A1 WO 2006012824 A1 WO2006012824 A1 WO 2006012824A1 DE 2005001175 W DE2005001175 W DE 2005001175W WO 2006012824 A1 WO2006012824 A1 WO 2006012824A1
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Prior art keywords
preparation
hydrochloride
dimethylaminoarglabin hydrochloride
chromatography
dimethylaminoarglabin
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Ceased
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PCT/DE2005/001175
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German (de)
French (fr)
Inventor
Klaus-Dieter GÖHLER
Joachim Engelmann
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CHEMIEANLAGENBAU CHEMNITZ GmbH
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CHEMIEANLAGENBAU CHEMNITZ GmbH
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Priority to EP05763725A priority Critical patent/EP1771232A1/en
Priority to EA200700070A priority patent/EA200700070A1/en
Publication of WO2006012824A1 publication Critical patent/WO2006012824A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

  • the innovation relates to a process for the preparation of dimethylaminoarglabin hydrochloride from in the aerial parts of the plant Artemisia glabella kz. et kirg. occurring Arglabin.
  • Dimethylaminoarglabin hydrochloride is used in the field of cancer therapeutics.
  • the amination is carried out by dissolving the crystalline arglabine in alcohol with addition of dimethylamine in the form of an aqueous solution until the pH of 12.3 to 12.4 is reached.
  • the formation and isolation of the hydrochloride from the Aminoarglabin now carried out by distilling off the alcohol and addition of chloroform, separation of the remaining water and filtration of the solution, evaporation of the chloroform and addition of alcohol, introducing hydrogen chloride to the pH of the solution 5.0 - 5.5, evaporation of the alcohol and addition of ethyl acetate.
  • the invention specified in claim 1 is therefore based on the problem to provide a process for the preparation of dimethylaminoarglabin hydrochloride, which eliminates these disadvantages.
  • This object is achieved by the invention in that from the above-ground parts of plants of Artemisia glabella kz. et kirg. after air drying, purification of worthless substances, extraction and chromatography, the amination and hydrochloride formation is carried out successively in a reactor without repeated intermediate isolation, such as evaporation, filtration or dehydration, with only one change of organic polar solvent.
  • the aboveground plant parts of Artemisia glabella kz. et kirg. are dried in the air and then ground. After transfer of the ground material in a o mixer-drier, the abortion of essential oils takes place first by adding water and steam under reduced pressure. Thereafter, the starting material is dried under reduced pressure in the same apparatus to a residual moisture content of 5-7%. The pretreated and dried starting material is transferred to the extraction basket of the carbon dioxide extraction unit 5.
  • the extraction with supercritical carbon dioxide also by known modifiers in its extraction power modified carbon dioxide, depending on the plant material, temperature, extraction pressure and composition of the carbon dioxide provides a crude extract with a value of 20 - 35% by weight of arglabin.
  • the HPLC purification is an isocratic chromatography on a reverse phase silica gel with RP-8 or RP-18 silica gel 5 and an aqueous-organic phase, preferably mixtures of acetonitrile / water or alcohols and water.
  • the recyclable fraction is determined using a UV detector as the detector.
  • a rinse step with acetonitrile or alcohols is performed to eliminate late elution from the separation column. Subsequently, with the respective eluent system, the separation column preconditioned.
  • the arglabin is recovered by means of liquid / liquid extraction. Extractants are especially aliphatic ethers that do not mix with water, especially t-butyl methyl ether.
  • the non-aqueous organic phase with the valuable material is concentrated to dryness and the recyclable material is recrystallized from preferably n-hexane.
  • arglabin is carried out in polar solvents such as alcohols or acetonitrile with the reagent DIMCARB (dimetylammonium dimethylcarbamate). Under room temperature, a conversion of up to 98% with high purity takes place in a very short time. After separation of the solvent and traces of DIMCARB and redissolving in preferably ethyl acetate or t-butyl-methyl ether, the salt formation takes place by introducing dry gaseous hydrogen chloride. The end product dimethylaminoarglabin hydrochloride precipitates in crystalline form and is separated off and recrystallized again by means of preferably ethyl acetate.
  • DIMCARB dimetylammonium dimethylcarbamate

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a method for producing dimethylaminoarglabine hydrochloride which is used as an agent during cancer therapy. The aim of the invention is achieved by virtue of the fact that parts of the plant Artemisia glabella kz. et kirg, which are above the ground, are treated after the air drying thereof, useless substances are eliminated, extraction and chromatography takes place, subsequently amination and then hydrochloride is formed in a reactor without repeated intermediate isolations, such as evaporation, filtration or dehydration, and with only one change of organic polar solvents.

Description

Verfahren zur Herstellung von Dimethylaminoarglabin-HydrochloridProcess for the preparation of dimethylaminoarglabin hydrochloride

Die Neuerung bezieht sich auf ein Verfahren zur Herstellung von Dimethylaminoarglabin-Hydrochlorid aus in den oberirdischen Teilen der Pflanze Artemisia glabella kz. et kirg. vorkommendem Arglabin. Dimethylaminoarglabin- Hydrochlorid wird im Bereich Krebstherapiemittel verwendet.The innovation relates to a process for the preparation of dimethylaminoarglabin hydrochloride from in the aerial parts of the plant Artemisia glabella kz. et kirg. occurring Arglabin. Dimethylaminoarglabin hydrochloride is used in the field of cancer therapeutics.

Aufgrund des kommerziellen Interesses an dieser Verbindung wurde bereits ein Herstellungsverfahren in WO 98/28303 beansprucht. Es umfasst die für die Aufarbeitung von pflanzlichen Ausgangstoffen bekannten Arbeitsschritte Extraktion aus den Pflanzenteilen, Reinigung von wertlosen Substanzen, Auftrennen des Extraktes durch Säulenchromatographie zum Roharglabin, Umkristallisation, Aminierung und Hydrochlorierung zum Aminoarglabin-Hydrochlorid, dessenDue to the commercial interest in this compound, a production process has already been claimed in WO 98/28303. It comprises the steps known for the processing of plant raw materials extraction from the plant parts, purification of worthless substances, separation of the extract by column chromatography to Roharglabin, recrystallization, amination and hydrochlorination to Aminoarglabin hydrochloride whose

Umkristallisation, Trocknung und Lyophilisierung. Dabei erfolgt die Aminierung durch Lösen des kristallinen Arglabins in Alkohol unter Addition von Dimethylamin in Form einer wässrigen Lösung bis der pH-Wert von 12,3 - 12,4 erreicht wird. Die Bildung und Isolierung des Hydrochlorids aus dem Aminoarglabin erfolgt nunmehr durch Abdestillation des Alkohols und Zugabe von Chloroform, Abtrennung des verbliebenen Wassers und Filtration der Lösung, Abdampfen des Chloroforms und Zugabe von Alkohol, Einleiten von Chlorwasserstoff bis der pH-Wert der Lösung 5,0 - 5,5 erreicht, Abdampfen des Alkohols und Zugabe von Äthylacetat.Recrystallization, drying and lyophilization. The amination is carried out by dissolving the crystalline arglabine in alcohol with addition of dimethylamine in the form of an aqueous solution until the pH of 12.3 to 12.4 is reached. The formation and isolation of the hydrochloride from the Aminoarglabin now carried out by distilling off the alcohol and addition of chloroform, separation of the remaining water and filtration of the solution, evaporation of the chloroform and addition of alcohol, introducing hydrogen chloride to the pH of the solution 5.0 - 5.5, evaporation of the alcohol and addition of ethyl acetate.

Nachteilig an dem obigen Verfahren bleibt somit: -> Erzeugung des Rohextraktes mit Chloroform, -> Vorreinigung des Chloroformextraktes liefert einen Extrakt mit ca.A disadvantage of the above process thus remains: -> production of the crude extract with chloroform, -> pre-purification of the chloroform extract provides an extract with approx.

7% Wirkstoffgehalt, -> Chromatographie an Silicagel mit geringer Trennleistung; -> Als Laufmittel wird das als cancerogen einzustufende Benzol verwendet,7% active ingredient content, -> chromatography on silica gel with low separation efficiency; -> The eluent used is the benzene classified as carcinogenic,

-> Die Chromatographie liefert kein reines Produkt, ca. 65 % Wirkstoffgehalt,-> The chromatography gives no pure product, about 65% active ingredient content,

-> die stationäre Phase lässt sich nur schwer regenerieren,-> the stationary phase is difficult to regenerate,

-> der Einsatz der wässrigen Aminkomponente verlangt die Abtrennung des Wassers aus dem Reaktionsansatz, -> Verwendung von Chloroform zur Abtrennung, -> mehrere Einzelschritte, wie Trocknung, Separation, Destillation und erneutes-> the use of the aqueous amine component requires the separation of the water from the reaction mixture, -> use of chloroform for separation, -> several individual steps, such as drying, separation, distillation and renewed

Lösen notwendig.Solve necessary.

Der im Anspruch 1 angegebenen Erfindung liegt damit das Problem zugrunde, ein Verfahren zur Herstellung von Dimethylaminoarglabin-Hydrochlorid bereitzustellen, das diese Nachteile beseitigt.The invention specified in claim 1 is therefore based on the problem to provide a process for the preparation of dimethylaminoarglabin hydrochloride, which eliminates these disadvantages.

Diese Aufgabe wird durch die Erfindung dadurch gelöst, dass aus den oberirdischen Pflanzenteilen von Artemisia glabella kz. et kirg. nach deren Lufttrocknung, Reinigung von wertlosen Substanzen, Extraktion und Chromatographie, die Aminierung und Hydrochloridbildung nacheinander in einem Reaktor ohne mehrmalige Zwischenisolierungen, wie Abdampfen, Filtrieren oder Entwässern, mit nur einmaligem Wechsel organisch polarer Lösungsmittel erfolgt.This object is achieved by the invention in that from the above-ground parts of plants of Artemisia glabella kz. et kirg. after air drying, purification of worthless substances, extraction and chromatography, the amination and hydrochloride formation is carried out successively in a reactor without repeated intermediate isolation, such as evaporation, filtration or dehydration, with only one change of organic polar solvent.

Die mit der Erfindung erzielten Vorteile bestehen insbesondere darin, dass die Verwendung von auch nur verdachtsweise cancerogenen Lösungsmitteln ausgeschlossen ist und somit nicht durch menschliches oder technisches Versagen Lösungsmittelreste in der pharmazeutischen Zusammensetzung, auch nicht in Spuren, erscheinen können. Ein weiterer technischer Vorteil ist die Arbeitsmöglichkeit in einem Reaktor ohne Zwischenisolierungen. Weitere vorteilhafte Ausgestaltungen einzelner Verfahrensschritte der Erfindung sind in den Unteransprüchen angegeben.The advantages achieved by the invention are, in particular, that the use of only suspected carcinogenic solvents is excluded and thus can not appear by human or technical failure solvent residues in the pharmaceutical composition, even in traces. Another technical advantage is the ability to work in a reactor without intermediate insulation. Further advantageous embodiments of individual method steps of the invention are specified in the subclaims.

Die Erfindung soll nachfolgend an einem bevorzugten Ausführungsbeispiel / Rezeptur näher erläutert werden.The invention will be explained in more detail below on a preferred embodiment / recipe.

Die oberirdischen Pflanzenteile von Artemisia glabella kz. et kirg. werden an der Luft getrocknet und danach gemahlen. Nach Überführung des Mahlgutes in einen o Mischer-Trockner erfolgt zunächst durch Zusatz von Wasser und Dampf bei vermindertem Druck die Abtreibung ätherischer Öle. Danach wird in gleicher Apparatur das Ausgangsmaterial bis zu einer Restfeuchte von 5 - 7% unter vermindertem Druck getrocknet. Das vorbehandelte und getrocknete Ausgangsmaterial wird in den Extraktionskorb der Kohlendioxidextraktionsanlage 5 überführt. Die Extraktion mit superkritischem Kohlendioxid, auch durch bekannte Modifikatoren in seiner Extraktionsleistung verändertem Kohlendioxid, liefert abhängig vom Pflanzenmaterial, Temperatur, Extraktionsdruck und Zusammensetzung des Kohlendioxids einen Rohextrakt mit einem Wertstoffgehalt von 20 - 35 Masse% Arglabin. 0 Durch Lösen dieses Rohextraktes mit Acetonitril zu einer 4%igen Extraktlösung und verdünnen mit Wasser erfolgt die Abscheidung von wachsartigen Verunreinigungen, die abfiltriert werden. Das Filtrat dieser Vorreinigung ist das Ausgangsmaterial der chromatographischen Reinigung. Die HPLC-Reinigung ist eine isokratische Chromatographie an einem Reversphasen-Silicagel mit RP-8 oder RP-18 Silicagel 5 und einer wässrig-organischen Phase, bevorzugt Mischungen aus Acetonitri l/Wasser oder Alkoholen und Wasser. Zeitgesteuert wird die Wertstofffraktion ermittelt, wobei als Detektor ein UV-Detektor eingesetzt wird. Nach dem Wertstoffpeak erfolgt ein Spülschritt mit Acetonitril oder Alkoholen, um Späteluierer aus der Trennsäule zu eliminieren. Anschließend wird mit dem jeweiligen Laufmittelsystem die Trennsäule vorkonditioniert.The aboveground plant parts of Artemisia glabella kz. et kirg. are dried in the air and then ground. After transfer of the ground material in a o mixer-drier, the abortion of essential oils takes place first by adding water and steam under reduced pressure. Thereafter, the starting material is dried under reduced pressure in the same apparatus to a residual moisture content of 5-7%. The pretreated and dried starting material is transferred to the extraction basket of the carbon dioxide extraction unit 5. The extraction with supercritical carbon dioxide, also by known modifiers in its extraction power modified carbon dioxide, depending on the plant material, temperature, extraction pressure and composition of the carbon dioxide provides a crude extract with a value of 20 - 35% by weight of arglabin. 0 By dissolving this crude extract with acetonitrile to a 4% extract solution and diluting with water, the deposition of waxy impurities, which are filtered off. The filtrate of this pre-purification is the starting material of the chromatographic purification. The HPLC purification is an isocratic chromatography on a reverse phase silica gel with RP-8 or RP-18 silica gel 5 and an aqueous-organic phase, preferably mixtures of acetonitrile / water or alcohols and water. Time-controlled, the recyclable fraction is determined using a UV detector as the detector. After the recyclable peak, a rinse step with acetonitrile or alcohols is performed to eliminate late elution from the separation column. Subsequently, with the respective eluent system, the separation column preconditioned.

Aus der Wertstofffraktion wird das Arglabin mittels flüssig/flüssig Extraktion zurückgewonnen. Extraktionsmittel sind hierbei insbesondere aliphatische Äther, die sich nicht mit Wasser mischen, insbesondere t-Butyl-methyl-Äther. Die nicht wässrige organische Phase mit dem Wertstoff wird zur Trockne eingeengt und der Wertstoff aus vorzugsweise n-Hexan umkristallisiert.From the recyclable fraction, the arglabin is recovered by means of liquid / liquid extraction. Extractants are especially aliphatic ethers that do not mix with water, especially t-butyl methyl ether. The non-aqueous organic phase with the valuable material is concentrated to dryness and the recyclable material is recrystallized from preferably n-hexane.

Bei der Aufarbeitung über die Stufen Vorbehandlung, Chromatographie, Extraktion des Wertstoffes und Umkristallisation wurde eine Wiederauffindung von 88-90% des im Kohlendioxidextraktes enthaltenen Arglabin erreicht. Dabei konnte eine Reinheit von ca. 99,5% festgestellt werden.In the workup through the stages of pretreatment, chromatography, extraction of the recyclable material and recrystallization, a recovery of 88-90% of the arglabin contained in the carbon dioxide extract was achieved. In this case, a purity of about 99.5% could be found.

Eine Normaldruck-Chromatographie liefert unter gleichen Aufarbeitungsbedingungen bei schlechterer Gesamtausbeute nur ein Arglabin mit schlechterem Reinheitsgrad (> 96%), was aber dem angegebenen Stand der Technik ebenfalls noch übertrifft.A normal pressure chromatography under the same workup conditions with poorer overall yield only an arglabine with worse degree of purity (> 96%), but this also exceeds the stated state of the art.

Die Derivatvisierung des Arglabin erfolgt in polaren Lösungsmitteln, wie Alkoholen oder Acetonitril mit dem Reagenz DIMCARB (Dimetylammoniumdimethylcarbamat). Unter Raumtemperatur erfolgt dabei in kürzester Zeit ein Umsatz von bis zu 98% mit hoher Reinheit. Nach Abtrennung des Lösungsmittels und von Spuren von DIMCARB und erneutem Lösen in vorzugsweise Äthylacetet oder t-Butyl-methyl-Äther erfolgt die Salzbildung durch Einleiten von trockenem gasförmigen Chlorwasserstoff. Das Endprodukt Dimethylaminoarglabin-Hydrochlorid fällt kristallin aus und wird abgetrennt und nochmals mittels vorzugsweise Äthylacetet umkristallisiert. Derivatization of arglabin is carried out in polar solvents such as alcohols or acetonitrile with the reagent DIMCARB (dimetylammonium dimethylcarbamate). Under room temperature, a conversion of up to 98% with high purity takes place in a very short time. After separation of the solvent and traces of DIMCARB and redissolving in preferably ethyl acetate or t-butyl-methyl ether, the salt formation takes place by introducing dry gaseous hydrogen chloride. The end product dimethylaminoarglabin hydrochloride precipitates in crystalline form and is separated off and recrystallized again by means of preferably ethyl acetate.

Claims

PATENTANSPRÜCHE 1. Verfahren zur Herstellung von Dimethylaminoarglabin-Hydrochlorid aus den oberirdischen Pflanzenteilen von Artemisia glabella kz. et kirg. nach deren1. A process for the preparation of dimethylaminoarglabin hydrochloride from the above-ground parts of plants of Artemisia glabella kz. et kirg. after their Lufttrocknung, Reinigung von wertlosen Substanzen, Extraktion, Chromatographie, Aminierung und Hydrochloridbildung, dadurch gekennzeichnet, dass die Aminierung und Hydrochloridbildung nacheinander in einem Reaktor ohne mehrmalige Zwischenisolierungen, wie Abdampfen, Filtrieren oder Entwässern, mit nur einmaligem Wechsel organisch polarer Lösungsmittel erfolgt.Air drying, purification of worthless substances, extraction, chromatography, amination and hydrochloride formation, characterized in that the amination and hydrochloride formation takes place successively in a reactor without repeated intermediate insulation, such as evaporation, filtration or dehydration, with only one change of organic polar solvent. 2. Verfahren zur Herstellung von Dimethylaminoarglabin-Hydrochlorid nach Anspruch 1 dadurch gekennzeichnet, dass die Extraktion des Wertstoffes Arglabin mittels superkritischem Kohlendioxid erfolgt.2. A process for the preparation of dimethylaminoarglabin hydrochloride according to claim 1, characterized in that the extraction of the valuable substance arglabin takes place by means of supercritical carbon dioxide. 3. Verfahren zur Herstellung von Dimethylaminoarglabin-Hydrochlorid nach Anspruch 2, dadurch gekennzeichnet, dass das superkritische Kohlendioxid mittels bekannter Modifikatoren in seiner Extraktionsleistung verbessert wurde.3. A process for the preparation of dimethylaminoarglabin hydrochloride according to claim 2, characterized in that the supercritical carbon dioxide has been improved by means of known modifiers in its extraction performance. 4. Verfahren zur Herstellung von Dimethylaminoarglabin-Hydrochlorid nach einem oder mehreren der vorgenannten Ansprüche, dadurch gekennzeichnet, dass die Chromatographie des flüssigen Überstandes nach dem bekanntermaßen erfolgten Abtrennen der lipophilen Inhaltsstoffe bevorzugt als Flüssig-/Flüssig- Verteilungschromatographie oder Reversphasen-HPLC mit bekannter Regenerierung der stationären Phase und unbedenklichem organisch/wässrigem Laufmittel ausgeführt wird.4. A process for the preparation of dimethylaminoarglabin hydrochloride according to one or more of the preceding claims, characterized in that the chromatography of the liquid supernatant after the known carried out separating the lipophilic ingredients preferably as liquid / liquid partition chromatography or reverse-phase HPLC with known regeneration of stationary phase and harmless organic / aqueous eluent is performed. 5. Verfahren zur Herstellung von Dimethylaminoarglabin-Hydrochlorid nach einem oder mehreren der vorgenannten Ansprüche, dadurch gekennzeichnet, dass aus der Wertstofffraktion der Chromatographie durch nichtcancerogene organische Lösungsmittel, wie bevorzugt aliphatische Äther, dabei insbesondere t-Butyl- methyl-Äther, die mit dem Lösungsmittel der Wertstofffraktion nicht mischbar sind, der Wertstoff extrahiert wird.5. A process for the preparation of dimethylaminoarglabin hydrochloride according to one or more of the preceding claims, characterized in that from the recyclable fraction of the chromatography by noncancerogenic organic solvents, such as preferably aliphatic ether, in particular t-butyl methyl ether, which are immiscible with the solvent of the recyclable fraction, the valuable substance is extracted. 6. Verfahren zur Herstellung von Dimethylaminoarglabin-Hydrochlorid nach einem oder mehreren der vorgenannten Ansprüche, dadurch gekennzeichnet, dass nach bekannter Umkristallisation, vorzugsweise mittels n-Hexan, die Derivatisierung mit einer Aminkomponente, bevorzugt DIMCARB, in einem organischen polaren Lösungsmittel, bevorzugt Alkohole oder Acetonitril, erfolgt, wodurch eine Wasserabtrennung entfällt.6. A process for preparing dimethylaminoarglabin hydrochloride according to one or more of the preceding claims, characterized in that according to known recrystallization, preferably by means of n-hexane, the derivatization with an amine component, preferably DIMCARB, in an organic polar solvent, preferably alcohols or acetonitrile , takes place, whereby a water separation is eliminated. 7. Verfahren zur Herstellung von Dimethylaminoarglabin-Hydrochlorid nach einem oder mehreren der vorgenannten Ansprüche, dadurch gekennzeichnet, dass nach Abtrennen des Lösungsmittels und verbliebener Spuren der Aminkomponente und erneutem Lösen in vorzugsweise t-Butyl-methyl-Äther die Salzbildung mit trockenem gasförmigen Chlorwasserstoff erfolgt und das angefallene kristalline Endprodukt Dimethylaminoarglabin-Hydrochlorid abgetrennt wird. 7. A process for the preparation of dimethylaminoarglabin hydrochloride according to one or more of the preceding claims, characterized in that after separation of the solvent and remaining traces of the amine component and redissolving in preferably t-butyl methyl ether, the salt formation is carried out with dry gaseous hydrogen chloride and the resulting crystalline end product dimethylaminoarglabin hydrochloride is separated off.
PCT/DE2005/001175 2004-07-30 2005-07-03 Method for producing dimethylaminoarglabine hydrochloride Ceased WO2006012824A1 (en)

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EP05763725A EP1771232A1 (en) 2004-07-30 2005-07-03 Method for producing dimethylaminoarglabine hydrochloride
EA200700070A EA200700070A1 (en) 2004-07-30 2005-07-03 Method of producing hydrochloride dimethylaminoarglabin

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DE102004037002A DE102004037002B4 (en) 2004-07-30 2004-07-30 Process for the preparation of dimethylaminoarglabin hydrochloride
DE102004037002.8 2004-07-30

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WO2008035958A1 (en) * 2006-09-19 2008-03-27 Adekenov Sergazy Mynzhasarovic Method for production of hydrochloride 1(10) beta-epoxy-13-dimethylamino-5,7alpha,6,11beta (h)-guaia-3(4)-en-6,12-olide, the lyophilized antitumor preparation 'arglabin'
EA015557B1 (en) * 2006-09-19 2011-08-30 Сергазы Мынжасарович Адекенов METHOD FOR PRODUCTION OF HYDROCHLORIDE 1(10) BETA-EPOXY-13-DIMETHYLAMINO-5,7α,6,11β(H)-GUAIA-3(4)-EN-6,12-OLIDE, LYOPHILIZED ANTITUMOR PREPARATION "ARGLABIN"
CN102190662A (en) * 2010-03-02 2011-09-21 石药集团中奇制药技术（石家庄）有限公司 Method for preparing dimethylaminoarglabin hydrochloride
CN102190662B (en) * 2010-03-02 2014-06-25 石药集团中奇制药技术（石家庄）有限公司 Method for preparing dimethylaminoarglabin hydrochloride
CN103382208A (en) * 2012-05-03 2013-11-06 天津尚德药缘科技有限公司 Preparation method of Arglabin
WO2013163936A1 (en) * 2012-05-03 2013-11-07 天津尚德药缘科技有限公司 Preparation method of arglabin
CN103382208B (en) * 2012-05-03 2016-08-03 天津尚德药缘科技有限公司 The preparation method of Arglabin

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