WO2003099746A1 - Procede pour produire des acides amines alpha fluores au 18f - Google Patents

Procede pour produire des acides amines alpha fluores au 18f Download PDF

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Publication number
WO2003099746A1
WO2003099746A1 PCT/DE2003/001692 DE0301692W WO03099746A1 WO 2003099746 A1 WO2003099746 A1 WO 2003099746A1 DE 0301692 W DE0301692 W DE 0301692W WO 03099746 A1 WO03099746 A1 WO 03099746A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
amino
acid
hydrogen
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Application number
PCT/DE2003/001692
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German (de)
English (en)
Inventor
Simon Mensah Ametamey
Yurij Belokon
Olga S. Fedorova
Raisa N. Krasikova
Stepan Vyskocil
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Abx Gmbh
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Publication of WO2003099746A1 publication Critical patent/WO2003099746A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention relates to a process for the preparation of 18 F-fluorinated ⁇ -amino acids and 18 F-fluorinated ⁇ -amino acid derivatives. It relates in particular to a process for the preparation of 2- [ 18 F] -fluoro-L-tyrosine.
  • PET centers with positron emitters marked in this way can be supplied by the so-called satellite concept.
  • the satellite concept provides that the radioactively labeled substances are produced in a synthesis center, which has a cyclotron, when requested by the PET center and then transported to the PET center, for example by plane.
  • the distance between the synthesis center and the PET center should be covered in a time that corresponds to two to four times the half-life of the radionuclide used.
  • this satellite concept requires an uncomplicated process for producing the tracer, with which, for example, L-FTYR can be produced in high yields and in a short time.
  • it is necessary that the production can be carried out using fully automated modules, which are absolutely necessary when using highly radioactive substances in order to avoid contamination and damage to the environment.
  • the previously known manufacturing processes for L-FTYR do not meet these requirements.
  • L-FTYR has so far mainly been produced by non-regioselective electrophilic fluorination of o-acetyltyrosine via [ 18 F] - acetyl hypofluoride (Coenen, HH, Kling, P., Stocklin, G., Cerebral metabolism of L- [2-18F] fluoro tyrosine: a new PET tracer of protein synthesis, J. Nucl.
  • L-LTYR a process for the production of L-LTYR is known, in which a chiral inductor is used in the presence of an auxiliary base (Lemaire, C, Damhaut, P., Plenevaux, A., Comar, D., Enantioselective synthesis of 6 - [fluorine-18] - fluoro-L-dopa from no-carrier-added fluorine-18-fluoride, J. Nucl. Med. 1994, 35, 1996-2002; Lemaire,
  • Rx and R 2 independently represent hydrogen, a hydroxy group, a benzyloxy group or an alkoxy group having 1 to 5 carbon atoms or R x and R 2 together form a -0-CH 2 -0 group;
  • X represents a halogen, a tosyl, mesyl or trifluoromethanesulfonyl group; with an achiral or chiral Ni (II) complex of a Schiff base of a compound of formula II
  • RI, R2 and R3 are as defined above.
  • the L or D form of these 18 F-fluorinated ⁇ -amino acids and 18 F-fluorinated ⁇ -amino acid derivatives can be produced using the process according to the invention.
  • Preferred 18 F-fluorinated ⁇ -amino acids and 18 F-fluorinated ⁇ -amino acid derivatives are shown in Table 1. The enantiomeric forms were not shown.
  • 2- [ 18 F] -fluoro-p-tyrosine means both 2- [ 18 F] -fluoro-pL-tyrosine and 2- [ 18 F] -fluoro-pD-tyrosine.
  • X has the meaning given above for the compound of the formula I. It should be expressly mentioned that X in compound I represents a leaving group, so that other suitable groups can also be used as X in addition to those already specified.
  • Ni (II) complex is preferably an achiral Ni (II) complex of a Schiff base of N- (2-benzoylphenyl) pyridine-2-carbamide and a compound of the formula II
  • R 3 represents hydrogen or an unbranched or branched alkyl group having 1 to 5 carbon atoms.
  • the compound of formula (II) is preferably glycine or alanine.
  • Ni (II) complex from a boat base from
  • N- (2-benzoylphenyl) pyridine-2-carbamide and glycine or alanine thus has the following structure:
  • R 3 is hydrogen when glycine was used and CH 3 when alanine was used.
  • R 4 and R 5 independently of one another represent hydrogen, an unbranched or branched alkyl group having 1 to 5 carbon atoms, a phenyl group, an adamantyl group or a - (CH 2 ) n OH group, where n represents 1 to 3.
  • R4 and R5 in formula III are each hydrogen.
  • the chiral catalyst can be a compound of formula IV
  • Process step (a) is preferably carried out in a polar or non-polar organic solvent, methylene chloride or dichloroethane being particularly preferred as the solvent.
  • step (c) converting the 2-amino-3- (2- [ 18 F] -fluoro-4-methoxy-phenyl) -propionic acid obtained in step (b) to 2- [ 18 F] - fluoro-L-tyrosine.
  • the radionuclide was obtained from the QMC resin by adding 2 ml of one Eluates (K 2 C0 3 , MeCN, Kryptofix and water; the water content was 4% by volume) were passed over the QMC resin. The solvent was then evaporated to dryness at 130 ° C. under a stream of nitrogen.
  • 2- [ 18 F] -Fluoro-4-methoxy-benzaldehyde 1 is prepared by nucleophilic substitution from 4-methoxy-2-nitro-benzaldehyde 2 in the presence of a crown ether as an ion scavenger.
  • step AI The residue obtained in step AI was treated with a solution of 15 mg of compound 1 in 1 ml of DMSO. The reaction mixture was then heated to 180 ° C. for 5 minutes. After cooling, the reaction mixture was diluted with 8.5 ml of water.
  • the diluted reaction mixture was passed over a C18 Supelco column (600 mg C18 packed into a 6 ml column), previously with 10 ml methanol and 15 ml Water had been conditioned.
  • the C18 column was cleaned twice with 5 ml of water.
  • the bromination was carried out in methylene chloride at room temperature using 60 to 80 mg of Ph 3 PBr 2 (available from Aldrich) as the standardizing agent.
  • Ph 3 PBr 2 available from Aldrich
  • the use of this brominating agent is known from R. Iwata et al. , A new convenient method for the preparation of 4- [ 18 F] fluorobenzyl halides, Applied Radiation Isotopes, 2000, 52, pp. 87-92.
  • the conversion rate which was measured by radio TLC and / or HPLC, is between 65 and 93%.
  • the reaction product obtained was purified by passing it through a commercially available Basic Alumina Supleco column (1 g A1B). The purified solution was collected directly in the chiral alkylation vessel.
  • reaction mixture was diluted with 50 ml of water and the reaction product, Ni-BPB, extracted with chloroform. The solvent was evaporated in vacuo and the residue was then purified by column chromatography (column 50 ⁇ 3.5 cm; silica gel 40/100 micron; chloroform: acetone 5: 1: flow rate 5 ml / min).
  • the reaction product Ni-BPB had a melting point of 207 to 210 ° C and a dark red color. The reaction product was stable at room temperature.
  • Ni-PBP achiral nickel
  • the asymmetric alkylation was carried out under phase transfer catalysis conditions. Solid, freshly finely powdered NaOH (20 mg) with Ni-PBP (22 mg) and (S) -NOBIN (2 mg) in anhydrous CH 2 C1 2 (1 ml; the solvent comes from the preparation of compound 4), which was stirred under argon for 3 min at room temperature by vortex. Then compound 4 was added under argon and the reaction mixture was stirred for 3 to 5 minutes by vortex. The reaction was then stopped by adding 0.5 ml of 57% HI Heating quenched. The solvent was evaporated at 40 ° C under vacuum and the crude product refluxed for 5 minutes at 170 ° C in a closed reaction vessel (deprotection) to give the target compound. L-FTYR 7 was then obtained by reverse phase HPLC.

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

Abstract

La présente invention concerne un procédé pour produire des acides aminés α fluorés au 18F et des dérivés d'acides aminés α fluorés au 18F. Ce procédé consiste (a) à mettre en réaction un composé fluoré au 18F de formule (I), dans laquelle R1 et R2 représentent indépendamment hydrogène, un groupe hydroxy, un groupe benzyloxy ou un groupe alkoxy présentant de 1 à 5 atomes de carbone ou R1 et R2 forment conjointement un groupe -O-CH2-O-, et X représente un halogène ou un groupe tosyl-, mésyl- ou trifluorméthane-sulfonyle, avec un complexe Ni(II) achiral ou chiral d'une base de Schiff d'un composé de formule (II), dans laquelle R3 représente hydrogène ou un groupe alkyle ramifié ou non ramifié présentant de 1 à 5 atomes de carbone, en présence d'un catalyseur chiral et d'une base auxiliaire, puis (b) à effectuer le clivage du composé obtenu à l'étape (a).
PCT/DE2003/001692 2002-05-25 2003-05-23 Procede pour produire des acides amines alpha fluores au 18f WO2003099746A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10223451.5 2002-05-25
DE2002123451 DE10223451A1 (de) 2002-05-25 2002-05-25 Verfahren zur Herstellung von 18F-fluorierten alpha-Aminosäuren

Publications (1)

Publication Number Publication Date
WO2003099746A1 true WO2003099746A1 (fr) 2003-12-04

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DE (1) DE10223451A1 (fr)
WO (1) WO2003099746A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071505A2 (fr) * 2003-02-11 2004-08-26 Mallinckrodt Inc. Acides amines de type d radiomarques, utilises pour la tomographie monophotonique d'emission et la tomographie par emission de positons ainsi que dans la therapie isotopique systemique
WO2004110500A1 (fr) * 2002-08-02 2004-12-23 Mallinckrodt Inc. Analogues d'acides amines etiquetes par marqueurs radioactifs, leur preparation et utilisation
WO2008052788A1 (fr) * 2006-11-01 2008-05-08 Bayer Schering Pharma Aktiengesellschaft Acide l-glutamique marqué au [f-18], l-glutamine marquée au [f-18], leurs dérivés et leur utilisation, ainsi que leur procédé de fabrication
EP1923382A1 (fr) * 2006-11-18 2008-05-21 Bayer Schering Pharma Aktiengesellschaft L-acide glutamique marqué au fluor 18, glutamine marquée au fluor 18, leurs derivés ainsi que procédés de leur préparation
US9308282B2 (en) 2008-05-20 2016-04-12 Piramal Imaging Sa [F-18]-labelled L-glutamic acid and L-glutamine derivatives (I), their use and processes for their preparation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BELOKON Y N ET AL: "HIHGLY EFFICIENT CATALYTIC SYNTHESIS OF ALPHA-AMINO ACIDS UNDER PHAS-TRANSFER CONDITIONS WITH A NOVEL CATALYST/SUBSTRATE PAIR", ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, VERLAG CHEMIE. WEINHEIM, DE, vol. 40, no. 10, 18 May 2001 (2001-05-18), pages 1948 - 1951, XP001065313, ISSN: 0570-0833 *
KUKHAR, VALERI P. ET AL.: "Asymmetric Synthesis of Organoelement Analogues of Natural Products; Part 12: General Method for the Asymmetric Synthesis of Fluorine-Containing Phenylalanines and alpha-Methyl(phenyl)alanines via Alkylation of the Chiral Nickel(II)Schiff's Base Complexes of Glycine and Alanine", SYNTHESIS, 1993, pages 117 - 20, XP002255542 *
R.N. KRASIKOVA ET AL.: "Asymmetric Synthesis of 6-[18F]Fluoro-L-DOPA using a Chiral Nickel Complex of the Schiff Base of (S)-O-[(N-Benzylprolyl)-amino]benzophenone and glycine", J. LABELLED CPD. RADIOPHARM., vol. 42, no. 1, 1999, pages S102 - S104, XP008022474 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004110500A1 (fr) * 2002-08-02 2004-12-23 Mallinckrodt Inc. Analogues d'acides amines etiquetes par marqueurs radioactifs, leur preparation et utilisation
JP2006516547A (ja) * 2002-08-02 2006-07-06 マリンクロッド・インコーポレイテッド 放射性標識アミノ酸類似体、それらの製造および使用
US7189383B2 (en) 2002-08-02 2007-03-13 Mallinckrodt Inc. Radioactively labelled amino acid analogues, their preparation and use
WO2004071505A2 (fr) * 2003-02-11 2004-08-26 Mallinckrodt Inc. Acides amines de type d radiomarques, utilises pour la tomographie monophotonique d'emission et la tomographie par emission de positons ainsi que dans la therapie isotopique systemique
WO2004071505A3 (fr) * 2003-02-11 2004-10-21 Mallinckrodt Inc Acides amines de type d radiomarques, utilises pour la tomographie monophotonique d'emission et la tomographie par emission de positons ainsi que dans la therapie isotopique systemique
WO2008052788A1 (fr) * 2006-11-01 2008-05-08 Bayer Schering Pharma Aktiengesellschaft Acide l-glutamique marqué au [f-18], l-glutamine marquée au [f-18], leurs dérivés et leur utilisation, ainsi que leur procédé de fabrication
EA017713B1 (ru) * 2006-11-01 2013-02-28 Байер Шеринг Фарма Акциенгезельшафт [f-18]-меченая l-глутаминовая кислота, [f-18]-меченый l-глутамин, их производные и их применение, а также способ их получения
US20140301948A1 (en) * 2006-11-01 2014-10-09 Bayer Schering Pharma Aktiengesellschaft [f-18]-labeled l-glutamic acid, [f-18]-labeled l-glutamine, derivatives thereof and use thereof and processes for their preparation
US9375497B2 (en) 2006-11-01 2016-06-28 Piramal Imaging Sa [F-18]-labeled L-glutamic acid, [F-18]-labeled L-glutamine, derivatives thereof and use thereof and processes for their preparation
EP1923382A1 (fr) * 2006-11-18 2008-05-21 Bayer Schering Pharma Aktiengesellschaft L-acide glutamique marqué au fluor 18, glutamine marquée au fluor 18, leurs derivés ainsi que procédés de leur préparation
US9308282B2 (en) 2008-05-20 2016-04-12 Piramal Imaging Sa [F-18]-labelled L-glutamic acid and L-glutamine derivatives (I), their use and processes for their preparation

Also Published As

Publication number Publication date
DE10223451A1 (de) 2003-12-24

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