WO2001002339A1 - Procede universel de synthese d'iso-dtpa - Google Patents

Procede universel de synthese d'iso-dtpa Download PDF

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Publication number
WO2001002339A1
WO2001002339A1 PCT/US2000/017825 US0017825W WO0102339A1 WO 2001002339 A1 WO2001002339 A1 WO 2001002339A1 US 0017825 W US0017825 W US 0017825W WO 0102339 A1 WO0102339 A1 WO 0102339A1
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WO
WIPO (PCT)
Prior art keywords
compound
benzyl
phenyl
synthesis
butyl
Prior art date
Application number
PCT/US2000/017825
Other languages
English (en)
Inventor
Samuel I. Achilefu
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 AU57752/00A priority Critical patent/AU5775200A/en
Publication of WO2001002339A1 publication Critical patent/WO2001002339A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters

Definitions

  • This invention relates generally to the synthesis of esters of diethylenetriaminepentaacetic acid (DTP A) and of intermediates useful in the synthesis of such esters.
  • DTP A diethylenetriaminepentaacetic acid
  • These esters are well known, and have the general formula:
  • R R 2 , and R 3 are typically t-butyl, and R 4 and R 5 are typically H (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, 1 151-1158 (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:
  • 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, 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; and each R ⁇ 5 is a linking moiety having 1 to 10, desirably 1 to 6, preferably 1 to 4, and most preferably 2 carbon atoms;.
  • the Compound (XII) is more useful in fluorenylmethoxycarbonyl (Fmoc) peptide synthesis, and if R, is benzyl or a similar group, the Compound (XII) is more useful in acid labile t- butoxycarbonyl (Boc) peptide synthesis.
  • R 4 and Rg are as defined above;
  • Y is alkyloxy, alkyl, or H, preferably methyl, methoxy, or H, and most preferably H;
  • Z is phenyl or a phenyl derivative such as methoxy phenyl or nitrophenyl, preferably phenyl or methoxy phenyl, and most preferably phenyl;
  • X is a group that will react with the amine of Compound (XIII), desirably a halide, mesylate, or triflate, more desirably a halide, preferably Cl or Br, and most preferably Br.
  • Y is H
  • Z is phenyl
  • X is Br
  • R ⁇ is ethyl
  • R 4 is t-butyl.
  • Rg is hydrogen or a C, to C 50 alkyl, carbohydrate, oxyethyleneglycol, hydroxyl, or nitrile moiety, desirably such as that taught by US 5,514,810 (inco ⁇ orated herein by reference), preferably hydrogen; and R 5 is a removable protecting group different from and removable separately from Redefined 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
  • 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:
  • the ether solution was decanted and the oil was again triturated with a 500 ml portion of ether.
  • the ether was decanted and the combined ether solutions allowed to stand for about 2 hours to allow the triphenylphosphine oxide to crystallize.
  • the ether solution was decanted from the crystals and the solid washed with 500 ml of ether.
  • the volume of the combined ether abstracts was reduced with vacuum until a volume of about 80 ml was obtained. This was allowed to stand over night at 0°C.
  • Ether 100 ml was added to the cold mixture which was mixed to suspend the solid. The mixture was filtered and washed ten times with 4 ml of ether.
  • 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 432 A 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 hexafiuorophosphate (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)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne la synthèse de composés représentés par la formule (XII). Ces composés s'utilisent comme intermédiaires dans la synthèse de composés représentés par les formules (XI) et (X). Les composés selon l'invention s'utilisent dans la préparation de produits pharmaceutiques nucléaires tels que ceux utilisés dans la formation d'images de tumeurs ou le traitement de tumeurs.
PCT/US2000/017825 1999-07-01 2000-06-28 Procede universel de synthese d'iso-dtpa WO2001002339A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57752/00A AU5775200A (en) 1999-07-01 2000-06-28 Versatile method for the synthesis of iso-dtpa

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14199899P 1999-07-01 1999-07-01
US60/141,998 1999-07-01

Publications (1)

Publication Number Publication Date
WO2001002339A1 true WO2001002339A1 (fr) 2001-01-11

Family

ID=22498152

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/017825 WO2001002339A1 (fr) 1999-07-01 2000-06-28 Procede universel de synthese d'iso-dtpa

Country Status (2)

Country Link
AU (1) AU5775200A (fr)
WO (1) WO2001002339A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5514810A (en) * 1995-02-21 1996-05-07 Schering Aktiengesellschaft Process for the production of DTPA-tetraesters of terminal carboxylic acids
US5618513A (en) * 1995-06-07 1997-04-08 Mallinckrodt Medical, Inc. Method for preparing radiolabeled peptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5514810A (en) * 1995-02-21 1996-05-07 Schering Aktiengesellschaft Process for the production of DTPA-tetraesters of terminal carboxylic acids
US5618513A (en) * 1995-06-07 1997-04-08 Mallinckrodt Medical, Inc. Method for preparing radiolabeled peptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PIER LUCIO ANELLI ET AL.: "L-glutamic Acid and L-Lysine as Useful Building Blocks for the Preparation of Bifunctional DTPA-like Ligands", BIOCONJUGATE CHEMISTRY, vol. 10, no. 1, 18 January 1999 (1999-01-18), US, pages 137 - 140, XP002148891 *

Also Published As

Publication number Publication date
AU5775200A (en) 2001-01-22

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