Synthesis of substituted [11C]ureas and [11C] sulphonylureas by Rh(I)-mediated carbonylation

Article abstract of DOI:10.1002/jlcr.1803

The urea moiety is present in many biologically active compounds and thus an attractive target for ¹¹C-labelling. To extend the scope of the rhodium(I)-mediated carbonylative cross-coupling reaction between an azide and an amine and investigate

Full text of DOI:10.1002/jlcr.1803

Research Article
Received 24 December 2009,
Revised 4 May 2010,
Accepted 7 May 2010
Published online 5 August 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1803
Synthesis of substituted [11C]ureas and
[11C]sulphonylureas by Rh(I)-mediated
carbonylation
y
Ã
˚
Ola Aberg , and Bengt Langstrom
˚
¨
The urea moiety is present in many biologically active compounds and thus an attractive target for 11C-labelling. To extend
the scope of the rhodium(I)-mediated carbonylative cross-coupling reaction between an azide and an amine and investigate
its tolerance for functional groups, we have synthesized eight ureas and two sulphonylureas that were 11C-labelled in the
carbonyl position. The decay-corrected analytical radiochemical yields were in the range of 14–96% (from [11C]carbon
monoxide). For example: starting from 1.33 GBq [11C]carbon monoxide, 0.237 GBq (66%) of the cytotoxic sulphonylurea
[
11C]LY-181984 11 was isolated within 60 min from end of bombardment. The mild reaction conditions and generality
regarding functional groups of this method make it an attractive alternative to the [11C]phosgene method for the synthesis
of 11C-labelled ureas.
Keywords: urea; sulphonylurea; carbonylation; [11C]carbon monoxide; rhodium(I)
were used, and lower yields when the weak nucleophile aniline
(110 mM) was used.12
Introduction
The urea and sulphonylurea moieties are commonly used in the
design of biologically active compounds, including KATP-channel
antagonists,1 angiotensin II AT1 antagonists,2 cytotoxic agents,3
and CXCR2 chemokine receptor antagonists.4
It has been shown in large-scale chemistry that rhodium(I)-
complexes can catalyse the carbonylative cross-coupling
between an azide and a nucleophile, under very mild conditions
(1 bar, 25–501C), to form the corresponding urea, carbamate, or
thiocarbamate.13–17 This reaction has been adapted to small-
scale 11C-labelling chemistry using [11C]carbon monoxide in a
model reaction to form N,N0-diphenyl[11C]urea and ethyl
phenyl[11C]carbamate.18 Recently, this method was used to
11C-label a small library of dual VEGFR-2/PDGFR-b inhibitors at
the urea position.19
We wish to extend the potential use of the rhodium(I)-
mediated [11C]urea synthesis by describing its tolerance for a
number of common functional groups. The 11C-labelling of the
biologically active insulin secretagogue tolbutamide 10 and the
cytotoxic agent LY-181984 11 is also described.
The use of positron emission tomography (PET) in drug
development has the potential to speed up the progression of a
lead compound toward its first test in man by radiolabelling of
the drug.5 PET is also extensively used as a clinical diagnostic
tool. The radionuclide 11C (b1, t1/2 = 20.4 min) can be used to
label a native compound. Because of the short half-life, 11C
should preferably be introduced in a one-pot procedure in the
last step in the synthetic route. Therefore robust, general, mild
and high-yielding methods that are suitable for automation are
highly desirable.
The most commonly used method to synthesize [11C]ureas is
the [11C]phosgene method. [11C]Phosgene can be obtained via
chlorination of [11C]methane to [11C]Cl4 and subsequent
oxidation over a metal or metal oxide.6–8 This multistep method
is tedious and often gives low specific activity. [11C]Phosgene
can also be obtained via chlorination of [11C]carbon monoxide
at elevated temperatures over PtCl4,8 or photolytically using
elemental chlorine gas.9 Several alternative routes to [11C]ureas
have been developed, including the selenium-mediated carbo-
nylation, which gives high yields of cyclic ureas and carbamates
in very high specific activity. As a consequence of the
mechanism of this reaction and the use of very low concentra-
tion of [11C]carbon monoxide, this method works best with
primary amines.10 Symmetric ureas have been prepared directly
from [11C]carbon dioxide and the corresponding amine.11
Reactive triphenylphosphine imines and [11C]carbon dioxide
gave moderate yields of [11C]ureas when strong nucleophiles
Experimental section
11C was prepared by the 14N(p,a)11C nuclear reaction using 17 MeV
proton beam produced by a Scanditronix MC-17 Cyclotron at
Uppsala Imanet, GE Healthcare and obtained as [11C]carbon
dioxide. The target gas used was nitrogen (AGA Nitrogen 6.0)
Department of Biochemistry and Organic Chemistry, Box 576, Husargatan 3,
BMC, S-751 23 Uppsala, Sweden
˚
*Correspondence to: Bengt Langstro¨m, Department of Biochemistry and Organic
Chemistry, Box 576, Husargatan 3, BMC, S-751 23 Uppsala, Sweden.
E-mail: bengt.langstrom@biorg.uu.se
yCurrent address: Imperial College, Hammersmith Campus, Faculty of Medicine
Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
J. Label Compd. Radiopharm 2011, 54 38–42
Copyright r 2010 John Wiley & Sons, Ltd.

˚
O. Aberg and B. Langstrom
˚
¨
containing 0.05% oxygen (AGA Oxygen 4.8). The carbonylation the solvent gave the product (1.736 g, 84%) as a colourless oil. 1H
reactions were carried out in a 200-ml stainless steel micro- NMR (500 MHz, CDCl3, 251C) d: 7.84 (AA0XX, 2H, Ar-H), 7.40 (AA0XX0,
autoclave according to a previously described method.20, 21 THF 2H, Ar-H), 2.48 (s, 3H, CH3) ppm. 13C NMR (125 MHz, CDCl3, 251C):
was freshly distilled over sodium and benzophenone under a 146.3, 135.6, 130.4, 127.6, 21.9 ppm. IR l: 2121 (s, azide), 1595 (m),
nitrogen atmosphere. All other chemicals were purchased from 1366(s), 1158(s), 1084(s), 812(s), 742(s), 655(s) cmꢁ1. Direct inlet
Aldrich/Fluka and used without further purification. The identities EI1 for m/z: 155 (azide radical, 93%), 91(100), 65(52).21
of the 11C-labelled compounds were determined by using
analytical HPLC using authentic samples as references. Analytical Reference urea compounds
HPLC was performed on a Beckman system, equipped with a
Beckman 126 pump, a Beckman 166 UV detector in series with a
Bioscan b1-flow count detector, and a Beckman Ultrasphere ODS
General procedure
dp 5 m column (250 ꢀ 4.6 mm). A Gilson 231 XL was used as the
auto-injector. Mobile phase: (A) 50 mM Ammonium formate pH 3.5
and (B) Acetonitrile. Purification with semi-preparative HPLC was
performed on a similar Beckman system equipped with a Genesis
C18 120 4m (250 ꢀ 10 mm). Mobile phase: (A) 50 mM Ammonium
formate pH 3.5 and (B) Acetonitrile. 1H and 13C NMR spectra were
recorded on a Varian 400 or 500 MHz spectrometer and chemicals
shifts are given in ppm (d) using CHCl3 (7.26 ppm for 1H, and 77.16
A solution of the aniline (1.68 mmol) in dichloromethane or THF
(2.5–5 ml) was added dropwise to an ice-cold solution of phenyl
isocyanate (0.200 g, 1.68 mmol) in dichloromethane or THF
(2.5–5 ml) under N2. After 30 min, the reaction mixture was
allowed to warm to r.t. and stirred for 2–6 h. After concentration
to approximately half volume, the precipitate was collected and
recrystallized in an appropriate solvent.
1
for 13C) or DMSO-dn (2.50 ppm for H, and 39.52 for 13C) as the
1-(4-Hydroxyphenyl)-3-phenyl-urea 222
internal standard. IR spectra were recorded on neat compounds
using a Perkin Elmer Spectrum 100 FT/IR spectrometer.
1H NMR (400 MHz, DMSO-d6, 251C) d: 8.96 (s, 1H), 8.45 (s, 1H),
8.25 (s, 1H), 7.43 (m, 2H, Ar-H), 7.25 (m, 1H, Ar-H), 7.21 (m, 1H, Ar-
H), 6.94 (m, 1H, Ar-H), 6.69 (m, 1H, Ar-H) ppm. 13C NMR (100 MHz,
DMSO-d6, 251C) d: 152.7, 152.5, 139.9, 131.0, 128.5, 120.4, 118.0,
115.1 ppm. LC-MS ESI1 m/z for C13H12N2O2 [M1H]: 229, [M1H
1MeCN]: 270, [2 ꢀ M1H]: 457.
Labelling chemistry
General labelling method exemplified with 1-(4-hydroxyphenyl)-3-
phenyl[11C]urea 2
To a capped and argon-purged 1.2-ml vial containing cyclooc-
tadiene rhodium(I) chloride dimer, [RhCl(COD)]2 (0.75 mg,
1.5 mmol), was added a solution of triphenylphosphine, PPh3
(0.82 mg, 3.12 mmol), in THF (1.00 ml). The mixture was shaken
vigorously until everything was dissolved. Of the resulting
rhodium complex solution, 100 ml was transferred to a capped
and argon-purged 0.8-ml vial and phenyl azide (0.95 mg,
8.0 mmol) was added as a solution in THF (100 ml). The reaction
mixture was kept in r.t. for approx 10 min before 4-aminophenol
(4.35 mg, 40 mmol) was added as a solution in THF (100 ml). The
resulting solution was injected on to a 200-ml loop and then
transferred to a 200-ml micro-autoclave containing [11C]carbon
monoxide (approx. 30 nmol) and helium. The reaction was kept
at a constant temperature of 801C for 5 min before it was
ejected into a capped and evacuated 5-ml vial. The micro-
autoclave was pressurized once more and ejected into the vial,
where the radioactivity was measured. The solvent was removed
under a stream of nitrogen in a heating block at 701C and the
radioactivity was measured again. The residue was dissolved in
acetonitrile (1 ml) and an aliquot was taken for analysis by using
analytical UV-radio-HPLC. Co-injection of an authentic sample
was performed to identify the product peak, which was isocratic
4-(3-Phenyl-ureido)-benzoic acid 3
1H NMR (400 MHz, DMSO-d6, 251C) d: 12.5 (br s, 1H), 9.14 (s, 1H),
8.87 (s, 1H), 7.86 (m, 2H), 7.55 (m, 2H), 7.46 (m, 2H), 7.30 (m, 2H),
7.00 (m, 1H) ppm. LC-MS ESI1 m/z for C14H12N2O3 [M1H]: 257,
[M1H1MeCN]: 298, [2 ꢀ M1H]: 513.
1-(2-Iodo-phenyl)-3-phenyl-urea 423
1H NMR (400 MHz, DMSO-d6, 251C) d: 9.35 (s, 1H), 7.85–7.83 (m,
3H), 7.47 (m, 2H), 7.34 (m, 1H), 7.30 (m, 1H), 7.27 (m, 1H), 6.84 (m,
1H) ppm. 13C NMR (100 MHz, DMSO-d6, 251C)d: 152.3, 139.8,
139.5, 138.8, 128.7, 128.4, 124.9, 123.0, 121.9, 118.2, 91.2 ppm.
LC-MS ESI1 m/z for C13H11IN2O [M1H]: 339, [M1H1MeCN]:
380, [2 ꢀ M1H]: 677.
1-(3-Cyano-phenyl)-3-phenyl-urea 5
1H NMR (400 MHz, DMSO-d6, 251C) d: 8.92 (s, 1H), 8.75 (s, 1H),
7.96 (s, 1H), 7.66 (m, 1H), 7.47 (m, 4H), 7.29 (m, 2H), 6.98 (m, 1H)
ppm. LC-MS ESI1 m/z for C14H11N3O [M1H]: 238, [M1H1
MeCN]: 279, [2 ꢀ M1H]: 475.
1-(4-Acetyl-phenyl)-3-phenyl-urea 624
40% B for 10 min then 95%B for 15 min at 1 ml minꢁ1
,
Rt = 8.9 min. The crude product was purified using semi-
preparative HPLC in isocratic 40% B, 4 ml minꢁ1, Rt = 9.0 min.
1H NMR (400 MHz, DMSO-d6, 251C) d: 9.06 (s, 1H), 8.76 (s, 1H),
7.88 (m, 2H), 7.54 (m, 2H), 7.42 (m, 2H), 7.25 (m, 2H), 6.95 (m, 1H)
ppm. 13C NMR (100 MHz, DMSO-d6, 251C) d: 196.3, 152.2, 144.4,
139.3, 130.4, 129.7, 128.9, 122.3, 118.4, 117.1, 23.4 ppm. LC-MS
ESI1 m/z for C15H14N2O2 [M1H]: 255, [M1H1MeCN]: 296,
[2 ꢀ M1H]: 509.
Azides
4-Methyl-benzenesulphonyl azide 1c20
To an ice-cold solution of p-TsCl (2.00 g, 10.5mmol) was added
dropwise an aqueous solution of NaN3 (0.683 g, 10.5 mmol). The
reaction mixture was allowed to warm to r.t. and stirred for 4 h,
then extracted with ether and dried over MgSO4. Evaporation of
Piperidine-1-carboxylic acid phenyl amide 725
1H NMR (400 MHz, DMSO-d6, 251C) d: 8.34 (s, 1H), 7.47 (m, 2H),
7.22 (m, 2H), 6.91 (m, 1H), 3.41 (m, 4H), 1.58 (m, 2H), 1.50 (m, 4H)
J. Label Compd. Radiopharm 2011, 54 38–42
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

˚
O. Aberg and B. Langstrom
˚
¨
ppm. 13C NMR (100 MHz, DMSO-d6, 251C) d: 154.8, 140.7, 158.0, Using an in situ formed rhodium–phosphine complex has
121.3, 119.5, 44.6, 25.4, 24.0 ppm. LC-MS ESI1 m/z for previously been shown superior to the use of Wilkinson’s
C12H16N2O [M1H]: 205, [M1H1MeCN]: 246.
catalyst.18 To the rhodium complex was added an azide (1a-c)
and just before the reaction mixture was injected onto a loop an
amine was added. The reaction mixture was transferred to a
micro-autoclave pre-charged with [11C]carbon monoxide
(8–80 nmol, the variation is due to unwanted isotopic dilution
origin from the target gas as well as surface bound CO2 on the
Zn granules used for the online reduction of [11C]O2) in helium
and pressurized with solvent (35 MPa) and kept at 801C for
5 min.30 The partial pressure of [11C]carbon monoxide in the gas
mixture during the reaction is very low, 8–80 Pa. This is one of
the differences between small-scale [11C]carbon monoxide
chemistry and large-scale chemistry, where carbon monoxide
pressures of 100–1 ꢀ 105 kPa are common.
We recently showed that higher radiochemical yields can
generally be obtained in this reaction by increasing the
concentration of the nucleophile.19 The standard nucleophile
concentration (100 mM) used in this report was chosen to
reflect the influence of the substituents rather than to
maximize the yields. Three azides and nine amine nucleophiles
(Scheme 2) were used to synthesize 10 labelled compounds
(Figure 1).
Piperazine-1-carboxylic acid phenyl amide 826
The addition order was reversed, however, a significant portion
of the formed product was the corresponding N1,N4-diphenyl-
piperazine-1,4-dicarboxamide. LC-MS ESI1 m/z for C11H15N3O
[M1H]: 206, [M1H1MeCN]: 247, [2 ꢀ M1H]: 410.
1-Butyl-3-phenyl-urea 9
1H NMR (400 MHz, DMSO-d6, 251C) d: 8.37 (s, 1H), 7.38 (m, 2H),
7.20 (m, 2H), 6.87 (m, 1H), 6.09 (m, 1H), 3.05 (m 2H), 1.39 (m, 2H),
1.31 (m, 2H), 0.89 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (100 MHz,
DMSO-d6, 251C) d: 155.2, 140.6, 128.7, 120.9, 117.6, 38.7, 31.9,
19.6, 13.7 ppm. LC-MS ESI1 m/z for C11H16N2O [M1H]: 193, [M1
H1MeCN]: 234, [2 ꢀ M1H]: 385.
N-[(4-chlorophenyl)amino]carbonyl-4-methylbenzenesulphona-
mide 11
1H NMR (500 MHz, CDCl3:DMSO-d6, 251C) d: 9.95 (br s, 1H), 8.00
(br s, 1H), 7.65 (m, 2H), 7.06 (m, 4H), 6.93 (m, 2H), 2.17 (s, 3H)
ppm. LC-MS ESI1 m/z for C14H13ClN2O3S [M1H]: 325.
Generally, when phenylazide 1a (Route A) was used as
substrate and strong nucleophiles were used, the reactions
were very clean and gave high radiochemical yields of the
expected [11C]ureas, while weaker nucleophiles gave lower
yields and formation of by-products. Both acidic and basic
Results and discussion
The lack of a general one-pot procedure for synthesizing functional groups were well tolerated in the nucleophiles
differently substituted [11C]ureas from simple starting materials (Table 1, Entries 1, 2, 7–9). The radiochemical yields roughly
in high specific activity and high yields prompted us to further correlates with the nuclophilicity of the amines secondary
explore the Rh(I)-mediated carbonylation using [11C]carbon amines 4 primary amines = activated anilines4deactivated
monoxide.18–19 Because carbon monoxide is less abundant in anilines.31 However, piperidine (Table 1, Entry 7) gave an
the air than carbon dioxide, the use of online produced unexpectedly low yield compared with butylamine (Table 1,
[11C]carbon monoxide as the labelled precursor generally Entry 9), possibly due to its very hygroscopic properties.
results in labelled products with lower isotopic dilution and
Aryl iodides are generally good substrates for oxidative
higher specific activity. We have previously shown that addition to transition metal complexes, such as Rh(I), and could
[11C]ureas synthesized via Rh(I)-mediated carbonylative cross- potentially lead to unwanted side reactions. Indeed, when
coupling can be obtained in specific activities in the order of 1-azido-2-iodobenzene 1b (Route B) was used as the substrate
100–600 GBq ꢂ mmolꢁ1 10, 18–19
.
and aniline was the nucleophile, two distinct products
The radioactivity was produced via the 14N(p,a)11C nuclear accounted for over 95% of the converted [11C]carbon monoxide;
reaction and was obtained in the target as [11C]carbon dioxide. urea 4 was the minor product of the two (Table 1, Entry 4).
The radioactivity was concentrated at ꢁ1961C, transferred online When instead azide 1a (Route A) was used as substrate and
via a helium flow to the hotcell and concentrated once again on 2-iodoaniline was used as nucleophile, low [11C]O-conversion
a silica column at ꢁ1961C. The helium-carrier-added [11C]carbon and 36% radiochemical yield was the result. Still, this reaction
dioxide was reduced to [11C]carbon monoxide over zinc at 4001C, was cleaner and 70% of the converted [11C]carbon monoxide
concentrated on silica at ꢁ1961C, and transferred to a 200-ml was converted to the desired urea 4. Thus, the lower yield is to
micro-autoclave using a previously described technique.27, 28
a high degree a reflection of the low nucleophilicity of the
The active rhodium complex was prepared by mixing the 2-iodoaniline rather than formation of unwanted by-products
cyclooctadiene rhodium(I) chloride dimer [Rh(cod)Cl]2 with (Table 1, Entry 3). Thus, an aromatic iodide in the substrate
triphenylphosphine (Rh:P = 1:1). The actual active complex (Table, Entry 4) is more problematic than an iodide in the
achieved was not characterized but it is likely that Rh(I)-dimer nucleophile (Table 1, Entry 3), despite that there is five
is split into two Rh(I)(cod)PPh3Cl on coordination of
a
times as much nucleophile present. The nucleophile is always
triphenylphosphine according to the first step in Scheme 1.29 added as the last reagent to the reaction mixture before
excess PPh3
Ph3P
Ph3P
PPh3
Rh
Cl
Cl
Rh Rh
Cl
2 PPh3
PPh3
Cl
2 x
= cycloocta-1,5-diene
2 x
Rh
Wilkinson's catalyst
Scheme 1. Formation of the active Rh(I)-phosphine complex.
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Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 38–42

˚
O. Aberg and B. Langstrom
˚
¨
Route A
11C]O
Rh(I)-complex
PPh3
Route B
11C]O
Rh(I)-complex
PPh3
N3
[
[
H
H
1a
I
N
N
R'
R
Amine
+
or
Amine
+
O
THF
80 oC
5 min
THF
80 oC
5 min
N3
2-11
1b
O
S
N3
11C]
O
1c
Scheme 2. Rhodium(I)-mediated carbonylative cross-coupling of an azide and an amine to form a [11C]urea.
H
N
H
N
H
N
H
N
H
H
N
N
O
O
O
HO
NC
HOOC
I
3
4
2
H
N
H
N
H
N
H
N
O
O
O
6
5
NH
H
N
H
N
H
N
H
N
N
N
O
O
O
8
9
7
H
N
H
N
H
N
H
N
11C]
S
S
O
O
O
O
O
O
Cl
10 (Tolbutamide)
11 (LY-181984)
Figure 1. Urea derivatives labelled with 11C at the carbonyl position.
Table 1. Rh(I)-mediated [11C]urea synthesis
Entry
Product
Azide
Amine
[11C]O-conv. (%)a,b
Anal. RCY (%)b,c
1
2
3
4
5
6
7
8
2
3
4
4
5
6
7
8
9
1a
1a
1a
1b
1a
1a
1a
1a
1a
1c
1c
1c
4-Hydroxyaniline
4-Carboxyaniline
2-Iodoaniline
Aniline
3-Cyanoaniline
4-Acetoaniline
Piperidine
Piperazine
Butylamine
Butylamine
4-Chloroaniline
4-Chloroaniline
8971 (2)
5973 (2)
5273 (2)
7679 (2)
7177 (4)
2771 (2)
8470 (2)
9671 (2)
8873 (2)
9073 (2)
93
8871 (2)
5674 (2)
3670 (2)
26713 (2)
2477 (4)
1471 (2)
6272 (2)
9671 (2)
8873 (2)
8371 (2)
79
9
10
11d
12e
10 (Tolbutamide)
11 (LY-181984)
11 (LY-181984)
92
78
Standard conditions were: helium-carrier-added [11C]carbon monoxide (0.05–0.5 mM) pressurized in a 200-ml micro-autoclave to
35MPa with a solution of [Rh(cod)Cl]2 (0.40 mM), triphenylphosphine (0.80 mM), a phenylazide (1a or 1b) or p-toluenesulpho-
nylazide 1c (20 mM) and an amine (100mM) in THF at 801C for 5 min.
aDecay-corrected conversion yield of [11C]carbon monoxide to non-volatile products remaining in the reaction mixture after
removal of solvent via a stream of nitrogen at 701C. When the reaction mixture was transferred from the micro-autoclave to a 5-ml
evacuated vial, the radioactivity in the vial was measured. The radioactive residues left in the micro-autoclave were estimated to be
less than 1%. Hence, the amount of initial radioactivity of [11C]carbon monoxide could be determined.
bThe numbers in parentheses indicate the number of experiments.
cAnaytical radiochemical yield as the sum of the decay-corrected analytical HPLC radiochromatogram and the decay-corrected
conversion of [11C]carbon monoxide.
dAmine (370 mM), 1c (16 mM).
eAmine (185mM), 1c (16 mM), [Rh(cod)Cl]2 (0.20 mM), triphenylphosphine (0.40 mM).
J. Label Compd. Radiopharm 2011, 54 38–42
Copyright r 2010 John Wiley & Sons, Ltd.
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˚
O. Aberg and B. Langstrom
˚
¨
injection to the micro-autoclave, which suggests that coordina-
tion or oxidative addition of the azide to the rhodium(I)
complex under these reaction conditions may prevent the
oxidative addition of the iodide. The formation of a nitrene
complex on loss of molecular nitrogen is also a plausible
reaction mechanism.16
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Meta-cyanoaniline is a weak nucleophile and yielded a very
lipophilic byproduct as the major labelled product, whereas the
desired urea 5 was produced in only 24% radiochemical yield
(Table 1, Entry 5). The deactivated p-acetylaniline gave low
[11C]O-conversion and resulted in low a yield of urea 6, probably
due to its low nucleophilicity (Table 1, Entry 6). The reaction with
the strong nucleophile n-butylamine and phenylazide 1a gave
the urea 9 as the only labelled product. The related reaction
using p-toluenesulphonylazide 1c as the substrate gave a
slightly lower yield of [11C]tolbutamide 10 (Table 1, Entries 9
and 10). The loss of product on purification (compared with the
analytical radiochemical yield) were in the range of 10–30% as
exemplified by compounds 2 and 11 that were isolated using
semi-preparative HPLC in 61 and 68% decay-corrected radio-
chemical yield, respectively.
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Rh(I)-mediated carbonylations of azides to form [11C]ureas
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aromatic iodide in the substrate competes for coordination/
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Acknowledgement
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(2006.01) ed. (Ed.: A. PLC), Sweden, 2002.
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This work was conducted in collaboration with Uppsala Imanet,
GE Healthcare. Assoc. Prof. Tor Kihlberg and Dr. Tamara Church
are gratefully acknowledged for linguistic advice and comment-
ing on the text.
www.jlcr.org
Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 38–42