NZ619465B2 - Fluorination of aromatic ring systems - Google Patents

Abstract

This disclosure relates to reagents and methods useful in the synthesis of aryl fluorides, for example, in the preparation of 18F labelled radiotracers. The reagents and methods provided herein may be used to access a broad range of compounds, including aromatic compounds, heteroaromatic compounds, amino acids, nucleotides, and synthetic compounds. amino acids, nucleotides, and synthetic compounds.

Description

.

Fluorination of Aromatic Ring Systems FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT The US. ment has certain rights in this invention pursuant to Grant No. CHE—0717562 awarded by the National e Foundation.

CROSS-REFERENCE TO RELATED APPLICATIONS This ation claims priority to US. Application Serial No. 13/172,953, filed on June 30, 2011, entitled FLUORINATION OF IC RING SYSTEMS, the disclosure of which is incorporated herein by nce.

TECHNICAL FIELD This disclosure s to reagents and methods useful in the synthesis of aryl fluorides, for example, in the preparation of 18F labeled radiotracers. The reagents and s provided herein may be used to access a broad range of compounds, including aromatic compounds, heteroaromatic compounds, amino acids, nucleotides, and synthetic compounds.

BACKGROUND Aryl fluorides are structural moieties in natural products as well as a number of therapeutically important compounds, including positron emission aphy (PET) tracers and pharmaceuticals. Therefore s and reagents for producing such aryl fluorides, for example efficient methods for producing aryl fluorides, are desirable.

SUMMARY Provided herein are methods of preparing substituted aryl and heteroaryl ring systems using diaryliodonium compounds and intermediates. For example, iodonium salts and diaryliodonium fluorides, as provided herein, can undergo decomposition to prepare aryl fluorides. 2012/044954 24742004333705.

For example, provided herein is a method for making a compound of Formula (1): Arz—X n Ar2 is an aryl or heteroaryl ring system; and X is a moiety wherein the pKa of the acid H-X is less than 12. In one embodiment, the method includes ng in a polar solvent a compound MX, wherein M is a counter ion and X is as defined in Formula (1), and a compound of Formula (2): Ar‘——I/ wherein Ar1 is an electron rich aryl or heteroaryl ring system; Y is a leaving group; Ar2 and X are as defined above. ing reaction, the polar solvent can be removed from the reaction mixture and the remaining mixture can be combined with a nonpolar solvent and heated. In some embodiments, the contaminant salts in the solution of the reaction mixture ofMX and a compound of Formula (2) in the polar solvent can be removed by chromatography prior to g. For example, the contaminant salts can be removed by size exclusion, gel filtration, reverse phase, or other tographic method prior to heating.

In another embodiment, a solution comprising a nonpolar solvent, a compound MX, and a compound of Formula (2) can be heated to provide a compound of a (1).

In some embodiments, the nonpolar solution of the reaction e ofMX and a compound of Formula (2) can be d prior to heating. The filtration step can remove any insoluble material (e.g., ble salts) that remain in the reaction mixture. In some embodiments, the solvent can be removed from the filtrate prior to heating (i.e., the residue can be heated neat).

In further embodiments, the nonpolar solution of the reaction mixture of MX and a compound of Formula (2) can be filtered prior to heating, the nonpolar solvent can be removed (e. g., by evaporation), and the heating of the sample can be performed in a ent solvent.

In some embodiments, the contaminant salts in the solution of the reaction mixture ofMX and a compound of Formula (2) in the nonpolar solvent can be 04333785. removed by chromatography prior to heating. For example, the contaminant salts can be removed by size exclusion, gel ion, reverse phase, or other chromatographic method prior to heating.

In some embodiments, X can be chosen from halide, aryl carboxylate, alkyl ylate, phosphate, phosphonate, phosphonite, azide, thiocyanate, cyanate, phenoxide, trifiate, trifiuoroethoxide, thiolates, and stabilized enolates. For example, X can be chosen from fluoride, chloride, bromide, iodide, trifiate, roacetate, benzoate, acetate, phenoxide, trifluoroethoxide, cyanate, azide, thiocyanate, thiolates, phosphates, and ized enolates. In some embodiments, X is fluoride. In some 1O embodiments, X is a radioactive isotope, for example, X can be a radioactive isotope of fluoride (e. g., 18F).

The s described herein can be used to prepare fiuorinated aryl or heteroaryl ring systems (e. g., a radiolabeled fluorinated aryl or heteroaryl ring system). For example, provided herein is a method of preparing a nd of Formula (3): Ar2—F wherein Ar2 is an aryl or heteroaryl ring system. In one ment, the method includes reacting in a polar solvent a compound MF, wherein M is a counter ion, and a nd of a (2), as bed above. Following reaction, the polar solvent can be removed from the reaction mixture and the remaining mixture can be combined with a ar solvent and heated. In another embodiment, a solution comprising a nonpolar solvent, a compound MF, and a compound of Formula (2) can be heated to e a compound of Formula (3).

In some embodiments, the nonpolar solution of the reaction mixture of MF and a compound of Formula (2) can be filtered prior to heating. The filtration step can remove any insoluble material (e.g., insoluble salts) that remain in the reaction mixture. In some embodiments, the solvent can be removed from the filtrate prior to g (i.e., the residue can be heated neat).

In further embodiments, the nonpolar solution of the reaction mixture of MF and a compound of Formula (2) can be filtered prior to heating, the nonpolar solvent can be removed (e.g., by evaporation), and the heating of the sample can be performed in a different solvent.

GD43WGE Ar1 is an electron rich aryl or aryl ring . For example, Arl—H can be more easily oxidized than benzene. In some embodiments, the moiety Ar1 can be substituted with at least one substituent having a Hammett op value of less than zero.

For example, the substituent can be chosen from: -(C1-C10)alkyl, 10)haloalkyl, (C2—C10)alkenyl, (C2—C10)alkynyl, —O—(C1—C10)alkyl, —C(O)—O—(C1—C10)alkyl, aryl, and heteroaryl. In some embodiments, Ar1 can be: wherein R1, R2, R3, R4, and R5 are independently Chosen from: H, -(C1-C10)alkyl, -(C1— C10)haloalkyl, (C2—C10)alkenyl, (C2-C10)alkynyl, —O—(C1—C10)alkyl, —C(O)—O—(C1- C10)alkyl, aryl, and heteroaryl, or two or more of R1, R2, R3, R4, and R5 come together to form a fused aryl or heteroaryl ring system.

Ar2 is an aryl or heteroaryl ring system. In some embodiments, Ar2 is Chosen from a phenylalanine derivative, tyrosine derivative, typtophan tive, histidine derivative, and estradiol derivative. In some embodiments, Ar2 is chosen from: M W OMe CN MeO OMe Me M OMe CFs 2012/044954 24742-0043WGE WO 03734 24742-0043WGE PL ,P2 N PL ,P2 éops PL ,P2 O‘P5 PL ,P2 b \E/ PL ,P2 2012/044954 24742-0434SWO: PL ,P2 3 Aw P\O \ PLN/ PLO P7—oE j P7-O P7-o 0P3 0P3 J‘L 0P3 0P3 PLN,P2 PLN/P2 P7-O PLO O ‘31? ‘5 \ 0171’ 0P3 0P3 0P4 CN / / l l \ ”<\N\ \ \\ N % N \\ '75 .11; 571/ ON ON <8 OP3 \N zN \ \ “‘a, \ a, \x‘ P4—o CN 0P3 CN P4_O J\IW wherein each of P1, P2 and P6 are independently a nitrogen protecting group, or P1 and P2 come together to form a single nitrogen protecting group; each of P3, P4, and P7 are 24742-(J043WGE independently an alcohol ting group, or P3 and P4 come together to form a single oxygen protecting group; and P5 is a carboxylic acid protecting group.

Also provided herein is a method of making a compound of Formula (6): wherein each of Pland P2 are independently a nitrogen protecting group, or P1 and P2 come together to form a single nitrogen protecting group; each of P3, and P4 are independently an alcohol protecting group, or P3 and P4 come together to form a single oxygen protecting group; and P5 is a carboxylic acid ting group. In one embodiment, the method includes reacting in a polar solvent a compound MF, wherein M is a counter ion, and a compound of a (7): PL ’ P2 r O‘P5 Ar1/I 0 wherein Ar1 is an electron rich aryl or heteroaryl ring system; Y is a leaving group; and P1,P2, P3, P4 and P5 are as defined above. Following reaction, the polar solvent can be removed from the reaction mixture and the remaining mixture can be combined with a nonpolar t and heated. In another embodiment, a solution sing a nonpolar solvent, a nd MF, and a compound of Formula (7) can be heated to provide a compound of Formula (6).

In some embodiments, the nonpolar solution of the reaction e of MF and a compound of Formula (7) can be filtered prior to heating. The filtration step can remove any insoluble material (e.g., insoluble salts) that remain in the reaction mixture. In some embodiments, the solvent can be removed from the filtrate prior to heating (i.e., the residue can be heated neat). 24742604333705.

In further embodiments, the nonpolar solution of the reaction mixture of MP and a compound of Formula (7) can be filtered prior to heating, the nonpolar solvent can be removed (e. g., by evaporation), and the heating of the sample can be performed in a different solvent.

In the methods described above, Y can be any leaving group, for example, Y can be, for example, triflate, mesylate, nonaflate, ate, tosylate, nosylate, ate, perfluoroalkyl sulfonate, tetraphenylborate, hexafluorophosphate, trifluoroacetate, tetrafluoroborate, perchlorate, roalkylcarboxylate, chloride, bromide, or iodide. 1O M can vary depending on the nature of the X moiety. In some embodiments, M can be ium, sodium, , complexes of lithium, sodium, potassium, or cesium with cryptands or crown ethers, tetrasubstituted ammonium cations, or phosphonium cations.

The nonpolar solvent used in the methods described herein can be, for example, e, toluene, 0-xylene, m—xylene, p—xylene, ethyl benzene, carbon tetrachloride, hexane, cyclohexane, fluorobenzene, chlorobenzene, nitrobenzene, or mixtures thereof. In some embodiments, the nonpolar solvent comprises benzene. In some embodiments, the nonpolar solvent comprises toluene.

The polar solvent used in the methods described herein can be, for example, acetonitrile, acetone, dichloromethane, ethyl acetate, ydrofuran, dimethylformamide, fluorobenzene, benzotrifluoride or mixtures f. g of the reaction mixture can include heating at a temperature ranging from about 25° C to about 250° C. In some embodiments, the heating can occur for from about 1 second to about 25 minutes. In some embodiments, the heating is accomplished by a flash sis method, a tional heating method, or by a microwave method. 24742AGD43WGE In some embodiments, the compound2of Formula (2) is chosen from: PL ,P2 PLN,P1 2 N P‘N’P T O‘P5 O‘P5 Arl/I OAr1/| 0 OP3 Ar1\| 0P4 | Y OP4 P1\N’PPZ‘N M57 £7 0%; wherein each of Pland P2 are independently a nitrogen protecting group, or P1 and P2 come together to form a single nitrogen protecting group; each of P3, and P4 are independently an alcohol protecting group, or P3 and P4 come er to form a single oxygen protecting group; and P5 is a carboxylic acid protecting group. For example, the compound of Formula (2) can be: PL ,P T P5 Ar1/| 0 n each of Pland P2 are independently a nitrogen ting group, or P1 and P2 come together to form a single nitrogen protecting group; each of P3, and P4 are independently an alcohol protecting group, or P3 and P4 come together to form a single oxygen protecting group; and P5 is a carboxylic acid protecting group. In some embodiments, the nd of Formula (2) can be: 0 O t—Bu\OJLNJJ\O/t-Bu Y ““%O\ NV: 0 2012/044954 24742:0043VVC£ In some embodiments, the compound of Formula (2) can be: 0 O t_Bu\OJJ\ JL /t-BU N o M90O | 0 In some embodiments, the compound of Formula (2) is chosen from: O /' /' \ Y Y \N \ T N \ ' % i\1 \ \ |\Ar1 I\Ar1 0 Ar 0” CN 3 S ’<\ \ l ’N Y (x Y / Y N % N i % i Q i \Ar1 \Ar1 \Ar1 CN CN CN In some embodiments, the compound of Formula (2) is chosen from: Arl/| P4—o P4—o Y’ \Ar1 wherein each of P3 and P4 are independently an alcohol protecting group.

WO 03734 24742:0043VVC£ In some embodiments, the compound of Formula (1) or Formula (3) is chosen from: P1N PL”, <9$$ (an? :95: wherein each of P1and P2 are independently a nitrogen protecting group, or P1 and P2 come together to form a single nitrogen protecting group; each of P3, and P4 are independently an l protecting group, or P3 and P4 come together to form a single oxygen protecting group; and P5 is a carboxylic acid protecting group.

In some embodiments, the compound of Formula (1) or Formula (3) is chosen from: / / O I I N \ \N \ Q§ \\ \\ F F CN CN 3 S ’4 \ <\N\ /N N % F % F % F ON CN 2012/044954 24742A6043WGE In some embodiments, the nd of Formula (1) or Formula (3) is chosen from: Pit—O P4—o wherein each of P3 and P4 are independently an alcohol protecting group.

In some embodiments, the compound of a (1) or Formula (3) can be: P1 P2 F 0 wherein each of Pland P2 are independently a nitrogen protecting group, or P1 and P2 come together to form a single nitrogen protecting group; each of P3, and P4 are independently an alcohol protecting group, or P3 and P4 come together to form a single oxygen protecting group; and P5 is a carboxylic acid protecting group. For example, the compound of Formula (1) or Formula (3) can be: O 0 t—Bu\OJLNJJ\O/t-Bu \‘\\K[(O\ F O In some embodiments, the compound of Formula (1) or Formula (3) can be: ”:2 H2 F O 24742AGD43WGE In some embodiments, the compound of Formula (7) can be: 0 O t—Bu\OJLNJJ\O,t-Bu Y \\“Hro\ Arl/i O For e, the compound of Formula (7”) can be: 0 O t-Bu\OJL MeOO IHZ T‘fO In some embodiments, the compound of Formula (6) can be: 0 O t-BuxoiNJJxO/t-Bu \‘\\S‘/O\ F O Also provided herein is a method for making a nd of Formula (1) that can include heating a mixture sing a nonpolar solvent and a compound of Formula (5): wherein Ar1 is an electron rich aryl or heteroaryl ring system; and Ar2 and X are as defined for Formula (1). In some embodiments, the reaction mixture is filtered (i.e., to remove insoluble material) prior to heating. In some embodiments, the reaction e is filtered and the nonpoloar solvent is removed and the resulting residue is dissolved in a polar solvent prior to heating. In some embodiments, X is F (e.g., 18F).

WO 03734 24742AGD43WGE Also provided herein is a method for making a compound of Formula (3) that can include heating a mixture comprising a nonpolar solvent and a compound of Formula (4): wherein Ar1 is an electron rich aryl or heteroaryl ring system; and Ar2 is as defined for Formula (3). In some embodiments, the reaction mixture is filtered (i.e., to remove insoluble material) prior to heating. In some embodiments, the reaction mixture is d and the nonpoloar t is removed and the resulting residue is dissolved in a polar solvent prior to heating.

Further provided herein is a compound of Formula (8): wherein Ar1 is an electron rich aryl or heteroaryl ring system; each of Pland P2 are independently a nitrogen protecting group, or P1 and P2 come together to form a single nitrogen protecting group; each of P3, and P4 are independently an alcohol ting group, or P3 and P4 come together to form a single oxygen protecting group; and P5 is a carboxylic acid protecting group. In some embodiments, the compound of Formula (8) is: O O t—Bu\OJLNJJ\O,t-Bu F \\\‘K[ro\ Ar“: 0 24’242AGD43WGE In some embodiments, the compound of Formula (8) is: 0 0 M60O 5 ,' 0 A compound of Formula (6) is also provided. The nd can be prepared using any of the methods described herein.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

DESCRIPTION OF GS shows the decomposition of MTEB-I-F in acetonitrile at 90 °C. shows the decomposition of MTEB-I-F in e at 90 °C. details the 1H NMR of 6-Fluoro-L-DOPA details the ”P NMR of 6-Fluoro-L-DOPA.

DETAILED DESCRIPTION Definitions Unless defined otherwise, all technical and scientific terms used herein have the same g as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All s, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section l unless stated otherwise.

As used herein, the singular forms “a,” “an,” and “the” e plural referents unless the context clearly es otherwise.

In general, the term “aryl” includes groups having 5 to 14 carbon atoms which form a ring structure and have an aromatic character, including 5- and 6—membered single-ring aromatic groups, such as benzene and . Furthermore, the term “aryl” includes polycyclic aryl groups, e.g., tricyclic, bicyclic, such as naphthalene and anthracene.

GD43W01 The term “heteroaryl” includes groups having 5 to 14 atoms which form a ring structure and have an aromatic character, including 5- and 6-membered single-ring aromatic groups, that have from one to four heteroatoms, for example, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and dine, and the like. Furthermore, the term “heteroaryl” includes polycyclic heteroaryl groups, e.g., lic, ic, such as benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, ine, isoquinoline, napthridine, indole, uran, purine, benzofuran, deazapurine, indazole, or indolizine. 1O The term “substituted” means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group. For aryl and heteroaryl , the term “substituted”, unless otherwise indicated, refers to any level of substitution, namely mono, di, tri, tetra, or penta substitution, where such substitution is permitted. The tuents are independently ed, and substitution may be at any chemically accessible position.

The compounds provided herein may encompass various stereochemical forms and tautomers. The compounds also encompasses diastereomers as well as optical isomers, e. g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual s or selective synthesis of the individual s is accomplished by application of various methods which are well known to practitioners in the art.

The term “electron rich”, as used herein, refers to an aryl or heteroaryl ring system which is more easily ed than benzene. For example the aryl or heteroaryl ring system may be substituted with one or more substituents having a Hammett op value of less than zero.

The term “fluorine” unless itly stated ise includes all fluorine isotopes. Multiple fluorine isotopes are known, however, only 19F is stable. The radioisotope 18F has a half-life of 109.8 minutes and emits positrons during radioactive decay. The relative amount of 18F t at a designated site in a compound of this disclosure will depend upon a number of factors including the isotopic purity of 18F labeled reagents used to make the compound, the efficiency of incorporation of 18F in the various synthesis steps used to prepare the compound, and the length of time since the 18F has been produced. When a position is designated specifically as 18F in the methods and compounds of the present disclosure, the 24742004333705. position is understood to have at least about 0.01%, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about %, at least about 35%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 85% 18F incorporation at that site.

Methods ofPreparing Substituted Aryl and Heteroaryl Ring Systems Provided herein are methods of preparing substituted aryl and heteroaryl ring 1O systems using iodonium compounds and intermediates. For example, diaryliodonium salts and diaryliodonium fluorides, as provided herein, can undergo decomposition to prepare an aryl fluoride.

For example, provided herein is a method for making a compound of Formula (1): ArZ—X wherein Ar2 is an aryl or heteroaryl ring system; and X is a moiety wherein the pKa of the acid H-X is less than 12. In some ments, a nd of Formula (1) can be prepared as shown in Scheme 1.

Scheme 1.

Y X I M Ar1—I—Ar2 —X> Ar2 —> x—Ar2 2 1 In some embodiments, the method can include reacting in a polar solvent a nd MX, n M is a counter ion and X is as defined in Formula (1), and a compound of Formula (2): wherein Ar1 is an electron rich aryl or heteroaryl ring ; Y is a leaving group; and Ar2 and X are as defined above in Formula (1). The polar solvent can then be d from the reaction mixture. The remaining mixture can then be combined with a nonpolar solvent and heated to produce a compound of Formula (1).

In some embodiments, the method can include heating a mixture comprising a nonpolar solvent, a compound MX, and a compound of Formula (2). 24742-04MSWGE In some embodiments, the nonpolar solution of the reaction mixture ofMX andacompmmdomenmhtZanbefihmedpfimflohmumg.ThefihmfimimQ) can remove any insoluble material (e.g., insoluble salts) that remain in the reaction mixture. In some embodiments, the t can be removed from the filtrate prior to heating (i.e., the residue can be heated neat).

In further embodiments, the nonpolar solution of the reaction mixture of MX and a compound of Formula (2) can be ed prior to heating, the nonpolar solvent can be removed (e.g., by evaporation), and the heating of the sample can be performed in a different solvent. 1O In some embodiments, contaminant salts are removed from the solution of the reaction mixture ofMX and a compound of Formula (2) in the polar or nonpolar solution by chromatography. For e, the inant salts can be removed by size exclusion, gel filtration, reverse phase, or other chromatographic method prior to heating.

Substituted aryls and heteroaryls which are prepared using the methods described herein can have an X moiety which includes any moiety in which the pKa of H-X (i.e., the conjugate acid of X) is less than about 12. In some cases, X is a radioactive isotope (e. g., 18F, 123’I, 1311, and compounds having 32F and 3"2’P). In some embodiments, X can be chosen from halide, aryl carboxylate, alkyl carboxylate, phosphate, phosphonate, phosphonite, azide, anate, cyanate, phenoxide, triflate, trifluoroethoxide, thiolates, and stabilized es. For example, X can be fluoride, chloride, bromide, iodide, trifluoroacetate, benzoate, and acetate. In some ments, X is fluoride. In some embodiments, is a ctive isotope of fluoride (e. g., 18F). chbemywmmbbwmggmm.Msmmemmflmwm&YmawwMy nating anion (i.e., an anion that coordinates only weakly with iodine). For example, Y can be the conjugate base of a strong acid, for example, any anion for which the pKa of the conjugate acid (H—Y) is less than about 1. For example, Y can be triflate, mesylate, nonaflate, hexaflate, toluene sulfonate (tosylate), nitrophenyl sulfonate (nosylate), bromophenyl sulfonate (brosylate), perfluoroalkyl sulfonate (e.g., perfluoro C240 alkyl ate), henylborate, hexafluorophosphate, trifluoroacetate, perfluoroalkylcarboxylate, tetrafluoroborate, perchlorate, hexafluorostibate, hexachlorostibate, chloride, bromide, or iodide. In some embodiments, a slightly more basic g group such as acetate or benzoate may be used. 24742AGG43WGE The counter ion M can be any suitable cation for the d X. The choice of the source of X, and accordingly M, is readily within the dge of one of ordinary skill in the art. For example, M can be chosen from an alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Metal cations may also be complexed to cryptands or crown ethers to enhance their solubility and to labilize the X moiety. M can also include organic salts made from quaternized amines derived from, for example, N,N' dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine hylglucamine) and procaine. In some ments, M can be a lithium, sodium, potassium, or cesium with cryptands or crown ethers, a tetrasubstituted ammonium cation, or phosphonium cation. When X is fluoride, the choice of fluoride source is also readily within the knowledge of one of ordinary skill in the art. A variety of fluoride sources can be used in the ation of the fluorinated aryl and heteroaryl compounds as provided herein, including but not d to NaF, KF, CsF, tetrabutylammonium fluoride, and tetramethylammonium fluoride. In certain instances the choice of fluoride source will depend on the functionality present on the compound of Formula (2).

The methods described above can be useful in the preparation of fluorinated aryl and heteroaryl ring systems. For example, the methods can be used to prepare a compound of Formula (3): ArZ—F wherein Ar2 is an aryl or aryl ring system. In particular, the methods can be used to prepare radiolabeled fluorinated aryl and heteroaryl ring systems (e. g., PET radiotracers). In some embodiments, the method can include reacting in a polar solvent a nd MF and a compound of Formula (2). The polar solvent can then be d from the on mixture. The remaining mixture can then be combined with a nonpolar t and heated to produce a nd of Formula (3).

In some embodiments, the method can include heating a mixture comprising a nonpolar solvent, a compound MF, and a compound of Formula (2).

In some embodiments, the nonpolar solution of the reaction mixture of MF and a compound of Formula (2) can be d prior to heating. The filtration step can remove any insoluble material (e.g., insoluble salts) that remain in the on mixture. In some embodiments, the solvent can be removed from the filtrate prior to heating (i.e., the residue can be heated neat). 24'}42-(}4)43V»"Gi In some embodiments, the nonpolar solution of the reaction mixture of MF and a compound of Formula (2) can be filtered prior to heating, the nonpolar t can be removed (e. g., by evaporation), and the heating of the sample can be performed in a different t.

In some embodiments, contaminant salts are removed from the nonpolar solution of the reaction mixture of MF and a compound of Formula (2) by chromatography. For example, the contaminant salts can be removed by size exclusion, gel filtration, reverse phase, or other chromatographic method prior to heating. 1O In some embodiments, the compound of Formula (3) can be a compound of Formula (6): PL ,P2 wherein each of Pland P2 are independently a nitrogen protecting group, or P1 and P2 come together to form a single nitrogen protecting group; each of P3, and P4 are ndently an l protecting group, or P3 and P4 come together to form a single oxygen protecting group; and P5 is a carboxylic acid protecting group. In some embodiments, the method can include reacting in a polar solvent a compound MF and a compound of Formula (7): PL ,P2 Y 0*” AH/I 0 0P4 wherein Ar1 is an electron rich aryl or heteroaryl ring system; Y is a leaving group; and P1,P2, P3, P4 and P5 are as defined in Formula (6). The polar solvent can then be removed from the reaction mixture. The remaining mixture can then be combined with a nonpolar solvent and heated to produce a compound of a (6).

In some ments, the method can e g a mixture comprising a nonpolar t, a compound MF, and a compound of Formula (7). 24742aflfl43VVCfi In some embodiments, the nonpolar solution of the reaction mixture of MF and a compound of Formula (7) can be filtered prior to heating. The filtration step can remove any insoluble material (e.g., insoluble salts) that remain in the on mixture. In some embodiments, the solvent can be removed from the filtrate prior to heating (i.e., the e can be heated neat).

In some embodiments, contaminant salts are removed from the nonpolar solution of the reaction mixture of MF and a compound of Formula (7) by chromatography. For e, the contaminant salts can be removed by size exclusion, gel filtration, e phase, or other chromatographic method prior to 1O heating.

The compound of Formula (6) can be, for example, P1 P2 F 0 In some embodiments, the compound of Formula (6) is: O O t—Bu\ JL A /t-Bu O N O 24742AGD43WGE In some embodiments, the compound of Formula (7) can be: 0 O t—Bu\OJLNJJ\O,t-Bu Y \\“Hro\ Ar1/i O In some embodiments, the compound of a (7) can be: 0 O t-Bu\OJL N -BU MeOO I O T‘fO The moiety Ar1 can be an electron—rich aryl or heteroaryl ring system. For example, in some embodiments, Arl—H is more easily oxidized than benzene. In some embodiments, Ar1 can be substituted with at least one substituent having a Hammett op value of less than zero (see, for example, “A survey of Hammett substituent constants and resonance and field parameters”, Corwin. Hansch, A. Leo, R. W. Taft Chem. Rev., 1991, 91 (2), pp 165—195). For example, Ar1 can be substituted with at least one of —(C1—C10)alkyl, —(C1-C10)haloalkyl, 0)alkenyl, o)alkynyl, —O—(C1—C10)alkyl, —C(O)—O—(C1-C10)alkyl, aryl, and heteroaryl. In some embodiments, Ar1 is: wherein R1, R2, R3, R4, and R5 are independently chosen from: H, -(C1-C10)alkyl, -(C1— C10)haloalkyl, (C2—C10)alkenyl, (C2—C10)alkynyl, —O—(C1—C10)alkyl, —C(O)—O—(C1— kyl, aryl, and heteroaryl, or two or more of R1, R2, R3, R4, and R5 come together to form a fused aryl or heteroaryl ring system.

In some embodiments, Ar1 is the same as Arz. In some embodiments, Ar1 is more easily oxidized than Arz.

In some embodiments, Ar1 can be substituted with a solid support. A “solid support” may be any suitable solid—phase support which is insoluble in any solvents to 24742.4)043‘93781 be used in the process but which can be covalently bound (e.g., to Ar1 or to an optional linker). Examples of suitable solid supports include polymers such as polystyrene (which may be block d, for example with polyethylene glycol), polyacrylamide, or polypropylene or glass or silicon coated with such a polymer. The solid t may be in the form of small discrete particles such as beads or pins, or as a coating on the inner e of a reaction vessel, for example a cartridge or a microfabricated . See, for example, US. Patent Application No. 2007/0092441.

In some embodiments, the solid support is covalently bound to Ar1 through the use of a linker. A “linker” can be any suitable organic group which serves to space the 1O Ar1 from the solid support structure so as to maximize reactivity. For example, a linker can include a C1_20 alkyl or a C120 alkoxy, attached to the solid support, for example, a resin by an amide ether or a sulphonamide bond for ease of synthesis. The linker may also be a polyethylene glycol (PEG) . Examples of such linkers are well known to those skilled in the art of solid—phase chemistry.

The methods described herein can be used with a variety of aryl and heteroaryl ring systems. As is well understood by one of skill in the art, to carry out efficient nucleophilic substitution of the aryl and heteroaryl ring s described herein, it is necessary that Ar1 be more easily ed (i.e., more electron rich) than Arz. Within that boundary, however, the Ar2 moiety can be any aryl or heteroaryl ring system in which substitution by X (e. g., F such as 18F) is desired. For example, Ar2 can be a phenylalanine, tyrosine, typtophan, or histidine tive, and an estradiol derivative.

In some embodiments, Ar2 can be chosen from: OMe CN MeO OMe Me MN OMe CFs WO 03734 24742-0043WGE }4)43W01 P1 P2 ‘N ’ P \N,P1 2 PL , P2 O‘P5 0‘P5 9“ 0 ”\w 0 \ 34/ \ N N \P6 \P6 PLN’PZ PLN’PZ P’LN’PZ P5 0‘ P5 0\ 0 O O ‘5 \ \ N N ‘P6 3% \PS N‘ps ""‘\N P1\ l P2 PLN’PZ PLN’PZ 45‘" N N\ N\ \PB P6 P6 PLN’PZ P1\N,P2 PLN/Pz fl: \ \ N N ‘PB N‘ “a ‘P6 6 / P .M’" 24742434343wo: PL [P2 P1 P2 P1 P2 N \N/ \N/ \ \ \ \ \ \ O o o N\ N N 6 ‘ ‘ P 6 6 ”h P P PL / p1 1 2 N \N'P2 p1 [p2 N P\N’P P —07 pkg P7—0 P7-o 0P3 0P3 3‘; 0P3 0P3 OP4 ”.W P\N,P1 2 PL ,P2 N o ‘31? ‘5 \ 0177: 0P3 0P3 0P4 CN <\ \ N \\ is: P4_O P4_O J\IW wherein each of P1, P2 and P6 are independently a nitrogen protecting group, or P1 and P2 come together to form a single en protecting group; and each of P3, P4, P5 and P7 are independently an oxygen protecting group, or P3 and P4 come together to form 2012/044954 24742AGQ43WOE a single oxygen ting group. In some ments, Ar2 is an electron rich aryl or heteroaryl ring system.

Protecting groups can be a temporary substituent which protects a ially reactive functional group from undesired chemical transformations. The choice of the particular protecting group employed is well within the skill of one of ordinary skill in the art. A number of considerations can determine the choice of protecting group including, but not limited to, the functional group being protected, other functionality present in the molecule, on conditions at each step of the synthetic ce, other protecting groups present in the molecule, functional group tolerance to 1O conditions required to remove the protecting group, and reaction conditions for the thermal decomposition of the compounds provided herein. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2.sup.nd ed.; Wiley: New York, 1991).

A nitrogen protecting group can be any temporary substituent which protects an amine moiety from undesired chemical transformations. Examples of such protecting groups e, but are not limited to allylamine, benzylamines (e.g., bezylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine, and tritylamine), acetylamide, trichloroacetammide, trifluoroacetamide, pentenamide, phthalimides, carbamates (e.g., methyl carbamate, t-butyl carbamate, benzyl carbamate, allyl carbamates, 2,2,2-trichloroethyl carbamate, and enylmethyl carbamate), imines, and amides (e. g., benzene sulfonamide, p-toluenesulfonamide, and p— nitrobenzenesulfonamide).

An oxygen protecting group can be any temporary substituent which protects a hydroxyl moiety from undesired al ormations. Examples of such protecting groups include, but are not limited to esters (e.g., acetyl, t—butyl carbonyl, and benzoyl), benzyl (e. g., benzyl, p-methoxybenzyl, and 2,4-dimethoxybenzyl, and trityl), ates (e. g., methyl carbonate, allyl carbonate, 2,2,2-trichloroethyl carbonate and benzyl carbonate) ketals, and acetals, and ethers. 24742412433705.

In some embodiments, a compound of Formula (2), as provided herein, can be chosen from: PLN,P2 PLN,P2 PLNlpz O\ 0‘ T P5 P5 0‘ T P5 /| 0 /| O Ar1 Ar1 0 OP3 Ark OP4 0P4 4/ OP4 P1\N,P2 PLN,P2 P2\N’P1 /| O O O Ar1 |\Ar1 0P3 OP3 0P3 Y/kAH wherein: each of Pland P2 are ndently a nitrogen protecting group, or P1 and P2 come together to form a single nitrogen protecting group; each of P3 and P4 are independently an oxygen protecting group, or P3 and P4 come er to form a single oxygen protecting group, and P5 is a carboxylic acid protecting group. For example, a compound of Formula (2) can be: PL ,P2 T P5 Ar1/I 0 In some embodiments, a nd of Formula (2) can be: t-Bu\ i i -Bu 0 N CA 1 \“‘S(O\ Arl/I O 24742:0043VVC£ In some embodiments, a compound of Formula (2) can be: 0 O t'Bu\OJJ\NJJ\O/t-Bu M90O E | O In some embodiments, a nd of Formula (2) is chosen from: / / O I I \ Y \ Y Y N \ I N Q ' % l\ \ |\Ar1 |\Ar1 0 Ar1 ON CN 3 S RN ’—<\N \ \ ’N Y / | <\N \ Y \ \ T \ |\Ar1 \ |\Ar1 \ |\Ar1 ON ON ON In other embodiments, a compound of Formula (2) is chosen from: Ar1/| P4—o P4-o Y/ \Ar1 wherein: each of P3 and P4 are independently an alcohol protecting group. 247424M43WG1 In some embodiments, a compound of Formula (1) or Formula (3) can be chosen from: P1N PLN ,P ISCWélLSW (an? :95: wherein each of P1and P2 are independently a nitrogen protecting group, or P1 and P2 come together to form a single en protecting group; and each of P3 and P4 are independently an alcohol protecting group, or P3 and P4 come together to form a single oxygen protecting group, and P5 is a carboxylic acid protecting group. For examples, a compound of Formula (1) or Formula (3) can be: P ,P2 o\P5 F 0 In some embodiments, a nd of Formula (1) or Formula (3) can be: t—Bu\OJOL ftN O,t—Bu \\‘\S(O\ F O 24742aflfl43VVCfi In some embodiments, a compound of Formula (1) or Formula (3) can be: [“2 H2 F O In some embodiments, a compound of Formula (1) or Formula (3) can be chosen from: Q Q F F ON CN S ’4 \ <\N \ ,N N % F § F % F ON ON ON In some embodiments, a compound of Formula (1) or Formula (3) is chosen from: Pit—O P4—o F wherein each of P3 and P4 are independently an alcohol protecting group.

A nonpolar solvent can be any solvent having a dielectric constant of less than about 10. For example, a nonpolar solvent can be chosen from e, toluene, 0— xylene, m-xylene, p-xylene, ethyl benzene, carbon tetrachloride, hexane, cyclohexane, enzene, chlorobenzene, nitrobenzene, and mixtures f. In some embodiments, the nonpolar solvent ses benzene. In some embodiments, the nonpolar solvent comprises toluene. In some embodiments, the ar solvent WO 03734 24742004333105. ses cyclohexane. In some embodiments the nonpolar solvent is a mixture, for example a mixture of exane and toluene.

A polar solvent is a solvent having a dielectric constant greater than about 10.

In some embodiments, the polar solvent is a polar aprotic solvent, such as acetonitrile, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, 1,2- difluorobenzene, benzotrifluoride, and mixtures thereof. In some embodiments, the polar c solvent is acetonitrile.

Heating can be accomplished by conventional means (e. g., heating bath, oven, heat gun, hot plate, Bunsen , heating mantle, and the like), by the use of a ave, or by flash pyrolysis. Typically, the reaction mixture is heated at a temperature ranging from about 25° C to about 250° C (e. g., between about 80° C to about 200° C, 100° C to about 200° C, about 120° C to about 170° C, about 120° C to about 160° C, about 120° C to about 150° C, and about 130° C to about 150° C). In some embodiments, the reaction mixture is heated to about 140 °C. Heating can occur for any time necessary to complete the reaction. For example, g can occur for from about 1 second to about 25 s (e.g., about 2 seconds, about 5 seconds, about 10 seconds, about 30 seconds, about 1 minute, about 90 s, about 2 minutes, about 3 minutes, about 5 minutes, about 8 minutes, about 10 minutes, about 12 minutes, about 15 minutes, about 20 minutes, and about 24 minutes). In some embodiments, heating can occur for from about 1 second to about 15 minutes.

Further provided herein is a method of making a compound of Formula (1) that includes heating a mixture comprising a nonpolar solvent and a compound of Formula (5): wherein Ar1 is an electron rich aryl or heteroaryl ring system; and Ar2 and X are as defined for Formula (1). In some embodiments, the method can include filtering the mixture prior to heating. Filtering, as described above, can remove insoluble materials such as insoluble salts. In another embodiment, the method can include, prior to heating, filtering the mixture, removing the nonpolar solvent, and subsequently g a solution of the remaining reaction e and a polar t.

In some embodiments, contaminant salts are removed from the nonpolar solution of a compound of Formula (5) by chromatography. For example, the 24742AGG43WGE contaminant salts can be removed by size exclusion, gel filtration, e phase, or other chromatographic method prior to heating.

As described above, the methods described herein can be used to prepare ated (e. g., 18F) aryl and heteroaryl ring systems. Accordingly, further provided herein is a method for making a compound of Formula (3) that includes heating a mixture comprising a nonpolar t and a compound of Formula (4): Ar1—I: n Ar1 is an electron rich aryl or heteroaryl ring system; and Ar2 is as defined for Formula (3). In some embodiments, the method can include filtering the mixture prior to heating. Filtering, as bed above, can remove insoluble materials such as insoluble salts. In another embodiment, the method can include, prior to heating, filtering the mixture, removing the nonpolar solvent, and subsequently heating a solution of the remaining reaction mixture and a polar solvent.

In some embodiments, contaminant salts are removed from the nonpolar solution a nd of Formula (4) by chromatography. In some embodiments, a relatively mild chromatographic desalting technique is used. For example, size exclusion chromatography (also referred to as gel ion) can provide a reliable means to separate diaryliodonium salts from the contaminating inorganic (e.g., sodium or potassium carbonate, bicarbonate, hydroxide, or triflate) or organic (e.g., tetraalkylammonium, cryptand complexes of alkalai metal ions) salts that can contaminate radiochemical ations. Removal of these contaminant salts can assist in increasing the yield of the uorination of this substrate class.

In the methods described herein, a pressure tube or other reinforced closed system can be used in instances where the desired temperature is above the boiling point of the solvent utilized.

The reaction can be conducted in the presence of an inert gas such as en or argon. In some embodiments, steps are taken to remove oxygen and/or water from the reaction solvent and starting materials. This can be accomplished by a number of s including distillation of solvents in the ce of agents that react with and/or sequester water and under an atmosphere of inert gas; and purging the reaction vessel with an inert gas.

The methods described herein can be used when MX (e. g., MP) is reacted in an amount g from about 1 picomole to about 10 millimoles (e.g., about 1 GD43WGE picomole to about 5 oles; about 1 le to about 1 millimole; about 1 picomole to about 500 micromoles; about 1 picomole to about 100 micromoles; about 1 picomole to about 50 micromoles; about 1 picomole to about 5 micromoles; about 1 picomole to about 1 micromole; about 1 picomole to about 500 les; about 1 picomole to about 100 nanomoles; about 1 picomole to about 50 nanomoles; about 1 picomole to about 5 nanomoles; about 1 picomole to about 1 nanomole; about 100 picomoles to about 10 millimoles; about 500 picomoles to about 10 millimoles; about 1 nanomole to about 10 oles; about 50 nanomoles to about 10 millimoles; about 100 nanomoles to about 10 millimoles; about 500 nanomoles to about 10 millimoles; about 1 micromole to about 10 millimoles; about 50 micromoles to about 10 millimoles; about 100 oles to about 10 millimoles; about 500 micromoles to about 10 millimoles and about 1 millimole to about 10 millimoles). In some embodiments, MX is reacted in the sample in an amount of less than about 10 millimoles. In many cases, the compound of Formula (2) is used in an excess when compared to the amount of MX present in the sample. In some embodiments, the reaction mixture having MX further contains additional compounds which may be present in an excess compared to MX. For example, the onal compounds may be present in more than one n fold excess compared to MX.

Compounds Diaryliodonium compounds, for example, compound of Formula (2), (4), (7) and (8), are further provided . For example, a compound of Formula (8) is provided, wherein Ar1 is an electron rich aryl or heteroaryl ring system; each of Pland P2 are independently a nitrogen protecting group, or P1 and P2 come together to form a single nitrogen protecting group; each of P3, and P4 are ndently an alcohol protecting group, or P3 and P4 come together to form a single oxygen protecting 247424fl343WGi group; and P5 is a carboxylic acid ting group. In some embodiments, the compound of Formula (8) can be: 0 O t-BU\OJLNJJ\O/t_Bu M600 5 1' 0 The diaryliodonium compounds of Formula (2), (4) and (7) can be prepared from commercially available starting materials using various methods known to those of ordinary skill in the art. The method used for synthesizing the compounds will depend on the electronics and functionality present in ofArz. Potentially reactive onal groups present in Ar2 can be masked using a protecting group prior to the synthesis of the iodonium compound. The particular method employed for preparing the diaryliodonium nds will be readily apparent to a person of ordinary skill in the art. For example, the compounds can be made using the following generic reactions as shown in Scheme 2. 24742.4)043‘93701 Scheme 2. r r Arl—I + HY + Ar2-H —..> Ar1—I—Ar2 | COHdItIOhS Y T Arl—H + Arz—I —..> Ar1—I—Ar2 + HY | ions r r Arl—I + W + Ar2-M —..> Ar1—I—Ar2 I COHdItIOflS r r Arl—M + Arz—l —> Ar1—I—Ar2 + W | conditions For compounds that bear sensitive functionality on the accepting group, organometallic reagents that e more covalent (more ) C—M bonds can be used. For example, organometallic compounds including tin, boron, and zinc. If there is no functional group incompatibility, more basic organometallic reagents (organolithium, Grignard, etc.) can be used to prepare the diaryliodonium salts.

Persons skilled in the art will be aware of variations of, and alternatives to, the processes described which allow the compounds defined herein to be obtained.

It will also be appreciated by s skilled in the art that, within certain of the processes described, the order of the synthetic steps ed may be varied and will depend inter alia on s such as the nature of other functional groups present in a ular substrate, the availability of key intermediates, and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps.

The skilled person will appreciate that the diaryliodonium compounds described could be made by methods other than those herein described, by adaptation of the methods herein described and/or tion of methods known in the art, for example US 2007/0092441, or using standard textbooks such as "Comprehensive Organic Transformations--A Guide to Functional Group Transformations", R C Larock, Wiley—VCH (1999 or later editions) and Science of Synthesis, Volume 3 la, 2007 n—Weyl, Thieme) It is to be understood that the synthetic transformation methods mentioned herein are exemplary only and they may be carried out in various different sequences in order that the desired compounds can be efficiently assembled. The skilled chemist 24'}424}043W01 will exercise his judgment and skill as to the most efficient sequence of reactions for synthesis of a given target compound.

As exemplified in the examples below, certain diaryliodonium es can be ed by H2SO4 zed electrophilic aromatic substitution of the aromatic fluorine precursor with ArI(OAc)2, ed by ion exchange. The desired diaryliodonium fluoride is formed by reacting the resulting diaryliodonium salt with a fluoride source, such as tetrabutylammonium fluoride, as illustrated in Scheme 3 shown below.

Scheme 3. 1. ArI(OAc)2 x9 Catalytic H2804 2. IonExchange/[j/fiB\© TBAF F\© R —I;II/©/ Diaryliodonium fluorides can also be prepared by the reaction of the corresponding tributylstannanyl derivative of the aromatic fluorine precursor with p- MeOPhI(OH)(OTs), ed by ion exchange, and reaction of the resulting diaryliodonium salt with a fluoride source, such as tetrabutylammonium fluoride, as illustrated in Scheme 4.

Scheme 4. 1. p-(MeOPh| OH)()(OAc) '7 ROSH(BU)—>3 2. Ion Exchange ROI00mTBAF ROIOOMe The choice of fluoride source is readily within the knowledge of one of ordinary skill in the art. A variety of fluoride sources can be used in the preparation of the diaryliodonium fluorides as provided herein, including but not limited to NaF, KF, CsF, tetrabutylammonium e, and tetramethylammonium fluoride. In certain instances the choice of fluoride source will depend on the functionality present on the ic fluoride precursor. r ed are compounds of Formula (1) and a (3) which are prepared by the methods described herein. For e, a compound of Formula (6) is provided, wherein the compound is prepared as described above.

Also provided herein are kits and devices. Typically, a kit or device is used to prepare and/or administer a compound of Formula (1) or Formula (3) as provided 04)43V\fۤi herein. In some ments, the kit or device is used to e a compound of Formula (1) or Formula (3) and incorporates a chromatographic desalting step prior to heating the eluted solution comprising the on product of MX and a compound of Formula (2). In some embodiments, a kit or device can include one or more delivery systems, e. g., for a nd of Formula (1) or Formula (3), and directions for use of the kit (e.g., instructions for administering to a subject). In some embodiments, the kit or device can include a compound of Formula (1) or Formula (3) and a label that indicates that the ts are to be administered to a subject prior to PET imaging. 1O EXAMPLES General Methods.

Tetramethylammonium fluoride (TMAF, Aldrich) and diphenyliodonium nitrate were dried at 60-80° C in a drying pistol (charged with P205) under dynamic vacuum for one week. Hexabutylditin and tributyltin chloride (Aldrich) were distilled into flame—dried storage tubes under dry nitrogen. Acetonitrile and acetonitrile-d3 were refluxed with P205, benzene and benzene-d6 were refluxed with CaHz, overnight and distilled directly into flame-dried storage tubes under dry nitrogen. All glassware, es, and NMR tubes were oven dried (140° C) for more than 24 hours before they were transferred into the glove box for use. All other reagents were purchased from commercial sources and were used as received. All NMR experiments were performed using a Bruker Avance 400 MHz NMR spectrometer.

Example I - Preparation ofp-methoxyphenyfiodoniam diacetate p-methoxyphenyliodonium diacetate: 2.34 g (10 mmol) p—iodoanisole was dissolved in 90 mL of glacial acetic acid. The solution was stirred, heated to 40° C and 13.6 g (110 mmol) sodium perborate tetrahydrate was added gradually over an hour. The reaction mixture was kept at 40° C for 8 hours before being cooled to room temperature. Half of the acetic acid (~45 mL) was removed and 100 mL of DI. water was added. 3 X 40 mL romethane was used to t the aqueous solution.

The combined organic layers were dried over sodium sulfate and solvent was evaporated to give 2.25 g (64%) of p—methoxyiodonium diacetate, which was dried in vacuo and used without r purification. o-methoxyphenyliodonium diacetate (65%), m—cyanohenyliodonium diacetate (70%), m—trifluoromethyliodnium ate (80%), and 2,6—dimethoxyphenyliodoniu diacetate (83%) were synthesized using a similar procedure from corresponding iodoarenes. 04333701 Example 2 - Preparation ofbism-methoxyphenyl)iodoniam triflaoroacetate Bis(p-methoxyphenyl)iodonium trifluoroacetate: Under N2 protection, 1.41 g (4 mmol) p—methoxyphenyliodonium diacetate was dissolved in 30 mL of dry dichloromethane and the solution was cooled to —30° C. 0.61 mL (8 mmol) of trifluoroacetic acid was added and the solution was slowly brought back to room temperature and stirred for 30 minutes. The on was, again, cooled to —30° C and 0.44 mL (4 mmol) anisole was added slowly and the mixture was warmed back up to room temperature and d for 1 hour. The solvent was evaporated and the residual solid was tallized from diethylether/dichloromethane to give 1.53 g bis(p— 1O methoxyphenyl)iodonium trifluoroacetate (71%).

Example 3 - Preparation ofBiSQD-methoxyphenyl)iodonz'am tosylate Bis(p—methoxyphenyl)iodonium tosylate: Under N2 protection, 352 mg (1 mmol) p—methoxyphenyliodonium diacetate was dissolved in 1.5 mL of dry itrile. The solution was combined with a solution of 190 mg (1 mmol)tosy1ic acid monohydrate in 1.5 mL of dry acetonitrile. After addition of 0.11 mL (1 mmol) p-iodoanisole, the mixture was allowed to react at room temperature for 2 hours. The t was then removed and the remaining solid was recrystallized from diethylether/dichloromethane to give 422 mg bis(p-methoxyphenyl)iodonium tosylate (82%).

Example 4 - Preparation ofBisay—methoxyphenyl)iodoniam hexaflaorophosphate Bis(p—methoxyphenyl)iodonium hexafluorophosphate: Under N2 protection, 352 mg (1 mmol) p-methoxyphenyliodonium diacetate was dissolved in 1.5 mL of dry acetonitrile. The solution was combined with a solution of 190 mg (1 mmol) c acid monohydrate in 1.5 mL of dry itrile. After addition of 0. 11 mL (1 mmol) p-iodoanisole, the mixture was allowed to react at room temperature for 2 hours. 10 mL of water was added to the reaction mixture followed by extraction with 3 X 5 mL hexanes. The water layer was treated with 502 mg (3 mmol) NaPF6. The white precipitation was taken up in dichloromethane and recrystallization with diethylether/dichloromethane provided 391 mg bis(p-methoxyphenyl)iodonium hexafluorophosphate (80.5%). 90433785.

Example 5 - Preparation ofPhenyl—4-methoxypltenyliodoniam hexaflaorophosphate Phenylmethoxyphenyliodonium hexafluorophosphate was synthesized ing to the procedure described for the synthesis of bis(p— methoxyphenyl)iodonium orophosphate from the corresponding aryliodonium diacetate and e. (77.9%) Example 6 - Preparation of2-methoxyplzenyl—4 ’-metlzoxyphenyliodoniam hexaflaorophosphate 2-methoxypheny1-4’-methoxyphenyliodonium hexafluorophosphate was 1O synthesized ing to the procedure described for the synthesis of bis(p— methoxyphenyl)iodonium hexafluorophosphate from the corresponding aryliodonium diacetate and anisole. ) Example 7 - Preparation of3-cyanoplzenyl—4 ’—methoxyphenyliodoniam kexafluorophosphate 3-cyanopheny1-4’-methoxyphenyliodonium hexafluorophosphate was synthesized according to the procedure described for the synthesis of bis(pmethoxyphenyl )iodonium hexafluorophosphate from the corresponding aryliodonium ate and anisole. (73.7%) Example 8 — Preparation of3-(trz’fluoromethy0phenyl—4 ’-methoxyphenyliodonium hexaflaorophosphate 3 -(trifluoromethyl)pheny1—4’ —methoxyphenyliodonium hexafluorophosphate was synthesized according to the ure described for the synthesis of bis(p— methoxyphenyl)iodonium hexafluorophosphate from the corresponding aryliodonium diacetate and anisole. (96.1%) Example 9 - Preparation of2, 6-dimethoxyphenyl—4 ’-methoxyphenyliodoniam hexaflaorophosphate 2,6-dimethoxyphenyl-4’-methoxypheny1iodonium hexafluorophosphate was synthesized according to the procedure described for the synthesis of bis(p— methoxyphenyl)iodonium hexafluorophosphate from the corresponding aryliodonium diacetate and anisole. (86%) 2012/044954 24742411435705. e 10 - Preparation 0f2-Br0m0-4, 5—dimethoxylbenzeneethanamine 2-Bromo-4, 5-dimethoxylbenzeneethanamine: Bromine (1.1 mL, 22 mmol) in acetic acid (10 mL) was slowly added into a vigorously stirred solution of 2—(3,4— dimethoxyphenyl)ethylamine (3.4 mL, 20 mmol) in 50 mL acetic acid. 2-bromo—4, 5— dimethoxylbenzeneethanamine precipitated out after 15 minutes. The mixture was stirred for another two hours, filtered, and washed with dichloromethane 10 mL X 3 and petroleum ether 10 mL X 3. The resulting solid was taken up in water and the pH was brought to 10 with aqueous KOH solution. Extraction with romethane followed by evaporation of the solvent yielded 4.12 g (78%) 2-Bromo—4, 5— 1O dimethoxylbenzeneethanamine. The crude product was dried under dynamic vacuum ght and used without further purification.

Example 11 - Preparation 0f2—Br0m0-4, 5—dz'meth0xyl—(2-phthalimidoethybbenzene 2—Bromo-4, 5-dimethoxyl-(2-phthalimidoethy1)benzene: 2-Bromo-4, 5- oxylbenzeneethanamine (3.5 g 13.2 mmol) was dissolved and stirred in 50 mL dry acetonitrile. 2.14 mL (1.1 equiv) phthaloyl dichloride and 7 mL(3 equiv) Hfinig’s base were added. The mixture was stirred at room temperature overnight. Acetonitrile was then removed, and the remaining product was taken up in dichloromethane and washed with basic water (pH=11). The aqueous wash was ted with romethane 3 X 15 mL. The organic fractions were combined and dried over sodium sulfate. Solvent was removed to give the crude product, which was then purified by column chromatography. Calculated yield: 1.8g (34%).

Example 12 - Preparation of3, 4-dimeth0xyphenyllribalyltin 3,4-dimethoxyphenyltributyltin: Under N2 protection, 1.085 g (5 mmol) 4— eratrole and 289 mg (5 mol%) Pd(0)(PPh3)4 was dissolved in 15 mL of dry toluene, the solution was transferred into a e tube equipped with a Teflon Chemcap Seal, and 3.19 g (5 mmol) hexabutylditin was added. The tube was sealed, heated to, and kept at 1200 C for 48 hours. The reaction mixture was allowed to cool to room temperature, and diluted with 15 mL hexane. 15 mL of saturated aqueous KF solution was added and the mixture was stirred for 30 minutes followed by filtration h celite. The organic layer was separated; t was d to provide the crude product as a yellow oil. The crude was purified by column chromatography (hexane/dichloromethane 98/2, basic aluminum) to give 1.69 g (79.1%) pure 3,4— dimethoxyphenyltributyltin.

WO 03734 24742004333705.

Example 13 - Preparation of3, 4-dimethoxy—Z-methylphenyltribalyltin 3,4-dimethoxymethylphenyltributyltin was synthesized in a r fashion as described in the procedure for the synthesis of 3,4—dimethoxyphenyltributyltin from the corresponding bromo precursor. (76.2%) Example 14 - Preparation of3, 4-dimeth0xy—2—(2-phthalimid0)phenyltribatyltin 3,4-dimethoxy(2-phthalimido)phenyltributyltin was synthesized in a similar n as described in the ure for the synthesis of 3,4— dimethoxyphenyltributyltin from the corresponding bromo precursor. (20%) Example 15 - 3,4-a’imeth0xyphenyl—4 ’-mezh0xyphenyli0d0niam orophosplzate 3 ,4-dimethoxyphenyl-4’ -methoxyphenyliodonium hexafluorophosphate: Under N2 protection, 352 mg (1 mmol) p—methoxyphenyliodonium ate was dissolved in 1.5 mL of dry acetonitrile. The on was combined with a solution of 190 mg (1 mmol) tosylic acid monohydrate in 1.5 mL of dry acetonitrile. After addition of 427 mg(l mmol) 3,4-dimethoxyphenyltributyltin, the mixture was allowed to react at room temperature for 2 hours. 10 mL of water was added to the reaction mixture followed by extraction with 3 X 5 mL hexanes. The water layer was treated with 502 mg (3 mmol) NaPF6. The white precipitation was taken up in romethane and recrystallization with diethylether/dichloromethane provided 370 mg (71.7%) 3,4—dimethoxyphenyl—4’—methoxyphenyliodonium hexafluorophosphate.

Example I 6 - Preparation of 3, 4-dimeth0xy—2-melkylphenyl—4 ’- methoxyphenyliodoniam hexafluorophosphale 3,4-dimethoxymethylphenyl—4’—methoxyphenyliodonium hexafluorophosphate was synthesized in a similar fashion as 3,4-dimethoxyphenyl-4’— methoxyphenyliodonium hexafluorophosphate from p-methoxyphenyliodonium diacetate and the corresponding aryl tin precursor. (75%) 24742AGD43W81 Example I 7 - Preparation of 3, 4-dimethoxy—2—(2-phthalimidoethprhenyl-4 ’- methoxyphenyliodoniam hexaflaorophosphate 3,4-dimethoxy(2-phthalimidoethyl)phenyl-4’-methoxyphenyliodonium hexafluorophosphate hexafluorophosphate was synthesized in a r fashion as 3,4— dimethoxyphenyl-4’-methoxyphenyliodonium hexafluorophosphate from p- methoxyphenyliodonium diacetate and the corresponding aryl tin precursor. (55%) Example 18 - Preparation of2-methoxypnenyl—4 ’-metlzoxyphenyliodoniamfluoride 2-methoxyphenyl-4’-methoxyphenyliodonium fluoride: Under N2 protection, 1O 97.2 mg (0.2 mmol) 2-methoxyphenyl-4’—methoxyphenyliodonium hexafluorophosphate and 17.7 mg (0.95 equiv) anhydrous tetramethylammonium fluoride (TMAF) were dissolved in 1 mL dry acetonitrile. The solvent was removed in vacuo followed by addition of 5 mL of dry benzene. The insoluble TMAPF6 was removed by filtration; the t was again removed in vacao to give 30.3 mg (42%) oxyphenyl—4’ -methoxyphenyliodonium fluoride.

Example 19 - Preparation ofPlzenyl—4-methoxyphenyliodoniamfluoride Phenylmethoxyphenyliodonium fluoride was synthesized in a r n as the procedure described for 2-methoxyphenyl-4’-methoxyphenyliodonium e from corresponding hexafluorophosphate. (96%) Example 20 - Preparation of3-cyanophenyl—4 ’-methoxyphenyliodoniumfluoride 3-cyanophenyl—4’—methoxyphenyliodonium fluoride was synthesized in a similar fashion as the procedure described for 2-methoxyphenyl-4’- methoxyphenyliodonium fluoride from corresponding hexafluorophosphate. (25%) Example 21 - ation rzfluoromethy0phenyl-4 ’-methoxyphenyliodonium fluoride 3-(trifluoromethyl)phenyl-4’-methoxyphenyliodonium fluoride was synthesized in a similar fashion as the procedure described for 2-methoxyphenyl-4’- methoxyphenyliodonium fluoride from ponding hexafluorophosphate. (56%) 24742004333781 Example 22 - Preparation of2, 6-dimethoxyphenyl—4 ’-methoxyphenyliodoniam fluoride 2,6-dimethoxyphenyl-4’-methoxyphenyliodonium fluoride was synthesized in a similar fashion as the procedure described for oxyphenyl-4’- methoxyphenyliodonium fluoride from corresponding hexafluorophosphate. (15%) Example 23 - Preparation of3, 4-dimetlzoxyphenyl—4 ’-methoxyphenyliodoniam fluoride 3,4-dimethoxyphenyl-4’-methoxyphenyliodonium fluoride was synthesized in a similar fashion as the procedure described for 2—methoxyphenyl-4’- methoxyphenyliodonium fluoride from corresponding hexafluorophosphate. (90%) Example 24 - ation of3, 4—dimetlzoxy—2—methylphenyl—4 ’- methoxyphenyliodoniamfluoride 3,4—dimethoxy-Z-methylphenyl-4’—methoxyphenyliodonium fluoride was synthesized in a r fashion as the procedure described for 2-methoxyphenyl-4’- methoxyphenyliodonium fluoride from corresponding hexafluorophosphate. (80%) Example 25 - Preparation of3, 4-dimethoxy-Z-(Z—phthalimidoethprlzenyl-4 ’- methoxyphenyliodoniamfluoride 3,4-dimethoxy—Z—(Z—phthalimidoethyl)phenyl-4’-methoxyphenyliodonium fluoride was synthesized in a similar fashion as the procedure described for 2— methoxyphenyl—4’—methoxyphenyliodonium fluoride from corresponding hexafluorophosphate. (45%) Example 26 - Preparation ofBis(p-methoxyphenyl)ioa’oniamfluoride Bis(p-methoxyphenyl)iodonium fluoride: To a mixture of 454 mg (1 mmol) methoxyphenyl)iodonium trifluoroacetate and 262 mg ) anhydrous TBAF was added 1 mL of dry tetrahydrofuran (THF). The on was allowed to stand for lhour, the white precipitate was collected and washed with 3 X 0.5 mL THF.

Calculated yield: 288.7mg (80.2%) 24742-04Il43WOi Example 27 - Diaryliodoniumfluoride decomposition In a glove box, 0.5 mL dry d6—benzene was added to 0.02 mmol of the diaryliodonium fluoride, the solution/mixture was transferred to a J-Young NMR tube. The tube was heated to and kept at 1400 C for 5 -15 minutes. The resulting solution was analyzed by NMR and GC for product determination.

Observed yields of thermal ositions of the iodonium fluorides prepared above are described in Table l. 24'}424’}043W01 Table 1.

I Yield of total Entry Diaryliodonium fluoride fluoro Yield of ArF Conditions aromatics benzene MGM)0 0 5744804)0 0 ’ 140°C,15min acetonitrile 650074)0 0 4047040 0 1400015000 0 0 e, 99 A0 (94)AD 86 4”" (80)4’)0 0 140°C, 18min acetonitrile 43 A0(38)A00 0 43 “3 8 4’)0 0 140°C, 18min benzene 82 A)(80 4’)0 0 49 “48 4’)0 0 ’ 140°C, 15min acetonitrile 60 A0(58 A0)0 0 40 A0(38A0)0 0 140°C, 15min 4? A0(44A0)0 0 19A0(17A0)0 0 9 140°C, 15min benzene 89A0(90A0)0 0 89A0(90A0)0 0 ’ 140°C 5 in itrile 78A0 (77A0)0 0 78A0(77 A0)0 0 140°C 5min I benzene 95 A0( 92 A0)0 0 85 A0(84)A0)0 0 ’ 140°C, 10min acetonitrile 67A0 (76A0)0 0 68 A0(76A0)0 0 140°C, 10min (n0 benzene, fluoroanisole 140°C, 15min detected) 24742004333705. benzene, 140°C, 15min ( ) determined by GC * benzyne chemistry led to the formation of 3—fluoroanisole Examples 28 - Impact ofadditional salts on F—MTEB.

The effect of salt present in solution during the decomposition of (3—cyano—5— ((2—methylthiazolyl)ethynyl)phenyl)(4—methoxyphenyl)iodonium triflate (Ar- MTEB—OTf) was examined at 900 C in benzene and acetonitrile. Each solvent was tested in the absence of salt, presence of 1 equivalent of salt, and presence of 2 equivalents of salt. The preparation of each reaction ion is summarized below.

A TMAF stock solution of 3.3 mg/mL in dry, ed acetonitrile was prepared for on to each reaction tube.

B-OTf Acetonitrile no salt Iodonium triflate precursor (0.004 g, 6.6 umol) was ved in 0.38 mL of dry, degassed acetonitrile, under nitrogen atmosphere, with 18 uL of TMAF (6.6 umol) stock solution. Next, 0.4 mL of dry, degassed benzene was added to the residue and passed twice through 0.22 um PTFE membrane filter. The solution was again subjected to vacuum to remove solvent and the remaining residue was dissolved in 0.4 mL of dry, degassed tonitrile. The reaction mixture was placed in a silicon oil bath and monitored at 90 °C. 24742004333705.

Acetonitrile + 1 eg. TMAOTf Under nitrogen atmosphere, iodonium triflate precursor (0.004 g, 6.6 umol) was dissolved in 0.38 mL dry, degassed d3—acetonitrile, and combined with 18 uL of TMAF (6.6 umol) stock solution. The reaction e was placed in silicon oil bath and monitored at 90° C.

Acetonitrile + 2 eg. TMAOTf Under nitrogen atmosphere, iodonium triflate precursor (0.004g, 6.6 umol) was dissolved in 0.38 mL dry, degassed d3—acetonitrile and combined with 18 ”L of TMAF (6.6 umol) stock solution, with a subsequent addition of tetramethylammonium triflate (0.0015g, 6.6 umol) to the reaction mixture. The solution was then placed in a n oil bath and monitored at 90° C.

Benzene no salt Under nitrogen atmosphere, iodonium triflate precursor g, 6.6 umol) was dissolved in 0.38 mL dry degassed acetonitrile and ed with 18 uL of TMAF (6.6 umol) stock solution. The itrile was removed by vacuum and the remaining residue was redissolved in 0.4 mL dry, ed d6-benzene. The solution was passed twice through 0.22 pm PTFE filter, sealed under nitrogen, and monitored in silicon oil bath at 90° C.

Benzene + 1 eg. TMAOTf Under nitrogen atmosphere, um triflate precursor (0.004g, 6.6 umol) was dissolved in 0.38 mL dry, degassed acetonitrile and combined with 18 ”L of TMAF (6.6 umol) stock solution. The acetonitrile was removed by vacuum and the remaining residue was redissolved in 0.4 mL dry, ed d6—benzene. The on mixture was sealed under nitrogen and monitored in silicon oil bath at 90 °C.

Benzene + 2 eg. TMAOTf Under nitrogen atmosphere, iodonium triflate precursor (.004g, 6.6 umol) was dissolved in 0.38 mL dry, degassed d3—acetonitrile and combined with 18 uL of TMAF (6.6 umol) stock solution, with a subsequent addition of tetramethylammonium triflate g, 6.6 umol) to the reaction mixture. The 24742004333705. acetonitrile was removed by vacuum and the remaining residue was redissolved in 0.4 mL d6-benzene. The solution was then placed in a silicon oil bath and monitored at 90 The results of these experiments are shown in FIGs. l and 2. It is clear that added salt has a large negative impact on the yield of the reaction in itrile, but not as significant an impact on the results for the decomposition reaction performed in the nonpolar t benzene. This latter result may be due to the fact that TMAOTf is only sparingly soluble in benzene.

Example 29 — Fluorinations ofradiofluorination ofMTEB under conventional conditions For each reaction the um precursor Ar—MTEB-OTf (2 mg) was vent in 300 uL of either acetonitrile, DMF, or DMSO.

Preparation of Kryptoflx 222/K2CO3 18F source: A mixture of 50—100 11L of H20 with [18F]fluoride + 15 uL of 1 M ch03 (aq) + 800 uL CH3CN was heated for 3 s in a microwave cell at 20 W. The mixture was treated with 800 uL of CH3CN and heated again. Excess solvent was removed under a stream of dry nitrogen at 80° C.

Run 1: A solution of Ar—MTEB—OTf (2 mg) in 300 uL DMF was added to the dried Kryptofix 222/K2CO3 KlgF source and heated in a microwave (50 W, 1.5 min).

No able radiolabeled MTEB was seen by radio-TLC. Additional ave heating for 3 or 6 minutes resulted in no EB.

Run 2: A solution of Ar-MTEB—OTf (2 mg) in 300 uL DMSO was added to the dried Kryptoflx 222/K2CO3 KISF source and heated in a conventional oil bath at 120° C for 15 minutes. No detectable radiolabeled MTEB was seen by radio—TLC.

Further heating for 15 or 30 minutes resulted in the formation of no detectable 18F- MTEB.

For runs 3 and 4, a solution of [18F]TBAF was prepared by addition of TBAOH to the [180]H20 on containing [18F]fluoride. Drying was performed in 24742004333705. vacuo. The resulting solid was treated with 800 uL of CH3CN and dried by heating to 80° C under a stream of dry nitrogen.

Run 3: A solution of Ar-MTEB-OTf (2 mg) in 300 uL DMF was added to the [18F]TBAF and heated in at 150° C oil bath for 15 minutes, 30 minutes, and one hour.

No detectable radiolabeled MTEB was seen by radio—TLC.

Run 6: A solution of Ar—MTEB-OTf (2 mg) in 300 uL DMSO was added to the [18F]TBAF and heated in at 120° C oil bath for 15 minutes, 30 minutes, and one hour. A yield of 6.3% of radiolabeled MTEB was seen by radio—TLC.

Example 30 - Preparation ofI8F—MTEB with salt removal. [18F]TBAF was dried twice with MeCN at 90° C under reduced pressure (-10 mmHg). Ar—MTEB—OTf (2 mg) was ved in MeCN (300 uL) and added to the vial containing the dried [18F]TBAF. The reaction mixture was stirred at 90° C and the MeCN was evaporated under d pressure (- 10 mm Hg). The remaining residue was re-dissolved in 2 mL of dry benzene, passed through 0.22-mm syringe filter, and heated to 100° C for 20 minutes (radiochemical yield (RCY)= ca 70 %, determined by radio-HPLC and radio-TLC) Example 31 - Preparation MTEB with salt removal.

BAF was dried twice with MeCN at 90° C under reduced pressure (—10 mmHg). Ar—MTEB—OTf (2 mg) was ved in MeCN (300 uL) and added to the vial containing the dried [18F]TBAF. The reaction e was stirred at 90° C and the MeCN was evaporated under reduced pressure (-10 mm Hg). The remaining residue was re—dissolved in 2 mL of dry benzene, passed through 0.22—mm syringe filter, and heated to 130° C for 20 minutes (radiochemical yield (RCY)= ca 90 %, determined by radio-HPLC and radio-TLC) 24’}42J)043WGE Example 32 - Preparation ]-6—FIaoro—L-DOPA.

O O t'BuxoiNJJxO/t-Bu MeO\©\ 5 I O Ar—LDOPA-OTf Ar—LDOPA—OTf (2 mg) is dissolved in 300 uL of dry acetonitrile and added to a vial containing dry [18F]TBAF. The solution is warmed to 90° C and the solvent is removed under reduced pressure. Dry toluene (500 uL) is added to the residue and the solution is passed through a 0.22 pm PTFE ne filter and heated (in a sealed vessel) to 130° C for 20 minutes. The solvent is removed under reduced pressure and the residue is treated with 48% HBr (500 uL) and heated at 140° C for 8 minutes to remove the protecting groups. The [18F]F1uoro-L-DOPA is purified by reverse phase chromatography.

Example 33 - Generalprocedurefor the preparation offluorinated aryl amino acids and their derivatives.

The appropriate (4—methoxypheny1)ary1iodoniumtriflate (2—3 mg) is dissolved in 300 uL of dry itrile and added to a vial containing dry [18F]TBAF. The solution is warmed to 90° C and the solvent is removed under reduced pressure. Dry toluene or benzene (500 uL) is added to the e and the solution is passed through a 0.22 pm PTFE membrane filter and heated (in a sealed ) to 130° C for 20 minutes. The solvent is removed under d pressure and the residue is treated with 48% HBr (500 uL) and heated at 140° C for 8 minutes to remove the protecting groups. The [18F]—fluorinated aryl amino acid or tive is purified by reverse phase chromatography.

Example 34 - Preparation 0f6—FZa0r0-L-DOPA.

The precursor Ar—LDOPA—OTf (20 mg) was dissolved in 0.7 mL of dry CD3CN and treated with one equivalent . The solvent was removed and the 2012/044954 24742004333705. residue was dissolved in 0.7 mL of d6—benzene, placed in an NMR tube equipped with a PTFE valve, and heated to 140 0C for 20 minutes. 1H and 19F NMR spectra (FIGs. 3 and 4) indicated that the yield of the reaction was 85% and that the yield of 4- fluoroanisole was approximately 1%.

Example 35 - Deprotection 0f6—FIu0r0-L—DOPA.

The solvent was removed from the reaction mixture containing crude 6-fluoro— L—DOPA (Example 34). The residue was dissolved in 1 mL of 48% aqueous HBr and the solution was heated to 140 °C for 10 minutes. The solution was neutralized with sodium onate and the water was evaporated. 1H and 19F NMR spectra (D20) were identical to the authentic standard, as was confirmed by adding independently obtained 6-fluoro-L-DOPA to the NMR tube.

Example 36 — Contaminant salts removed by size exclusion chromatography To demonstrate the efficacy of this size exclusion chromatography, the following procedure was utilized. A Jordi Gel DVB 100 A column (250 mm) was equilibrated with acetonitrile for 30 minutes prior to injection. Acetonitrile solutions of tris(neopenty1)methylammonium tosylate and bis(4-methoxyphenyl)iodonium fluoride were ed (1 mg/mL) and the two ons were mixed together and stirred for 5 minutes. A 10 uL aliquot of the mixed solution was injected for analysis into the Jordi Gel . The mixture was separated via size—exclusion chromatography under a pressure of 1500 psi, flow rate of 0.7 mL/min, and followed by UV detection. ing elution, bis(4-methoxypheny1)iodonium fluoride showed a retention time of 10.26 minutes eopentyl)methy1ammonium tosylate showed a retention time of 11.87 minutes. The identity of the eluted materials was confirmed by ng the retention times to those of purified standards.

The HPLC chromatogram demonstrates that the tetraalkylammonium tosylates can be removed cleanly from diaryliodonium fluorides using this technique. It should be emphasized that this is a particularly challenging example of a separation, since this chromatographic technique works by entiating the solutes in terms of their l size. Here the iodonium salt is only slightly larger than the tetraalkylammonium te contaminant. In order to synthesize radiotracers from 24742AK’M4SWOE iodonium salts, the precursors of interest will be significantly larger than in the example given here, and the competing anions will generally be r than tosylate.

A number of embodiments of the invention have been described.

Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims (30)

WHAT IS CLAIMED IS:

1. A method for making a compound of Formula (3): ArZ—F wherein: Ar2 is a substituted or unsubstituted aryl or heteroaryl ring system; and F is a radioactive isotope of fluorine; the method comprising: a) first reacting in a polar solvent a compound MF, wherein M is a counter ion and F is a radioactive isotope of fluorine, and a compound of a (2): A 1——Ir wherein: ArI is a tuted or unsubstituted electron rich aryl or heteroaryl ring system; Y is a leaving group; and Ar2 is as defined above; b) ng contaminant salts from the solution comprising the reaction product ofMF and the compound of Formula (2) of step a) by chromatography; and c) heating the eluted on of step b) comprising the reaction product of MF and the compound of Formula (2) of step a) to prepare the compound of Formula (3).

2. A method for making a compound of a (3): Arz—F wherein: Ar2 is a substituted or unsubstituted aryl or heteroaryl ring system; and F is a radioactive isotope of fluorine; the method comprising: a) first ng in a ar solvent a compound MF, n M is a counter ion and F is a radioactive isotope of fluorine, and a compound of Formula (2): Ar1-|/ wherein: Arl is a substituted or unsubstituted electron rich aryl or heteroaryl ring system; Y is a leaving group; and Ar2 is as defined above; b) removing contaminant salts from the solution comprising the reaction product ofMP and the compound ofFormula (2) of step a) by chromatography; and c) g the eluted solution of step b) comprising the reaction product of MF and the compound of Formula (2) of step a) to prepare the compound of Formula (3).

. The method of any one of claims 1 and 2, wherein Arl is substituted with at least one substituent having'a Hammett 61, value of less than zero.

. The method of claim 3, wherein the substituent is selected from the group ting of ~(C1- C10)alkyl, ~(C1—C10)haloalkyl, (Cg—Clo)alkenyl, (Cg-Clo)alkynyl, —O—(C1—C10)alkyl, —C(O)—O— (C1—C10)alkyl, aryl, and aryl.

. The method of any one of claims 1-4, wherein Ar1 and Ar2 are the same.

. The method of any one of claims 1 and 2, wherein Arl is: wherein: R1, R2, R3, R4, and R5 are independently selected from the group consisting of : H, -(C1— C10)alkyl, -(C1-Cio)haloalkyl, (C2—C10)alkenyl, (C2—C1o)alkynyl, -O—(C1—C10)alkyl, -C(O)— O—(C1-C10)alkyl, aryl, and heteroaryl, or two or more of R1, R2, R3, R4, and R5 come together, with the carbon atoms to which they are bound, to form a fused aryl or heteroaryl ring system.

7. The method any one of claims 1—4, wherein Ar2 is selected from the group consisting of: a phenylalanine, tyrosine, phan, histidine, and an estradiol.

8. The method of any one of claims 1—4, wherein Ar2 is selected from the group consisting of: OMe CN MeO OMe OMe CFa N, N \P5 \P5 25‘ o \x 0 0 0P3 /E OP4 0P4 0P4 , , 2 P1 2 P1\N’P2 N P5 O\P5 O\ o 0 F) a: 0 0P3 0P3 0P3 , . ’ Pl ,P2 Pl P2 1 \ (P N N/ 0 0\ \P5 P5 \g 0 0 0 , ’ I a lN’P2 1 P2 1 \ /P2 N \N/ O o\ \P5 P5 0 O / N / ‘9? N_.// N [5* 0P3 Pg 6/ P 0P4 1 \ P2 \ N/ P2 N/ 0/12) l P2 1,P2 p1 p2 1 P2 N \N’ \N, p3 3 3 \o \ P\ \ R \ O O \ N N P6 ‘P5 \P6 P\N/1 l J32 l /P2 1 P2 N N \N/ P ‘O7 P o7. P 07. p70 0P3 0P3 0P3 0P3 9 3 9 1 2 1 2 P\N/P \N’P P7 0 P70 0 0P3 OF’3

9 0P4 7 CN 9 / / I l \ \ f-‘QN‘ \ N Q N Q \ CN CN , , <\ \ RN N \ \ § 5 P40 and CN CN P4-o wherein: each of P1 and P2, and P6 are independently a en ting group, or P1 and P2 come together, with the N atom to which they are bound, to form a single nitrogen protecting group; each of P3, P4 and P7 are independently an alcohol protecting group, or P3 and P4 come together, with the atoms through which they are bound, to form a single oxygen protecting group; and P5 is a carboxylic acid protecting group. The method of any one of claims 2—8, wherein the ar solvent is selected from the group consisting of: benzene, toluene, ne, m—xylene, p-Xylene, ethyl benzene, carbon tetrachloride, hexane, cyclohexane, fluorobenzene, chlorobenzene, nitrobenzene, and mixtures thereof.

10. The method of claim 9, wherein the nonpolar solvent comprises toluene.

ll. The method of any one of claims 1—10, wherein the heating comprises heating at a temperature ranging from about 25° C to about 250° C.

12. The method of any one of claims 1—1 1, wherein the heating occurs for from about 1 second to about 25 minutes.

13. The method of any one of claims 1—12, wherein the heating is accomplished by a flash pyrolysis method, a conventional heating method, or by a ave method.

14. The method of any one of claims 1, 2—8, and 11—13, wherein the polar solvent is selected from the group consisting of: acetonitrile, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, ylformamide, fluorobenzene, benzotrifluoride and mixtures thereof.

15. The method of any one of claims 1-14, wherein Y is selected from the group consisting of triflate, mesylate, nonaflate, hexaflate, tosylate, nosylate, brosylate, perfluoroalkyl sulfonate, tetraphenylborate, hexafluorophosphate, trifluoroacetate, tetrafluoroborate, perchlorate, perfluoroalkylcarboxylate, de, bromide, and iodide.

16. The method of any one of claims 1—15, wherein M is selected from the group consisting of: potassium, sodium, cesium, xes of lithium, sodium, potassium, or cesium with cryptands or crown ethers, tetrasubstituted ammonium cations, and phosphonium cations.

17. The method of any one of claims 1, 2, and 9—16 wherein the compound of a (2) is selected from the group consisting of: PlN/PZ PlN,P2 PlN’Pz 0\ 0\ Y P5 Y P5 0\ Arl/l O Arl/l O 0 OP3 AFH 0P4 0P4 , t 0P4 , PLNJD2 P1 2 1 \N/ P2 P\N,P O\ O\ Y P5 P5 P5/O 1 Y /| O O O Ar1 |\Arl 0P3 0P3 and , , 0P3 Y \Ar1 wherein: each of Pland P2 are independently a nitrogen protecting group, or P1 and P2 come together, with the N atom to which they are bound, to form a single nitrogen protecting group; each of P3, and P4 are independently an alcohol protecting group, or P3 and P4 come together, with the atoms through which they are bound, to form a single oxygen protecting group; P5 is a carboxylic acid protecting group.

18. The method of any one of claims 1, 2, and 9-16, wherein the compound of Formula (3) is selected from the group consisting of: PlN,P2 PlNPZ PlN,P2 O\P5 O\P5 O\P5 F o F o 0 OP3 F 0P4 OP4 0P4 , 3 2 1 PlN/PZ P1\N,P2 P\N’P O F F o 0 0P3 0P3 , and wherein: each of P1 and P2 are independently a nitrogen protecting group, or P1 and P2 come er, with the N atom to which they are bound, to form a single en protecting group; each of P3, and P4 are independently an alcohol protecting group, or P3 and P4 come together, with the atoms through which they are bound, to form a single oxygen protecting group; P5 is a ylic acid protecting group; and F is a radioactive isotope of fluorine.

19. The method of any one of claims 1, 2, and 9—16, wherein the compound of Formula (2) is selected from the group consisting of: / / O I \ Y Y Y N \ l \Nl \ I % l\ \ \ 0 1 |\Ar1 [\Ar1 CN CN CN 5 3 S 4\ \ l ./N Y <\ Y / Y N N % i \\ i Q i \Ar1 \Ar‘ \Ar1 CN , CN ,and ON

20. The method of any one of claims 1, 2, and 9—16, wherein the compound of Formula (3) is ed from the group consisting of: / / O I I N \ \N \ Q \ F \ F CN CN CN , , , S S RN ,,<\ \ (\N \ ’IN N § F \\ F \\ F ’ and CN CN = ON and F is a radioactive isotope of fluorine.

21. The method of any one of claims 1, 2, and 9—16, wherein the compound of Formula (2) is selected from the group consisting of: wherein: each of P3 and P4 are independently an alcohol ting group.

22. The method of any one of claims 1, 2, and 9—16, wherein the compound of Formula (3) is selected from the group consisting of: 0P3 . 4 mg; F and P '0 wherein: each ofP3 and P4 are independently an alcohol protecting group.

23. The method of any one of claims 1, 2, and 9—16, wherein the compound of Formula (2) is: P \N/P1 2 Y “PS Arl/I O wherein: each of P1 and P2 are independently a nitrogen protecting group, or P1 and P2 come together, with the N atom to which they are bound, to f01m a single nitrogen protecting group; each of P3, and P4 are independently an l protecting group, or P3 and P4 come together, with the atoms through which they are bound, to form a single oxygen ting group; P5 is a carboxylic acid protecting group.

24. The method of any one of claims 1, 2, and 9—16, wherein the compound of Formula (2) is: O O t—Bu\OJLNAO/t—Bu Y ““Sflk Arl/i O

25. The method of any one of claims 1, 2, and 9—16, wherein the compound of Formula (2) is: O O t-Bu \O/IL NAO/t-Bu M800 _: /' 0

26. The method of any one of claims 1, 2, and 9—16, wherein the compound of Formula (3) is: wherein: each of P1 and P2 are ndently a nitrogen protecting group, or P1 and P2 come together, with the N atom to which they are bound, to form a single nitrogen protecting group; each of P3, and P4 are independently an alcohol protecting group, or P3 and P4 come together, with the atoms through which they are bound, to form a single oxygen ting group; P5 is a carboxylic acid protecting group; and F is a radioactive isotope of fluorine.

27. The method of any one of claims 1, 2, and 9—16, wherein the compound of Formula (3) is: O O t-Bu\ /U\ JL /t-Bu and F is a radioactive isotope of e.

28. The method of any one of claims 1, 2, and 9—16, wherein the compound of Formula (3) is: F 0 and F is a radioactive isotope of fluorine.

29. The method of any one of claims 1-28, wherein the chromatography is size ion chromatography.

30. The method according to any one of claims 1 to 29 and substantially as herein described with reference to the Examples and/or Drawings.