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WO2006012824A1 - Procede pour produire de l'hydrochlorure de dimethylaminoarglabine - Google Patents

Procede pour produire de l'hydrochlorure de dimethylaminoarglabine 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
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
hydrochloride
dimethylaminoarglabin hydrochloride
chromatography
dimethylaminoarglabin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/DE2005/001175
Other languages
German (de)
English (en)
Inventor
Klaus-Dieter GÖHLER
Joachim Engelmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CHEMIEANLAGENBAU CHEMNITZ GmbH
Original Assignee
CHEMIEANLAGENBAU CHEMNITZ GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by CHEMIEANLAGENBAU CHEMNITZ GmbH filed Critical CHEMIEANLAGENBAU CHEMNITZ GmbH
Priority to EA200700070A priority Critical patent/EA200700070A1/ru
Priority to EP05763725A priority patent/EP1771232A1/fr
Publication of WO2006012824A1 publication Critical patent/WO2006012824A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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

Landscapes

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

Abstract

L'invention concerne un procédé servant à produire de l'hydrochlorure de diméthylaminoarglabine utilisé comme agent thérapeutique dans le traitement du cancer. Selon l'invention, on procède sur les parties aériennes de la plante Artemisia glabella kz. et kirg., après leur séchage à l'air, l'élimination des substances sans intérêt, l'extraction et la chromatographie, successivement à l'amination et la formation d'hydrochlorure dans un réacteur, et ce sans isolations partielles répétées, telles qu'évaporation, filtrage ou déshydratation, et avec un seul changement des solvants organiquement polaires.
PCT/DE2005/001175 2004-07-30 2005-07-03 Procede pour produire de l'hydrochlorure de dimethylaminoarglabine Ceased WO2006012824A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EA200700070A EA200700070A1 (ru) 2004-07-30 2005-07-03 Способ получения гидрохлорида диметиламиноарглабина
EP05763725A EP1771232A1 (fr) 2004-07-30 2005-07-03 Procede pour produire de l'hydrochlorure de dimethylaminoarglabine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004037002A DE102004037002B4 (de) 2004-07-30 2004-07-30 Verfahren zur Herstellung von Dimethylaminoarglabin-Hydrochlorid
DE102004037002.8 2004-07-30

Publications (1)

Publication Number Publication Date
WO2006012824A1 true WO2006012824A1 (fr) 2006-02-09

Family

ID=35045299

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE2005/001175 Ceased WO2006012824A1 (fr) 2004-07-30 2005-07-03 Procede pour produire de l'hydrochlorure de dimethylaminoarglabine

Country Status (4)

Country Link
EP (1) EP1771232A1 (fr)
DE (1) DE102004037002B4 (fr)
EA (1) EA200700070A1 (fr)
WO (1) WO2006012824A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008035958A1 (fr) * 2006-09-19 2008-03-27 Adekenov Sergazy Mynzhasarovic Procede de production de 1(10) beta-epoxy-13-dimethylamino-5,7alpha,6,11beta (h)-guaia-3(4)-en-6,12-olide hydrochlorure et preparation antitumorale lyophilisee 'arglabine'
CN102190662A (zh) * 2010-03-02 2011-09-21 石药集团中奇制药技术（石家庄）有限公司 一种二甲氨基阿格拉宾盐酸盐的制备方法
CN103382208A (zh) * 2012-05-03 2013-11-06 天津尚德药缘科技有限公司 Arglabin的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466451A (en) * 1992-01-31 1995-11-14 Schaper & Bruemmer Gmbh & Co., Kg Pharmaceutically active composition extracted from tanacetum parthenium, process for its extraction, and pharmaceutical composition containing same
WO1998028303A1 (fr) * 1996-12-20 1998-07-02 Tovarischestvo S Ogranichennoi Otvetstvennostju 'tabifarm' PROCEDE ET DISPOSITIF DE PRODUCTION D'HYDROCHLORURE-1β,10β-EPOXY-13-DIMETHYLAMINO-GUAIA-3(4)-EN-6,12-OLIDE LYOPHILISE
US6080741A (en) * 1997-07-03 2000-06-27 Paracure, Inc. Arglabin compounds and therapeutic uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466451A (en) * 1992-01-31 1995-11-14 Schaper & Bruemmer Gmbh & Co., Kg Pharmaceutically active composition extracted from tanacetum parthenium, process for its extraction, and pharmaceutical composition containing same
WO1998028303A1 (fr) * 1996-12-20 1998-07-02 Tovarischestvo S Ogranichennoi Otvetstvennostju 'tabifarm' PROCEDE ET DISPOSITIF DE PRODUCTION D'HYDROCHLORURE-1β,10β-EPOXY-13-DIMETHYLAMINO-GUAIA-3(4)-EN-6,12-OLIDE LYOPHILISE
US6080741A (en) * 1997-07-03 2000-06-27 Paracure, Inc. Arglabin compounds and therapeutic uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HESS U ET AL: "Synthese von beta-Aminosaeurederivaten durch Hydrodimethylaminierung ungesaettigter Carbonsaeurederivate in Dimcarb (Dimethylamin-CO2-Additionsverbindung)", PHARMAZIE, DIE, PHARMAZEUTISCHER VERL., ESCHBORN, DE, vol. 48, no. 8, August 1993 (1993-08-01), pages 591 - 597, XP002164373, ISSN: 0031-7144 *
KREHER, U. P. ET. AL.: "Self-associated, "Distillable" Ionic Media", MOLECULES, vol. 9, 31 May 2004 (2004-05-31), pages 387 - 393, XP002349345 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008035958A1 (fr) * 2006-09-19 2008-03-27 Adekenov Sergazy Mynzhasarovic Procede de production de 1(10) beta-epoxy-13-dimethylamino-5,7alpha,6,11beta (h)-guaia-3(4)-en-6,12-olide hydrochlorure et preparation antitumorale lyophilisee 'arglabine'
EA015557B1 (ru) * 2006-09-19 2011-08-30 Сергазы Мынжасарович Адекенов СПОСОБ ПОЛУЧЕНИЯ ГИДРОХЛОРИДА 1(10)β-ЭПОКСИ-13-ДИМЕТИЛАМИНО- 5,7α,6,11β(Н)-ГВАЙ-3(4)-ЕН-6,12-ОЛИДА, ЛИОФИЛИЗИРОВАННОГО ПРОТИВООПУХОЛЕВОГО СРЕДСТВА "АРГЛАБИН"
CN102190662A (zh) * 2010-03-02 2011-09-21 石药集团中奇制药技术（石家庄）有限公司 一种二甲氨基阿格拉宾盐酸盐的制备方法
CN102190662B (zh) * 2010-03-02 2014-06-25 石药集团中奇制药技术（石家庄）有限公司 一种二甲氨基阿格拉宾盐酸盐的制备方法
CN103382208A (zh) * 2012-05-03 2013-11-06 天津尚德药缘科技有限公司 Arglabin的制备方法
WO2013163936A1 (fr) * 2012-05-03 2013-11-07 天津尚德药缘科技有限公司 Procédé de préparation d'arglabine
CN103382208B (zh) * 2012-05-03 2016-08-03 天津尚德药缘科技有限公司 Arglabin的制备方法

Also Published As

Publication number Publication date
EP1771232A1 (fr) 2007-04-11
EA200700070A1 (ru) 2007-06-29
DE102004037002B4 (de) 2006-06-14
DE102004037002A1 (de) 2006-03-23

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