WO2004029006A2 - Process for the preparation of fluorohaloalkanes - Google Patents

Process for the preparation of fluorohaloalkanes Download PDF

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Publication number
WO2004029006A2
WO2004029006A2 PCT/GB2003/004026 GB0304026W WO2004029006A2 WO 2004029006 A2 WO2004029006 A2 WO 2004029006A2 GB 0304026 W GB0304026 W GB 0304026W WO 2004029006 A2 WO2004029006 A2 WO 2004029006A2
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formula
compound
alkyl
haloalkyl
group
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WO2004029006A3 (en
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Frank Brady
Sajinder Luthra
Yongjun Zhao
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Hammersmith Imanet Ltd
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Hammersmith Imanet Ltd
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Priority to EP03798241A priority Critical patent/EP1554231B1/en
Priority to AU2003264895A priority patent/AU2003264895A1/en
Priority to JP2004539176A priority patent/JP2006500419A/en
Priority to US10/528,645 priority patent/US7405332B2/en
Priority to DE60314167T priority patent/DE60314167T2/en
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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
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids

Definitions

  • the present invention relates to a process for the preparation of fluorohaloalkane compounds such as [ 18 F]bromofluoromethane.
  • [ 18 F]Fluorohaloalkanes are important reagents for performing O-, N-, and S-[ 18 F]fluoroalkylations and are commonly used to radiolabel radioligands for use in positron emission tomography
  • [ 18 F]Fluorohaloalkanes have previously been prepared by nucleophilic displacement, by [ 18 F]F " , of a leaving group from a suitable precursor compound.
  • Zhang et al, Applied Radiation and Isotopes 57, 335-342 (2002) describes synthesis of [ 18 F]fluoroethyl bromide by nucleophilic displacement of 2-trifluoromethanesulphonyloxy ethylbromide with [ 18 F]F " and Seung-Jun et al Applied Radiation and Isotopes (1999), 51 , 293-7 describes an analogous synthesis of 3-[ 18 F]fluoropropylbromide.
  • n is as defined for the compound of formula (I); and R', R", and R'" are independently selected from C ⁇ - 6 alkyl and C ⁇ _ 6 haloalkyl; and R" may alternatively be the group:
  • the fluorohaloalkane of formula (I) is a [ 18 F]fluorohaloalkane. Therefore, according to a further aspect of the present invention, there is provided a process for preparation of a [ 18 F]fluorohaloalkane of formula (la)
  • n is as defined for the compound of formula (la); and R', R", and R'" are independently selected from C ⁇ _ 6 alkyl and C ⁇ . 6 haloalkyl; and R" may alternatively be the group:
  • formula (I) which may be prepared using the present process, include fluorobromomethane, fluoroiodomethane, fluorobromoethane, fluoroiodoethane, fluorobromopropane, and fluoroiodopropane, each of which is suitably prepared in [ 18 F]-labelled form.
  • the reaction of a compound of formula (II) or (lla) with a compound of formula (III) may be performed in the presence of a catalyst, suitably a tetra (C ⁇ . 6 alkyl) ammonium salt, such as a tetra (C ⁇ _ 6 alkyl) ammonium fluoride salt, for example tetrabutylammonium fluoride or tetraethylammonium fluoride; and in a suitable solvent for example acetonitrile or an alcohol such as methanol or ethanol at elevated temperature, for example 50°C to 150°C, suitably 70°C to 120°C.
  • a catalyst suitably a tetra (C ⁇ . 6 alkyl) ammonium salt, such as a tetra (C ⁇ _ 6 alkyl) ammonium fluoride salt, for example tetrabutylammonium fluoride or tetraethylammonium fluoride
  • a suitable solvent for example
  • the resulting compound of formula (I) or (la) may be isolated from the reaction mixture, for example, by distillation followed by chromatography, suitably gas or liquid chromatography.
  • chromatography suitably gas or liquid chromatography.
  • the crude reaction mixture is distilled and the distillate is then passed under a stream of inert gas, such as helium, through a temperature controlled GC column packed with silica gel.
  • the resulting compound of formula (I) or (la) may also be converted to a corresponding fluoroalkylsulphonyl ester of formula (V) or (Va) respectively:
  • C- ⁇ - 6 alkyl for example, methyl
  • C ⁇ - 6 perfluoroalkyl for example, trifluoromethyl
  • aryl for example, phenyl
  • tolyl for example, para-tolyl
  • perfluoroaryl for example, perfluorophenyl
  • perfluorotolyl for example, perfluoro para-tolyl
  • a [ 18 F]fluorohaloalkyl compound of formula (la) may be converted to a [ 18 F]fluoroalkyltosylate of formula (Va) such as [ 18 F]fluoromethyltosylate.
  • Fluoroalkylsulphonyl esters of formulae(V) and (Va) are also useful as fluoroalkylating agents.
  • Conversion of a compound of formula (I) or (la) to a compound of formula (V) or (Va) respectively may be effected by reaction with the appropriate sulphonic acid of formula R 1 SO 2 OH or a salt thereof, such as a silver salt. Depending on the particular compound to be prepared, this conversion may be performed in solution phase, or in gaseous phase, for example by methods analogous to those described by Iwata et al, Applied Radiation and Isotopes, 57 (2002), 347-352.
  • the resulting compound of formula (I) or (la), or a corresponding compound of formula (V) or (Va) as described above, may be used in the preparation of a fluoroalkyl ligand or radiotracer, for example a [ 18 F]fluoroalkylated radioligand or [ 18 F]-radiotracer suitable for use in a PET study.
  • a fluoroalkyl ligand or radiotracer for example a [ 18 F]fluoroalkylated radioligand or [ 18 F]-radiotracer suitable for use in a PET study.
  • Examples of [ 18 F]fluoroalkylated radioligands and [ 18 F]-radiotracers which may be prepared using the compounds of formula (la) or (Va) include 2-(1 ,1-dicyanopropen-2-yl)-6-(2-[ 18 ⁇ -fluoroC 1 .
  • [ 18 F]fluoroC ⁇ alkyl)spiperone for example 3-(2'-[ 18 F]fluoroethyl)spiperone
  • n is preferably 1, 2, or 3 such that the fluorohaloalkane prepared in the process is a fluorohalomethane, fluorohaloethane, or fluorohalopropane.
  • halo means fluoro, chloro, iodo, or bromo.
  • X is halo, and is preferably bromo or iodo.
  • Y is halo, preferably bromo or iodo, and is preferably the same asX, such that the compound of formula (III) is preferably Br 2 or l 2 .
  • R', R", and R'" are suitably selected from C ⁇ . 6 alkyl and for example methyl, ethyl, propyl, and isopropyl, typically methyl.
  • R is the group:
  • the “Solid Support” may be any suitable material which is insoluble in any solvents to be used in the process but to which the "Linker” and/or compound of formula (II) or (lla) can be covalently bound.
  • suitable solid support include polymers such as polystyrene (which may be block grafted, for example, with polyethylene glycol), polyacrylamide, and polypropylene or glass or silicon suitably coated with such a polymer.
  • the solid support may be in the form of small discrete particles such as beads or pins, or as a coating on the inner surface of a cartridge or on a microfabricated vessel; and
  • the “Linker” may be any suitable organic group which serves to space the reactive site sufficiently from the solid support structure so as to maximise reactivity.
  • the Linker comprises an organic group of from 1 to 12 carbon atoms and from 0 to 6 heteroatoms selected from oxygen, nitrogen, and sulphur. Examples of such linkers are well known to those skilled in the art of solid-phase chemistry, but include phenyl(C ⁇ . 6 alkyl) and phenyl.
  • n is an integer of from 1 to 6;
  • R' and R"' are independently selected from C-i- ⁇ alkyl and C ⁇ _ 6 haloalkyl; and R" is the group:
  • n is an integer of from 1 to 6;
  • R', R", and R m are independently selected from C- ⁇ -6 alkyl and C ⁇ _ 6 haloalkyl;
  • R" may alternatively be the group:
  • n, R ⁇ R", and R'" are as defined for the compound of formula (II) or (lla) and L is a leaving group;
  • F a source of F " , preferably 18 F ⁇ suitably an alkali metal fluoride salt such as Na 18 F, K 18 F, or Cs 18 F, tetraalkylammonium 18 F fluoride, or tetraalkylphosphonium 18 F fluoride.; in the presence of a phase transfer catalyst, suitably 18-crown-6 or a cryptand such as Kryptofix 2.2.2., Kryptofix 2.2.2B., Kryptofix 2.2.1. (all available from Aldrich).
  • the reaction may be performed in a suitable solvent such as acetonitrile and at elevated temperature, suitably 50°C to 100°C.
  • the leaving group, L, in the compound of formula (IV) is suitably a sulphonyl ester group i.e. -OSO 2 R 2 wherein R 2 is selected from C ⁇ _ 6 alkyl (for example, methyl), C- ⁇ - 6 perfluoroalkyl (for example, trifluoromethyl), aryl (for example, phenyl), tolyl (for example, para-tolyl), perfluoroaryl (for example, perfluorophenyl), and perfluorotolyl (for example, perfluoro para-tolyl).
  • R 2 is selected from C ⁇ _ 6 alkyl (for example, methyl), C- ⁇ - 6 perfluoroalkyl (for example, trifluoromethyl), aryl (for example, phenyl), tolyl (for example, para-tolyl), perfluoroaryl (for example, perfluorophenyl), and perfluorotolyl (for example, perfluoro para-toly
  • n is an integer of from 1 to 6;
  • R', R", and R'" are independently selected from C-
  • L is a group -OSO 2 R 2 wherein R 2 is selected from alkyl, C ⁇ - 6 perfluoroalkyl, aryl, perfluoroaryl, tolyl, and perfluorotolyl; provided that:
  • R" is C ⁇ _ 6 alkyl or C ⁇ - 6 haloalkyl and n is 2 to 6, L is not -OSO 2 CH 3 or -OSO 2 (para-methyl)phenyl.
  • Compounds of formula (IV) are either commercially available (for example, from Aldrich), or a readily prepared from commercially available starting materials using methods available to the person skilled in the art.
  • the compound of formula (IV) is prepared by reaction of the corresponding azide with the appropriate sulphonic acid or a salt thereof, for example using methods analogous to those described in Al-Busafi et al, Tetrahedron Letters, 39, 12 (1998).
  • the invention will now be illustrated by way of the following Example.
  • Trimethylsilylmethyl trifluoromethanesulphonate (Aldrich) (5mg) in acetonitrile (1 ml) was added to fully dried 18 F7Kryptofix 2.2.2 complex prepared by standard methods, for example as described in Hammacher et al, J. Nuclear Medicine, 27, 235-8 (1986). The mixture was heated at 75° C for 5 minutes. l o Tetrabutylammonium fluoride (16mg) in acetonitrile (0.5ml) and bromine (8mg) in methanol (0.5ml) were added to the reaction mixture. The reaction vessel was then sealed and heated at 110°C for 3 to 4 minutes.
  • Suitable solvents include acetonitrile,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Inorganic Compounds Of Heavy Metals (AREA)
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Abstract

The invention provides a process for preparation of a fluorohaloalkane, preferably an [18F]fluorohaloalkane of formula (I) wherein X is halo and n is an integer of from 1 to 6; which comprises: reaction of the corresponding organosilicon compound of formula (II): wherein n is as defined for the compound of formula (I); and R', R', and R'' are independently selected from C1-6 alkyl and C1-6 haloalkyl; and R'' may alternatively be the group, with a compound of formula (III), wherein X is as defined for the compound of formula (I) and Y is halo. Intermediates having use in such processes are also claimed.

Description

CHEMICAL PROCESS
The present invention relates to a process for the preparation of fluorohaloalkane compounds such as [18F]bromofluoromethane. [18F]Fluorohaloalkanes are important reagents for performing O-, N-, and S-[18F]fluoroalkylations and are commonly used to radiolabel radioligands for use in positron emission tomography
(PET) studies.
[18F]Fluorohaloalkanes have previously been prepared by nucleophilic displacement, by [18F]F", of a leaving group from a suitable precursor compound. Thus, for example Zhang et al, Applied Radiation and Isotopes 57, 335-342 (2002), describes synthesis of [18F]fluoroethyl bromide by nucleophilic displacement of 2-trifluoromethanesulphonyloxy ethylbromide with [18F]F" and Seung-Jun et al Applied Radiation and Isotopes (1999), 51 , 293-7 describes an analogous synthesis of 3-[18F]fluoropropylbromide. A similar method is described in Comagic et al Applied Radiation and Isotopes (2002), 56, 847-851 wherein 2- bromo-1-[18F]fluoroethane is prepared by nucleophilic displacement of 1,2- dibromoethane with [18F]F".
In view of the importance of [i8F]Fluorohaloalkanes as radiolabelling reagents, there exists the need for synthetic 'methods for their preparation in good radiochemical yield and in which isolation of the product is more readily achievable. Furthermore, there is also a need for such synthetic methods which are amenable to automation.
Therefore, according to the present invention, there is provided a process for preparation of a fluorohaloalkane of formula (I)
χ_(CH2)n-F (I)
wherein X is halo and n is an integer of from 1 to 6; which comprises: reaction of the corresponding organosilicon compound of formula (II):
R'
I R"— Si— (CH2)n-F (II)
I Rm
wherein n is as defined for the compound of formula (I); and R', R", and R'" are independently selected from Cι-6 alkyl and Cι_6 haloalkyl; and R" may alternatively be the group:
Figure imgf000003_0001
with a compound of formula (III):
XY (III)
wherein X is as defined for the compound of formula (I) and Y is halo.
In a preferred aspect of the invention, the fluorohaloalkane of formula (I) is a [18F]fluorohaloalkane. Therefore, according to a further aspect of the present invention, there is provided a process for preparation of a [18F]fluorohaloalkane of formula (la)
Figure imgf000003_0002
wherein X is halo and n is an integer of from 1 to 6; which comprises: reaction of the corresponding organosilicon compound of formula (lla):
R'
1 R"— Si— (CH2)n— F (lla)
I R"'
wherein n is as defined for the compound of formula (la); and R', R", and R'" are independently selected from Cι_6 alkyl and Cι.6 haloalkyl; and R" may alternatively be the group:
Figure imgf000004_0001
with a compound of formula (III):
XY (III)
wherein X is as defined for the compound of formula (la) and Y is halo.
Examples of formula (I) which may be prepared using the present process, include fluorobromomethane, fluoroiodomethane, fluorobromoethane, fluoroiodoethane, fluorobromopropane, and fluoroiodopropane, each of which is suitably prepared in [18F]-labelled form.
The reaction of a compound of formula (II) or (lla) with a compound of formula (III) may be performed in the presence of a catalyst, suitably a tetra (Cι.6 alkyl) ammonium salt, such as a tetra (Cι_6 alkyl) ammonium fluoride salt, for example tetrabutylammonium fluoride or tetraethylammonium fluoride; and in a suitable solvent for example acetonitrile or an alcohol such as methanol or ethanol at elevated temperature, for example 50°C to 150°C, suitably 70°C to 120°C.
The resulting compound of formula (I) or (la) may be isolated from the reaction mixture, for example, by distillation followed by chromatography, suitably gas or liquid chromatography. In a preferred isolation method, the crude reaction mixture is distilled and the distillate is then passed under a stream of inert gas, such as helium, through a temperature controlled GC column packed with silica gel.
The resulting compound of formula (I) or (la) may also be converted to a corresponding fluoroalkylsulphonyl ester of formula (V) or (Va) respectively:
R1SO2-O— (CH2)n— F (V)
R1SO2-O — (CH2)n— 18F (Va) wherein n is as defined for the compound of formula (I) or (la), and R1 is selected from C-ι-6 alkyl (for example, methyl), Cι-6 perfluoroalkyl (for example, trifluoromethyl), aryl (for example, phenyl), tolyl (for example, para-tolyl), perfluoroaryl (for example, perfluorophenyl), and perfluorotolyl (for example, perfluoro para-tolyl). Thus, for example a [18F]fluorohaloalkyl compound of formula (la) may be converted to a [18F]fluoroalkyltosylate of formula (Va) such as [18F]fluoromethyltosylate. Fluoroalkylsulphonyl esters of formulae(V) and (Va) are also useful as fluoroalkylating agents.
Conversion of a compound of formula (I) or (la) to a compound of formula (V) or (Va) respectively, may be effected by reaction with the appropriate sulphonic acid of formula R1SO2OH or a salt thereof, such as a silver salt. Depending on the particular compound to be prepared, this conversion may be performed in solution phase, or in gaseous phase, for example by methods analogous to those described by Iwata et al, Applied Radiation and Isotopes, 57 (2002), 347-352.
The resulting compound of formula (I) or (la), or a corresponding compound of formula (V) or (Va) as described above, may be used in the preparation of a fluoroalkyl ligand or radiotracer, for example a [18F]fluoroalkylated radioligand or [18F]-radiotracer suitable for use in a PET study. Examples of [18F]fluoroalkylated radioligands and [18F]-radiotracers which may be prepared using the compounds of formula (la) or (Va) include 2-(1 ,1-dicyanopropen-2-yl)-6-(2-[18η-fluoroC1.6alkyl)- methylamino)naphthalene (for example, 2-(1,1-dicyanopropen-2-yl)-6-(2-[ 8F]- fluoroethyl)-methylamino)naphthalene, FDDNP), 3-(2'-
[18F]fluoroC^alkyl)spiperone (for example 3-(2'-[18F]fluoroethyl)spiperone), [18F][2- fluoroC1.6alkoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenyl- piperidin-3-yl)-amine (for example, [18F][2-fluoromethoxy-5-(5-trifluoromethyl- tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenyl-piperidin-3-yl)-amine), 2-beta- carbomethoxy-3-beta-(4-iodophenyl)-8-(3-[18F]fluoroC .6alkyl)-nortropane (for example, 2-beta-carbomethoxy-3-beta-(4-iodophenyl)-8-(3-[18F]fluoropropyl)- nortropane, [ 8F]fluoroCι-6alkylflumazenil (for example, [18F]fluoroethylflumazenil), [18F]fluoroCι-6aIkyl-choline (for example, [18F]fluoromethyl-choline or [ 8F]fluoroethyl-choline), O-2[18F]fluoroalkyl tyrosine (for example O- 2[18F]fluoroethyl tyrosine or O-2[18F]fluoropropyl tyrosine), and 1-amino-3-[18F]- fluoroalkylcyclobutane-1-carboxylic acid (for example, 1-amino-3-[18F]- fluoromethylcyclobutane- -carboxylic acid, (FMACBC)). Other [18F]fluoroalkylated radioligands and [18F]-radiotracers which may be prepared using the compounds of formula (la) or (Va) include [18F]-benzyl derivatives.
In the compounds of formulae (I), (la), (II), and (lla), n is preferably 1, 2, or 3 such that the fluorohaloalkane prepared in the process is a fluorohalomethane, fluorohaloethane, or fluorohalopropane.
Throughout the specification, the term "halo" means fluoro, chloro, iodo, or bromo.
In the compounds of formulae (I), (la), and (III), X is halo, and is preferably bromo or iodo.
In the compounds of formula (111), Y is halo, preferably bromo or iodo, and is preferably the same asX, such that the compound of formula (III) is preferably Br2 or l2.
In the compounds of formula (II) and (lla), R', R", and R'" are suitably selected from Cι.6alkyl and
Figure imgf000006_0001
for example methyl, ethyl, propyl, and isopropyl, typically methyl.
Where R" is the group:
Figure imgf000006_0002
the "Solid Support" may be any suitable material which is insoluble in any solvents to be used in the process but to which the "Linker" and/or compound of formula (II) or (lla) can be covalently bound. Examples of suitable solid support include polymers such as polystyrene (which may be block grafted, for example, with polyethylene glycol), polyacrylamide, and polypropylene or glass or silicon suitably coated with such a polymer. The solid support may be in the form of small discrete particles such as beads or pins, or as a coating on the inner surface of a cartridge or on a microfabricated vessel; and
the "Linker" may be any suitable organic group which serves to space the reactive site sufficiently from the solid support structure so as to maximise reactivity. Suitably, the Linker comprises an organic group of from 1 to 12 carbon atoms and from 0 to 6 heteroatoms selected from oxygen, nitrogen, and sulphur. Examples of such linkers are well known to those skilled in the art of solid-phase chemistry, but include phenyl(Cι.6alkyl) and phenyl.
Certain of the compounds of formula (II) and (lla) are novel and thus form a separate aspect of the invention.
Accordingly, there is provided a compound of formula (II):
R'
I R"— Si— (CH2)n— F (II)
I R-
wherein n is an integer of from 1 to 6; and
R' and R"' are independently selected from C-i-β alkyl and Cι_6 haloalkyl; and R" is the group:
Figure imgf000007_0001
Further, there is provided a compound of formula (lla):
R'
1 R"— Si— (CH2)π— F (lla)
R" wherein n is an integer of from 1 to 6; and
R', R", and Rm are independently selected from C-ι-6 alkyl and Cι_6 haloalkyl; and
R" may alternatively be the group:
Figure imgf000008_0001
Compounds of formula (II) or (lla) may be prepared from the corresponding compound of formula (IV):
R'
I R"— Si— (CH2)n— L (IV)
I R„.
wherein n, R\ R", and R'" are as defined for the compound of formula (II) or (lla) and L is a leaving group;
by reaction with a source of F" , preferably 18F ~ suitably an alkali metal fluoride salt such as Na18F, K18F, or Cs18F, tetraalkylammonium 18F fluoride, or tetraalkylphosphonium 18F fluoride.; in the presence of a phase transfer catalyst, suitably 18-crown-6 or a cryptand such as Kryptofix 2.2.2., Kryptofix 2.2.2B., Kryptofix 2.2.1. (all available from Aldrich). The reaction may be performed in a suitable solvent such as acetonitrile and at elevated temperature, suitably 50°C to 100°C.
The leaving group, L, in the compound of formula (IV) is suitably a sulphonyl ester group i.e. -OSO2R2 wherein R2 is selected from Cι_6 alkyl (for example, methyl), C-ι-6 perfluoroalkyl (for example, trifluoromethyl), aryl (for example, phenyl), tolyl (for example, para-tolyl), perfluoroaryl (for example, perfluorophenyl), and perfluorotolyl (for example, perfluoro para-tolyl).
Certain of the compounds of formula (IV) are novel, and therefore according to a further aspect of the invention there is provided a compound of formula (IV):
R'
I R"— Si— (CH2)n— L (IV)
I Rm
wherein n is an integer of from 1 to 6; R', R", and R'" are independently selected from C-|.6 alkyl and C-|.6 haloalkyl; and R" may alternatively be the group:
Figure imgf000009_0001
L is a group -OSO2R2 wherein R2 is selected from
Figure imgf000009_0002
alkyl, Cι-6 perfluoroalkyl, aryl, perfluoroaryl, tolyl, and perfluorotolyl; provided that:
(a) when R" is Ci-e alkyl or Cι-6 haloalkyl, n is not 1 ; and
(b) when R" is Cι_6 alkyl or Cι-6 haloalkyl and n is 2 to 6, L is not -OSO2CH3 or -OSO2(para-methyl)phenyl.
Compounds of formula (IV) in which R" is the group
Figure imgf000009_0003
are a particularly useful class of intermediates and thus form a separate aspect of the invention.
Compounds of formula (IV) are either commercially available (for example, from Aldrich), or a readily prepared from commercially available starting materials using methods available to the person skilled in the art. In one suitable method, the compound of formula (IV) is prepared by reaction of the corresponding azide with the appropriate sulphonic acid or a salt thereof, for example using methods analogous to those described in Al-Busafi et al, Tetrahedron Letters, 39, 12 (1998). The invention will now be illustrated by way of the following Example.
Example
Preparation of r 8F1fluorobromomethane
5
Trimethylsilylmethyl trifluoromethanesulphonate (Aldrich) (5mg) in acetonitrile (1 ml) was added to fully dried 18F7Kryptofix 2.2.2 complex prepared by standard methods, for example as described in Hammacher et al, J. Nuclear Medicine, 27, 235-8 (1986). The mixture was heated at 75° C for 5 minutes. l o Tetrabutylammonium fluoride (16mg) in acetonitrile (0.5ml) and bromine (8mg) in methanol (0.5ml) were added to the reaction mixture. The reaction vessel was then sealed and heated at 110°C for 3 to 4 minutes.
[18F]fluorobromomethane produced was then distilled from the vessel at the same
15 temperature. The distillate containing [18F]fluorobromomethane was passed under a stream of helium through a temperature controlled GC column (7.8 x 80 mm) packed with silica gel (70 to 270 mesh, Aldrich). The output from the GC column was examined by a radioactive detector and the fraction with a retention time identical to that of authentic bromofluoromethane was directed to a cooled
20 trapping vial containing a suitable solvent. Suitable solvents include acetonitrile,
N,N-dimethylformamide, dimethylsulphoxide, tetrahydrofuran, acetone, acetic acid, and chlorobenzene. Other fractions were vented to waste. The overall radiochemical yield for [18F]fluorobromomethane from [18F]fluoride was 55-70% and the total time for the preparation was approximately 45 minutes from the end 5 of radionuclide production.

Claims

Claims
1. A process for preparation of a fluorohaloalkane of formula (I)
χ_(CH2)n-F (I)
wherein X is halo and n is an integer of from 1 to 6; which comprises: reaction of the corresponding organosilicon compound of formula (II):
R'
I R"-Si-(CH2)n-F (II)
I R'"
wherein n is as defined for the compound of formula (I); and
R', R", and R'" are independently selected from Cι_6 alkyl and Cι.6 haloalkyl; and
R" may alternatively be the group:
Figure imgf000011_0001
with a compound of formula (III):
XY (III)
wherein X is as defined for the compound of formula (I) and Y is halo.
A process according to claim 1 for preparation of a [ F]fluorohaloalkane of formula (la)
18r
X-(CH2)n-,0F (la)
wherein X is halo and n is an integer of from 1 to 6; which comprises: reaction of the corresponding organosilicon compound of formula (lla): R'
Figure imgf000012_0001
wherein n is as defined for the compound of formula (la); and
R\ R", and R'" are independently selected from C^ alkyl and Cι.6 haloalkyl; and
R" may alternatively be the group:
Figure imgf000012_0002
with a compound of formula (III):
XY (III)
5 wherein X is as defined for the compound of formula (la) and Y is halo.
3. A process according to claim 1 or 2 which comprises the further step:
(i) isolation of the compound of formula (I) or (la); and/or 0 (ii) conversion of the compound of formula (I) or (la) to a corresponding fluoroalkylsulphonyl ester of formula (V) or (Va) respectively:
R1SO2-O— (CH2)n— F (V) R1SO2-O — (CH2)n— 18F (Va) 5 wherein n is as defined for the compound of formula (I) or (la), and R1 is selected from Ci_6 alkyl, Cι.6 perfluoroalkyl, aryl, tolyl, perfluoroaryl, and perfluorotolyl.
4. A process according to any one of claims 1 to 3 which comprises the further o step:
(i) use of the resulting compound of formula (I) or (la) in the preparation of a fluoroalkyl ligand or radiotracer, such as a [18F]fluoroalkylated radioligand or [18F]- radiotracer.
5. A process according to claim 4 wherein the radioligand or radiotracer prepared is selected from:
2-(1 ,1-dicyanopropen-2-yl)-6-(2-[18F]-fluoroC1.6alkyl)-methylamino)naphthalene, 3-(2'-[18F]fluoroC1.6alkyl)spiperone,
[18F][2-fluoroC1.5alkoxy-5-(5-trifIuoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-2-phenyl- piperidin-3-yl)-amine,
2-beta-carbomethoxy-3-beta-(4-iodophenyl)-8-(3-[18F]fluoroC1.6alkyl)-nortropane, [18F]fluoroCι-6alkylflumazenil, and [18F]fluoroCι_6alkyl-choline.
6. A process according to claim 4 or 5 wherein the [18F]fluoroalkylated radioligand prepared is selected from:
2-(1 , 1 -dicyanopropen-2-yl)-6-(2-[18F]-fluoroethyl)-methylamino)naphthalene, 3-(2'-[18F]fluoroethyl)spiperone,
[18F][2-fluoromethoxy-5-(5-trifluoromethyl-tetrazoI-1-yl)-benzyl]-([2S,3S]-2-phenyl- piperidin-3-yl)-amine),
2-beta-carbomethoxy-3-beta-(4-iodophenyl)-8-(3-[18F]fluoropropyl)-nortropane,
[18F]fluoroethylflumazenil), [18F]fluoromethyf-choline, and
[18F]fluoroethyI-choline).
7. A process for the preparation of a compound of formula (II) or (lla) as defined in claim 1 or 2 which comprises reaction of a compound of formula (IV):
R'
R"— Si— (CH2)n— L (IV)
I R"'
wherein n, R\ R", and R"' are as defined for the compound of formula (II) or (lla), and L is a leaving group; with a source of F" , preferably 8F ~ in the presence of a phase transfer catalyst.
8. A compound of formula (II):
R*
R"-Si-(CH2)n-F (II)
I Rm
wherein n is an integer of from 1 to 6; and
R' and R'" are independently selected from Cι_6 alkyl and Ci-β haloalkyl; and R" is the group:
/Solid Linker (Support/
9. A compound of formula (lla):
R'
RM— Si- -(CH2)n-18F (lla)
R"
wherein n is an integer of from 1 to 6; and
R', R", and R'" are independently selected from C-ι-6 alkyl and Cι.6 haloalkyl; and R" may alternatively be the group:
Figure imgf000014_0001
10. A compound of formula (IV):
R'
! R"— Si— (CH2)n— L (IV)
I Rm
wherein n is an integer of from 1 to 6; R\ R", and R'" are independently selected from C^e alkyl and Cι.6 haloalkyl; and R" may alternatively be the group:
Figure imgf000015_0001
L is a group -OSO2R2 wherein R2 is selected from Cι_6 alkyl, Cι„6 perfluoroalkyl, aryl, perfluoroaryl, tolyl, and perfluorotolyl; provided that:
(a) when R" is C-i_6 alkyl or Cι_6 haloalkyl, n is not 1 ; and
(b) when R" is Cι-6 alkyl or C^e haloalkyl and n is 2 to 6, L is not -OSO2CH3 or -OSO2(para-methyl )phenyl .
PCT/GB2003/004026 2002-09-27 2003-09-18 Process for the preparation of fluorohaloalkanes Ceased WO2004029006A2 (en)

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WO2007067074A1 (en) * 2005-12-08 2007-06-14 Hammersmith Imanet Limited Method for the preparation of [18f]fluoroalkylhalides
EP1545525A4 (en) * 2002-09-24 2009-07-01 Merck & Co Inc RADIOMARTIC ANTAGONISTS OF THE NEUROKININ-1 RECEPTOR
WO2010117557A1 (en) 2009-03-31 2010-10-14 Hammersmith Imanet Limited Radiolabelling methods
CN102186796A (en) * 2008-10-20 2011-09-14 哈默史密斯网上成像有限公司 Radiofluorination
US8309054B2 (en) 2006-08-03 2012-11-13 Hammersmith Imanet Limited Method for the purification of radiolabelled compounds

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GB0410448D0 (en) * 2004-05-11 2004-06-16 Hammersmith Imanet Ltd Purification methods

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JPH0834021B2 (en) 1987-07-08 1996-03-29 日立電子株式会社 VTR splicing method
JPH02290885A (en) * 1989-04-28 1990-11-30 Rikagaku Kenkyusho Organosilicon compound and its manufacturing method
DE3935638A1 (en) 1989-10-26 1991-05-02 Consortium Elektrochem Ind ORGANOSILYL ALKYL FLAVORS
US5536732A (en) 1990-04-27 1996-07-16 Merrell Pharmaceuticals Inc. N-derivatives of 1-deoxy nojirimycin
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EP1545525A4 (en) * 2002-09-24 2009-07-01 Merck & Co Inc RADIOMARTIC ANTAGONISTS OF THE NEUROKININ-1 RECEPTOR
WO2007067074A1 (en) * 2005-12-08 2007-06-14 Hammersmith Imanet Limited Method for the preparation of [18f]fluoroalkylhalides
US8614360B2 (en) 2005-12-08 2013-12-24 Hammersmith Imanet Limited Method for the preparation of [18F]fluoroalkylhalides
US8309054B2 (en) 2006-08-03 2012-11-13 Hammersmith Imanet Limited Method for the purification of radiolabelled compounds
CN102186796A (en) * 2008-10-20 2011-09-14 哈默史密斯网上成像有限公司 Radiofluorination
WO2010117557A1 (en) 2009-03-31 2010-10-14 Hammersmith Imanet Limited Radiolabelling methods

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