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WO2000058265A1 - Préparation d'esters d'acide diéthylènetriaminepentaacétique (dpta) à l'aide de différents groupes esters - Google Patents

Préparation d'esters d'acide diéthylènetriaminepentaacétique (dpta) à l'aide de différents groupes esters Download PDF

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Publication number
WO2000058265A1
WO2000058265A1 PCT/US2000/007539 US0007539W WO0058265A1 WO 2000058265 A1 WO2000058265 A1 WO 2000058265A1 US 0007539 W US0007539 W US 0007539W WO 0058265 A1 WO0058265 A1 WO 0058265A1
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WO
WIPO (PCT)
Prior art keywords
benzyl
compound
butyl
compounds
carbon atoms
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.)
Ceased
Application number
PCT/US2000/007539
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English (en)
Inventor
Samuel I. Achilefu
Ananthachari Srinivasan
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.)
Mallinckrodt Inc
Original Assignee
Mallinckrodt Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Mallinckrodt Inc filed Critical Mallinckrodt Inc
Priority to AU40190/00A priority Critical patent/AU4019000A/en
Publication of WO2000058265A1 publication Critical patent/WO2000058265A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates generally to the synthesis of esters of diethylenetriaminepentaacetic acid (DTPA) and of intermediates useful in the synthesis of such esters.
  • DTPA diethylenetriaminepentaacetic acid
  • R, and R 2 are H, and R 3 , R 4 , and R 5 are t-butyl (compound (II)) or a similar protecting group.
  • Such compounds are useful in the preparation of nuclear pharmaceuticals where they serve as a metal chelate and a link between a peptide and a radionuclide.
  • Activation of the free dicarboxylic acid rapidly forms intramolecular acid anhydride which then reacts with the amino group on a peptide to form the DTPA-peptide conjugate.
  • Acid mediated cleavage of the esters gives free tetra-carboxylic acid which readily forms stable metal complexes with the radionuclide of choice.
  • Compound (IV) is commercially available.
  • Compound (III) was prepared by the method taught in Rapoport, J. Org. Chem. 1993, 58, 1151-1158 (incorporated herein by reference). This reaction yields two compounds in about a 1 :4 ratio.
  • the minor product is:
  • reaction product of (VI) and (VII) is:
  • This compound is subjected to catalytic hydrogenation at room temperature to yield
  • WO 98/05626 (Bracco: P. L. Anelli, et al.) teaches compounds that are similar to the compounds made by the instant invention.
  • the invention comprises a method of synthesis of compounds of the formula
  • the invention includes a method for synthesizing compounds of the formula:
  • R-g and R 8 are each a linking moiety having 1 to 10, desirably 1 to 6, preferably 1 to 4, and most preferably 2 carbon atoms; each R 4 is a removable protecting group, generally (a) an alkyl group having 1 to 15, desirably 2 to 10, more desirably 2 to 8, preferably 3 to 6, and more preferably 4 carbon atoms, and most preferably being t-butyl or (b) benzyl or a benzyl derivative such as methoxy benzyl or nitrobenzyl, preferably benzyl.
  • the compound (X) is more useful in fluorenylmethoxycarbonyl (Fmoc) peptide synthesis, and if R 4 is benzyl or a similar group, the compound (X) is more useful in acid labile t-butoxycarbonyl (Boc) peptide synthesis; and Re, is hydrogen or a to C 50 alkyl moiety such as that taught by US 5,514,810 (incorporated herein by reference), preferably hydrogen.
  • X is a group that will react with the secondary amine of compound (XIII), desirably a halide, mesylate, active ester, alkyl ester, or triflate, more desirably an allyl ester, a methyl ester, an ethyl ester, or a halide, preferably Cl or Br, and most preferably Br; and Y is a protecting group that is different from Z, preferably trifluoroacetyl, chlorotrityl, methoxybenzyl, or nitrobenzyl, and preferably benzyl.
  • the resultant compound is Y
  • X is a group that will react with the amines of compound (XXII), desirably a halide, a mesylate, or a triflate, more desirably a halide, preferably Cl or Br, and most preferably Br; and R 4 is as defined above.
  • Rg is hydrogen or a to C 50 alkyl moiety, desirably such as that taught by US 5,514,810 (incorporated herein by reference), preferably hydrogen; and R 5 is a removable protecting group different from and removable separately from R 4 (defined below), generally (a) t-butyl, allyl, or chlorotrityl, preferably t-butyl or (b) allyl, benzyl, or a benzyl derivative such as methoxy benzyl or nitrobenzyl, preferably benzyl or methoxy benzyl, and most preferably benzyl; and X is a group that will react with the amine of compound (XXIII), desirably a halide, a mesylate, or a triflate, more desirably a halide, preferably Cl or Br, and most preferably Br.
  • Rg is hydrogen or a to C 50 alkyl moiety, desirably such as that taught by US 5,514,
  • R 5 is preferably benzyl or a benzyl derivative, and if R 4 is benzyl or a similar group, R 5 is preferably t-butyl or allyl.
  • the reaction product is:
  • N,N,N",N"-bis(Phthaloyl)diethylenetriamine (10 g, 27.54 mmol), benzyl bromide (5.65 g; 33.05 mmol) and diisopropylethylamine (6 g, 38.55 mmol) were added to
  • N'-benzyl-N,N,N",N"-bis( ⁇ hthaloyl) diethylenetriamine (7.6 g, 16.77 mmol) and hydrazine (1.1 g; 34.38 mmol) were added to 100 ml of ethanol and the mixture was heated to a gentle reflux for 20 minutes.
  • Hydrochloric acid 1.0 M, 10 ml
  • the mixture was heated at reflux for 30 minutes , the precipitate was filtered and washed with 10% aqueous HCl (3 x 20 ml).
  • the catalyst was filtered over celite and the residue was washed with chloroform (30 ml). The combined filtrate was concentrated to dryness. Chloroform (10 ml) was added to precipitate the excess ammonium formate. After filtration, the filtrate was evaporated to give the pure compound as the formate salt (4.5 g, quantitative).
  • DTPA-Octreotate derivative Synthesis of DTPA-Octreotate derivative.
  • the DTPA-Octreotate conjugate was prepared by solid phase synthesis using pre-loaded fluorenemethoxycarbonyl- threonine (Fmoc-Thr) Wang resin on 0.025 mmol scale.
  • Commercially available automated peptide synthesizer from Applied Biosystems Model 432A SYNERGY Peptide Synthesizer
  • Cartridges containing Fmoc-protected amino acids were used in the solid phase synthesis. Cysteines were protected with acetamidomethyl group.
  • Coupling reaction was carried out with 0.075 mmol of the protected amino acid and 2-(lH-benzotriazole-lyl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU)/N-hydroxybenzotriazole (HOBT).
  • the amino acids and tetra-t-butyl DTPA (compound X) cartridges were placed on the peptide synthesizer and the product was synthesized from the C-terminal to the N-terminal position. After the synthesis was completed, the product was cleaved from the solid support with a cleavage mixture containing trifluoroacetic acid (85%):water (5%):phenol (5%):thioanisole (5%) for 6 hours.

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

Abstract

Cette invention a trait à la synthèse de composés correspondant à la formule (XI). Dans cette formule, chaque R4 représente un groupe protecteur supprimable, R5 représente un groupe protecteur supprimable différent de R4 et pouvant être enlevé séparément de R4, chaque R6 et chaque R6 représentent une fraction de liaison portant de 1 à 10 atomes de carbone et R9 représente un hydrogène ou une fraction alkyle portant de 1 à 50 atomes de carbone. Ces composés se révèlent d'utiles intermédiaires dans la synthèse de composés correspondant à la formule (X). Ces composés s'avèrent utiles dans la préparation de produits de pharmacie nucléaire, tels que ceux qui sont employés pour l'imagerie de tumeurs ou dans le cadre d'une thérapie antitumorale.
PCT/US2000/007539 1999-03-26 2000-03-21 Préparation d'esters d'acide diéthylènetriaminepentaacétique (dpta) à l'aide de différents groupes esters Ceased WO2000058265A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU40190/00A AU4019000A (en) 1999-03-26 2000-03-21 Preparation of dtpa esters with different ester groups

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12638299P 1999-03-26 1999-03-26
US60/126,382 1999-03-26

Publications (1)

Publication Number Publication Date
WO2000058265A1 true WO2000058265A1 (fr) 2000-10-05

Family

ID=22424529

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/007539 Ceased WO2000058265A1 (fr) 1999-03-26 2000-03-21 Préparation d'esters d'acide diéthylènetriaminepentaacétique (dpta) à l'aide de différents groupes esters

Country Status (2)

Country Link
AU (1) AU4019000A (fr)
WO (1) WO2000058265A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5679852A (en) * 1995-06-02 1997-10-21 Schering Aktiengesellschaft Process for the production of DTPA-monoamides of the central carboxylic acid and their use as pharmaceutical agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5679852A (en) * 1995-06-02 1997-10-21 Schering Aktiengesellschaft Process for the production of DTPA-monoamides of the central carboxylic acid and their use as pharmaceutical agents

Also Published As

Publication number Publication date
AU4019000A (en) 2000-10-16

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