fluorination of aromatic ring systems

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University of Nebraska - Lincoln
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12-10-2013
FLUORINATION OF AROMATIC RING
SYSTEMS
Stephen G. DiMagno
University of Nebraska-Lincoln, [email protected]
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US008604213B2
United States Patent
(12) (10) Patent No.: US 8,604,213 B2
Dimagno (45) Date of Patent: Dec. 10,2013
(54) FLUORINATION OF AROMATIC RING OTHER PUBLICATIONS
SYSTEMS
Zhang et al., "A practical route for synthesizing a PET ligand con
(75) Inventor: Stephen Dimagno, Lincoln, NE (US) taining [18F] flourobenzene using reaction of diphenyliodonium salt
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( *) Notice: Subject to any disclaimer, the term of this
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PCT Pub. Date: Apr. 29, 2010
Sun et ai., "Fluoride relay: a new concept for the rapid preparation of
anhydrous nucleophilic fluoride salts from KF," Chemical Commu
(65) Prior Publication Data
nications, 2007, (5):528-529.
US 2012/0004417 Al Jan. 5, 2012 Authorized Officer Young Jin Kang, PCT IUS20091061308, Interna
tional Search Report and Written Opinion of the International
Searching Authority, mailed Apr. 30, 2010, 9 pages.
Authorized Officer Gijsbertis Beijer, PCTIUS20091061308, Interna
Related U.S. Application Data
tional Preliminary Report on Patentability, issued Apr. 26, 2011, 7
(60) Provisional application No. 611107,156, filed on Oct. pages.
Abboud et ai., "Hydrogen Bonding in the Gas Phase and in Solution.
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(52) U.S. CI. Halide Salts with Pentafluorophenyl Substituted Cations," JAm.
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U.S. PATENT DOCUMENTS Bielawski et ai., "High-yielding one-pot synthesis of diaryliodonium
triflates from arenes and iodine or aryl iodides," Chem. Commun.,
8,377,704 B2 212013 DiMagno et ai. 2007,2521-2523.
2005/0226776 Al 1012005 Bradyet ai. Biffinger et al., "The Polar Hydrophobicity of Fluorinated Com
2006/0120958 Al 612006 Bradyet ai.
pounds," ChemBiochem, 2004, 5:622-627.
2006/0128031 Al 6/2006 Robotti et al.
2006/0292060 Al 1212006 Wadsworth et ai. (Continued)
2007/0092441 Al 412007 Wadsworth et ai.
200910286992 Al 1112009 Carroll et ai.
201110091982 Al 4/2011 Dimagno et al. Primary Examiner - Zinna Northington Davis
201110144344 Al 6/2011 Woodcraft (74) Attorney, Agent, or Firm - Fish & Richardson P.c.
201110190505 Al 8/2011 Dimagno
201110313170 Al 1212011 Dimagno (57) ABSTRACT
FOREIGN PATENT DOCUMENTS This disclosure relates to reagents and methods useful in the
synthesis of aryl fluorides, for example, in the preparation of
WO WO 03/002157 112003 18F labeled radiotracers. The reagents and methods provided
WO WO 2005/021472 3/2005 herein may be used to access a broad range of compounds,
WO WO 2005/061415 7/2005
including aromatic compounds, heteroaromatic compounds,
WO WO 2005/097713 10/2005
WO WO 2008/082695 7/2008 amino acids, nucleotides, and synthetic compounds.
WO WO 20101008522 112010
WO WO 2010/048170 4/2010 37 Claims, 4 Drawing Sheets
US 8,604,213 B2
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1998,221-232. National Academy Press, 1990,37-40.
u.s.
Patent
Dec. 10,2013 Sheet 1 of 4 US 8,604,213 B2
MTEB-I-F Decomposition in Acetonitrile at 90°C
90.0%
80.0%
'V
70.0%
'tI60.0%
<Il
§50.0% -.-no salt
.g
1X14O.O% - ....... 1 eq. salt
w
1-30.0% -....... 2 eq. salt
~20.0% ~ -
•
-~.-----
<f.10.0% ftI*-•.
0.0%
0 500 1000 1500 2000 2500
Time (min)
FIG. 1
u.s.
Patent
Dec. 10,2013 Sheet 2 of 4 US 8,604,213 B2
MTEB-I-F Decomposition in Benzene at 90°C
_.
100.0%
90.0% ..
80.0% .-/' . -
~ .-. ....
70.0%
( ,;::;:Y
"0 --~
60.0%
Q) ~ --no salt
r'il
j50.0%
if -1 eq. salt
aWl 40.0 % -.-2 eq. salt
~30.0%
U. 20.0%
o~ 10.0%
0.0%
o 200 400 600 800 1000
Time (min)
FIG. 2
~
ID Proton NMR \XJ 7Jl
•
before heating
BRUKER ~
L><.-) ~
~
=~
AAJI[ bir-D72i1:l-!?-ILU:1d,[:irt1aC\-dUlOOOOl'Ji.
rnm 1.
P.&OO:::NQ 1 ~
D~t'"'_ 2~i::9{i'aln
!l.o;; '!.5.16
mSnUl! !lp.;o.;:;t
rR.orum !; ~ .;&f .l1:3( 13
YUr.J>1'.!X zg3,D
TO 'S53.~
S;)J..V'!.Nr ~~Qt
,_Jl )oess, If•; c
5'<" S~{j.O.t[} Hz.
t~ Ar~..Q;t. D~ l.U H, tlS·.UJI2l~3n:6i J.:;30;z1. C (~.'.D. .
IJIi 5{l.~~lJ. 'J~.c.
DE: E. 5G iJ~~-C
_f~~. L 0IE1 ~ .O~~tlIS(.-lICo~.!ai K~c : ~O
"I. ,""",,-,.-.-,' I. ,....·...-r-T·-.-I~ • . ,....,. rrTl"'" ~,. ".-"1 -""'"- .-, .,....,1 '""""-""'"- .-,' I'' """''-,,-<,-,' I. .-, ro,' -"'1-'-'. ,...., ro,' -'1"'" -.-,. .-,' "I "''''''- .-,. .-,1 """',, -,,-,-,- .-.' Ir o,, .--.-,-,-'"..-,- n,' ''''1-'-'. .-,. ---,' '''-,-' -.-, ~,- n'1 "'-""'". .-,' I, ,"""-,,--,:,->,--f~~I1,D W~ C~Sll_ . . C:iik, h.~.-.n l!l~1l~ 1;_,' _UI~J.i ~1:.i" _:U!_1.'-;- _! : o(.N.,H. .
8.5 8.0 7.5 7.0 .6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5~ 1.0 ppm~ ," •. "i~~~:H1l'
JI.~f~\~ [~I f~VI~' (I~\ I)~\ (~ll~~lk\~~, ( ~f :~~
l ... I~IO: 101 ,.... ~,,;I 01 to iOlcil~I~IMI I )1, Hz r=F J
('D
(..'D...
(,H
o... .
.j;o.
d
rJl
10000,0000,000'1'" 0,0000,000 0,00 00,0000,0 0 0,0 TO 0 I 0000 I 0000 10000 I 0 00. r'-"Tr"-CTI QO
~-rTTOTrno 0..,
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm =
i(O1"~ I,0 ):!)0,o,.!\!i (1COJ.>0lJi1 ! !r!Q.~;J .r.< ~:.~1.> "N,.f .; " ' <~N,'l l 1~t'?)0 ~0~0 II0"~'"- : l 0N'- ;11) ~m~0.1; ~jii! ta~~l'~)I~~ I... ~., f1:. ,01jI'.'( ',~)' ',:~...I. Cr1';); r1r~:~.~ <;:t>: ''d :1 Nw"~"" '"
I~ =
FIG. 3
N
~
7Jl
a~ •
~
~
~
"""" ::r..r-O"2()95'-:n•.1 Y.)rtru.tLo~dll:!ooDOPA =~
ID:.PlCC
~ROC»:' 1
D'll;!a:.'tQQ _ 2:)D9H.D.9S2Ge=: ~
lltSnttm ';?Q'=t
..E?.'RO OLSFAHDO C 5 m '~F'!t~~{~
10 Ulil72
SO'L\lDlf c:~O&.
1';
OS o c
S'tE 75U7. 9;f.s: R~
HDRES D. S'?3~·:loS: 82-
AQ ~. 'S'1Hi1SS DOiC ('D
"""" 1,.2 '25(.;5< ll:QI:! ~... .
0< t.:3D-",~Q;;:
!t
C'II 30WiC ~O
r---------' J'1:0. ~. __ cHAl;W:J, I!l c1= _ _ o.N.. .
-20 -40 -60 -80 -100 -120 -140 -~ffO .... 1lID" •• = ppm
l"Ll -3. =:-:ac de (.H
SFOl 37~. t6D71€-.t M.t:i ...
6:1 ~3S.36
SF 316, .:tse3S';(C ME=..
W"UIf EM·
B:5S ~
La D.3c<n:
o
F19 "' 1. "" r=F J
140C. 25min
('D
(..'D...
.j;o.
o... .
.j;o.
I I -1
-124.5 -125.0 ppm
d
~I I~(
rJl
QO
0..,
I I I I I I no I =
-20 -40 -60 -80 -100 -120 -140 -160 -1BO ppm
~
© rWl N
w"""'"
=
FIG. 4
N
US 8,604,213 B2
1 2
l
FLUORINATION OF AROMATIC RING whereinAr is an electron rich aryl or heteroaryl ring system;
SYSTEMS Y is a leaving group; and
M and X are as defined above. Following reaction, the polar
CROSS-REFERENCE TO RELATED solvent can be removed from the reaction mixture and the
APPLICATIONS remaining mixture can be combined with a nonpolar sol
vent and heated. In another embodiment, a solution com
prising a nonpolar solvent, a compound MX, and a com
This application is a National Stage application under 35
pound of Formula (2) can be heated to provide a compound
U.S.c. §371 and claims the benefit under 35 U.S.c. §119(a)
of Formula (1).
ofIntemational Application No. PCT/US20091061308, hav
In some embodiments, the nonpolar solution of the reac-
ing an International Filing Date of Oct. 20, 2009, which 10
tion mixture of MX and a compound of Formula (2) can be
claims priority to U.S. Provisional Applications Ser. Nos.
filtered prior to heating. The filtration step can remove any
611107,156, filed on Oct. 21, 2008, and 611236,037, filed on
insoluble material (e.g., insoluble salts) that remain in the
Aug. 21,2009, both ofw hich are incorporated by reference in
reaction mixture. In some embodiments, the solvent can be
their entirety herein
15 removed from the filtrate prior to heating (i.e., the residue can
be heated neat).
FEDERALLY SPONSORED RESEARCH OR
In further embodiments, the nonpolar solution of the reac
DEVELOPMENT
tion mixture of MX and a compound of Formula (2) can be
filtered prior to heating, the nonpolar solvent can be removed
The U.S. Government has certain rights in this invention 20 (e.g., by evaporation), and the heating of the sample can be
pursuant to Grant No. CHE-0717562 awarded by the performed in a different solvent.
National Science Foundation. In some embodiments, X can be chosen from halide, aryl
carboxylate, alkyl carboxylate, phosphate, phosphonate,
TECHNICAL FIELD phosphonite, azide, thiocyanate, cyanate, phenoxide, triflate,
25 trifluoroethoxide, thiolates, and stabilized enolates. For
This disclosure relates to reagents and methods useful in example, X can be chosen from fluoride, chloride, bromide,
the synthesis of aryl fluorides, for example, in the preparation iodide, triflate, trifluoroacetate, benzoate, acetate, phenoxide,
of l8F labeled radiotracers. The reagents and methods pro trifluoroethoxide, cyanate, azide, thiocyanate, thiolates,
vided herein may be used to access a broad range of com phosphates, and stabilized enolates. In some embodiments, X
pounds, including aromatic compounds, heteroaromatic 30 is fluoride. In some embodiments, X is a radioactive isotope,
compounds, amino acids, nucleotides, and synthetic com for example, X can be a radioactive isotope of fluoride (e.g.,
l8F).
pounds.
The methods described herein can be used to prepare flu
BACKGROUND orinated aryl or heteroaryl ring systems (e.g., a radiolabeled
35 fluorinated aryl or heteroaryl ring system). For example, pro
Aryl fluorides are structural moieties in natural products as vided herein is a method ofp reparing a compound of Formula
well as a number of therapeutically important compounds, (3):
including positron emission tomography (PET) tracers and M-F
pharmaceuticals. Therefore methods and reagents for pro
ducing such aryl fluorides, for example efficient methods for 40 wherein M is an aryl or heteroaryl ring system. In one
embodiment, the method includes reacting in a polar sol
producing aryl fluorides, are desirable.
vent a compound MF, wherein M is a counter ion, and a
compound of Formula (2), as described above. Following
SUMMARY
reaction, the polar solvent can be removed from the reac
tion mixture and the remaining mixture can be combined
Provided herein are methods of preparing substituted aryl 45
with a nonpolar solvent and heated. In another embodi-
and heteroaryl ring systems using diaryliodonium com
ment, a solution comprising a nonpolar solvent, a com
pounds and intermediates. For example, diaryliodonium salts
pound MF, and a compound of Formula (2) can be heated
and diaryliodonium fluorides, as provided herein, can
to provide a compound of Formula (3).
undergo decomposition to prepare an aryl fluoride.
In some embodiments, the nonpolar solution of the reac-
For example, provided herein is a method for making a 50
tion mixture of MF and a compound of Formula (2) can be
compound of Formula (1):
filtered prior to heating. The filtration step can remove any
insoluble material (e.g., insoluble salts) that remain in the
M-X
reaction mixture. In some embodiments, the solvent can be
wherein Ar2 is an aryl or heteroaryl ring system; and X is a 55 removed from the filtrate prior to heating (i.e., the residue can
moiety wherein the pKa of the acid H-X is less than 12. In be heated neat).
one embodiment, the method includes reacting in a polar In further embodiments, the nonpolar solution of the reac
solvent a compound MX, wherein M is a counter ion and X is tion mixture of MF and a compound of Formula (2) can be
as defined in Formula (1), and a compound of Formula (2): filtered prior to heating, the nonpolar solvent can be removed
60 (e.g., by evaporation), and the heating of the sample can be
performed in a different solvent.
2 Arl is an electron rich aryl or heteroaryl ring system. For
example, Arl-H can be more easily oxidized than benzene.
In some embodiments, the moiety Arl can be substituted with
65 at least one substituent having a Harnmett op value ofless than
zero. For example, the substituent can be chosen from: -(Cl-
ClO)alkyl, -(Cl -ClO)haloalkyl, (C2-ClO)alkenyl, (C2-ClO)