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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
  • C07C233/00—Carboxylic acid amides
  • C07C233/88—Carboxylic acid amides having nitrogen atoms of carboxamide groups bound to an acyclic carbon atom and to a carbon atom of a six-membered aromatic ring wherein at least one ortho-hydrogen atom has been replaced
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
• • 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
• • 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
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T436/00—Chemistry: analytical and immunological testing
  • Y10T436/19—Halogen containing
  • Y10T436/196666—Carbon containing compound [e.g., vinylchloride, etc.]

Definitions

• the present invention relates to a practical method for synthesizing a radioligand having an 18 F-labeled fluorobenzene ring.
• the electrophilic substitution reaction a phenyltin derivative is used as a labeling raw material.
• the fluorine reagent 18 F fluorine gas is used.
• the electrophilic substitution reaction has the disadvantage of low labeling efficiency and reaction yield.
• specific activity which is an important factor in radiopharmaceuticals, the specific activity of the compound obtained by this reaction is only a few mCiZ / mol.
• the nucleophilic substitution reaction force S on the benzene ring by 18 F is often used.
• a high specific activity of the compound obtained with a high reaction yield can be expected.
• radioactive ligands are less demanding on the substrate and lacks generality.
• diphenyl-Luodonium salt and [ 18 F] F I thought about using the reaction with-.
• Non-Patent Document 1 describes a process for producing hydroxy (tosyloxy) sodobenzene.
• Non-Patent Document 2 describes a method for producing galeordony-nitrium triflates.
• Non-Patent Document 3 describes the reaction of gialordoneum triflate with [ 18 F] F—.
• Non-Patent Document 1 G. F. Koser et al., J. Org. Chem., 42, 1476 (1977)
• Non-Patent Document 2 T. Kitamura et al., Synthesis, 147 (1994)
• Non-Patent Document 3 V. W. Pike et al., J. Chem. Soc. Chem. Commun., 2215 (1995)
• R 3 , R 4 and R 5 are all hydrogen or an alkyl group
• R 1C represents an alkyl group
• the present invention also provides a general formula (4)
• the present invention also provides a hydroxytosyl benzene compound of the general formula (5).
• Ts represents a toluenesulfol group
• E represents a functional group that donates electrons to the ⁇ -electron system and ⁇ is 1, 2, 3, 4 or 5.
• R 3 , R 4 and R 5 may be the same or different and each represents a hydrogen, an alkyl group or a functional group containing a hetero atom.
• R 3 , R 4 and R 5 are all hydrogen or an alkyl group
• R 1C represents an alkyl group
• X is Br or I, preferably Br.
• R 2 , R 3 , R 4 and R 5 may be the same or different and each represents a hydrogen, an alkyl group or a functional group containing a hetero atom, provided that Except when R 3 , R 4 and R 5 are all hydrogen or alkyl groups.
• Heteroatom means organic chemistry! /, Atoms other than carbon and hydrogen !,, generally 0, N,
• Halogen atoms refer to F, Cl, Br and I atoms. F and C1 atoms are preferred. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, and n-butyl.
• C alkyl groups such as isobutyl, tert-butyl, pentyl and hexyl groups!
• Hetero atom-containing functional groups include amino groups, aminoalkyl groups, carbonylalkyl groups, acyl groups, acyloxy groups, carbonyl groups, alkyl carbonyl groups, alkyl groups. Carboalkyl group, arylamino group, alkyloxy group, alkoxy group, alkylthio group, haloalkyl group, aryloxy group, aralkoxy group, alkylthio group, alkylenedioxy group, acyl group, aroyl group, alkylsulfo group Group, alkylsulfol group, arylsulfol group, arylsulfolamino group, alkylsulfolumino group, dialkylamino group, ammonium group, heterocyclic group, heterocyclic group, and sulfonyl group.
• aminoalkyl group is an amino amino alkyl group.
• Alkylaminoalkyl is an amino amino alkyl group.
• An example of a group is a C alkylamino C alkyl group.
• carbonylalkyl group is a group having carbonylalkyl group.
• acyl groups are formyl, acetyl, etc.
• alkyl carbo yl groups are methyl carbo yl and ethyl
• alkylcarbonyl groups such as rubonyl.
• Alkyl carboalkyl group such as rubonyl.
• An example of is a C alkyl carbo C alkyl group.
• Examples of arylamine groups are
• alkoki phenylamine-containing naphthylami-containing benzylami-containing indanylamino and indenylamino groups.
• An example of a alkoxy group is a C alkaryl-o group.
• An example of a cis group is a C alkyl O group.
• Examples of alkylthio groups are C alkyl
• haloalkyl group is a halogen-C alkyl group. Ally
• ruoxy groups are phenoxy, naphthyloxy, benzyloxy, induloxy and induroxy groups.
• aralkoxy groups are:
• aralkylthio groups are ferro-C alkyl S groups, naphthyl C
• C alkylene dioxy groups such as methylene dioxy and ethylene dioxy groups
• acyl groups are C-acyl groups such as formyl, acetyl and butyryl groups.
• Examples of aroyl groups are ferro-CO groups, naphthyl-CO groups, benzyl-CO groups, indanileu-CO groups, indenyl-CO groups.
• An example of an alkylsulfol group is a C alkyl-SO- group.
• An example of an aralkylsulfol group is phenol C Alkyl SO— group, naphthyl C Alkyl SO— group, benzyl-C Al
• arylsulfol groups are phenol-SO-group, naphthyl-S.
• arylsulfo-lumino groups are ferro-SO NH group, naphthyl mono SO N
• alkylsulfo-lumino group is a C alkyl-SO NH- group.
• dialkylamino groups examples include (C
• N group 1-6 Kills
• ammo groups are trimethyl ammo and triethyl am
• a trialkylammo group such as a moo group
• heterocyclic groups include nitrogen-containing heterocyclic groups such as pyrrolyl, pyrrolidyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolidinyl, Forms such rings as tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolyl, imidazolidyl, virazolyl, virazolidyl, prill and indazolyl groups 5 or 6-membered ring, condensed ring or bridged ring heterocyclic group which may contain one or more nitrogen atoms as a hetero atom and further contain one or more oxygen
• 5- or 6-membered ring containing an atom or fused ring Is a heterocyclic group of the bridged ring.
• the heterocyclic carbonyl group means a heterocyclic CO group. These groups are amino groups, C alkylamino groups, carbo groups, C alkoxy groups,
• R 3 is a phenoxy group, R ⁇ R 4 and R 5 are hydrogen, and R 1 is —CH 2 CH 2 (NHR) COOR, R 3 and
• R 4 is --OR or OCOR
• R is, for example, a C alkyl group such as methyl, ethynole, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl groups
• R 1G represents an alkyl group.
• alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl groups.
• it is a C alkyl group, more preferably an n-butyl group.
• This step can be carried out by a method generally used for organic chemical synthesis reactions.
• This process consists of (B) —general formula (4)
• the odorous benzene compound is oxidized and then reacted with toluenesulfonic acid monohydrate in The general formula (5)
• Ts represents a toluenesulfol group
• E and n represent the same meaning as described above).
• Examples of functional groups that donate electrons to the ⁇ —electron system are one NR, one OR, one NHCOR.
• This step can be performed by a commonly used method described in literature (G. F. Koser et al., J. Org. Chem., 42, 1476 (1977)).
• a odobenzene compound of the general formula (4) is treated with peracetic acid or sodium borate (in acetic acid) as a periodine compound and treated with acetonitrile and monohydrate of tosylic acid in ether at room temperature.
• Hydroxyl benzene power with an electrophilic group If it is unstable, such as decomposition in the air, 1) perform all reactions in a nitrogen atmosphere 2) without isolating the compound A means such as that used in the reaction can be used.
• This step can be performed by a method and conditions generally employed for the reaction of a hydroxytosyl benzene compound and a ferrous tin compound.
• This process consists of reacting (D) -diphenyl salt of general formula (6) with [ 18 F] F- to give general formula (7)
• the radioligand having an 18 F-labeled fluorobenzene ring obtained in this way is expected to have useful physiological or pharmacological activity and be used for elucidation of biological functions.
• radioligands having various substituents and having physiological or pharmacological activity can be used.
• this labeling method has been used for the production of radioligands with 18 F-labeled fluorobenzene ring.
• it can be used for the synthesis of [ 18 F] FDOPA, [ 18 F] DAA1106, [ 18 F] Spiperone ⁇ [ 18 F] Ketaserine ⁇ [ 18 F] Flumazenil, [ 18 F] Resperidone, etc.
• these series of reactions have the advantage that the conditions are mild and the yield is high in a short time.
• Example 1 [2, 5-dimethoxybenzyl)-N-(5-(18 F) Furuoro 2 Fuenokishifue - Le) preparation of Asetoamido (hereinafter [18 F] DAA1106)
• AA1106 fraction was obtained.
• the solvent was removed from this fraction under reduced pressure, dissolved in physiological saline (lmL), passed through a 0.22'm Millipore filter, and [ 18 F] DAA110 6 (1.3 mCi, specific activity: 4 5CiZ w mol, radiochemical purity: 99%)

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