4-[18F]fluorophenyl ureas via carbamate-4-nitrophenyl esters and 4-[18F]fluoroaniline

Article abstract of DOI:10.1002/jlcr.1121

Four different no carrier added (n.c.a.) 4-[¹⁸F]fluorophenylurea derivatives are synthesized as model compounds via two alternative routes. In both cases carbamate-4-nitrophenylesters are used as intermediates. Either n.c.a. 4-[¹⁸F]fluoroaniline reacts with carbamates of several amines, or the carbamate of n.c.a. 4-[¹⁸F]fluoroaniline is formed at first and an amine is added subsequently to yield the urea derivative. The choice of the appropriate way of reaction depends on the possibilities of precursor synthesis. The radiochemical yields reach up to 80% after 50 min of synthesis time while no radiochemical by-products can be determined. These high yields were possible due to an optimized preparation of n.c.a. 4-[¹⁸F] fluoroaniline with a radiochemical yield of up to 90%. From the various ways of its radiosynthesis, the substitution with n.c.a. [¹⁸F]fluoride on dinitrobenzene is chosen, using phosphorous acid and palladium black for reduction of the second nitro group. Copyright

Full text of DOI:10.1002/jlcr.1121

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2006; 49: 1037–1050.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.1121
Research Article
4-[18F]fluorophenyl ureas via carbamate-4-nitrophenyl
esters and 4-[18F]fluoroaniline
Sebastian Olma, Johannes Ermert* and Heinz H. Coenen
Institut fur Nuklearchemie, Forschungszentrum Julich GmbH, D-52425 Julich, Germany
¨
¨
¨
Dedicated to Prof. Dr Dr h.c. S. M. Qaim on the occasion of his 65th birthday
Summary
Four different no carrier added (n.c.a.) 4-[18F]fluorophenylurea derivatives are
synthesized as model compounds via two alternative routes. In both cases carbamate-
4-nitrophenylesters are used as intermediates. Either n.c.a. 4-[18F]fluoroaniline reacts
with carbamates of several amines, or the carbamate of n.c.a. 4-[18F]fluoroaniline is
formed at first and an amine is added subsequently to yield the urea derivative. The
choice of the appropriate way of reaction depends on the possibilities of precursor
synthesis.
The radiochemical yields reach up to 80% after 50 min of synthesis time while
no radiochemical by-products can be determined. These high yields were possible
due to an optimized preparation of n.c.a. 4-[18F]fluoroaniline with a radiochemical
yield of up to 90%. From the various ways of its radiosynthesis, the substitution with
n.c.a. [18F]fluoride on dinitrobenzene is chosen, using phosphorous acid and
palladium black for reduction of the second nitro group. Copyright # 2006 John
Wiley & Sons, Ltd.
Received 2 June 2006; Revised 25 July 2006; Accepted 27 July 2006
Key Words: n.c.a. radiofluorination; [F-18]fluorophenyl ureas; [F-18]fluoroaniline;
carbamates
Introduction
There is a manifold of urea derivatives in pharmaceutical chemistry, which are
found as a structural element in a large variety of biologically active
molecules.1,2 Especially para substituted phenyl ureas (e.g. with halogen) are
*Correspondence to: J. Ermert, Institut fur Nuklearchemie, Forschungszentrum Julich GmbH, D-52425
¨
Julich, Germany. E-mail: j.ermert@fz-juelich.de
¨
¨
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S. OLMA ET AL.
found quite often.3,4 Until now, there is no example where these structures are
used for the preparation of no-carrier-added (n.c.a.) fluorine-18 labelled
analogue or original tracers for diagnostics with positron-emission-tomogra-
phy (PET). On the other hand, there are several urea derivatives known which
are labelled via 18F-fluoroalkylation or 18F-fluoroacylation5 indicating the
interest in this class of compounds. Also, a 4-[18F]fluorophenylguanidine was
prepared6 as an example of a related substance class.
While most known urea derivatives are pharmacologically highly potent, an
in vitro or in vivo application as radiotracer implies a high molar activity of
correspondingly 18F-labelled molecules. Therefore, a synthesis without
addition of isotopic carrier appears necessary.
In this study here a simple and effective method for the production of para-
[18F]fluorophenyl ureas ([18F]4a–4d) is described. The strategy followed
two alternative pathways to yield these ureas starting from previously
prepared 4-[18F]fluoroaniline ([18F]2).
Several methods for the preparation of n.c.a. 4-[18F]fluoroaniline can be
found in the literature.6ꢀ12 Those general concepts are partially adopted for
the procedure developed in this work, whereby the whole radiosynthesis is
optimized. In a second step the 4-[18F]fluoroaniline is then either converted
into a 4-[18F]fluorophenylcarbamate nitrophenylester ([18F]3e) and afterwards
reacted with a selected amine in order to yield various asymmetric substituted
ureas. Alternatively the 4-[18F]fluoroaniline is reacted directly with a
previously synthesized carbamate nitrophenylester (3a–3d) under formation
of ureas.
Results and discussion
There are many possibilities to prepare urea derivatives on the laboratory
scale. The simplest way is to combine an isocyanate compound with an
amine.13,14 In the case of fluorophenyl ureas this method works well.
Fluorophenyl isocyanate is commercially available and stable under standard
conditions. Further reaction with different amines leads to the correspondingly
desired products. A transfer of these results to radiolabelling reactions is not
quite simple.
First experiments for this work dealt with isotopic exchange reactions of
4-[19F]fluorophenyl isocyanate with n.c.a. [18F]fluoride. However, they failed
even under several harsh conditions tested. This could be expected, since the
isocyanate group is obviously not activating the aromatic ring enough for
enabling a nucleophilic substitution (Scheme 1).
Therefore, evasion to a multistep synthesis using 4-[18F]fluoroaniline as
intermediate became necessary. Generally organic isocyanates can be
made from this via a reaction with phosgene or a substitute for this highly
toxic gas.
Copyright # 2006 John Wiley & Sons, Ltd.
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4-[18F]FLUOROPHENYL UREAS VIA CARBAMATE-4-NITROPHENYL ESTERS 1039
Scheme 1. Direct labelling of 4-fluorophenyl isocyanate failed
N.c.a. 4-[18F]fluoroaniline
As mentioned above, the preparation of n.c.a. 4-[18F]fluoroaniline ([18F]2) was
described several times before. However, the methods described therein were
modified in several aspects. According to Scheme 2 the radiosynthesis starts
with dried potassium [18F]fluoride where potassium is complexed with
Kryptofix# 2.2.2 in a standard procedure.15 The precursor is dissolved in
DMSO.
Scheme 2. Preparation of para-[18F]fluoroaniline; (A) [K/2.2.2][ 18F]F, K2CO3,
DMSO, 1208C, 3 min; (B) Pd black, H3PO3, MeOH, reflux, 15 min
Two precursors were tested. 1,4-Dinitrobenzene and 4-chloronitrobenzene
lead to very high radiochemical yields after labelling with [18F]fluoride at
1208C for three minutes. The radiochemical yield of [18F]1 alluded to the dried
[18F]fluoride is constantly at least 85% after cartridge purification. The
purification is performed on a Waters C18+ cartridge conditioned with
ethanol and water. The reaction mixture is diluted with water and passed
through the cartridge. Elution of the product is achieved with dry methanol.
Subsequent reduction of the nitro group is the crucial step of this synthesis
approach. In order to avoid gaseous hydrogen, seven alternatives were
examined in equimolar and n.c.a. radiosyntheses (Table 1). From those, the
combination of phosphorous acid and palladium black in methanol at 808C
proved to be the best on the n.c.a. level. The reaction is quantitative within
15 min. The catalyst is filtered off easily, and the inorganic reagent is washed
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Table 1. Methods tested for reduction of 4-fluoronitrobenzene to 4-fluoroaniline
Reduction of 4-fluoronitrobenzene to 4-fluoroaniline
F
NO2
F
NH2
1
2
Equimolar synthesis
n.c.a. Radiosynthesis
In/acetic acid
Pd/BERa
Not quantitative
No conversion
Pd/[NH4][HCOO]
NaBH4
Not quantitative
No conversion
Pd/hydrazine
SnCl2
Not quantitative
Not quantitative
Pd/hydrazine
SnCl2
NiAc/NaBH4
Pd/H3PO3
Complete conversion
Not quantitative
No conversion
Complete conversion
a BER: borohydride, polymer supported.
out during cartridge purification. For this step, the cartridge used is a Merck
Lichrolut EN phase. Fixation is only achieved under alkaline conditions.
Afterwards, the charged cartridge is eluted with the solvent of choice for the
next reaction step. Referring to the dried [18F]fluoride the radiochemical yield
of [18F]2 is 84 ꢁ 5% within 30 min of preparation.
Both precursors 1,4-dinitrobenzene and 4-chloronitrobenzene show similar
results until this step. Nevertheless, the first molecule seems to be more suitable
for further reactions. Reduction of excess 1,4-dinitrobenzene yields
1,4-diaminobenzene which shows a completely different chemical behaviour
than 4-fluoroaniline. In contrast, from the excess of the other precursor,
4-chloroaniline is produced. Since it is not easy to separate this completely
from 4-[18F]fluoroaniline via HPLC or other quantitative methods, it may lead
to a non-isotopic dilution rendering a reduction of the apparent specific
activity of the product.
Approaches for n.c.a. 4-[18F]fluorophenyl isocyanate preparation
In order to avoid the synthesis of the isocyanate using phosgene, three
alternatives were tested. Diphosgene and triphosgene16–19 are colourless solids
and stable under ambient conditions. One molecule diphosgene releases two,
triphosgene three equivalents of phosgene in situ. Further, carbonyl
diimidazole is a direct substitute for phosgene, where the imidazole units
replace the chlorine atoms.20,21
These three substances were used in several experiments with n.c.a.
4-[18F]fluoroaniline but no conversion of the free amino group could ever
be observed. Tests included different solvents, temperatures and amounts of
reagents. Even additional drying of the eluted solution of 4-[18F]fluoroaniline
over sodium sulphate resulted in no success (Scheme 3).
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4-[18F]FLUOROPHENYL UREAS VIA CARBAMATE-4-NITROPHENYL ESTERS 1041
Scheme 3. Approaches of n.c.a. 4-[18F]fluorophenyl isocyanate preparation,
performed in chlorinated or etheric solvents at temperatures from 0 to 608C
N.c.a. 4-[18F]fluorophenyl carbamate 4-nitrophenylester ([18F]3e) and
4-[18F]fluorophenyl urea derivatives ([18F]4a24d)
Carbamate nitrophenylesters were therefore tested as alternative intermedi-
ates. Reactions of amines with 4-nitrophenyl chloroformate lead to carbamate
4-nitrophenylesters.3,22 These substances are stable under standard conditions
and easy to separate. Further reaction with another amine gives disparately
substituted ureas. This strategy is well known in organic chemistry and can be
applied for the radiosynthesis. Therefore, the n.c.a. [18F]2 is eluted from the
Merck EN-cartridge subsequently passing a cartridge filled with sodium
sulphate and kieselguhr powder. After addition of 4-nitrophenyl chlorofor-
mate the solution is stirred at room temperature. HPL- and thin layer
chromatograms show the conversion to the desired carbamate 4-nitropheny-
lester ([18F]3e) (Scheme 4).
Scheme 4. Preparation of 4-[18F]fluorophenylcarbamate nitrophenyle ester and
N-4-[18F]fluorophenyl-N0-substituted ureas; (A) THF, Na2SO4-cartridge, (B)
THF, n
For conversion to the desired urea, an amino compound of choice is added
to the carbamate. After stirring at slightly raised temperatures the urea
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derivative is obtained and can be separated by a further cartridge purification
step. The conversion takes place under alkaline conditions. The basicity of
aliphatic amines is high enough, so that addition of an excess of it is sufficient.
With aromatic amines, however, an assistant base such as ethyl diisopropyl
amine is necessary. The yields for labelled fluorophenyl ureas are listed in
Table 2.
Table 2. RCY of labelled fluorophenyl urea derivatives via [18F]fluorophenylcarbamate
nitrophenyl ester
Amine
Urea
RCY (referring
to dry [K ꢂ 2.2.2]
[18F]F) (%)
n-Propyl amine
c-Hexyl amine
Benzyl amine
Anilinea
N-4-[18F]fluorophenyl-N0-n-propyl urea ([18F]4a)
N-4-[18F]fluorophenyl-N0-c-hexyl urea ([18F]4b)
N-4-[18F]fluorophenyl-N0-benzyl urea ([18F]4c)
N-4-[18F]fluorophenyl-N0-phenyl urea ([18F]4d)
76
73
82
73
Temperature of coupling reaction: 30–408C.a Addition of ethyldiisopropyl amine (ca. 50 ml).
One of these last two steps in the radiosynthesis can be avoided, if it is
possible to form the carbamate 4-nitrophenylester of the non-radioactively
labelled part of the urea. In this case n.c.a. 4-[18F]fluoroaniline is added to a
carbamate (3a–3d) and the mixture stirred at 30–408C to yield the
corresponding urea derivative. The temperature is raised to accelerate the
conversion. This reaction concept is simpler but it does not work equally
effective with all tested amines, respectively, carbamates, as shown in Table 3
and Scheme 5.
Scheme 5. Preparation of N-4-[18F]fluorophenyl-N0-substituted ureas via
carbamate 4-nitrophenylesters; (a) THF, n; a–d, see Scheme 4
The 4-fluorophenyl carbamate 4-nitrophenylester (3e) is more reactive than
some aliphatic compounds, what becomes clear by comparison of the results
shown in Tables 2 and 3.
The choice of the right combination is obviously depending on the structure
and possibility of synthesis of the desired labelling product.
Copyright # 2006 John Wiley & Sons, Ltd.
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4-[18F]FLUOROPHENYL UREAS VIA CARBAMATE-4-NITROPHENYL ESTERS 1043
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Synthesis of carbamate 4-nitrophenylesters and corresponding 4-fluorophenyl
urea derivatives
Syntheses of carbamate 4-nitrophenylesters are well described for many
different substances.22 Nevertheless, some modifications are applied in this
work to optimize the results for the individual molecules. Four types of
substances were examined.
Benzyl, cyclohexyl and n-propyl amine represent several primary aliphatic
amines. The reaction of those with 4-nitrophenyl chloroformate takes place in
methylene chloride at room temperature and is completed after several hours.
As an assistant base ethyl diisopropyl amine is added in equimolar amounts.
This base is better suited than triethyl amine, because the formed ammonium
salt does not precipitate. The reaction mixture is washed with hydrochloric
acid and the precipitated product (3a–3c) is recrystallized from iso-propyl
alcohol. The yields with all three aliphatic compounds are high, and products
are pure after a simple purification procedure (Scheme 6).
Scheme 6. Preparation of carbamate 4-nitrophenylesters and 4-fluorophenyl
ureas; a–d, see Scheme 4
In contrast, the conversion of aniline derivatives is not as simple as of
aliphatic ones. The rapidly formed carbamate is not stable under alkaline
conditions. After a short time, the only product with 4-nitrophenyl
chloroformate and an excess of organic bases is bisphenyl urea. Hunigs base,
¨
ethyl diisopropyl amine, is used again in equimolar amounts. Cooling of the
reaction flask is neccessary. For purification, hydrochloric acid is used again.
Further washing, if necessary, is then done by suspending the solid product in
diethyl ether.
The four carbamate compounds 3a–3d described above are reacted in
methylene chloride with 2 to give the corresponding urea derivatives. This
simple procedure works out very well, except for the n-propyl compound (3a),
where nearly no reaction can be observed.
This finding corresponds to the results of the radiosyntheses where [18F]-2
does not react with 3a.
Reaction of n-propyl amine with 4-fluorophenyl carbamate nitrophenylester
(3e), on the other hand, leads to the desired urea with good yields (91%). The
Copyright # 2006 John Wiley & Sons, Ltd.
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4-[18F]FLUOROPHENYL UREAS VIA CARBAMATE-4-NITROPHENYL ESTERS 1045
4-fluorophenyl carbamate nitrophenylester was prepared like the phenyl
compound described above.
Experimental
Chemicals
All chemicals are purchased from Merck, KMF, Riedel-de Haen, Fluka or
¨
Aldrich in p.a. quality or as otherwise mentioned in the text.
HPLC
The HPLC-System used for standard and product identification consists of a
Sykam S1000 pump (constant flow 1 ml/min) and a Phenomenex Bondclone
(10 m C18, 300 ꢃ 3.8 mm) column. Detection was done by a Knauer UV
detector K2500 at 254 nm and an EG & G Ortec NaI radiodetector with an
ACE Mate Amplifier and BIAS supply.
Data acquisition and interpretation was performed via a Raytest Gina box
and the corresponding Gina Star software.
Thin layer chromatography
Thin layer chromatography was performed on TLC aluminium roll Silica gel
60 F254 from Merck. It was developed with diethyl ether/hexane (volume ratio
1:1) plus 20 ml acetic acid per 5 ml eluent.
Spots were visualized under a Desaga MinUVIS lamp at 254 nm or by
heating in a hot air stream after spraying with a solution of 0.45 g ninhydrin in
150 ml ethanol and 3 ml acetic acid.
Radio-TLC plates were measured on a Raytest Mini Gita system equipped
with a closed b-counting tube and interpreted with the accordant software.
NMR spectroscopy
1H-, 13C- and 19F-NMR spectra were recorded on a Bruker Avance 200
spectrometer with samples dissolved in solvents mentioned in the text. All
shifts are given in d ppm using the signals of the appropriate solvent as a
reference.
Melting points
¨
All melting points were measured in a BUCHI Melting Point B-540 apparatus
and data is corrected.
Organic syntheses
General method for preparation of alkyl-carbamate nitrophenylesters
(3a23c). In a 100-ml flask 10 mmol of 4-nitrophenyl chloroformate are
dissolved in 5 ml dry methylene chloride. 10 mmol of ethyl diisopropyl amine
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and 10 mmol of the accordant alkylamine are dissolved in 5 ml dry
dichloromethane and added dropwise. The solution is stirred for 4 h.
The solution is washed with 1 M hydrochloric acid three times. The organic
layer is dried over sodium sulphate and evaporated to dryness after filtration.
Recrystallization from iso-propyl alcohol leads to the desired alkyl
carbamate 4-nitrophenylester.
1
n-Propyl carbamate 4-nitrophenylester (3a). H-NMR (DMSO-d6): (2 H, d,
8.27 ppm Ar-H), (1 H, t, 8.06 ppm N-H), (2 H, d, 7.41 ppm Ar-H), (2 H, q,
3.07 ppm C-H2), (2 H, q, 1.51 ppm C-H2), (3 H, t, 0.91 ppm C-H3)
m.p.: 99.88C
MS (ESI): (m+H)/z = 225.2
Yield: 1.90 g (8.44 mmol; 84%)
1
cyclo-Hexyl carbamate 4-nitrophenylester (3b). H-NMR (DMSO-d6): (1 H,
s, 8.34 ppm N-H), (2 H, m, 7.40 ppm Ar-H), (2 H, m, 7.09 ppm Ar-H), (1 H, d,
6.03 ppm C-H), (10 H, b, 1.83–1.03 ppm C-H2)
m.p.: 135.88C
MS (ESI): (m+H)/z = 265.1
Yield: 2.32 g (8.75 mmol; 88%)
1
Benzyl carbamate 4-nitrophenylester (3c). H-NMR (DMSO-d6): (1 H, t,
8.62 ppm N-H), (2 H, m, 8.27 ppm Ar-H), (7 H, m, 7.34 ppm Ar-H), (2 H, d,
4.36 ppm C-H2)
m.p.: 131.08C
MS (ESI): (m+H)/z = 295.1
Yield: 2.80 g (9.5 mmol; 95%)
General method for preparation of aryl-carbamate nitrophenylesters
(3d23e). In a 100-ml flask 10 mmol of 4-nitrophenyl chloroformate are
dissolved in 5 ml dry methylene chloride. The flask is cooled in a water bath.
10 mmol ethyl diisopropyl amine and 10 mmol of the selected aniline derivative
are dissolved in 5 ml dry dichloromethane and added dropwise. This solution
is stirred for 3 h and afterwards washed three times with 1 M hydrochloric
acid. The organic layer is dried over sodium sulphate and evaporated to
dryness after filtration. The residue is the analytically pure aryl carbamate 4-
nitrophenylester.
1
Phenyl carbamate 4-nitrophenylester (3d). H-NMR (CDCl3): (1 H, s,
10.46 ppm N-H), (2 H, d, 8.32 ppm Ar-H), (4 H, m, 7.55 ppm Ar-H), (1 H, t,
7.12 ppm Ar-H)
m.p.: 148.68C
MS (ESI): (m+H)/z ¼ 259:3
Yield: 1.72 g (6.66 mmol; 67%)
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4-[18F]FLUOROPHENYL UREAS VIA CARBAMATE-4-NITROPHENYL ESTERS 1047
1
Fluorophenyl carbamate 4-nitrophenylester (3e). H-NMR (CDCl3): (2 H, d,
8.32 ppm Ar-H), (4 H, m, 7.47 ppm Ar-H), (2 H, m, 7.11 ppm Ar-H), (1 H, b,
7.01 ppm N-H)
m.p.: 157.18C
MS (ESI): (m+H)/z ¼ 277:2
Yield: 2.29 g (8.30 mmol; 83%)
General method for preparation of fluorophenyl urea derivatives (4a24d). The
corresponding alkyl or aryl carbamate nitrophenyl ester (5 mmol) is dissolved
in 5 ml dry THF. After addition of 5 mmol 4-fluoroaniline (or n-propylamine)
and 5 mmol of ethyl diisopropyl amine the mixture is stirred for several hours
at room temperature. The solvent is evaporated under reduced pressure and
the residue dissolved in ethyl acetate.
The solution is washed three times with 1 M sodium hydroxide solution and
1 M hydrochloric acid. The organic layer is dried over sodium sulphate and
evaporated to dryness after filtration.
N-Fluorophenyl-N’-n-propyl urea (4a). Preparation via fluorophenyl carba-
mate nitrophenyl ester and n-propyl amine.
1H-NMR (DMSO-d6): (1 H, s, 8.19 ppm N-H), (2 H, m, 7.30 ppm Ar-H),
(2 H, m, 6.88 ppm Ar-H), (1 H, b, 5.90 ppm N-H), (2 H, q, 3.07 ppm C-H2),
(2 H, m, 1.46 ppm C-H2), (3 H, t, 0.88 ppm C-H3)
m.p.: 155.08C
MS (ESI): (m+H)/z ¼ 197:1
Yield: 0.90 g (4.57 mmol; 91%)
1
N-Fluorophenyl-N’-cyclohexyl urea (4b). H-NMR (DMSO-d6): (1 H, s,
8.31 ppm N-H), (2 H, m, 7.38 ppm Ar-H), (2 H, t, 7.05 ppm Ar-H), (1 H, d,
6.03 ppm N-H), (1 H, b, 3.4 ppm C-H), (5 H, b, 1.83–1.54 ppm C-H2), (5 H, b,
1.42–1.08 ppm C-H2)
m.p.: 104.48C
MS (ESI): (m+H)/z ¼ 237:2
Yield: 0.65 g (2.74 mmol; 55%)
1
N-Fluorophenyl-N’-benzyl urea (4c). H-NMR (DMSO-d6): (1 H, s, 8.62 ppm
N-H), (7 H, m, 7.36 ppm Ar-H), (2 H, t, 7.08 ppm Ar-H), (1 H, t, 6.62 ppm N-
H), (2 H, d, 4.31 ppm C-H2)
m.p.: 179.08C
MS (ESI): (m+H)/z ¼ 245:1
Yield: 1.10 g (4.49 mmol; 90%)
1
N-Fluorophenyl-N’-phenyl urea (4d). H-NMR (DMSO-d6): (1 H, d,
8.66 ppm N-H), (4 H, m, 7.48 ppm Ar-H), (2 H, t, 7.30 ppm Ar-H), (2 H, t,
7.13 ppm Ar-H), (1 H, t, 6.97 ppm Ar-H)
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m.p.: 235.08C
MS (ESI): (m+H)/z ¼ 231:2
Yield: 0.96 g (4.15 mmol; 83%)
Radiochemical syntheses
Production of n.c.a. [18F]fluoride. N.c.a. [18F]fluoride is produced via the
18O(p,n)18F nuclear reaction by bombardment of an isotopically enriched
[18O]water target with a 17 MeV proton beam at the BC 1710 cyclotron (JSW),
as described previously.23
N.c.a. 4-[18F]fluoroaniline (½18Fꢄ1). The aqueous [18F]fluoride solution
(10–50 ml, e.g. 64.2 MBq) is added to 20 mg of Kryptofix 2.2.2. and 26 ml
of a 1 M potassium carbonate solution. The mixture is diluted with 0.9 ml
of dry acetonitril (5 0.003% H2O) and transferred via syringe to a 5 ml
conical vial (Reactivial) closed with a silicon septum. The solvent is evaporated
under a stream of argon at 808C and 750 mbar. The azeotropic drying is
repeated with 1 ml acetonitrile, followed by evaporation of the dry
Reactivial for 5 min to 40–50 mbar. The dry cryptate complex (52.9 MBq,
reference activity) and approx. 4 mg of 1,4-dinitrobenzene are solubilized
in 0.2 ml of dry DMSO. The stirred solution is heated in an oil bath at 1208C
for 3 min.
Afterwards the reaction mixture is diluted with 10 ml of water and passed
through a Waters C18+ cartridge (500 mg, conditioned with 10 ml of ethanol
and 10 ml of water).
The 1,4-[18F]fluoronitrobenzene ([18F]1, 45.3 MBq, RCY: 88%) is eluted
with 2 ml of methanol into a two necked flask. After addition of approx. 10 mg
palladium black and approx. 100 mg phosphorous acid the flask is closed with
a plug and a septum. A cannula in the septum is needed for pressure
equalization, while the flask is heated under stirring in an oil bath at 608C for
15 min. The reaction mixture is diluted with 20 ml of a 1 M sodium hydroxide
solution and passed through a Merck EN cartridge (500 mg, conditioned with
10 ml of ethanol and 10 ml of a 1 M sodium hydroxide solution). After a
synthesis time of 30 min 34.9 MBq (RCY: 82%) of n.c.a. 4-[18F]fluoroaniline
([18F]2) are fixed on the cartridge. No radioactive by-products can be
determined by radio HPL- or thin layer chromatography.
N.c.a. 4-[18F]fluorophenyl ureas (½18Fꢄ4a24d). [18F]2 is eluted from the
cartridge see above with 2 ml of dry THF and the solution passed through a
Merck Lichrolut cartridge filled with a mixture of kieselguhr powder and
anhydrous sodium sulphate (volume ratio 1:1, wetted with 2 ml THF).
Urea synthesis via n.c.a. 4-[18F]fluorophenyl carbamate 4-nitrophenylester
(½18Fꢄ3e). About 30 mg of 4-nitrophenyl chloroformate are added to the THF
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1037–1050
DOI: 10.1002/jlcr

4-[18F]FLUOROPHENYL UREAS VIA CARBAMATE-4-NITROPHENYL ESTERS 1049
elution containing n.c.a. 4-[18F]fluoroaniline ([18F]2) in a Reactivial. The
mixture is stirred at room temperature for 15 min. Afterwards 40 ml of
the corresponding amine are added. In the case of aniline addition of an
assistance base, e.g. 30 ml Hunigs base, is necessary. After another 15 min
¨
of stirring at slightly raised temperature (30–408C) in an oil bath HPL- and
thin layer chromatography show the desired ureas [18F]4a–4d as the only
radioactive products. Fixing the ureas on a Merck EN cartridge is done
after dilution of the reaction mixture with 20 ml of a 1 M sodium
hydroxide solution (cartridge conditioned with 10 ml of ethanol and 10 ml
of a 1 M sodium hydroxide solution). The radiochemical yields are listed
in Table 2.
Synthesis of ureas ½18Fꢄ4a24d via n.c.a. 4-[18F]fluoroaniline and carbamate
4-nitrophenylesters (3a–3d). About 30 mg of the corresponding carbamate-
4-nitrophenylester 3a–3d are added to the THF elution containing n.c.a.
4-[18F]fluoroaniline in a Reactivial. The mixture is stirred at slightly raised
temperature for 15 min. After this time, HPL- and thin layer chromatography
show the desired ureas [18F]4b–4d as the major or exclusive products.
Nearly no conversion is observed with the n-propyl derivative [18F]4a. The
remaining radioactivity signals could be identified in all cases as
4-[18F]fluoroaniline.
Fixing the ureas on a Merck EN cartridge is done after dilution of the
reaction mixture with 20 ml of a 1 M sodium hydroxide solution (cartridge
conditioned with 10 ml of ethanol and 10 ml of a 1 M sodium hydroxide
solution). The radiochemical yields are listed in Table 3.
Conclusion
Phenyl urea derivatives become more and more important in many fields of
pharmaceutical chemistry. This work provides two simple routes for
production of a variety of n.c.a. 4-[18F]fluorophenyl ureas via 4-[18F]fluoroani-
line. Both strategies proceed via carbamate-4-nitrophenyl esters. The choice of
the corresponding synthetic pathway depends on the chemical behaviour of
the precursor molecules. With radiochemical yields of up to 80% and a
synthesis time of 50 min, this concept gives the possibility to adapt the
physiological properties of fluorophenyl urea derivatives for radiopharma-
ceutical applications with positron-emission-tomography .
Acknowledgements
The authors wish to thank the personnel of the ‘BABY Cyclotron’ at the
Research Centre Julich for providing the [18F]fluoride. Furthermore, the vital
¨
discussion with Dr M. Holschbach and the NMR spectra recorded by him are
gratefully acknowledged.
Copyright # 2006 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2006; 49: 1037–1050
DOI: 10.1002/jlcr

1050
S. OLMA ET AL.
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