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EP2580184A2 - Process for preparing crystalline 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid and use for production of primovist® - Google Patents

Process for preparing crystalline 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid and use for production of primovist®

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Publication number
EP2580184A2
EP2580184A2 EP11724612.4A EP11724612A EP2580184A2 EP 2580184 A2 EP2580184 A2 EP 2580184A2 EP 11724612 A EP11724612 A EP 11724612A EP 2580184 A2 EP2580184 A2 EP 2580184A2
Authority
EP
European Patent Office
Prior art keywords
tris
triaza
ethoxybenzyl
carboxymethyl
undecanedioic acid
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.)
Withdrawn
Application number
EP11724612.4A
Other languages
German (de)
French (fr)
Inventor
Johannes Platzek
Wilhelm Trentmann
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.)
Bayer Intellectual Property GmbH
Original Assignee
Bayer Intellectual Property GmbH
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Filing date
Publication date
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Priority claimed from DE201010023890 external-priority patent/DE102010023890A1/en
Priority claimed from BRPI1002466 external-priority patent/BRPI1002466A2/en
Application filed by Bayer Intellectual Property GmbH filed Critical Bayer Intellectual Property GmbH
Publication of EP2580184A2 publication Critical patent/EP2580184A2/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

Definitions

  • the invention relates to a process for the preparation of crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of the formula I.
  • EOB-DTPA 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid
  • Gd-EOB-DTPA 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid
  • Primovist® is offered and used as a 0.25 molar solution as a contrast agent for parenteral use.
  • the purification of this substance in a quality which can be used in injection (iv) preparations is very complicated, expensive and requires a chromatographic purification of the penta- tert -butyl ester of ferrum according to the known state of the art II anda would be used in the presence of estrone with trifluoroacetic acid and acidification of the reaction mixture with ion exchanger.
  • the mono-sodium salt thus obtained is not crystalline and can only be obtained by freeze-drying in solid form.
  • Primovist® formulation (commercial product) was initially in dissolving the previously freeze-dried gadolinium complex as a di-sodium salt in water, with the addition of commercially available buffers, and with the addition of an excess of EO B-DTPA, usually in the form of the calcium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4 - (4-ethoxybenzyl) -undecane-d acid.
  • This complexing agent excess (excess ligands) or of calcium (Ca) salt is described in detail in patent EP 0 270 483 B2.
  • the object of the invention is to provide a process and thus EOB-DTPA qualities in which one can directly prepare the gadolinium complex from the ligand (EOB-DTPA) and gadolinium oxide.
  • EOB-DTPA gadolinium complex from the ligand
  • the availability of highly pure ligand is sufficient and more stable in storage Form essential.
  • the invention relates to a process for the preparation of crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of the formula I in which
  • the process can be carried out by dissolving the ester of formula II in a lower alcohol, such as ethanol, n-propanol, isopropanol or, preferably, methanol, with from 5 to 7 equivalents of 8 to 12 molar alkali metal hydroxide. Solution (preferably sodium hydroxide solution) and hydrolyzed at the boiling temperature of the reaction mixture until the reaction is complete, which can be easily determined by thin layer chromatography (TLC) or gas chromatography (GC) analysis in a conventional manner.
  • TLC thin layer chromatography
  • GC gas chromatography
  • the solvent is preferably substantially removed by vacuum distillation, the residue dissolved in water and the resulting reaction mixture is concentrated, the residue dissolved in water and the resulting solution by slowly adding an aqueous inorganic acid, preferably 12 to 25% sulfuric acid to a pH Value of from 2.1 to 2.8, but preferably from 2.5 to 2.7, acidified.
  • the dosage is such that the addition is interrupted at the onset of turbidity and then continued as the crystallization proceeds. If the adjusted pH after 12 hours is still constant at 2.1 to 2.8, preferably 2.5 to 2.7, the crystals are filtered off.
  • This crystallizate can be further recrystallized from 4-8 times the amount of boiling water be purified by crystallization, taking care to ensure that the cooling rate of the solution does not exceed 10 ° C per hour maximum.
  • the ligand thus prepared by the process according to the invention (EOB-DTPA) is not hygroscopic and is characterized by very high purities (> 98.75%,> 99.0%) by HPLC (100% method).
  • the residual methanol solvent content of a product prepared by the process according to the invention is ⁇ 0.01%, well below the specification limit (0.1%). It also shows that the enantiomeric excess is improved by the crystallizations, thereby reaching enantiomeric excesses of> 99% e.e.
  • the substance is very stable on storage and can be further processed as needed at a later date.
  • the overall process is thus highly compatible, which means that there is no need to redefine the cost of chromatography steps and ion exchange desalting. The technically difficult handling of freeze-dried material is also eliminated.
  • test method related substances / decomposition products is combined with the test method content.
  • the test and reference solutions must be prepared and aliquoted at the same temperature.
  • a solution of 1, 00 mg / mL (0.95 - 1, 05 mg / mL) of test substance is prepared by dissolving test substance in mobile phase A without heating, cP1 / P2.
  • test substance 10.00 mg are dissolved in mobile phase A in a 10 mL volumetric flask without heating and made up to the mark.
  • EOB-DTPA a solution of 1, 00 mg / mL (equivalent to 0.95 - 1, 05 mg / mL) EOB-DTPA is prepared by dissolving at least 10 mg EOB-DTPA, working standard, m, in mobile phase A in a volumetric flask with the Volume V [V] produced.
  • VK coefficient of variation
  • the pH is adjusted to pH 7.2 (optionally with either a 5% aqueous HCl or a 5% aqueous sodium hydroxide solution).
  • the total volume of the solution is adjusted to 250.8 L by adding water.
  • the solution is filtered through a membrane (nitrogen pressure) and can then be filled in commercial vials and sterilized.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Crystallography & Structural 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 process for preparing crystalline 3,6,9-triaza- 3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid of the formula (I) by hydrolysis of di-tert-butyl 3,6,9-triaza-3,6,9-tris(tert- butoxycarbonylmethyl)-4-(4-ethoxybenzyl)undecanedioate of the formula (II) in an aqueous alkali metal hydroxide solution, and to the use of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid of the formula I for preparation of the gadolinium complex of 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid[(Gd-EOB-DTPA) = Primovist®].

Description

Verfahren zur Herstellung kristalliner  Process for the preparation of crystalline
3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure und die  3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid and the
Verwendung zur Herstellung von Primovist®.  Use for the production of Primovist®.
Die Erfindung betrifft ein Verfahren zur Herstellung kristalliner 3,6,9-Triaza-3,6,9- tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure der Formel I The invention relates to a process for the preparation of crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of the formula I.
durch Verseifung von 3,6,9-Triaza-3,6,9-tris(tert.butoxycarbonylmethyl)-4-(4-ethoxybenzyl)- undecandisäure-di-tert.-butylester der Formel II, by saponification of 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-ethoxybenzyl) undecanedioic di-tert-butyl ester of the formula II,
und die Verwendung von 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)- undecandisäure der Formel I zur Herstellung des Gadolinium-Komplex der 3,6,9-Triaza- 3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure (Gd-EOB-DTPA=Primovist®). 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure (EOB-DTPA) ist ein Komplexbildner bzw. Chelator, dessen Komplexe mit Lanthanoiden zur Herstellung von Mitteln für die NMR- und Röntgen-Diagnostik sowie in der Strahlentherapie Anwendung finden. (EP 405 704 B1 ). and the use of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of the formula I for the preparation of the gadolinium complex of the 3,6,9-triaza- 3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (Gd-EOB-DTPA = Primovist®). 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (EOB-DTPA) is a complexing agent or chelator whose complexes with lanthanides are used to prepare agents for the NMR and X-ray diagnostics as well as in radiotherapy application. (EP 405 704 B1).
Der Gadolinium-Komplex der 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)- undecandisäure (Gd-EOB-DTPA) ist als Di-Natrium-Salz unter dem Namen Eovist bzw. Primovist® (gadoxetic acid) in der Literatur bekannt  The gadolinium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (Gd-EOB-DTPA) is known as a di-sodium salt under the name Eovist or Primovist® (gadoxetic acid) in the literature
Gd-EOB-DTPA Gd-EOB-DTPA
und ist seit 2004 als Kontrastmittel für die Kernspintomographie als Leber-Kontrast-Mittel zugelassen. and has been approved since 2004 as a contrast agent for magnetic resonance imaging as a liver contrast agent.
Primovist® wird als 0,25 molare Lösung als Kontrastmittel für die parenterale Anwendung angeboten und eingesetzt. Die Reindarstellung dieser Substanz in einer Qualität, die in lnjektions-(i.v.) Präparaten verwendet werden kann, ist nach dem bekannten Stand der Technik sehr aufwendig, teuer und erfordert eine chromatographische Reinigung des Penta- tert.-butyl este rs d e r F o rm e l I I u n d a n sc h l i e ße n d e Ve rse ifu n g d es E ste rs m it Trifluoressigsäure und Ansäuern der Reaktionsmischung mit lonentauscher. Das so erhaltene Mono-Natriumsalz ist nicht kristallin und kann lediglich durch Gefriertrocknung in fester Form gewonnen werden. Die Synthese wird in EP 0 405 704 B1 (Beispiel 8) und in Schmitt-Willich H., Brehm M., Ewers C.L., Michl G., Muller-Fahrnow A., Petrov O., Platzek J., Raduchel B., Sulzle D. Synthesis and Physicochemical Characterization of a New Gadolinium Chelate: The Liver-Specific Magnetic Resonance Imaging Contrast Agent Gd- EOB-DTPA. Inorg Chem. 1999; 38(6): 1 134-1 144 beschrieben. Dieses Verfahren in aber für die Produktion ungeeignet. Primovist® is offered and used as a 0.25 molar solution as a contrast agent for parenteral use. The purification of this substance in a quality which can be used in injection (iv) preparations is very complicated, expensive and requires a chromatographic purification of the penta- tert -butyl ester of ferrum according to the known state of the art II anda would be used in the presence of estrone with trifluoroacetic acid and acidification of the reaction mixture with ion exchanger. The mono-sodium salt thus obtained is not crystalline and can only be obtained by freeze-drying in solid form. The synthesis is described in EP 0 405 704 B1 (Example 8) and in Schmitt-Willich H., Brehm M., Ewers CL, Michl G., Muller-Fahrnow A., Petrov O., Platzek J., Raduchel B. Sulzle D. Synthesis and Physicochemical Characterization of a New Gadolinium Chelate: The Liver-Specific Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA. Inorg Chem. 1999; 38 (6): 1 134-1 144. This method in but unsuitable for production.
Die eigentliche Herstellung der Primovist®-Formulierung (Handelsprodukt) bestand zu Anfang im Lösen des zuvor gefriergetrockneten Gadolinium-Komplexes als Di-Natrium-Salz in Wasser, unter Zusatz von handelsüblichen Puffern, sowie unter Zusatz eines Überschuss an EO B-DTPA, in der Regel in Form des Kalzium-Komplexes der 3,6,9-Triaza-3,6,9- tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecan-d i s ä u re . D i e V e rw e n d u n g d i e s e s Komplexbildner Überschusses (Überschuss-Liganden) oder von Kalzium(Ca)-Salz wird im Patent EP 0 270 483 B2 ausführlich dargestellt. The actual production of Primovist® formulation (commercial product) was initially in dissolving the previously freeze-dried gadolinium complex as a di-sodium salt in water, with the addition of commercially available buffers, and with the addition of an excess of EO B-DTPA, usually in the form of the calcium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4 - (4-ethoxybenzyl) -undecane-d acid. The use of this complexing agent excess (excess ligands) or of calcium (Ca) salt is described in detail in patent EP 0 270 483 B2.
Da der Gadolinium-Komplex als Di-Natriumsalz sehr hygroskopische Eigenschaften besitzt, ist ein „Up-Scaling" dieses Prozesses sehr schwierig. Es wurden dafür großtechnische Gefriertrockner eingesetzt, die das Produkt in relativ schwankender Wasser-Gehalts-Qualität liefern. Auch die Folgeschritte, das Abfüllen und Lagern der Drug-Substanz gestaltet sich ebenfalls als sehr schwierig. Vorteilhafter wäre es, wenn man einen Prozess hätte, bei den man direkt den Gadolinium-Komplex aus dem Liganden (EOB-DTPA) und Gadoliniumoxid herstellen könnte. Voraussetzung hierfür ist aber die Verfügbarkeit von hochreinen Chargen des Liganden (Chelator = 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)- undecandisäure).  Since the gadolinium complex has very hygroscopic properties as a di-sodium salt, it is very difficult to "scale up" this process by using large-scale freeze-dryers which deliver the product in relatively varying water content quality. Filling and storing the drug substance is also very difficult, but it would be more advantageous to have a process that would allow the direct formation of the gadolinium complex from the ligand (EOB-DTPA) and gadolinium oxide the availability of high purity batches of the ligand (chelator = 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid).
Es ist nun gelungen, den Liganden kristallin in sehr hoher Qualität und Ausbeute in die Hand zu bekommen, ohne aufwendige Chromatographie- und Ionenaustauscher-Behandlungen anwenden zu müssen. Eine Zwischen-Isolierung nach Gefriertrocknung entfällt somit. It has now been possible to obtain the ligand crystalline in very high quality and yield, without having to resort to complex chromatography and ion exchange treatments. An intermediate isolation after freeze-drying is thus eliminated.
Aufgabe der Erfindung ist es, einen Prozess und somit EOB-DTPA-Qualitäten bereit zu stellen, bei der man direkt den Gadolinium-Komplex aus dem Liganden (EOB-DTPA) und Gadoliniumoxid herstellen kann. Dazu ist aber die Verfügbarkeit von hochreinem Liganden (=3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure) (EOB-DTPA) in ausreichender Menge und in lagerstabiler Form essentiell. The object of the invention is to provide a process and thus EOB-DTPA qualities in which one can directly prepare the gadolinium complex from the ligand (EOB-DTPA) and gadolinium oxide. However, the availability of highly pure ligand (= 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid) (EOB-DTPA) is sufficient and more stable in storage Form essential.
Die Erfindung betrifft ein Verfahren zur Herstellung kristalliner 3,6,9-Triaza-3,6,9- tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure der Formel I, worin man The invention relates to a process for the preparation of crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of the formula I in which
3,6,9-Triaza-3,6,9-tris(tert.butoxycarbonylmethyl)-4-(4^ 3,6,9-triaza-3,6,9-tris (tert.butoxycarbonylmethyl) -4- (4 ^
butylester der Formel II butyl ester of formula II
II mit einer wäßrigen Alkalimetallhydroxid-Lösung hydrolysiert, einengt, den Rückstand in Wasser löst und die erhaltene Lösung ansäuert oder alternativ in einem niederen Alkohol löst, mit 5 bis 7 Äquivalenten einer wäßrigen Alkalimetallhydroxid-Lösung bei 50°C bis 90°C hydrolysiert, die erhaltene Reaktionsmischung einengt, den Rückstand in Wasser löst und die erhaltene Lösung durch langsame Zugabe einer wäßrigen anorganischen Säure auf einen pH-Wert von 2 , 1 bis 2 ,8 , bevorzugt aber bei 2 ,5 bis 2 ,7 , ansäuert u nd vom Niederschlag filtriert.  II hydrolyzed with an aqueous alkali metal hydroxide solution, concentrated, the residue dissolved in water and the resulting solution is acidified or alternatively dissolved in a lower alcohol, with 5 to 7 equivalents of an aqueous alkali metal hydroxide solution at 50 ° C to 90 ° C hydrolyzed concentrated reaction mixture, the residue is dissolved in water and the resulting solution by slow addition of an aqueous inorganic acid to a pH of 2, 1 to 2, 8, but preferably at 2, 5 to 2, 7, acidified and the precipitate filtered.
Nach dem Verfahren ist es nicht erforderlich den Penta-tert. -butylester der Formel I I zu reinigen ; zudem hat dieses Verfahren den Vorzug, daß das Verfahrensprodu kt in kristalliner Form anfällt. Das Verfahren kann in der Weise durchgeführt werden, daß man den Ester der Formel II in einem niederen Alkohol, wie Ethanol, n-Propanol, Isopropanol oder vorzugsweise Methanol löst, m it 5 bis 7 Äq uivalenten ei ner 8 bis 1 2 molaren Alkalimetallhydroxid-Lösung (vorzugsweise Natriumhydroxid-Lösung) versetzt und bei der Siedetemperatur der Reaktionsmischung bis zur Beendigung der Umsetzung hydrolysiert, welche durch Dünnschichtchromatographie (DC)- oder Gaschromatographie (GC)-Analyse in an sich bekannter Weise leicht ermittelt werden kann.  After the process, it is not necessary the penta-tert. butyl ester of formula I I to clean; Moreover, this method has the advantage that the Verfahrensprodu kt obtained in crystalline form. The process can be carried out by dissolving the ester of formula II in a lower alcohol, such as ethanol, n-propanol, isopropanol or, preferably, methanol, with from 5 to 7 equivalents of 8 to 12 molar alkali metal hydroxide. Solution (preferably sodium hydroxide solution) and hydrolyzed at the boiling temperature of the reaction mixture until the reaction is complete, which can be easily determined by thin layer chromatography (TLC) or gas chromatography (GC) analysis in a conventional manner.
Nach erfolgter Hydrolyse wird das Lösungsmittel vorzugsweise mittels Vakuumdestillation weitgehend entfernt, der Rückstand in Wasser gelöst und die erhaltene Reaktionsmischung einengt, den Rückstand in Wasser gelöst und die erhaltene Lösung durch langsame Zugabe einer wäßrigen anorganischen Säure, vorzugsweise 12 bis 25%ige Schwefelsäure auf einen pH-Wert von 2,1 bis 2,8, bevorzugt aber bei 2,5 bis 2,7, ansäuert. Die Dosierung erfolgt so, daß die Zugabe bei beginnender Trübung unterbrochen und dann bei fortschreitender Kristallisation fortgesetzt wird. Wenn der eingestellte pH-Wert nach 12 Stunden immer noch konstant bei 2,1 bis 2,8, bevorzugt bei 2,5 - 2,7 liegt, filtriert man das Kristallisat ab. Dieses Kristallisat kann durch Umkristallisation aus der 4-8 fachen Menge siedendem Wasser weiter mittels Kristallisation gereinigt werden , wobei man darauf achten zu achten ist, daß die Abkühlungsrate der Lösung maximal 10°C pro Stunde nicht überschreitet. After hydrolysis, the solvent is preferably substantially removed by vacuum distillation, the residue dissolved in water and the resulting reaction mixture is concentrated, the residue dissolved in water and the resulting solution by slowly adding an aqueous inorganic acid, preferably 12 to 25% sulfuric acid to a pH Value of from 2.1 to 2.8, but preferably from 2.5 to 2.7, acidified. The dosage is such that the addition is interrupted at the onset of turbidity and then continued as the crystallization proceeds. If the adjusted pH after 12 hours is still constant at 2.1 to 2.8, preferably 2.5 to 2.7, the crystals are filtered off. This crystallizate can be further recrystallized from 4-8 times the amount of boiling water be purified by crystallization, taking care to ensure that the cooling rate of the solution does not exceed 10 ° C per hour maximum.
Der mittels erfindungsgemäßen Verfahrens so hergestellte Ligand (EOB-DTPA) ist nicht hygroskopisch und zeichnet sich durch sehr hohe Reinheiten (> 98,75 %, > 99,0 %) nach HPLC (100% Methode) aus. Der Methanol-Restlösungsmittelgehalt eines nach dem erfindungsgemäßen Verfahren hergestellten Produktes liegt mit <0,01 % weit unter der Spezifikationsgrenze (0,1 %). Es zeigt sich ebenfalls, dass durch die Kristallisationen der Enantiomeren-Überschuss verbessert wird, dadurch erreicht man Enantiomeren- Überschüsse von > 99% e.e. Die Substanz ist sehr gut lagerstabil und kann je nach Bedarf zum späteren Zeitpunkt weiter verarbeitet werden. Der Gesamtprozess ist somit stark vere i nfa cht word en , was s i ch d u rch e i n e Kosten red u kti on d a rste l lt, d a te u re Chromatographie-Schritte, sowie Ionenaustauscher-Entsalzungen nicht mehr nötig sind. Die technische schwierige Handhabung von gefriergetrocknetem Material entfällt ebenfalls. The ligand thus prepared by the process according to the invention (EOB-DTPA) is not hygroscopic and is characterized by very high purities (> 98.75%,> 99.0%) by HPLC (100% method). The residual methanol solvent content of a product prepared by the process according to the invention is <0.01%, well below the specification limit (0.1%). It also shows that the enantiomeric excess is improved by the crystallizations, thereby reaching enantiomeric excesses of> 99% e.e. The substance is very stable on storage and can be further processed as needed at a later date. The overall process is thus highly compatible, which means that there is no need to redefine the cost of chromatography steps and ion exchange desalting. The technically difficult handling of freeze-dried material is also eliminated.
Die Verwendung von 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)- undecandisäure zur Herstellung des Gadolinium-Komplex der 3,6,9-Triaza-3,6,9- tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure (Gd-EOB-DTPA) erfolgt durch Umsetzung von Di-Gadolinium-tri-oxid in Wasser und anschließender Gefriertrocknung, wie in der DE 39 22 005 A1 beschrieben und die Verwendung von kristalliner 3,6,9-Triaza-3,6,9- tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure der Formel I zur Herstellung einer galenischen Formulierung des Gadolinium-Komplex der 3,6,9-Triaza-3,6,9- tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure (Gd-EOB-DTPA) für diagnostische Zwecke, besonders für die MR-Tomographie. The use of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid for the preparation of the gadolinium complex of 3,6,9-triaza-3,6, 9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (Gd-EOB-DTPA) is carried out by reacting di-gadolinium tri-oxide in water and subsequent freeze-drying, as described in DE 39 22 005 A1 and the use of crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of formula I to prepare a galenic formulation of the gadolinium complex of 3,6,9 -Triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (Gd-EOB-DTPA) for diagnostic purposes, especially for MRI.
Beispiele Examples
Beispiel 1 example 1
Kristalline 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecan-disäure:  Crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecane diacid:
200 L einer methanolischen Lösung 3,6,9-Triaza-3,6,9-tris(tert.butoxycarbonylmethyl)-4-(4- ethoxybenzyl)-undecandisäure-di-tert.-butylester (1 95 Mol Rohester aus Vorstufe, ohne chromatographische Aufreinigung, hergestellt nach: Schmitt-Willich H . , Brehm M. , Ewers C.L., Michl G., Muller-Fahrnow A., Petrov O., Platzek J., Raduchel B., Sulzle D. Synthesis and Physicochemical Characterization of a New Gadolinium Chelate: The Liver-Specific Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA. Inorg C em. 1999; 38(6)) werden mit 280 L Methanol versetzt. Die erhaltene Lösung wird zu einer Lösung aus 45,1 kg (1 130 Mol) Natriumhydroxid und 121 L Wasser gegeben. Das Reaktionsgemisch wird 2,5 Stunden unter Rückfluß erhitzt und danach unter vermindertem Druck auf ca. 200 L eingedampft. Das zurückbleibende Öl wird mit Wasser bis auf ein Gewicht von 397 kg verdünnt. Zu der Lösung werden 182 L einer 25%igen Schwefelsäure langsam zugetropft (pH der Lösung: 2,63). Nach beginnender Kristallisation wird durch weitere Zugabe von Schwefelsäure erneut auf einen pH-Wert von 2,6 eingestellt. Das Reaktionsgemisch rührt 12 Stunden bei 20°C nach . Die entstandenen Kristalle werden abfiltriert und aus Wasser umkristallisiert. Dabei ist die Einhaltung einer Abkühlrate von maximal 10°C / h notwendig. Nach Trocknung im Vakuum (50°C) werden 74,7 kg der 3,6,9-Triaza-3,6,9- tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure in Form von farblosen Kristallen erhalten. Ausbeute: 68% der Theorie 200 L of a methanolic solution 3,6,9-triaza-3,6,9-tris (tert-butoxycarbonylmethyl) -4- (4-ethoxybenzyl) undecanedioic acid di-tert-butyl ester (1,995 mol of crude ester from precursor, without chromatographic purification, prepared according to: Schmitt-Willich H., Brehm M., Ewers CL, Michl G., Muller-Fahrnow A., Petrov O., Platzek J., Raduchel B., Sulzle D. Synthesis and Physiochemical Characterization of a New Gadolinium Chelates: The Liver-Specific Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA Inorg Cem 1999, 38 (6)) are added to 280 L of methanol. The resulting solution is added to a solution of 45.1 kg (1 130 mol) of sodium hydroxide and 121 L of water. The reaction mixture is heated under reflux for 2.5 hours and then evaporated under reduced pressure to about 200 L. The remaining oil is used with water to a weight of 397 kg diluted. 182 L of a 25% strength sulfuric acid are slowly added dropwise to the solution (pH of the solution: 2.63). After the onset of crystallization is adjusted by further addition of sulfuric acid again to a pH of 2.6. The reaction mixture is stirred for 12 hours at 20 ° C after. The resulting crystals are filtered off and recrystallized from water. It is necessary to maintain a cooling rate of max. 10 ° C / h. After drying in vacuo (50 ° C.), 74.7 kg of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid are obtained in the form of colorless crystals. Yield: 68% of theory
Schmelzpunkt 125°C (Zersetzung). [a]D 20= + 8,2 (EtOH) Melting point 125 ° C (decomposition). [a] D 20 = + 8.2 (EtOH)
Analyse: C23H33N3O-1 -| x 4 H2O Analysis: C23H33N3O-1 - | x 4 H2O
C N H C N H
Ber. 46,07 7,01 6,89  Ber. 46.07 7.01 6.89
Gef. 45,89 6,75 6,78  Gef. 45.89 6.75 6.78
Reinheit (100% Methode, HPLC): > 99% Purity (100% method, HPLC):> 99%
Methodenbeschreibung (HPLC, 100%-Methode)  Method description (HPLC, 100% method)
Reagenzien reagents
• Acetonitril für Chromatographie  • acetonitrile for chromatography
• Schwefelsäure größer 97 %  Sulfuric acid greater than 97%
• Tetrabutylammoniumhydrogensulfat  • tetrabutylammonium hydrogen sulfate
• Wasser  • Water
• EOB-DTPA, Arbeitsstandard Prüfverfahren  • EOB-DTPA, working standard test procedure
Das Prüfverfahren Verwandte Substanzen / Abbauprodukte wird mit dem Prüfverfahren Gehalt kombiniert. Die Prüf- und Vergleichslösung müssen bei der gleichen Temperatur hergestellt und aliquotiert werden.  The test method related substances / decomposition products is combined with the test method content. The test and reference solutions must be prepared and aliquoted at the same temperature.
Prüflösungen P1 und P2  Test solutions P1 and P2
Eine Lösung mit 1 ,00 mg/mL (0,95 - 1 ,05 mg/mL) Prüfsubstanz wird durch Lösen von Prüfsubstanz in mobiler Phase A ohne Erwärmung hergestellt, cP1/P2.  A solution of 1, 00 mg / mL (0.95 - 1, 05 mg / mL) of test substance is prepared by dissolving test substance in mobile phase A without heating, cP1 / P2.
Beispiel:  Example:
10,00 mg Prüfsubstanz, werden in einem 10-mL-Messkolben in mobiler Phase A ohne Erwärmung gelöst und zur Marke aufgefüllt.  10.00 mg of test substance are dissolved in mobile phase A in a 10 mL volumetric flask without heating and made up to the mark.
Vergleichslösung V  Comparative solution V
Eine Lösung mit 1 ,00 mg/mL (entspr. 0,95 - 1 ,05 mg/mL) EOB-DTPA wird durch Lösen von mindestens 10 mg EOB-DTPA, Arbeitsstandard, m, in mobiler Phase A in einem Messkolben mit dem Volumen V[V] hergestellt. Beispiel: A solution of 1, 00 mg / mL (equivalent to 0.95 - 1, 05 mg / mL) EOB-DTPA is prepared by dissolving at least 10 mg EOB-DTPA, working standard, m, in mobile phase A in a volumetric flask with the Volume V [V] produced. Example:
10,00 mg EOB-DTPA, Arbeitsstandard werden in einem 10-mL-Messkolben in mobiler Phase A ohne Erwärmung gelöst und zur Marke aufgefüllt.  10.00 mg EOB-DTPA, working standard are dissolved in a 10 mL volumetric flask in mobile phase A without heating and made up to the mark.
Prüfbedingungen  test conditions
Injektion Prüflösung P: 10 μΙ_  Injection test solution P: 10 μΙ_
Injektion Vergleichslösung V 10 μΙ_  Injection Comparison solution V 10 μΙ_
Injektionsschema: z B. v, max. 3■ P1 und P2, V Injection scheme: z . v , max. 3 ■ P1 and P2, V
Detektor: UV-Detektor Detector: UV detector
Detektor-Wellenlänge: 225 nm  Detector wavelength: 225 nm
Säule: Stahl, Länge 12,5 cm, innerer d = 4,6 mm  Column: steel, length 12.5 cm, inner d = 4.6 mm
Stationäre Phase: Hypersil ODS, 3 μηη oder äquivalent  Stationary phase: Hypersil ODS, 3 μηη or equivalent
Mobile Phase A: 2 g Tetrabutylammoniumhydrogensulfat werden in Mobile phase A: 2 g of tetrabutylammonium hydrogensulfate are added in
900 ml_ Wasser für Chromatographie gelöst. Zu dieser Lösung werden 100 mL Acetonitril für Chromatographie gegeben. Der pH-Wert wird mit Schwefelsäure 97 % auf 1 ,4 eingestellt. Die mobile Phase kann mit 5 % Wasser bzw. 2 % Acetonitril für Chromatographie angepasst werden.  Dissolved 900 ml of water for chromatography. To this solution is added 100 mL acetonitrile for chromatography. The pH is adjusted to 1.4 with sulfuric acid 97%. The mobile phase can be adjusted with 5% water or 2% acetonitrile for chromatography.
Es können andere Volumina der mobilen Phase angesetzt werden bei gleichbleibender Konzentration.  Other volumes of the mobile phase can be used at constant concentration.
Mobile Phase B: Acetonitril Chromatographie Mobile phase B: acetonitrile chromatography
Gradientenprogramm: gradient program:
Temperatur: Raumtemperatur  Temperature: room temperature
Datenaufnahmezeit: 50 min  Data acquisition time: 50 min
Systemeignungstest: Der Variationskoeffizient (VK) aus mind. 6 Injektionen der Vergleichslösung V muss < 1.0 % sein.  System suitability test: The coefficient of variation (VK) of at least 6 injections of the reference solution V must be <1.0%.
Alle Peaks müssen integrierbar sein. Beispiel 2 All peaks must be integrable. Example 2
Herstellung einer 0,25 M Primovist-Formulierung unter Verwendung kristalliner 3,6, 9-Triaza- 3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure (Tris-HCI-Puffer plus Ca- Komplex-Überschuss)  Preparation of a 0.25 M Primovist formulation using crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (Tris-HCl buffer plus Ca complex -Excess)
56,0 g Calciumcarbonat werden in 1 ,344 kg 3,6 %iger aqu. Salzsäure gelöst und diese Lösung zu einer vorlegten Suspension bestehend aus 33,06 kg kristalliner 3,6,9-Triaza- 3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure, 14,944 kg einer 25 %igen wässrigen Natronlauge und 1 1 ,26 kg Gadoliniumoxid zugegeben und in 160 L Wasser gegeben. Man erhitzt auf 90°C für ca. 2 h; dabei löst sich das Gadoliniumoxid bis zur klaren Lösung auf. Man setzt anschließend 301 ,66 g Trometamol (Tris-Puffer) zu und lässt auf 30°C abkühlen. Der pH-Wert wird auf pH 7,2 eingestellt (wahlweise entweder mit einer 5% wässrigen HCl oder einer 5% wässrigen Natriumhydoxidlösung). Das Gesamt-Volumen der Lösung wird durch Zugabe von Wasser auf 250,8 L eingestellt. Die Lösung wird über eine Membran filtriert (Stickstoff-Druck) und kann anschließend in handelsüblichen Vials abgefüllt und sterilisiert werden. 56.0 g of calcium carbonate are in 1, 344 kg 3.6% aqu. Hydrochloric acid and this solution to give a suspension consisting of 33.06 kg of crystalline 3,6,9-triaza- 3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid, 14.944 kg of a 25% aqueous sodium hydroxide solution and 1 1, 26 kg of gadolinium oxide and added to 160 L of water. It is heated to 90 ° C for about 2 h; The gadolinium oxide dissolves to a clear solution. It then sets 301, 66 g trometamol (Tris buffer) and allowed to cool to 30 ° C. The pH is adjusted to pH 7.2 (optionally with either a 5% aqueous HCl or a 5% aqueous sodium hydroxide solution). The total volume of the solution is adjusted to 250.8 L by adding water. The solution is filtered through a membrane (nitrogen pressure) and can then be filled in commercial vials and sterilized.

Claims

Patentansprüche claims
1 .) Verfahren zur Herstellung kristalliner 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4- ethoxybenzyl)-undecandisäure der Formel I. 1) Process for the preparation of crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of the formula I.
dadurch gekennzeichnet, daß man 3,6,9-Triaza-3,6,9-tris-(tert.butoxy-carbonylmethyl)-4-(4- ethoxybenzyl)-undecandisäure-di-tert.-butylester der Formel II characterized in that 3,6,9-triaza-3,6,9-tris- (tert-butoxycarbonylmethyl) -4- (4-ethoxybenzyl) undecanedioic di-tert-butyl ester of the formula II
II  II
mit einer einer wäßrigen Alkalimetallhydroxid-Lösung hydrolysiert, einengt, den Rückstand in Wasser löst und die erhaltene Lösung ansäuert und vom Niederschlag filtriert. hydrolyzed with an aqueous alkali metal hydroxide solution, concentrated, the residue dissolved in water and the resulting solution was acidified and filtered from the precipitate.
2 ) Verfa h ren zu r H erstel l u n g kri sta l l i n er 3 , 6 , 9-Triaza-3,6,9-tris(carboxymethyl)-4-(4- ethoxybenzyl)-undecandisäure der Formel I. 2) Processes for Preparing Crystal Li 3, 6, 9-Triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic Acid of the Formula I.
dadurch gekennzeichnet, daß man 3,6,9-Triaza-3,6,9-tris(tert.butoxycarbonylmethyl)-4-(4- ethoxybenzyl)-undecandisäure-di-tert.-butylester der Formel II characterized in that 3,6,9-triaza-3,6,9-tris (tert.butoxycarbonylmethyl) -4- (4-ethoxybenzyl) undecanedioic di-tert-butyl ester of the formula II
II  II
in einem niederen Alkohol löst, mit einer wäßrigen Alkalimetallhydroxid-Lösung hydrolysiert, die erhaltene Reaktionsmischung einengt, den Rückstand in Wasser löst und die erhaltene Lösung durch langsame Zugabe einer wäßrigen anorganischen Säure ansäuert und vom Niederschlag filtriert. dissolved in a lower alcohol, hydrolyzed with an aqueous alkali metal hydroxide solution, the resulting reaction mixture is concentrated, the residue dissolved in water and the resulting solution is acidified by slow addition of an aqueous inorganic acid and filtered from the precipitate.
3) Verfahren zur Herstellung kristalliner 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4- ethoxybenzyl)-undecandisäure gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß man das erhaltenen Rohkristallisat in der 4- bis 6-fachen Menge siedenem Wasser löst und dieses mit einer Abkühlrate von maximal 10°C pro Stunde erkalten läßt. 3) A process for preparing crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid according to claim 1 or 2, characterized in that the obtained crude crystals in the Dissolve 4 to 6 times the amount of boiling water and allow it to cool at a maximum cooling rate of 10 ° C per hour.
4) V e r w e n d u n g v o n 3 , 6 , 9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)- undecandisäure der Formel I zur Herstellung des Gadolinium-Komplex der 3,6,9-Triaza- 3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure (Gd-EOB-DTPA). 4) Use of 3, 6, 9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of the formula I for the preparation of the gadolinium complex of the 3,6,9-triaza- 3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (Gd-EOB-DTPA).
5.) Verwendung von kristalliner 3,6, 9-Triaza-3, 6, 9-tris(carboxymethyl)-4-(4- ethoxybenzyl)-undecandisäure der Formel I zur Herstellung einer galenischen Formulierung des Gadolinium-Komplex der 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)- undecandisäure (Gd-EOB-DTPA). 5.) Use of crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of formula I to prepare a galenic formulation of the gadolinium complex of 3,6 , 9-Triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid (Gd-EOB-DTPA).
6) 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandisäure in einer Reinheit von größer 99 %. 6) 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) undecanedioic acid of greater than 99% purity.
EP11724612.4A 2010-06-11 2011-06-06 Process for preparing crystalline 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid and use for production of primovist® Withdrawn EP2580184A2 (en)

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DE201010023890 DE102010023890A1 (en) 2010-06-11 2010-06-11 Preparing crystalline 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(ethoxybenzyl)-undecanedioic acid comprises hydrolyzing 3,6,9-triaza-3,6,9-tris(tert-butoxy-carbonylmethyl)-4-(ethoxybenzyl)-undecanedioic acid-ditert-butylester and acidifying
BRPI1002466 BRPI1002466A2 (en) 2010-07-19 2010-07-19 process for the preparation of crystalline 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) uranic diacid and its use for the preparation of primovist
PCT/EP2011/059243 WO2011154333A2 (en) 2010-06-11 2011-06-06 Process for preparing crystalline 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid and use for production of primovist®

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EP3464237B1 (en) * 2016-05-30 2023-12-20 Biophore India Pharmaceuticals Pvt. Ltd. Novel process for the preparation of gadolinium complex of (4s)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9- triazaundecanedioic acid disodium (gadoxetate disodium)
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