WO2007065534A1 - Method for recovering iopromide suitable for pharmaceutical purposes from mother liquors - Google Patents

Method for recovering iopromide suitable for pharmaceutical purposes from mother liquors Download PDF

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Publication number
WO2007065534A1
WO2007065534A1 PCT/EP2006/010943 EP2006010943W WO2007065534A1 WO 2007065534 A1 WO2007065534 A1 WO 2007065534A1 EP 2006010943 W EP2006010943 W EP 2006010943W WO 2007065534 A1 WO2007065534 A1 WO 2007065534A1
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Prior art keywords
lopromide
pharmaceutical purposes
flow tube
mother liquors
crystallization
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PCT/EP2006/010943
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German (de)
French (fr)
Inventor
Hartmut Kagerer
Meike Dembeck
Hartmut Seba
Ingo Ortmann
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Bayer Schering Pharma Aktiengesellschaft
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Priority claimed from DE200510059191 external-priority patent/DE102005059191B4/en
Application filed by Bayer Schering Pharma Aktiengesellschaft filed Critical Bayer Schering Pharma Aktiengesellschaft
Priority to JP2008543678A priority Critical patent/JP2009518325A/en
Priority to CA2630413A priority patent/CA2630413C/en
Priority to EP06818545A priority patent/EP1960348A1/en
Publication of WO2007065534A1 publication Critical patent/WO2007065534A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B63/00—Purification; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring

Definitions

  • the invention relates to a process for the recovery of lopromide suitable for pharmaceutical purposes by thermal treatment of the mother liquors or the dissolved second crystallizate in a reactor and subsequent crystallization.
  • the two atropisomeric compounds differ in their physical properties, especially in their solubilities in water and organic solvents.
  • Only lopromide of a certain composition with regard to these atropisomers is approved as an X-ray contrast medium (40-51% isomer 1 and 49-60% isomer 2).
  • Cleaning processes for iodinated X-ray contrast media, such as lopamidol, are known from the prior art, see EP 1 025 067 B1 and GB 2 280 436. Crystallizations at elevated temperatures are described therein.
  • the document WO 2004 031 110 A2 discloses the isomerization of chiral compounds by thermal treatment. However, these procedures do not involve the treatment of lopromide mother liquors.
  • Iopromide for pharmaceutical purposes is obtained by crystallization from ethanol. This regularly results in a mixture consisting of approx. 48% isomer 1 and approx. 52% isomer 2.
  • the mother liquor contains about 60% of isomer 1 and only about 40% of isomer 2. For this reason, only a second crystallizate with the wrong composition regarding the atropisomers can be obtained from the mother liquor (contains too much isomer 1).
  • the disadvantages described above could surprisingly be solved by first obtaining a K2 from the lopromide, pure mother liquors by means of a suitable second crystallization, which then a suitable thermal treatment is isomerized in a continuous flow tube reactor according to the specification without significant decomposition of the substance.
  • the invention thus includes a method for recovering suitable for pharmaceutical purposes iopromide aud lopromidmutterlaugen or solutions of the second and Vietnamesekristallisats by thermal treatment of the solution, preferably in a flow tube reactor at 100-300 0 C, advantageously at 200-220 0 C, and then rapid cooling to room temperature and crystallization.
  • the thermal treatment in a flow reactor is advantageously carried out in aqueous solution with hydrodynamic residence times of 1 to 60 minutes.
  • the particular embodiments are listed in the claims.
  • the total yield of lopromide can be increased purely significantly by this method according to the invention, so that the economy increases. In addition, there is less halogen-containing waste.
  • a second crystallizate is first applied from the lopromide, pure mother liquors, by concentrating the ethanolic mother liquors by a factor of 2-16 and dissolving them in an alcohol at elevated temperature.
  • suitable alcohols are alkanols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol.
  • Ethanol, 1-propanol and 2-propanol are preferably used, particularly preferably 1-propanol, since the crystallization takes place particularly quickly and completely from this solvent and thus saves costs.
  • To initiate the crystallization can be inoculated with lopromid, pure. The K2 crystals are then isolated, washed and dried by known methods.
  • the second crystallizate obtained from the mother liquor has the following
  • the applied second crystallizate is then brought into solution, ie dissolved in water and thermally isomerized in a pressure-resistant, suitably designed, continuously operated tubular reactor.
  • hydrodynamic residence times of 1 to 60 minutes, preferably 1-30 minutes, more preferably 1 to 10 minutes at temperatures between 100 to 300 0 C, preferably from 150 0 C to 250 ° C, preferably from 180 0 C to 230 0 C, particularly preferably set from 200 ° C. to 220 ° C.
  • the thermally treated lopromid K2 solution is then rapidly cooled to room temperature in a downstream heat exchanger.
  • Iopromid-K2 from Example 1 280 g of Iopromid-K2 from Example 1 are dissolved in 520 g of water. The solution is then at a flow rate of 3 ml / min, by using a pressure retaining valve 20 bar provided flow tube at 208 - 209 0 C pumped.
  • the flow tube used has an inner diameter of 1.7526 mm and a heated length of 5.5 m (see Fig. 1).
  • a solution of the isomerized lopromide second crystallizate is then purified over ion exchange columns and crystallized from ethanol.
  • the yield of the lopromide crystallized from ethanol, based on the second crystallizate used in the isomerization, is 80% of.
  • the crystals show a content according to HPLC (standard method) of greater than 97.5% compared to external standards and have the following atropisomer ratio:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The invention relates to a method for recovering iopromide that is suitable for pharmaceutical purposes by thermally treating the mother liquors or the second crystallizate in a reactor and then crystallizing the same.

Description

Verfahren zur Rückgewinnung von für pharmazeutische Zwecke geeignetem lopromid aus Mutterlaugen.  Process for the recovery of pharmaceutical lopromide from mother liquors.
Die Erfindung betrifft ein Verfahren zur Rückgewinnung von für pharmazeutische Zwecke geeignetem lopromid durch thermische Behandlung der Mutterlaugen oder des gelösten Zweitkristallisates in einem Reaktor und anschließender Kristallisation. lopromid, 5-Methoxyacetylamino-2,4,6-triiod-isophthalsäure-[(2,3-dihydroxy-N- methyl-propyl)-(2,3-dihydroxypropyl)]-diamid, (DE 196 41 178 C und EP 0 015 867 B) ist ein jodhaltiges Röntgenkontrastmittel mit folgender chemischer Struktur: The invention relates to a process for the recovery of lopromide suitable for pharmaceutical purposes by thermal treatment of the mother liquors or the dissolved second crystallizate in a reactor and subsequent crystallization. lopromide, 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid - [(2,3-dihydroxy-N-methyl-propyl) - (2,3-dihydroxypropyl)] - diamide, (DE 196 41 178 C and EP 0 015 867 B) is an iodine-containing X-ray contrast agent with the following chemical structure:
Figure imgf000003_0001
lopromid
Figure imgf000003_0001
lopromide
Die sperrigen lodatome behindern die freie Rotation der in der Strukturformel mit 1 gekennzeichneten Bindung zwischen dem aromatischen Ring und der Amidgruppe mit der Dihydroxypropyl-methylamino-Gruppe durch die Anwesenheit der N-Methylgruppe erheblich, so dass zwei thermisch recht stabile Atropisomere auftreten. Solche Atropisomeren sind u. a. beschrieben in "Recent Advances in Atropisomerism" von M. Oki in Zeitschrift "Topics in Stereochemistry", 1983, Vol. 14, S. 1-81 und Tetrahedron Letters No. 38, Seiten 4593 - 4598, 1966. Bei einem der Atropisomeren liegt das substituierte Stickstoffatom oberhalb der Ringebene, beim anderen Isomer unterhalb der Ringebene. Die beiden atropisomeren Verbindungen (Isomer 1 und Isomer 2) unterscheiden sich in ihren physikalischen Eigenschaften, besonders in ihren Löslichkeiten in Wasser und organischen Lösungsmitteln. Nur lopromid einer bestimmen Zusammensetzung bezüglich dieser Atropisomeren ist als Röntgenkontrastmittel zugelassen (40-51 % Isomer 1 und 49-60% Isomer 2). Reinigungsverfahren für jodierte Röntgenkontrastmittel, wie beispielsweise lopamidol sind aus dem Stand der Technik bekannt, siehe EP 1 025 067 B1 und GB 2 280 436. Es werden darin Kristallisationen bei erhöhten Temperaturen beschrieben. In der Schrift WO 2004 031 110 A2 wird die Isomerisierung von chiralen Verbindungen durch thermische Behandlung offenbart. Diese Verfahren beinhalten jedoch nicht die Behandlung von lopromidmutterlaugen. lopromid für pharmazeutische Zwecke wird durch Kristallisation aus Ethanol erhalten. Hierbei fällt regelmäßig ein Gemisch an, das aus ca. 48% Isomer 1 und ca. 52% Isomer 2 besteht. In der Mutterlauge ist das Isomer 1 mit ca. 60% und das Isomer 2 nur zu ca. 40% enthalten. Aus diesem Grund kann aus der Mutterlauge nur ein Zweitkristallisat mit falscher Zusammensetzung bezüglich der Atropisomeren gewonnen werden (enthält zuviel Isomer 1). The bulky iodine atoms significantly hinder the free rotation of the bond labeled 1 in the structural formula between the aromatic ring and the amide group with the dihydroxypropylmethylamino group due to the presence of the N-methyl group, so that two thermally quite stable atropisomers occur. Such atropisomers are described, inter alia, in "Recent Advances in Atropisomerism" by M. Oki in the journal "Topics in Stereochemistry", 1983, Vol. 14, pp. 1-81 and Tetrahedron Letters No. 38, pages 4593 - 4598, 1966. In one of the atropisomers the substituted nitrogen atom lies above the ring plane, in the other isomer below the ring plane. The two atropisomeric compounds (isomer 1 and isomer 2) differ in their physical properties, especially in their solubilities in water and organic solvents. Only lopromide of a certain composition with regard to these atropisomers is approved as an X-ray contrast medium (40-51% isomer 1 and 49-60% isomer 2). Cleaning processes for iodinated X-ray contrast media, such as lopamidol, are known from the prior art, see EP 1 025 067 B1 and GB 2 280 436. Crystallizations at elevated temperatures are described therein. The document WO 2004 031 110 A2 discloses the isomerization of chiral compounds by thermal treatment. However, these procedures do not involve the treatment of lopromide mother liquors. Iopromide for pharmaceutical purposes is obtained by crystallization from ethanol. This regularly results in a mixture consisting of approx. 48% isomer 1 and approx. 52% isomer 2. The mother liquor contains about 60% of isomer 1 and only about 40% of isomer 2. For this reason, only a second crystallizate with the wrong composition regarding the atropisomers can be obtained from the mother liquor (contains too much isomer 1).
Bei der Herstellung von lopromid, rein wird eine finale Kristallisation aus Alkohol durchgeführt. Hierbei verbleibt ein Anteil von ca. 10% des lopromids in gelöster Form in der Mutterlauge, was sich als Ausbeuteverlust bemerkbar macht. Frühere Versuche, aus den anfallenden Mutterlaugen durch Zweitkristallisation weiteres lopromid auszukristallisieren und damit die Ausbeute zu erhöhen, schlugen fehl, da das aus den Mutterlaugen gewonnene lopromid K2 hinsichtlich des Atropisomerenverhältnisses nicht spezifikationskonform ist. Dieses Verhalten ist darauf zurückzuführen, dass sich in der Mutterlauge bestimmte Atropisomeren bevorzugt anreichern. In the production of lopromide, pure, a final crystallization from alcohol is carried out. A proportion of approx. 10% of the lopromide remains in dissolved form in the mother liquor, which is noticeable as a loss in yield. Previous attempts to crystallize further lopromide from the mother liquors obtained by means of second crystallization and thus to increase the yield failed, since the lopromide K2 obtained from the mother liquors does not conform to the specification with regard to the atropisomer ratio. This behavior is due to the fact that certain atropisomers accumulate preferentially in the mother liquor.
Aufgabe der Erfindung: Object of the invention:
Die nach dem Stand der Technik bekannten Herstellverfahren für lopromid, rein weisen den Nachteil auf, dass ein hoher Ausbeuteverlust in Kauf genommen werden muß und kein technisches Verfahren existiert, welches es gestattet, aus den Mutterlaugen lopromid zurückzugewinnen, das hinsichtlich des Atropisomeren-verhältnisses spezifikationskonform ist und sich somit für pharmazeutische Zwecke verwenden lässt. Lösung der Erfindung:  The production processes for lopromide, which are known according to the prior art, have the disadvantage that a high loss of yield has to be accepted and there is no technical process which allows lopromide to be recovered from the mother liquors, which conforms to the specifications with regard to the atropisomer ratio and can therefore be used for pharmaceutical purposes. Solution of the invention:
Die oben beschriebenen Nachteile konnten überraschenderweise dadurch gelöst werden, dass aus den lopromid, rein Mutterlaugen zunächst ein K2 durch eine geeignete Zweitkristallisation gewonnen wird, welches anschließend durch eine geeignete thermische Behandlung in einem kontinuierlichen Strömungsrohrreaktor spezifikationskonform isomerisiert wird, ohne dass es zu signifikanten Zersetzungen der Substanz kommt. Die Erfindung beinhaltet somit ein Verfahren zur Rückgewinnung von für pharmazeutische Zwecke geeignetem lopromid aud lopromidmutterlaugen oder Lösungen des Zweit- und Folgekristallisats durch thermische Behandlung der Lösung, vorzugsweise in einem Strömungsrohrreaktor bei 100 - 3000C, mit Vorteil bei 200 - 220 0C , und anschließendes schnelles Abkühlen auf Raumtemperatur und Kristallisation. Die thermische Behandlung in einem Strömungsreaktor erfolgt mit Vorteil in wässriger Lösung bei hydrodynamischen Verweilzeiten von 1 bis 60 Minuten. Die besonderen Ausführungsformen sind in den Patentansprüchen aufgeführt. Durch dieses erfindungsgemäße Verfahren kann die Gesamtausbeute an lopromid, rein signifikant gesteigert werden, so dass sich die Wirtschaftlichkeit erhöht. Zusätzlich fällt weniger halogenhaltiger Abfall an. The disadvantages described above could surprisingly be solved by first obtaining a K2 from the lopromide, pure mother liquors by means of a suitable second crystallization, which then a suitable thermal treatment is isomerized in a continuous flow tube reactor according to the specification without significant decomposition of the substance. The invention thus includes a method for recovering suitable for pharmaceutical purposes iopromide aud lopromidmutterlaugen or solutions of the second and Folgekristallisats by thermal treatment of the solution, preferably in a flow tube reactor at 100-300 0 C, advantageously at 200-220 0 C, and then rapid cooling to room temperature and crystallization. The thermal treatment in a flow reactor is advantageously carried out in aqueous solution with hydrodynamic residence times of 1 to 60 minutes. The particular embodiments are listed in the claims. The total yield of lopromide can be increased purely significantly by this method according to the invention, so that the economy increases. In addition, there is less halogen-containing waste.
Beschreibung des Verfahrens im Einzelnen: Description of the procedure in detail:
Aus den lopromid, rein Mutterlaugen wird zunächst ein Zweitkristallisat ausgebracht, indem die ethanolischen Mutterlaugen um den Faktor 2-16 eingeengt und in einem Alkohol bei erhöhter Temperatur gelöst werden. Beispiele für geeignete Alkohole sind Alkanole wie Methanol, Ethanol, 1- Propanol, 2-Propanol, 1-Butanol, 2-Butanol. Bevorzugt werden Ethanol, 1- Propanol und 2-Propanol eingesetzt, besonders bevorzugt 1-Propanol, da aus diesem Lösemittel die Kristallisation besonders rasch und vollständig und damit Kosten sparend geschieht. Zur Auslösung der Kristallisation kann mit lopromid, rein angeimpft werden. Das K2-Kristallisat wird anschließend nach bekannten Methoden isoliert, gewaschen und getrocknet.  A second crystallizate is first applied from the lopromide, pure mother liquors, by concentrating the ethanolic mother liquors by a factor of 2-16 and dissolving them in an alcohol at elevated temperature. Examples of suitable alcohols are alkanols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol. Ethanol, 1-propanol and 2-propanol are preferably used, particularly preferably 1-propanol, since the crystallization takes place particularly quickly and completely from this solvent and thus saves costs. To initiate the crystallization can be inoculated with lopromid, pure. The K2 crystals are then isolated, washed and dried by known methods.
Beispiel 1 : Example 1 :
Herstellung des K2-Kristallisates  Production of the K2 crystals
12000 g lopromid, rein Mutterlauge (Feststoffgehalt ca. 6,2 %) werden im Vakuum auf ein viskoses Öl von 892 g eingeengt. 877 g dieses Rückstandes werden in einem geeigneten Reaktionsgefäß bei einer Badtemperatur von 65 °C mit 439 ml 1-Propanol unter Rühren versetzt. Nach Animpfen mit 0,73 g lopromid, rein wird bei einer Badtemperatur von 65 0C für weitere 48h gerührt. Die Kristallsuspension wird anschließend auf 20 0C gekühlt, 1 h bei dieser Temperatur gerührt und über eine Nutsche abgesaugt. Nach Waschen mit 4 Portionen ä 110 ml Ethanol wird das Zweitkristallisat bei 40 0C im Vakuumtrockenschrank getrocknet. Ausbeute: 363,8 g (ca. 52 % v. E.) 12000 g of lopromide, pure mother liquor (solids content approx. 6.2%) are concentrated in vacuo to a viscous oil of 892 g. 877 g of this residue are mixed in a suitable reaction vessel at a bath temperature of 65 ° C with 439 ml of 1-propanol with stirring. After seeding with 0.73 g of iopromide, pure is stirred at a bath temperature of 65 0 C for an additional 48h. The crystal suspension is then cooled to 20 ° C., stirred at this temperature for 1 h and suction filtered through a suction filter. After washing with 4 portions of 110 ml of ethanol, the second crystals are dried at 40 ° C. in a vacuum drying cabinet. Yield: 363.8 g (approx. 52% of full scale)
Das aus der Mutterlauge gewonnene Zweitkristallisat weist folgendes The second crystallizate obtained from the mother liquor has the following
Atropisomeren-Verhältnis auf: Atropisomer ratio on:
Figure imgf000006_0001
Figure imgf000006_0001
Das ausgebrachte Zweitkristallisat wird anschließend in Lösung gebracht, d. h. in Wasser gelöst und in einem druckfesten, geeignet ausgelegten kontinuierlich betriebenen Rohrreaktor thermisch isomerisiert. Hierbei werden hydrodynamische Verweilzeiten von 1 bis 60 Minuten, bevorzugt 1 - 30 Minuten, besonders bevorzugt 1 bis 10 Minuten bei Temperaturen zwischen 100 bis 300 0C, bevorzugt 150 0C bis 250 °C, bevorzugt 180 0C bis 230 0C, besonders bevorzugt 200 0C bis 220 0C eingestellt. In einem nachgeschalteten Wärmetauscher wird die termisch behandelte lopromid K2-Lösung anschließend zügig auf Raumtemperatur abgekühlt. The applied second crystallizate is then brought into solution, ie dissolved in water and thermally isomerized in a pressure-resistant, suitably designed, continuously operated tubular reactor. Here, hydrodynamic residence times of 1 to 60 minutes, preferably 1-30 minutes, more preferably 1 to 10 minutes at temperatures between 100 to 300 0 C, preferably from 150 0 C to 250 ° C, preferably from 180 0 C to 230 0 C, particularly preferably set from 200 ° C. to 220 ° C. The thermally treated lopromid K2 solution is then rapidly cooled to room temperature in a downstream heat exchanger.
Beispiel 2: Example 2:
Thermische Isomerisierung des lopromid-Zweitkristallisates  Thermal isomerization of the lopromide second crystallizate
280 g Iopromid-K2 aus Beispiel 1 werden in 520 g Wasser gelöst. Die Lösung wird anschließend bei einem Volumenstrom von 3 ml/min, durch ein mit einem Druckhalteventil von 20 bar versehenes Strömungsrohr bei 208 - 209 0C gepumpt. Das verwendete Strömungsrohr hat einen Innendurchmesser von 1 ,7526 mm und eine beheizte Länge von 5,5 m (s. Abb. 1 ). 280 g of Iopromid-K2 from Example 1 are dissolved in 520 g of water. The solution is then at a flow rate of 3 ml / min, by using a pressure retaining valve 20 bar provided flow tube at 208 - 209 0 C pumped. The flow tube used has an inner diameter of 1.7526 mm and a heated length of 5.5 m (see Fig. 1).
Eine Lösung des isomerisierten lopromid Zweitkristallisat wird anschließend über lonentauschersäulen gereinigt und aus Ethanol kristallisiert. A solution of the isomerized lopromide second crystallizate is then purified over ion exchange columns and crystallized from ethanol.
Die Ausbeute des aus Ethanol kristallisierten lopromids liegt, bezogen auf das in die Isomerisierung eingesetzte Zweitkristallisat, bei 80 % v. E.  The yield of the lopromide crystallized from ethanol, based on the second crystallizate used in the isomerization, is 80% of. E.
Das Kristallisat zeigt einen Gehalt nach HPLC (Standardmethode) von größer 97,5 % gegenüber externen Standard und weist folgendes Atropisomeren- Verhältnis auf: The crystals show a content according to HPLC (standard method) of greater than 97.5% compared to external standards and have the following atropisomer ratio:
Figure imgf000006_0002
Figure imgf000006_0002

Claims

Patentansprüche Claims
1.) Verfahren zur Rückgewinnung von für pharmazeutische Zwecke geeignetem lopromid durch thermische Behandlung des Zweit- oder Folgekristallisates der Mutterlauge, gelöst in einem Lösungsmittel in einem Ströhmungsrohrreaktor und anschließender Kristallisation. 1.) Process for the recovery of lopromide suitable for pharmaceutical purposes by thermal treatment of the second or subsequent crystals of the mother liquor, dissolved in a solvent in a flow tube reactor and subsequent crystallization.
2.) Verfahren nach Anspruch 1 , worin das in der Mutterlauge oder Zweit- oder Folgekristallisates enthaltende lopromid ein für pharmazeutische Zwecke ungeeignetes Isomerenverhältnis aufweist und durch thermische Behandlung in einem Strömungsrohrreaktor, anschließendes Abkühlen auf Raumtemperatur und Kristallisation erhalten wird. 2.) Process according to claim 1, wherein the lopromide contained in the mother liquor or secondary or secondary crystals has an isomer ratio which is unsuitable for pharmaceutical purposes and is obtained by thermal treatment in a flow tube reactor, subsequent cooling to room temperature and crystallization.
3.) Verfahren nach Anspruch 1 oder 2, worin die thermische Behandlung in einem Strömungsrohrreaktor bei 100 - 300° C erfolgt. 3.) Method according to claim 1 or 2, wherein the thermal treatment in a flow tube reactor is carried out at 100-300 ° C.
4.) Verfahren nach mindestens einem der Ansprüche 1 - 2, worin die Kristallisation aus einem Alkohol erfolgt. 4.) Method according to at least one of claims 1-2, wherein the crystallization takes place from an alcohol.
5.) Verfahren nach mindestens einem der Verfahren der Ansprüche 1 - 4, wobei die spezifikationskonforme, für pharmazeutische Zwecke geeigneten lopromidmengen durch Temperaturbehandlung der in einem Lösungsmittel gelösten Atropisomeren erhalten werden. 5.) Method according to at least one of the methods of claims 1-4, wherein the specification-compliant amounts of lopromide suitable for pharmaceutical purposes are obtained by temperature treatment of the atropisomers dissolved in a solvent.
6.) Verfahren nach mindesten einem der Ansprüche 1 - 5, wobei die hydrodynamische Verweilzeiten der in einem Lösungsmittel gelösten Atropisomeren im Strömungsrohrreaktor 1 bis 60 Minuten betragen. 6.) Method according to at least one of claims 1-5, wherein the hydrodynamic residence times of the atropisomers dissolved in a solvent in the flow tube reactor are 1 to 60 minutes.
7.) Verfahren nach Anspruch 6, worin als Lösungsmittel Wasser verwendet wird. 7.) Method according to claim 6, wherein water is used as solvent.
PCT/EP2006/010943 2005-12-05 2006-11-10 Method for recovering iopromide suitable for pharmaceutical purposes from mother liquors WO2007065534A1 (en)

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JP2008543678A JP2009518325A (en) 2005-12-05 2006-11-10 Method for recovery of iopromide from mother liquor suitable for pharmaceutical purposes
CA2630413A CA2630413C (en) 2005-12-05 2006-11-10 Process for recovery of iopromide, suitable for pharmaceutical purposes, from mother liquors
EP06818545A EP1960348A1 (en) 2005-12-05 2006-11-10 Method for recovering iopromide suitable for pharmaceutical purposes from mother liquors

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DE200510059191 DE102005059191B4 (en) 2005-12-05 2005-12-05 Process for the recovery of pharmaceutically acceptable iopromide from mother liquors
DE102005059191.4 2005-12-05
US74817505P 2005-12-08 2005-12-08
US60/748,175 2005-12-08

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Publication number Priority date Publication date Assignee Title
US20110245347A1 (en) * 2008-12-05 2011-10-06 Daewoong Pharmaceutical Co., Ltd. Method for selectively crystallizing a z isomer of iopromide

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Publication number Priority date Publication date Assignee Title
EP0015867A1 (en) * 1979-03-08 1980-09-17 Schering Aktiengesellschaft Diamides of triiodo-isophthalic acids, their preparation and X-ray contrast agents containing them
WO1999018054A1 (en) * 1997-10-02 1999-04-15 Nycomed Imaging As Process for the crystallisation of sterically hindered compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0015867A1 (en) * 1979-03-08 1980-09-17 Schering Aktiengesellschaft Diamides of triiodo-isophthalic acids, their preparation and X-ray contrast agents containing them
WO1999018054A1 (en) * 1997-10-02 1999-04-15 Nycomed Imaging As Process for the crystallisation of sterically hindered compounds

Cited By (5)

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US20110245347A1 (en) * 2008-12-05 2011-10-06 Daewoong Pharmaceutical Co., Ltd. Method for selectively crystallizing a z isomer of iopromide
CN102239135A (en) * 2008-12-05 2011-11-09 大熊制药株式会社 Method for selectively crystallizing a z isomer of iopromide
JP2012510510A (en) * 2008-12-05 2012-05-10 ダエウン ファーマシューティカル カンパニー リミテッド Method for selectively crystallizing the Z isomer of iopromide
RU2481325C2 (en) * 2008-12-05 2013-05-10 Даевунг Фармасьютикал Ко., Лтд. Method for selective crystallisation of z-isomer of iopromide
US8541620B2 (en) * 2008-12-05 2013-09-24 Daewoong Pharmaceutical Co., Ltd. Method for selectively crystallizing a Z isomer of iopromide

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