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WO2000058267A1 - Renforcement de la selectivite dans la synthese d'esters d'acide diethylene triaminepenta acetique (dpta) a partir de diethylenetriamine - Google Patents

Renforcement de la selectivite dans la synthese d'esters d'acide diethylene triaminepenta acetique (dpta) a partir de diethylenetriamine Download PDF

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Publication number
WO2000058267A1
WO2000058267A1 PCT/US2000/007540 US0007540W WO0058267A1 WO 2000058267 A1 WO2000058267 A1 WO 2000058267A1 US 0007540 W US0007540 W US 0007540W WO 0058267 A1 WO0058267 A1 WO 0058267A1
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WIPO (PCT)
Prior art keywords
benzyl
compound
synthesis
butyl
carbon atoms
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Ceased
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PCT/US2000/007540
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English (en)
Inventor
Samuel I. Achilefu
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
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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 AU37676/00A priority Critical patent/AU3767600A/en
Publication of WO2000058267A1 publication Critical patent/WO2000058267A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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 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, 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.
  • R 4 is t-butyl or a similar group
  • the compound (X) is more useful in fluorenylmethoxycarbonyl (Fmoc) peptide synthesis
  • R 4 is benzyl or a similar group
  • the compound (X) is more useful in acid labile t-butoxycarbonyl (Boc) peptide synthesis
  • R 9 is hydrogen or a to C 50 alkyl moiety such as that taught by US 5,514,810 (incorporated herein by reference), preferably hydrogen.
  • Z is any protecting group that will react with primary amines but not (under the same conditions) with secondary amines.
  • Z is desirably trifluoroacetyl in the presence of crown ethers, 2-acetyldimedone (Dde) , or phthaloyl (Pth), preferably Pth for Fmoc procedures and preferably Dde for Boc procedures.
  • Compound (XII) is commercially available.
  • R 9 is hydrogen or a C, 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 (defmed 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 (XIII), desirably a halide, a mesylate, or a triflate, more desirably a halide, preferably Cl or Br, and most preferably Br.
  • R 9 is hydrogen or a C, to C 50 alkyl moiety, desirably such as that taught
  • 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:
  • X is a group that will react with the amines of compound (XVI), 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.
  • X is a group that will react with the amines of compound (XVI), 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.
  • the combined methylene chloride layers was washed with 10 ml of brine, and dried over magnesium sulfate.
  • the methylene chloride was removed with aspirator vacuum at ca. 35°C, and the remaining dimethylformamide was removed under vacuum at about 45°C.
  • the crude product obtained was purified by dry flash chromatography on silica gel column and the pure compound was eluted with 30% ethyl acetate in hexane.
  • R 9 and R 5 H).
  • a mixture of 10% palladium on carbon (0.1 g) and N'- (benzyloxycarbonylmethyl)-N,N,N",N"-tetrakis(t-butyloxycarbonylmethyl) diethylenetriamine (0.6 g, 0.85 mmol) in 30 ml of methanol was hydrogenolyzed at 45 psi for 2 hours. The mixture was filtered over celite and the residue was washed with methanol (50 ml). The solvent was evaporated to give the pure mono- carboxylic acid (0.5 g, 96%) as a viscous pale yellow oil.
  • 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)
  • Chemical Kinetics & Catalysis (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). 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/US2000/007540 1999-03-26 2000-03-21 Renforcement de la selectivite dans la synthese d'esters d'acide diethylene triaminepenta acetique (dpta) a partir de diethylenetriamine Ceased WO2000058267A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37676/00A AU3767600A (en) 1999-03-26 2000-03-21 Enhanced selectivity in the synthesis of dtpa esters fom diethylenetriamine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12639899P 1999-03-26 1999-03-26
US60/126,398 1999-03-26

Publications (1)

Publication Number Publication Date
WO2000058267A1 true WO2000058267A1 (fr) 2000-10-05

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/007540 Ceased WO2000058267A1 (fr) 1999-03-26 2000-03-21 Renforcement de la selectivite dans la synthese d'esters d'acide diethylene triaminepenta acetique (dpta) a partir de diethylenetriamine

Country Status (2)

Country Link
AU (1) AU3767600A (fr)
WO (1) WO2000058267A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5676923A (en) * 1995-02-21 1997-10-14 Schering Aktiengesellschaft Substituted DTPA monoamides of the central carboxylic acid group and their metal complexes
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
US5730956A (en) * 1995-02-21 1998-03-24 Schering Aktiengesellschaft DTPA di-alkyl monoamides for x-ray and MRI
US5736120A (en) * 1996-06-07 1998-04-07 Srinivasan; Ananthachari Method for preparing radiolabeled peptides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5676923A (en) * 1995-02-21 1997-10-14 Schering Aktiengesellschaft Substituted DTPA monoamides of the central carboxylic acid group and their metal complexes
US5730956A (en) * 1995-02-21 1998-03-24 Schering Aktiengesellschaft DTPA di-alkyl monoamides for x-ray and MRI
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
US5736120A (en) * 1996-06-07 1998-04-07 Srinivasan; Ananthachari Method for preparing radiolabeled peptides

Also Published As

Publication number Publication date
AU3767600A (en) 2000-10-16

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