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WO1993003045A1 - Procede de production de complexes chelateurs organiques a ion metal de purete superieure - Google Patents

Procede de production de complexes chelateurs organiques a ion metal de purete superieure Download PDF

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Publication number
WO1993003045A1
WO1993003045A1 PCT/US1992/006600 US9206600W WO9303045A1 WO 1993003045 A1 WO1993003045 A1 WO 1993003045A1 US 9206600 W US9206600 W US 9206600W WO 9303045 A1 WO9303045 A1 WO 9303045A1
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WIPO (PCT)
Prior art keywords
organic
iii
water
resin
metal
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PCT/US1992/006600
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English (en)
Inventor
David L. White
Robert G. Eason
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The Regents Of The University Of California
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Publication of WO1993003045A1 publication Critical patent/WO1993003045A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention describes a synthesis and purification of novel organic chelate metal ion (II) or
  • (III) complexes useful in a variety of applications, e.g. for producing purer metal complexes useful in diagnostics of a mammal, e.g., a human, such as magnetic resonance imaging (MRI) contrast agents, or for a chelate-metal radionuclide complex useful for scintillation counting.
  • MRI magnetic resonance imaging
  • the present invention provides improved production of 3-phenylglutaryl-ferroxamine and related analogs.
  • Literature syntheses have typically employed acylations of metal-free ligands under standard amide forming reaction conditions, for example, using anhydrous dimethyIformamide in addition to pyridine or a trialkylamine as base, and either an active acyl-species or a carboxylic acid and a carbodiimide coupling agent.
  • anhydrous dimethyIformamide in addition to pyridine or a trialkylamine as base
  • an active acyl-species or a carboxylic acid and a carbodiimide coupling agent for example, after an aqueous work-up and purification using, for example, column chromatography, the modified ligand is subjected to metal ion solution.
  • a complicating side reaction is usually observed in that the metal ion promoted hydrolysis of the specific amide bond just synthesized.
  • an additional purification step is usually necessary as well.
  • the present invention provides such as process.
  • the reaction conditions of the present novel approach are useful for the later purification of the reaction mixture of any coupling reaction using an organic coupling agent for metal ion complexes and using a water soluble organic coupling agent.
  • the present invention relates to an improved process to produce organic group-containing derivatives of organic chelate metal (II) or (III) polydentate coordination complexes, which process comprises:
  • step (b) contacting this aqueous solution of step (a) with an aqueous slurry of a water-insoluble adsorption resin at between about 15 and 50°C for a time sufficient to non-covalently adsorb the organic chelate-metal (II) or (III) ion complex to the water-insoluble resin;
  • step (c) separating the insoluble resin and aqueous portion of step (b);
  • step (e) separating the insoluble resin and aqueous liquid of step (d);
  • step (f) washing the separated insoluble resin of step (e) at least once with water until the wash water is essentially free of dissolved solids;
  • step (g) contacting the solid obtained in step (f) with water, an excess of a water-soluble organic coupling agent and a stoichiometrically equivalent amount of an organic diacid, acid amide, or acid ester of structure I:
  • Z is selected from -CH-, -CR 5 - or -N-, R and R 5 are each independently selected from hydrogen, aliphatic, aromatic, substituted aromatic, or heteroaromatic organic groups having from 5 to 20 carbon atoms,
  • Y is selected from -OH-, -OR 1 wherein R 1 is an aliphatic, alicyclic or an aromatic group having from 1 to 10 carbon atoms, or R 2 -N-R 3 , wherein R 2 independently selected from an aliphatic, alicyclic or aromatic group having from 1 to 10 carbon atoms, and R 3 is independently selected from H or R 2 , and
  • n and n are each independently selected from 0, 1, 2, 3 , 4 or 5;
  • step (h) adjusting the pH to between about 7 and 9 using aqueous base, stirring the slurry for between about 2 and 48 hr. at between about 20 and 50°C during which time the solid reagents substantially dissolve; (i) separating the liquid and insoluble solid resin obtained in step (h) followed by contacting the insoluble solid resin at least once with sufficient water to remove impurities or unreacted materials;
  • Embodiments where m and n are identical 1, 2 or 3 are preferred, especially 1.
  • the present invention relates to the process wherein in step (a) the organic chelate is desferrioxamine,
  • the water-insoluble adsorption resin is selected from BIOBEADS R (polystyrenedivinylbenezene copolymer);
  • step (g) the water-soluble coupling agent is EDC, and the organic diacid is one wherein Z is -CH-, R is phenyl, and Y is -OH;
  • the organic liquid is selected from alcohols having 1 to 6 carbon atoms.
  • the present invention is also useful to purify already formed chelate metal ion complexes. That is to say, the formed chelate metal ion complex is adsorbed onto the water-insoluble resin under the conditions described in step (b) above. Next the adsorbed resin is washed, separated etc. as described in steps (i), (j), (k), (l) and (m) hereinabove.
  • Figure 1 is a reaction sequence of the improved process using desferroxamine B and iron (III).
  • Figure 2 is a table describing reagents and various products which are obtained by use of the present invention.
  • Adsorption resin refers to a lipophilic water insoluble polymer. Usually an aromatic group is present in the polymer, and the polymer is crosslinked.
  • Alicyclic hydrocarbon refers to those saturated ring hydrocarbons having 4 to 10 carbon atoms such as cyclobutane, cyclohexane, methylcyclopentane, cyclononane methylcyclononane, cyclodecane, and the like.
  • Aliphatic hydrocarbon refers to those saturated straight or branched hydrocarbons having 4-10 carbon atoms, such as butane, pentane, hexane, isooctane, nonane, decane and the like.
  • Aromatic refers to phenyl, benzyl, naphthyl and the like.
  • Aromatic or aromatic hydrocarbon refers to unsaturated cyclic organic compounds having 1 to 10 carbon atoms, e.g. benzene, toluene, xylene, dihydro or tetrahydronaphthalene and the like or mixtures thereof. It also includes heterocyclic groups such as pyridine, pyrrole, thiophene, triazine and the like. The aromatic group can be substituted using alkyl C1-C6 or halogen.
  • Essentially pure refers to a term of art for chemical purity wherein the compound or isomer is usually present in greater than about 98 or 99% or higher purity.
  • EDC refers to 1-(3-dimethyl-amino-propyl)-3-ethyl carbodiimide hydrochloride.
  • EDTA refers to ethylenediaminetetraacetic acid.
  • DTPA refers to diethylenetriaminepentaacetic acid.
  • HEBD r ef er s to b i s - ( hydr oxy benzyl) ethylenediaminediacetic acid.
  • Metal of atomic number 12 and 13 refer to magnesium and aluminum. Aluminum III is preferred.
  • Metal of atomic number 21 to 31 refers to scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc and gallium respectfully. Iron, chromium, manganese, cobalt and gallium are preferred.
  • Metal of atomic number 39 to 50 refers to yttrium, zirconium, iridium, molybdenium, technetium, ruthenium, rhodium, palladium, silver, cadmium, iridium, or tin respectively. Technetium and iridium are preferred.
  • Metal (lanthanides) having an atomic number from 57 to 71 refers to lanthanum, cerium, praseodymium, etc. to lutetium, respectively. Gadolinium and dysprosium are preferred.
  • Metal of atomic number 72 to 82 refers to hafnium, tantalium, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, thallium or lead. Thallium is preferred.
  • substantially pure refers to a term of art for chemical priority wherein the compound or isomer is present usually about 90% or higher.
  • Substituted aromatic compound refers to ortho-, meta-, or para-substituted aryls. At least one group includes the alkyl groups (1 to 4 carbon atoms), halogen groups selected from fluoro-, chloro- or bromo- substituted aromatic hydrocarbons, trifluoromethyl, and alkoxy (where the alkyl group is C1-C4 atoms). p-Tert-butyl is preferred.
  • a procedure is described for the multi-gram synthesis and purification of the novel metal ion, e.g. iron (III), polydentate coordination complexes: e.g. 3-phenylglutarylferrioxamine B (FePGDF), and of its analogs.
  • the preparative method described herein represents a substantial improvement over available literature approaches to the synthesis of terminal-N-acyl-derivatives of the siderophore ferrioxamine B (FeDF) with regard to time, cost, and general synthetic utility.
  • the problems of the literature procedures are described hereinabove.
  • ferric ion present in ferrioxamine B is fully pre-complexed, does not interfere with subsequent amide formation at the free amine terminus. Furthermore, acylation proceeds smoothly under mild aqueous conditions, employing one of a variety of bifunctional non-activated carboxylic acids in the presence of the water-soluble carbodiimide, 1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide hydrochloride (EDC).
  • EDC 1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide hydrochloride
  • polystyrene divinylbenzene copolymer adsorption resin makes possible a one-flask two-reaction sequence leading directly to an aqueous solution of the complex, free of hydrolysis biproducts and, after washes, nearly as pure as the starting material.
  • a typical synthesis required one or two days to isolate up to 4 g of pure product in between about 25 to 50% yield.
  • Step (a) concerns the preparation of the chelated metal ion complex.
  • An aqueous solution of the organic chelate is contacted (usually added stepwise) at ambient temperature and pressure with at least one stoichiometrically equivalent amount an aqueous solution of the metal (II) or (III) ion usually as the metal halogen salt, e.g. CI, or Br, or metal hydroxide.
  • the aqueous solution is monitored for pH, using a pH meter.
  • the pH is maintained using an aqueous base, such as sodium hydroxide between about 2 and 9, preferably 3 and 8 when all of the metal ion is added.
  • Step (b) relates to the contact of the aqueous resin.
  • the water insoluble polymer is added, the slurry obtained is stirred briskly using a mechanical or magnetic stirrer for a time to adsorb the chelate metal complex, e.g. 10-60 min at between about 0 and 50°C, preferably between about 20 to 40°C, especially about 35°C for about 15 min.
  • Step (c) as a separation step is usually accomplished by filtration or centrifugation.
  • Step (d) relates the washing of the separated solid resin with water as many times as is necessary to remove the non-adsorbed substances, usually 2-10 washings with
  • Step (e) concerns the separation of the resin from the wash liquid.
  • the solid resin is in a separatory funnel (alternatively, a Buchner filter), and the wash liquid is already separated.
  • Step (f) concerns the optional washing of the resin to remove dissolved solids.
  • the solid resin is in a separatory funnel (alternatively, a Buchner filter) and washed with water at ambient conditions. Portions of the wash water are monitored visually or with an instrument to determine when the dissolved solids are removed.
  • Step (g) relates the coupling of the organic diacid, acid amide or acid ester in aqueous solution using a coupling agent.
  • the solid of step (f) is then contacted with water, a dissolved or partially dissolved water soluble organic coupling agent, e.g. EDC, present in between about 4 and 10 Molar excess, and a 1-fold stoichiometrically equivalent amount of an organic diacid, and a 2-fold equivalent of acid amide or acid ester of the structure shown herein above.
  • a dissolved or partially dissolved water soluble organic coupling agent e.g. EDC
  • Step (h) concerns the conditions necessary for covalent coupling.
  • the pH of the aqueous solution of the non-covalently bound metal chelate complex-resin is adjusted to between 7 to 9 using aqueous base, e.g. NaOH, or a non-ammonia containing carbonate, bi-carbonate, etc. is stirred for between 2 and 48 hr, preferably between about 5 and 24 hr at between about 20 and 50°C, preferably 50°C. During this period the solid reagents but not the resin substantially dissolve.
  • the pH will need to be adjusted by the addition of base.
  • Step (i) relates the separation of the liquid and solid resin followed by washing the resin with water to remove unreacted substances as described in step (d).
  • Step (j) concerns contact of the resin with a polar organic liquid to separate the metal complex from the solid resin.
  • Aromatic hydrocarbons such as benzene, toluene or mixtures thereof are useful. Generally, alcohols having 1 to 6 carbon atoms are preferred. Methanol is especially preferred.
  • Step (k) contacting the liquid of step (j) with water to extract the chelate complex into the water.
  • a volumetric equivalent or more is used.
  • Step (l) concerns the optional conventional washing of the aqueous layer of step (k) to remove organic impurities.
  • Step (m) is the recovery of the essentially pure organic chelate metal ion complex by removal of the water and organic liquid. This can be accomplished by cold vacuum evaporation or by lypholization under conventional conditions.
  • the complex is contacted in aqueous solution with wet water-insoluble resin under the conditions of step (b).
  • Bio-beads R SM-4, 20-50 mesh polystyrene adsorption resin was obtained from Bio-Rad Laboratories, Richmond, CA., (polystyrene divinylbenzene copolymer) and prepared for use as described below.
  • a bulk supply of adsorption resin was prepared as follows: 100g Biobeads R SM-4, 20-50 mesh (trademark of BioRad, Richmond, CA, supplied nearly dry) was covered with 250 ml methanol (Fisher, HPLC-grade) and stirred gently for 24 hr. The resin was then collected on a glass-fritted Buchner funnel, with suction applied gently to remove the visible methanol without drying-out the beads. Next, the procedure was repeated, using distilled water in place of methanol. After filtration, the resin was covered with water and stored in a sealed container away from sunlight prior to use.
  • Desferrioxamine mesylate (6.7 g, 1.0 mmol) was dissolved in distilled water (100 ml) in a 500 ml RB flask. Aqueous 1M ferric chloride (1.0 ml) was added in portions along with IN aqueous sodium bicarbonate (approx. 1.0 ml) to keep the pH in the broad range 3 to 8. Next a slurry of polystyrene adsorption resin (10-15 ml of hydrated Biobeads) was added (see Preparation A above) and the mixture stirred efficiently on shaker bath or rotary evaporator in a water bath at 35°C for 15 min. The pH was adjusted to 7.0 with bicarbonate, and stirring was continued for 15 min.
  • the methanolic FePGDF was filtered, and the resin was twice treated with additional methanol (2 x 100 ml) to extract nearly all of the orange color.
  • the combined methanol extracts were then concentrated to 100 ml, water was added (300 ml), and evaporation of the methanol continued until the deep-red solution was essentially aqueous.
  • the aqueous FePGDF was washed with ether (2 x 50 ml) to remove organic impurities and then evaporated to give a red paste, which was then redissolved in absolute etharibl (100 ml); evaporation of this solution at 35°C gave darkred flakes of solid FePGDF (sodium salt); 3.6 g, 44% (from Desferal R ).
  • Example 1 and Example 2(a) are repeated except that ferrioxamine is replaced with a stoichiometrically equivalent amount of gadolinium (III)- DTPA and the carboxylic acid is replaced by a primary or secondary amine, the corresponding substantially pure gadolinium (III)-DTPA-bisamide is obtained.
  • Example 1 and Example 2(a) are repeated except that desferrioxamine is replaced with a stoichiometrically equivalent amount of gadolinium (III)- DTPA and the carboxylic acid is replaced by a primary or secondary alcohol, the corresponding substantially pure gadolinium (III)-DTPA bis-ester is obtained.
  • Example 1 and Example 2(a) are repeated except that desferrioxamine is replaced with a stoichiometrically equivalent amount of al ⁇ minoxamine, the corresponding substantially pure 3-phenylglutaryl-aluminoamine is obtained.
  • Example 1 and Example 2(a) are repeated except that 3-phenylglutaric acid is replaced with a stoichiometrically equivalent amount of 3-phenylglutaric acid monomethyl ester, the corresponding substantially pure ferrioxamine 3-phenylglutaric monomethylester is obtained in good yield.
  • the beads were filtered on a medium frit, washed exhaustively with water until the wash water was nearly colorless (about 500 ml), and then placed in an Erlenmeyer flask with 125 ml absolute ethanol and stirred overnight (about 16 hr) at ambient conditions.
  • the beads were filtered and washed with ethanol (about 50 ml) less color remained in the resin than on previous occasions (using methanol repeating quick rinses).
  • the resin in fact, released no substantial color at all upon treatment with 100 ml fresh ethanol.
  • the red FePGDF/ethanol solution was concentrated, examined by HPLC (GEO702P) and found to contain the usual array of minor contaminants, some of which should be removable by ether wash.
  • the complex was made aqueous by addition of 100 ml water, followed by preparation of ethanol (and some water).
  • the red solution was washed twice with 75 ml ether, the pH measured (4.2) and was adjusted by addition of 1 N NaOH (several drops) to about 6.5-6.8.
  • the pH was measured again (5.2) when about half of the solvent remained and adjusted to just within the low side of 7. Finally, the volume was concentrated to the solubility point (at 40°C, stoppered and left at room temperature (final pH 6.90).
  • the volume of the solution in the volumetric flask was adjusted to exactly 25 ml using overflow solution.
  • the remaining overflow about 5 ml, was stripped of all liquid, leaving a dark-red residue coating the flask. This residue was further dried under high vacuum, labelled and set aside for future conversion to the ester.
  • HPLC analysis (GEO70 370 nm) showed the purity to be typical (>93%), the only significant contaminant was FeDF. (HPLC data at 220, 230, and 240 nanometers show no unusual peaks.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne la synthèse et la purification de nouveaux complexes à ion métal (II) ou (III) chélateurs organiques. Ces procédés sont utiles spécifiquement dans la production de complexes de pureté supérieure pour des agents de contraste utilisés en imagerie par résonnance magnétique (IRM). L'ion métal est premièrement transformé en complexe, mis en contact avec une résine d'adsorption insoluble dans l'eau afin d'adsorber le complexe, lavé avec de l'eau afin d'éliminer les solubles dissous, mis au contact d'un agent de couplage organique soluble dans l'eau et d'un diacide organique, d'une amide d'acide ou d'un ester d'acide, puis on sépare la résine solide, on la lave avec de l'eau, on met en contact ladite résine avec un liquide organique non aqueux polaire afin de désorber le complexe, et on purifie le complexe à ion métal chélateur organique désorbé. De même, on peut purifier des complexes à ion métal chélateurs organiques préformés par contact avec une boue aqueuse de résine organique suivi par les étapes décrites de purification et de séparation.
PCT/US1992/006600 1991-08-09 1992-08-07 Procede de production de complexes chelateurs organiques a ion metal de purete superieure WO1993003045A1 (fr)

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US74313491A 1991-08-09 1991-08-09
US743,134 1991-08-09

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001040164A1 (fr) * 1999-12-01 2001-06-07 Biogal Gyogyszergyar Rt Procede a etapes multiples pour la preparation de sel de deferoxamine sous forme de methanesulfonate
US6858414B2 (en) 1999-12-01 2005-02-22 BIOGAL Gyógyszergyár Rt. Multistage process for the preparation of highly pure deferoxamine mesylate salt
DE102007008655A1 (de) * 2007-02-20 2008-08-21 Henkel Ag & Co. Kgaa Siderophor-Metall-Komplexe als Bleichkatalysatoren
US12180328B2 (en) 2021-05-04 2024-12-31 Sachem, Inc. Strong binding metal-chelating resins
US12331155B2 (en) 2021-05-04 2025-06-17 Sachem, Inc. Strong binding metal-chelating resins using macrocycle molecules

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4687659A (en) * 1984-11-13 1987-08-18 Salutar, Inc. Diamide-DTPA-paramagnetic contrast agents for MR imaging
US4714607A (en) * 1984-05-30 1987-12-22 Nycomed As NMR contrast agents
US4999445A (en) * 1988-06-10 1991-03-12 The Regents Of The University Of California Contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system
US5051523A (en) * 1988-01-20 1991-09-24 Ciba-Geigy Corporation Process for the preparation of complex compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4714607A (en) * 1984-05-30 1987-12-22 Nycomed As NMR contrast agents
US4687659A (en) * 1984-11-13 1987-08-18 Salutar, Inc. Diamide-DTPA-paramagnetic contrast agents for MR imaging
US5051523A (en) * 1988-01-20 1991-09-24 Ciba-Geigy Corporation Process for the preparation of complex compounds
US4999445A (en) * 1988-06-10 1991-03-12 The Regents Of The University Of California Contrast agents for magnetic resonance imaging of the small intestine and hepatobiliary system

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001040164A1 (fr) * 1999-12-01 2001-06-07 Biogal Gyogyszergyar Rt Procede a etapes multiples pour la preparation de sel de deferoxamine sous forme de methanesulfonate
US6858414B2 (en) 1999-12-01 2005-02-22 BIOGAL Gyógyszergyár Rt. Multistage process for the preparation of highly pure deferoxamine mesylate salt
DE102007008655A1 (de) * 2007-02-20 2008-08-21 Henkel Ag & Co. Kgaa Siderophor-Metall-Komplexe als Bleichkatalysatoren
WO2008101909A1 (fr) 2007-02-20 2008-08-28 Henkel Ag & Co. Kgaa Complexes métalliques sidérophores utilisés comme catalyseurs de blanchiment
US12180328B2 (en) 2021-05-04 2024-12-31 Sachem, Inc. Strong binding metal-chelating resins
US12331155B2 (en) 2021-05-04 2025-06-17 Sachem, Inc. Strong binding metal-chelating resins using macrocycle molecules

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