WO2008000298A1 - Method for purifying betaines - Google Patents

Method for purifying betaines Download PDF

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Publication number
WO2008000298A1
WO2008000298A1 PCT/EP2006/063613 EP2006063613W WO2008000298A1 WO 2008000298 A1 WO2008000298 A1 WO 2008000298A1 EP 2006063613 W EP2006063613 W EP 2006063613W WO 2008000298 A1 WO2008000298 A1 WO 2008000298A1
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WIPO (PCT)
Prior art keywords
extraction
indocyanine green
purification
nai
betaines
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PCT/EP2006/063613
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German (de)
French (fr)
Inventor
Bernhard Dr. Hanke
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Pulsion Medical Systems Ag
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Priority to PCT/EP2006/063613 priority Critical patent/WO2008000298A1/en
Publication of WO2008000298A1 publication Critical patent/WO2008000298A1/en

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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
    • C09B67/0096—Purification; Precipitation; Filtration

Definitions

  • the present invention relates to a process for the purification of synthetically produced chemicals containing a betaine structure in the molecule.
  • indocyanine green a dye described in the American Pharmacopoeia.
  • Indocyanine green is 2- ⁇ 7- [1,3-dihydro-i, 1-dimethyl-3- (4-sulfobutyl) -2W-benz [e] indol-2-ylidene] -
  • Indocyanine green represents a green dye used in medicine & medicine. a is used for the diagnosis of heart, circulatory, microcirculation and liver function.
  • indocyanine green takes place, for example, by condensation of two indolinium molecules using sodium iodide.
  • the sodium iodide is added to the synthesis approach to precipitate the dye.
  • Conventional measures for reducing the Natriumiodidgeh old are complex and costly, resulting in significantly increased production cost of the dye.
  • the discontinuous Uieriiche processing of indocyanine green (ICG) with hooves of crystallization or precipitation is limited, a large-scale purification of the substance is almost impossible.
  • chromatographic methods for the purification of ICG are conceivable on a laboratory scale, larger quantities can not be cleaned in a single operation.
  • the present invention accordingly provides a process for the purification of chemical substances and chemical compounds containing a betaine structure in the 'molecule which is characterized in that reaction by-products, starting materials and / or other impurities that are insoluble in the selected organic solvent , separated by extraction.
  • the process of the invention takes advantage of the differences in solubility between the impurities and betaines.
  • the process for the purification of indocyanine green is particularly well-suited if sodium iodide (NaI) is used as the precipitation reagent in its preparation for the conversion of the acid into the corresponding Na salt.
  • NaI sodium iodide
  • indocyanine green natural substances which can be purified in this way from inorganic impurities, in particular alkaloids of the indole and isoquinoline type, are also suitable for the process according to the invention.
  • the extraction is carried out in an organic, preferably anhydrous solvent, in particular in aprotic solvents (for example CH 2 Cl 2 or ethyl acetate).
  • aprotic solvents for example CH 2 Cl 2 or ethyl acetate.
  • anhydrous solvent is used as the solvent.
  • the drying of the anhydrous solvents can be carried out in a conventional manner via molecular sieves, P 2 O 5, etc.
  • the extraction according to the invention can be carried out by shaking out (sequential extraction) or continuously.
  • the sequential extraction is usually carried out in a separatory funnel.
  • the shaking out of the substances is relatively cumbersome, time consuming and therefore less preferred.
  • the extraction is carried out continuously. Particularly suitable for this is the so-called Soxhlet extraction.
  • the material to be purified is preferably added to a sleeve permeable to the solvent or similar receiving device and continuously flushed with solvent just below its boiling point.
  • the soluble components are dissolved while leaving insoluble components in the receiver, i.e. in the purification of Indocyanin indispensable this compound is dissolved by the extraction solvent and removed from the template, while in the solvent used insoluble substances, eg. B. NaI, remain behind.
  • an indocyanine green obtained from a conventional industrial production and containing 4.6% NaI was subjected to continuous extraction in a Soxhlet apparatus.
  • anhydrous methylene chloride 500 ml of methylene chloride were dried over molecular sieves (4 ⁇ from Roth, 0.4 nm, bead form) and then distilled. 100 ml of the forerun were discarded so that about 400 ml of purified and dried methylene chloride were available for the subsequent continuous extraction.
  • the resulting indocyanine green contained ⁇ 0.4% NaI. This amount is more than 10 times lower than the tolerance specified by the USP for the parenteral use of Indocyanine Green for Injection. Extraction with solvents such as acetone resulted in extraction of NaI, which is to some extent soluble in them.

Abstract

A method is disclosed for purifying synthetically produced compounds with a betaine structure in the molecule, for example, indocyan green, characterised in that reaction byproducts, starting materials and/or other impurities such as the NaI used in production are separated off by extraction.

Description

"Verfahren zur Aufreinigunq von Betainen" "Process for the purification of betaines"
Die vorliegende Erfindung betrifft ein Verfahren zur Reinigung von synthetisch hergestellten chemischen Stoffen, die eine Betain-Struktur im Molekül enthalten.The present invention relates to a process for the purification of synthetically produced chemicals containing a betaine structure in the molecule.
Insbesondere ist dieses Verfahren zur Aufreinigung von Indocyaningrün (Indocyanine Green), einem in der amerikanischen Pharmacopoee beschriebenen Farbstoff, geeignet. Indocyaningrün ist 2-{7-[1 ,3-dihydro-i , 1-dimethyl-3-(4-sulfobutyl)-2W-benz[e]indol-2-yliden]-In particular, this process is suitable for the purification of indocyanine green (indocyanine green), a dye described in the American Pharmacopoeia. Indocyanine green is 2- {7- [1,3-dihydro-i, 1-dimethyl-3- (4-sulfobutyl) -2W-benz [e] indol-2-ylidene] -
1 ,3,5-heptatrienyl}-1 ,1-dimethyl-3-(4-sulfobutyl)-1H-benz[e]indolinium-hydroxid, Betain-Natriumsalz und wird durch folgende chemische Struktur charakterisiert:1, 3,5-heptatrienyl} -1, 1-dimethyl-3- (4-sulfobutyl) -1H-benz [e] indolinium hydroxide, betaine sodium salt and is characterized by the following chemical structure:
Figure imgf000002_0001
Figure imgf000002_0001
C43H4ZN2NaO6S2.C 43 H 4 ZN 2 NaO 6 S 2 .
Indocyaningrün stellt einen grünen Farbstoff dar, der in der Medizin u. a zur Diagnostik der Herz-, Kreislauf-, Mikrozirkulations- und Leberfunktion eingesetzt wird.Indocyanine green represents a green dye used in medicine & medicine. a is used for the diagnosis of heart, circulatory, microcirculation and liver function.
Die Herstellung von Indocyaningrün erfolgt z.B. durch Kondensation von zwei Indolinium- molekülen unter Verwendung von Natriumjodid. Das Natriumiodid wird dem Syntheseansatz zugefügt, um eine Fällung des Farbstoffes herbeizuführen. Herkömmliche Maßnahmen zur Reduzierung des Natriumiodidgeh altes sind aufwändig und kostenintensiv, was zu deutlich erhöhten Herstellungskosten des Farbstoffes führt. Die diskontin uieriiche Aufarbeitung von Indocyaningrün (ICG) mit Hufe von Kristallisation bzw. Ausfällungen ist nur eingeschränkt möglich, eine großtechnische Aufreinigung des Stoffes ist nahezu unmöglich. Auch chromatographische Methoden zur Aufreinigung von ICG sind zwar im Labormaßstab denkbar, größere Mengen lassen sich jedoch nicht in einem einzigen Arbeitsgang reinigen. Der vorliegenden Erfindung lag die Aufgabe zugrunde, ein Verfahren zur Aufretnigung von Betainen, insbesondere von Indocyaningrün, zur Verfügung zu stellen, bei welchem der aus dem Stand der Technik übliche und in großtechnischen Anlagen auch eingeführte Syntheseweg unverändert bleiben kann, so dass nur der Aufreinigungsschritt eine Veränderung erfährt.The production of indocyanine green takes place, for example, by condensation of two indolinium molecules using sodium iodide. The sodium iodide is added to the synthesis approach to precipitate the dye. Conventional measures for reducing the Natriumiodidgeh old are complex and costly, resulting in significantly increased production cost of the dye. The discontinuous Uieriiche processing of indocyanine green (ICG) with hooves of crystallization or precipitation is limited, a large-scale purification of the substance is almost impossible. Although chromatographic methods for the purification of ICG are conceivable on a laboratory scale, larger quantities can not be cleaned in a single operation. It is an object of the present invention to provide a process for the sedimentation of betaines, in particular indocyanine green, in which the synthesis route which is customary in the prior art and also introduced in industrial plants can remain unchanged, so that only the purification step one Change experiences.
Gegenstand der vorliegenden Erfindung ist demgemäß ein Verfahren zur Reinigung von chemischen Stoffen sowie von chemischen Verbindungen die eine Betain-Struktur im'Molekül enthalten, das dadurch gekennzeichnet ist, dass Reaktionsnebenprodukte, Ausgangsverbindungen und/oder sonstige Verunreinigungen, die in dem ausgewählten organischen Lösungsmittel unlöslich sind, durch Extraktion abgetrennt werden.The present invention accordingly provides a process for the purification of chemical substances and chemical compounds containing a betaine structure in the 'molecule which is characterized in that reaction by-products, starting materials and / or other impurities that are insoluble in the selected organic solvent , separated by extraction.
Das erfindungsgemäße Verfahren macht sich die Löslichkeitsunterschiede zwischen den Verunreinigungen und Betainen zunutze. Besonders gut geeignet ist das Verfahren zur Aufreinigung von Indocyaningrün, wenn bei dessen Herstellung zur Überführung der Säure in das entsprechende Na-SaIz Natriumiodid (NaI) als Fällungsreagenz eingesetzt wird.The process of the invention takes advantage of the differences in solubility between the impurities and betaines. The process for the purification of indocyanine green is particularly well-suited if sodium iodide (NaI) is used as the precipitation reagent in its preparation for the conversion of the acid into the corresponding Na salt.
Die Verwendung von NaI, das nach den bisherigen Aufreinigungsmethoden noch in mehreren % in handelsüblichen Produkten enthalten sein kann, könnte die Ursache sein, dass Art und Umfang des diagnostischen Einsatzes von ICG Einschränkungen erfahren.The use of NaI, which according to the previous purification methods can still be present in several% of commercially available products, could be the reason that the nature and extent of the diagnostic use of ICG is limited.
Neben dem Indocyaningrün kommen auch Naturstoffe, die auf diese Weise von anorganischen Verunreinigungen gereinigt werden können, insbesondere Alkaloide des Indol- und Isochinolintyps, für das erfindungsgemäße Verfahren in Betracht.In addition to the indocyanine green, natural substances which can be purified in this way from inorganic impurities, in particular alkaloids of the indole and isoquinoline type, are also suitable for the process according to the invention.
Die Extraktion wird in einem organischen, vorzugsweise wasserfreien Lösungsmittel, insbesondere in aprotischen Lösungsmitteln (z.B. CH2CI2 bzw. Essigester) durchgeführt. Die Möglichkeit, NaI aus Indocyaningrün zu entfernen bzw. davon durch Extraktion abzutrennen, ist insoweit überraschend, da das Indocyaningrün in dem bevorzugt eingesetzten wasserfreien Lösungsmittel CH2CI2 nur mäßig löslich, wohingegen NaI unlöslich ist.The extraction is carried out in an organic, preferably anhydrous solvent, in particular in aprotic solvents (for example CH 2 Cl 2 or ethyl acetate). The possibility of removing NaI from indocyanine green or separating it by extraction is surprising insofar as the indocyanine green is only moderately soluble in the anhydrous solvent CH 2 Cl 2 which is preferably used, whereas NaI is insoluble.
Da einige der zu entfernenden Verunreinigungen, wie z. B. anorganische Salze, so auch NaI, in Wasser löslich sind, wird als Lösemittel vorzugsweise wasserfreies Lösemittel eingesetzt. Die Trocknung der wasserfreien Lösemittel kann in an sich bekannter Weise über Molekularsiebe, P2O5 etc. erfolgen. Die erfindungsgemäße Extraktion kann durch Ausschütteln (sequentielle Extraktion) oder kontinuierlich durchgeführt werden. Die sequentielle Extraktion erfolgt üblicherweise in einem Schütteltrichter. Das Ausschütteln der Substanzen ist jedoch relativ umständlich, zeitaufwendig und daher weniger bevorzugt. Vorzugsweise wird daher die Extraktion kontinuierlich durchgeführt. Besonders geeignet ist hierfür die so genannte Soxhlet- Extraktion.Since some of the contaminants to be removed, such. As inorganic salts, including NaI, are soluble in water, preferably anhydrous solvent is used as the solvent. The drying of the anhydrous solvents can be carried out in a conventional manner via molecular sieves, P 2 O 5, etc. The extraction according to the invention can be carried out by shaking out (sequential extraction) or continuously. The sequential extraction is usually carried out in a separatory funnel. The shaking out of the substances, however, is relatively cumbersome, time consuming and therefore less preferred. Preferably, therefore, the extraction is carried out continuously. Particularly suitable for this is the so-called Soxhlet extraction.
Für die kontinuierliche Extraktion wird das aufzureinigende Gut vorzugsweise in eine für das Lösungsmittel durchlässige Hülse oder ähnliche Aufnahmevorrichtung gegeben und kontinuierlich von Lösemittel knapp unterhalb dessen Siedepunktes durchspült. Dabei werden die löslichen Bestandteile aufgelöst, während unlösliche Bestandteile in der Aufnahmevorrichtung zurückbleiben d.h. bei der Aufreinigung von Indocyaningrün wird diese Verbindung von dem Extraktionslösungsmittel gelöst und aus der Vorlage entfernt, während im verwendeten Lösungsmittel unlösliche Substanzen, z. B. NaI, zurückbleiben.For continuous extraction, the material to be purified is preferably added to a sleeve permeable to the solvent or similar receiving device and continuously flushed with solvent just below its boiling point. In doing so, the soluble components are dissolved while leaving insoluble components in the receiver, i.e. in the purification of Indocyaningrün this compound is dissolved by the extraction solvent and removed from the template, while in the solvent used insoluble substances, eg. B. NaI, remain behind.
Beispielexample
Zur Durchführung des erfindungsgemäßen Verfahrens wurde ein aus einer üblichen Industrieproduktion erhältliches Indocyaningrün, das 4,6 % NaI enthielt, in einer Soxhlet- Apparatur der kontinuierlichen Extraktion unterworfen.To carry out the process according to the invention, an indocyanine green obtained from a conventional industrial production and containing 4.6% NaI was subjected to continuous extraction in a Soxhlet apparatus.
Zur Herstellung von wasserfreiem Methylenchloήd wurden 500 ml Methylenchlorid über Molekularsieb (4 Ä von der Fa. Roth, 0,4 nm, Perlform) getrocknet und anschließend destilliert. 100 ml des Vorlaufs wurden verworfen, so dass für die nachfolgende kontinuierliche Extraktion ca. 400 ml gereinigtes und getrocknetes Methylenchlorid zur Verfügung standen.To produce anhydrous methylene chloride, 500 ml of methylene chloride were dried over molecular sieves (4 Å from Roth, 0.4 nm, bead form) and then distilled. 100 ml of the forerun were discarded so that about 400 ml of purified and dried methylene chloride were available for the subsequent continuous extraction.
266 mg Indocyaningrün wurden in eine für die Soxhlet-Apparatur geeignete Papierhülse eingewogen. Als Vorlage wurden 250 ml des gereinigten und getrockneten Methylenchlorids in einen 500 ml-Kolben gegeben. Die Apparatur enthielt weiter einen Rückflusskühler und ein darauf gesetztes, mit CaCI2 gefülltes Trockenrohr. Die Extraktion wurde über einen Zeitraum von 30 Stunden bei einer Wasserbadtemperatur von 480C durchgeführt. Anschließend wurde die erhaltene tiefgrüne Lösung am Rotationsverdampfer eingeengt und lyophilisiert.266 mg indocyanine green were weighed into a paper tube suitable for the Soxhlet apparatus. As a template, 250 ml of the purified and dried methylene chloride were placed in a 500 ml flask. The apparatus further contained a reflux condenser and a CaCI 2 filled drying tube. The extraction was carried out over a period of 30 hours at a water bath temperature of 48 0 C. Subsequently, the resulting deep green solution was concentrated on a rotary evaporator and lyophilized.
Das erhaltene Indocyaningrün enthielt < 0,4 % NaI. Diese Menge liegt um mehr als das 10- fache unterhalb des von der USP festgelegten Toleranzbereiches für die parenterale Anwendung von Indocyaningrün (Indocyanine Green for Injection). Extraktionen mit Lösungsmitteln wie Aceton führten dazu, dass NaI, welches in diesen in gewissem Umfang löslich ist, mit extrahiert wurde.The resulting indocyanine green contained <0.4% NaI. This amount is more than 10 times lower than the tolerance specified by the USP for the parenteral use of Indocyanine Green for Injection. Extraction with solvents such as acetone resulted in extraction of NaI, which is to some extent soluble in them.
Die Extraktion mit Lösungen kleiner wie z.B. die Extraktion mit Aceton, Chloroform, Cyclohexan und Heptan führte zu keiner Trennung der Stoffe Indocyaningrün und NaI. The extraction with solutions smaller than e.g. extraction with acetone, chloroform, cyclohexane and heptane did not lead to a separation of indocyanine green and NaI.

Claims

Patentansprüche claims
1. Verfahren zur Reinigung von synthetisch hergestellten Verbindungen, welche eine Betain-Struktur im Molekül aufweisen, dadurch gekennzeichnet, dass Reaktionsnebenprodukte, Ausgangsverbindungen und/oder sonstige Verunreinigungen durch Extraktion abgetrennt werden.1. A process for the purification of synthetically prepared compounds which have a betaine structure in the molecule, characterized in that reaction by-products, starting compounds and / or other impurities are separated by extraction.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Stoffe ausgewählt sind aus Indocyaningrün.2. The method according to claim 1, characterized in that the substances are selected from Indocyaningrün.
3. Verfahren nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, dass das abgetrennte Nebenprodukt ein Jodid, insbesondere Natriumjodid, ist.3. The method according to any one of claims 1 or 2, characterized in that the separated by-product is an iodide, in particular sodium iodide.
4. Verfahren nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass die Extraktion mit einem organischen Lösungsmittel, vorzugsweise Methylenchlorid, durchgeführt wird.4. The method according to any one of claims 1 to 3, characterized in that the extraction with an organic solvent, preferably methylene chloride, is performed.
5. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass die Extraktion kontinuierlich, insbesondere durch das Soxhlet-Verfahren durchgeführt wird. 5. The method according to any one of claims 1 to 4, characterized in that the extraction is carried out continuously, in particular by the Soxhlet method.
PCT/EP2006/063613 2006-06-28 2006-06-28 Method for purifying betaines WO2008000298A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT107134A (en) * 2013-08-28 2015-03-02 Mfobmx Unipessoal Lda BICYCLE PEDALURE TIGHTENING AND FASTENING SYSTEM
CN115093362A (en) * 2022-07-04 2022-09-23 深圳市罗素医药有限公司 Purification method of indocyanine green

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US2895955A (en) * 1957-06-05 1959-07-21 Eastman Kodak Co Tricarbocyanine infrared absorbing dyes
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WO1995007888A1 (en) * 1993-09-17 1995-03-23 Societe D'etudes Et De Recherches Biologiques Method for the preparation of high purity substituted benz[e]indoles and the alkaline salts thereof
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WO2004078109A2 (en) * 2003-03-07 2004-09-16 Merck Sharp & Dohme Limited PROCESS FOR SYNTHESISING USEFUL INTERMEDIATES FOR THE PREPARATION OF ανβ3 RECEPTOR ANTAGONISTS
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WO2006128451A2 (en) * 2005-06-01 2006-12-07 Pulsion Medical Systems Ag Methods for purification of betaines

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US2245249A (en) * 1938-10-21 1941-06-10 Eastman Kodak Co Cyclammonium quaternary salts
US2895955A (en) * 1957-06-05 1959-07-21 Eastman Kodak Co Tricarbocyanine infrared absorbing dyes
DE2046141A1 (en) * 1970-09-18 1972-03-23 Merck Patent Gmbh, 6100 Darmstadt Tricarbocyanine dyestuff mfr - using alkali alcoholate instead of sodium iodide to obtain iodine-free products
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT107134A (en) * 2013-08-28 2015-03-02 Mfobmx Unipessoal Lda BICYCLE PEDALURE TIGHTENING AND FASTENING SYSTEM
PT107134B (en) * 2013-08-28 2015-07-30 Mfobmx Unipessoal Lda BICYCLE PEDALURE TIGHTENING AND FASTENING SYSTEM
CN115093362A (en) * 2022-07-04 2022-09-23 深圳市罗素医药有限公司 Purification method of indocyanine green

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