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WO1993003045A1 - Process for purer organic metal ion chelate complexes - Google Patents

Process for purer organic metal ion chelate complexes 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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Prior art keywords
organic
iii
water
resin
metal
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PCT/US1992/006600
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French (fr)
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/en

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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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Abstract

The present invention describes a synthesis and purification of novel organic chelate metal ion (II) or (III) complexes. These processes are useful specifically for producing purer complexes for magnetic resonance imaging (MRI) contrast agents. The metal ion is first complexed, contacted with a water insoluble adsorption resin to adsorb the complex, washed with water to remove dissolved solids, contacted with a water soluble organic coupling agent and an organic diacid, acid amide, or acid ester, separating the solid resin, washing it with water, contacting the resin with polar non-aqueous organic liquid to desorb the complex followed by purification of the desorbed organic chelate metal ion complex. Similarly, preformed organic chelate metal ion complexes can be purified by contacting an aqueous slurry of organic resin followed by the described purification and separation steps.

Description

PROCESS FOR PURER
ORGANIC METAL ION CHELATE COMPLEXES
BACKGROUND OF THE INVENTION
This application is a continuation-in-part of U.S. Serial No. 743,134, filed August 9, 1991, which is incorporated herein by reference in its entirety.
Field of the Invention
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.
Specifically, the present invention provides improved production of 3-phenylglutaryl-ferroxamine and related analogs.
Description of Related Art
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. In the process of the art, 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. For the art process, an additional purification step is usually necessary as well.
General background in the use of MRI σonstrast agents and of their preparation and purification are described, for example, in:
H. Gries et al., U.S. Patent No. 4,647,447;
R.B. Lauffer et al., U.S. Patents 4,899,755 and 4,880,008; B.L. Engelstad et al., U.S. Patents 4,909,257 and 4,999,445;
B-A. Hoener et al., Magnetic Resonance in Medicine, Vol. 17, p. 509 (1991).
G.Y.A. Janoki et al., Int. Journal Radiat. Isot., Vol. 34(6), pp. 871 (1983).
S.J. Rodgers et al., J. of Medicinal Chemistry, Vol. 26, p. 439 (1983).
B-A. Hoener et al., J. Magnetic Resonance Imaging, p. 357 (May/June 1991).
All articles, patents, references, etc. cited are incorporated herein by reference in their entirety.
It would be very useful to have a process in which the metal ion is complexed prior to amide formation at the free amine terminus. 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.
SUMMARY OF THE INVENTION
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:
(a) contacting an aqueous solution of organic chelate with an aqueous solution of a metal (II) or (III) ion M, wherein M is independently selected from the group consisting of metals of atomic number 12 and 13, metals of atomic number 21 to 31, metals of atomic number 39 to 50, the lanthanide metals having an atomic number from 57 to 71, and metals of atomic number 72 to 82, and metals of atomic number 89-103.
concurrently adding an aqueous solution of a weak acid or base to maintain the pH of the solution in the range of between about 2 to 8 at between about 0 and 50°;
(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;
(c) separating the insoluble resin and aqueous portion of step (b);
(d) contacting the insoluble resin at least one time with water for a time sufficient to remove nonadsorbed substances;
(e) separating the insoluble resin and aqueous liquid of step (d);
(f) washing the separated insoluble resin of step (e) at least once with water until the wash water is essentially free of dissolved solids;
(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:
Figure imgf000005_0001
HO-(O=C)-(CH2)m-Z-(CH2)n-(C=O)-Y,
wherein Z is selected from -CH-, -CR5- or -N-, R and R5 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-, -OR1 wherein R1 is an aliphatic, alicyclic or an aromatic group having from 1 to 10 carbon atoms, or R2-N-R3, wherein R2 independently selected from an aliphatic, alicyclic or aromatic group having from 1 to 10 carbon atoms, and R3 is independently selected from H or R2, and
m and n are each independently selected from 0, 1, 2, 3 , 4 or 5;
(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;
(j) contacting the washed solid resin of step
(i) with sufficient polar nonaqueous organic liquid to desorb the resin adsorbed organic coupled-chelate-metal (II) or (III) complex from the insoluble resin into the organic liquid followed by separating the organic liquid from the solid resin;
(k) contacting the organic liquid with water sufficient to solubilize the organic group coupled-metal (II) or (III) complex, followed by selectively removing the organic liquid;
(l) optionally contacting the remaining aqueous portion with an immiscible organic liquid to remove organic impurities, separating the immiscible liquids and aqueous portion; and
(m) recovering the essentially pure organic group coupled-metal (II) or (III) complex.
Embodiments where m and n are identical 1, 2 or 3 are preferred, especially 1.
In another aspect, the present invention relates to the process wherein in step (a) the organic chelate is desferrioxamine,
in step (b) the water-insoluble adsorption resin is selected from BIOBEADSR (polystyrenedivinylbenezene copolymer);
in 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; and
in step (j) the organic liquid is selected from alcohols having 1 to 6 carbon atoms.
In another aspect in structure I, the -CH2-(C=O) -Y group can also be the guanidine or urea structure depending on the reagent used, -N-R4-(C=NH)Y or -NR4-(C=O)-Y, where R4 is hydrogen or alkyl having 1 to 4 carbon atoms. In one embodiment of the present invention structure I, (CH2)mZ(R)-(CH2)n can be-Q-Z'Q' where Z' can be (C=O), (C=S), (O=S=O) or (CNH), and Q and Q' are each independently selected from CH, NH, O, or S.
In another embodiment of the process, 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.
BRIEF DESCRIPTION OF THE FIGURE
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.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
Definitions
As used herein:
"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.
"Metals of atomic number 12 and 13" refer to magnesium and aluminum. Aluminum III is preferred.
"Metals 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.
"Metals 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.
"Metals 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.
The 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). In addition, the use of a 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.
Each step of the novel process is discussed in detail below and is summarized in Figure 1 for desferroxamine as a specific example:
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. At the same time 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.
It is important that the researcher review the available BioRad product literature for details about the proper handling of adsorption resins, such as BIOBEADSR. It is particularly important that the resin never become dry at any step, i.e. all water is removed from the surface of the resin. If this drying occurs, then the chelate metal ion complex will bind too tightly to the resin. Later separation will be very difficult, or impossible, requiring the use of stronger dipolar organic liquids such as dimethylformamide, acetonitrile, etc. The stronger liquids also remove undesirable components from the resin.
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
100-200 ml of water.
Step (e) concerns the separation of the resin from the wash liquid. Usually, 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. Usually 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.
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. Usually 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.
Those compounds where m and n are each equal 1, 2, or 3 or the easiest to produce and purify.
A number of the purer compounds produced by the present invention are found in Table 1 below.
Figure imgf000013_0001
PURIFICATION OF CHELATE METAL ION COMPLEXES
As stated above, specific steps of the present process are useful to purify the organic chelate metal ion complex. These complexes are often difficult to purify because of their polar nature and reactive functional groups.
After obtaining a less than pure chelate metal ion complex of the type described herein, the purification follows the general steps described above and below.
The complex is contacted in aqueous solution with wet water-insoluble resin under the conditions of step (b).
Steps (hh), (ii), (jj) (kk), (ll) and (mm) in the claims below are followed to recover a purified chelate metal ion complex.
The following Examples are presented for the purpose to further explaining and defining the present invention. They are not to be construed as being limiting in any manner.
General
All materials used were ACS reagent-grade, except as otherwise noted, and were used without further purification. 3-Phenylglutaric acid [4165-96-2] and 1-(3- dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) [25952-53-8] were obtained from Aldrich Chemical Co., Milwaukee, Wisconsin. Ferric chloride [10025-77-1], sodium bircarbonate [144-55-8], and sodium hydroxide [1310-73-2] were obtained from Fisher Scientific Supply Co. Fresh stock solutions of each were prepared prior to use. Desferrioxamine mesylate was obtained in pharmaceutical grade as DesferalR (CIBA-GEIGY Co., Summit, New Jersey). Bio-beadsR 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.
PREPARATION A
A bulk supply of adsorption resin was prepared as follows: 100g BiobeadsR 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.
Mixtures containing the adsorption resin were stirred by means of a Buchi rotary evaporator without vacuum applied.
Satisfactory physical data was collected for the reaction product, including mass spectra (MS), ultraviolet-visible (UV-VIS) and Fourier Transform Infrared (FT- IR) spectra, Fourier Transform Nuclear Magnetic Resonance (FT-NMR) of the decomplexed ligand, combustion elemental analysis (CHN) and atomic adsorption (AA) microanalysis for Fe(III) content.
EXAMPLE 1
DESFERRIOXAMINE METAL ION COMPLEX FORMATION
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. longer, after which time the resin was deep red. The yellow-orange supernatant was discarded, the resin was immersed in fresh water, and the mixture was again stirred for 15 min. The supernatant was again discarded. The resin was collected on a glass frit and washed with water until the filtrate was almost colorless. The resin was then returned to the flask along with 100 ml distilled water.
EXAMPLE 2
ORGANIC COUPLING REACTION
(a) 3-Phenylglutaric acid (PGA) (4.16 g, 2.0 mmol), the water-soluble carbodiimide reagent EDC (1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride), (7.6 g, 4.0 m mol), and additional distilled water (100 ml) were added to the resin-adsorbed ferrioxamine (FeDF) of Example 1. No effort was made to dissolve these reagents initially. The pH was adjusted to 7.5-8.0 with aqueous 1N NaOH, and the mixture was stirred for 24 hr at 35-40°C.
After this time the pH was below 6.9, and most of the 3-PGA and EDC had dissolved. 1 N NaOH was added to bring pH to 7.5-8.0, and stirring was resumed.
After stirring for 24 hr more, the clear yellow supernatant (pH 7.0) was decanted and 200 ml fresh water was added. The flask was stirred for 15 min, and the supernatant was again decanted. Fresh water added to the resin-adsorbed FePGDF. After 15 min additional turning, the resin was collected and washed with distilled water, returned (moist) to the flask, covered with methanol (200 ml), and then stirred for 15 min to remove the FePGDF from the resin.
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 DesferalR).
(b) Similarly, if 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.
(c) Similarly, if 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.
(d) Similarly, if Example 1 and Example 2(a) are repeated except that desferrioxamine is replaced with a stoichiometrically equivalent amount of alαminoxamine, the corresponding substantially pure 3-phenylglutaryl-aluminoamine is obtained.
(e) Similarly, if 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.
(f) Similarly, if 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 amide, the corresponding substantially pure ferrioxamine (III)-phenylglutaric monomethyl amide is obtained in good yield.
(g) Similarly, if Example 1 and Example 2(a) are repeated except that 3-phenylglutaric acid is replaced with a stoichiometrically equivalent amount of 3-aza-3- phenylglutaric acid (N-phenyliminodiacetic acid) the corresponding substantially pure 3-aza-3-phenylglutarylferrioxamine is obtained in good yield. EXAMPLE 3
PURIFICATION OF A PREFORMED CHELATE METAL ION COMPLEX PGDF Metal Complex Formation
(a) PGDF (greater than 93% pure by HPLC, 1.3 g, 1.73 mmol) was suspended in aqueous 1 M trisodium citrate (25 ml) and water (25 ml). To this suspension was added aqueous ferric chloride (1M, 2 ml) over a 2-3 min period. The pH was monitored and observed to fall from 6.8 to 5.9 over the course of the addition. The deep red solution obtained was nearly homogenous (some greater warming was required). The solution was stirred an additional 10 min, the water insoluble resin (BIOBEADSR SM-4, about 4 g damp prepared as described above). This mixture was stirred overnight (about 16 hr) at ambient temperature. After 2 days the beads were filtered, kept damp, washed twice with 50 ml of water on a #2 coarse frit filter funnel, and transferred into 100 ml of fresh water. The solid resin was stirred gently overnight (about 16 hr) at ambient temperature.
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.
Therefore, 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 volume was then reduced using rotary evaporation with a bath at T=40°C. 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).
After 2 days, the pH was chec ed and found to have risen to 8.6. The addition of IN hydrochloric acid very quickly overran the neutral point, and pH was carefully adjusted with dilute sodium hydroxide until just barely acidic. Several hours later, the pH was newly stable at pH 6.9 to 7.1.
The dark red solution, pH quasi-stable (slowly climbing) at about 7.0, was taken up in a syringe, filtered through a 0.2 μm Acrodisc into a volumetric flask (25 ml), and the overflow into a small round-bottom flask (wt. of empty flask = 66.661 g, not oven dried but clean) (about 6 ml). 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.
The 25 ml solution was transferred to a sterile bottle, stored at room temperature in the same cabinet. HPLC analysis (GEO70
Figure imgf000019_0001
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.
While only a few embodiments of the invention have been shown and described herein, it will become apparent to those skilled in the art that various modifications and changes can be made in the process to produce purer organic ligand metal (II) or (III) ion chelate complexes without departing from the spirit and scope of the present invention. All such modifications and changes coming within the scope of the appended claims are intended to be carried out thereby.

Claims

WE CLAIM:
1. An improved process to produce organic groupcontaining derivatives of organic chelate metal (II) or (III) polydentate coordination complexes, which process comprises:
(a) contacting an aqueous solution of organic chelate with an aqueous solution of a metal (II) or (III) ion M, wherein M is independently selected from the group consisting of metals of atomic number 12 and 13, metals of atomic number 21 to 31, metals of atomic number 39 to 50, the lanthanide metals having an atomic number from 57 to 71, and metals of atomic number 72 to 82, and metals of atomic number 89 to 103,
concurrently adding an aqueous solution of a weak acid or base to maintain the pH of the solution in the range of between about 2 to 8 at between about 0 and 50°;
(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;
(c) separating the insoluble resin and aqueous portion of step (b);
(d) contacting the insoluble resin at least one time with water for a time sufficient to remove nonadsorbed substances;
(e) separating the insoluble resin and aqueous liquid of step (d);
(f) washing the separated insoluble resin of step (e) at least once with water until the wash water is essentially free of dissolved solids;
(g) contacting the solid obtained in step (f) with water, a water-soluble organic coupling agent, and a twice stoichiometrically equivalent amount of an organic diacid, acidamide, or acid ester of the structure:
HO-(O=C)-(CH2)m-Z-(CH2)n-(C=O)-Y, (I)
Figure imgf000022_0001
wherein Z is selected from -CH-, -CR5- or -N-,
R and R5 are each independently selected from hydrogen, aliphatic, aromatic, or heteroaromatic organic group having from 5 to 20 carbon atoms
Y is selected from -OH-, -OR1 wherein R1 is an aliphatic, alicyclic or an aromatic group having from 1-10
Figure imgf000022_0002
carbon atoms, or R2-N-R3, wherein R2 independently selected from an aliphatic, alicyclic or aromatic group having from l to 10 carbon atoms, and R3 is independently selected from H or R2, and
m and n are each independently selected from 0, 1, 2 , 3, 4 or 5;
(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;
(j) contacting the washed solid resin of step (i) with sufficient polar nonaqueous organic liquid to desorb the resin adsorbed organic coupled-chelate-metal (II) or (III) complex from the insoluble resin into the organic liquid followed by separating the organic liquid from the solid resin;
(k) contacting the organic liquid with water sufficient to solubilize the organic group coupled-metal (II) or (III) complex, followed by selectively removing the organic liquid;
(l) optionally contacting the remaining aqueous portion with an immiscible organic liquid to remove organic impurities, separating the immiscible liquids and aqueous portion; and
(m) recovering the essentially pure organic group coupled-metal (II) or (III) complex.
2. The process of Claim 1 wherein m and n are each
3. The process of Claim 1 wherein the organic chelate is selected from desferrioxamine, bis- (hydroxybenzyl)ethylenediaminediacetic acid (HBED), diethylenetriamlnepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), or mixtures thereof.
4. The process of Claim 1 wherein the metal ion selected is a trivalent metal (III).
5. The process of Claim 4 wherein the metal is selected from iron (III), aluminum (III), gadolinium (III), dysprosium (III), gallium (III), indium (III), chromium (III) or manganese (III).
6. The process of Claim 1 wherein
in step (aa) the organic chelate is desferrioxamine,
in step (bb) the water-insoluble adsorption resin is selected from polystyrene divinylbenzene copolymer
in step (gg) the water-soluble coupling agent is EDC, and the organic diacid is one wherein Z is -CH, R is phenyl, and Y is -OH; and
in step (jj) the organic liquid selected from volatile aliphatic or alicyclic hydrocarbons having 4 to 10 carbon atoms, aromatic compounds, substituted aromatic compounds, alcohols, esters, ketones or mixtures thereof.
7. The process of Claim 6 wherein in structure I, Z is -CR5- where R5 is hydrogen.
8. The process of Claim 7 wherein R is selected from cycloalkyl having 5 to 10 carbon atoms, phenyl, -CH2-phenyl, or -CH2-2-naphthyl and Y is OH.
9. The process of Claim 7 wherein R is selected from cycloalkyl having 5 to 10 carbon atoms, phenyl, -CH2-phenyl, or -CH2-2-naphthyl and Y is CI.
10. The process of Claim 7 wherein R is selected from cycloalkyl having 5 to 10 carbon atoms, phenyl, -CH2-phenyl, or -CH2-2-naphthyl and Y is OR.
11. An improved process to purify organic group containing derivatives of organic chelate metal (II) or
(III) polydentate coordination complexes, which process comprises:
(aa) obtaining an aqueous solution of organic chelate metal (II) or (III) ion M complex, wherein M is independently selected from the group consisting of metals of atomic number 21 to 31, metals of atomic number 39 to
50, the lanthanide metals having an atomic number from 57 to 71, and metals of atomic number 72 to 81,
concurrently adding an aqueous solution of a weak acid to maintain the pH of the solution in the range of between about 2 to 8 at between about 0 and 50°;
(bb) contacting aqueous solution of step (aa) 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;
(hh) 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;
(ii) separating the liquid and insoluble solid resin obtained in step (hh) followed by contacting the insoluble solid resin at least once with sufficient water to remove impurities or unreacted materials;
(jj) contacting the washed solid resin of step (ii) with sufficient polar nonaqueous organic liquid to desorb the resin adsorbed organic coupled-chelate-metal (II) or (III) complex from the insoluble resin into the organic liquid followed by separating the organic liquid from the solid resin;
(kk) contacting the organic liquid with water sufficient to solubilize the organic group coupled-metal (II) or (III) complex, followed by selectively removing the organic liquid;
(ll) optionally contacting the remaining aqueous portion with an immiscible organic liquid to remove organic impurities, separating the immiscible liquids and aqueous portion; and
(mm) recovering the essentially pure organic group coupled-metal (II) or (III) complex.
12. The process of Claim 11 wherein the organic chelate is selected from desferrioxamine, HBED, DTPA, EDTA, or mixtures thereof.
13. The process of Claim 11 wherein the metal ion selected is a trivalent metal (III).
14. The process of Claim 13 wherein the metal is selected from iron (III), aluminum (III), gadolinium (III), gallium (III), indium (III), chromium (III) or manganese (III).
15. The process of Claim 11 wherein
in step (aa) the organic chelate is desferrioxamine,
in step (bb) the water-insoluble adsorption resin is selected from polystyrene divinylbenzene copolymer, in step (gg) the water-soluble coupling agent is EDC, and the organic diacid is one wherein Z is -CR5-, R5 is H, R is phenyl, and Y is -OH; and
in step (jj) the organic liquid selected from volatile aliphatic or alicyclic hydrocarbons having 4 to 10 carbon atoms, aromatic compounds, substituted aromatic compounds, alcohols, esters, ketones or mixtures thereof.
16. The process of Claim 15 wherein M is iron (III) or gadolinium (III) .
17. The process of Claim 16 wherein in step (jj) the organic liquid is selected from aliphatic alcohols having 1 to 6 carbons.
18. The process of Claim 17 wherein the aliphatic alcohol is methanol.
19. The process of Claim 1 wherein the product chelate is substantially pure having a purity of about 90% or greater.
20. The process of Claim 1 wherein the product chelate is essentially pure having a purity of about 98% or greater.
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WO2001040164A1 (en) * 1999-12-01 2001-06-07 Biogal Gyogyszergyar Rt A multistage process for the preparation of highly pure deferoxamine mesylate salt
US6858414B2 (en) 1999-12-01 2005-02-22 BIOGAL Gyógyszergyár Rt. Multistage process for the preparation of highly pure deferoxamine mesylate salt
DE102007008655A1 (en) * 2007-02-20 2008-08-21 Henkel Ag & Co. Kgaa Siderophore-metal complexes as bleach catalysts
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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Publication number Priority date Publication date Assignee Title
WO2001040164A1 (en) * 1999-12-01 2001-06-07 Biogal Gyogyszergyar Rt A multistage process for the preparation of highly pure deferoxamine mesylate salt
US6858414B2 (en) 1999-12-01 2005-02-22 BIOGAL Gyógyszergyár Rt. Multistage process for the preparation of highly pure deferoxamine mesylate salt
DE102007008655A1 (en) * 2007-02-20 2008-08-21 Henkel Ag & Co. Kgaa Siderophore-metal complexes as bleach catalysts
WO2008101909A1 (en) 2007-02-20 2008-08-28 Henkel Ag & Co. Kgaa Siderophore-metal- complexes used as bleach catalysts
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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