A simplified [11C]phosgene synthesis

Article abstract of DOI:10.1016/j.tetlet.2009.11.011

A new flow-through system for the production of [¹¹C]phosgene, a versatile labelling agent in radiochemistry for PET, is described. Cyclotron-produced [¹¹C]CH₄ is mixed with Cl₂ and converted into [¹¹C]CCl₄ by passing the mixture through an empty quartz tube at 510 °C. The outflow is directed through a Sb-filled guard that takes out Cl₂ and then, without intentional O₂ addition, through a second empty quartz tube at 750 °C, giving rise to [¹¹C]phosgene in 30-35% radiochemical yield.

Full text of DOI:10.1016/j.tetlet.2009.11.011

Tetrahedron Letters 51 (2010) 313–316
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1
1
A simplified [ C]phosgene synthesis
*
Yann Bramoullé, Dirk Roeda , Frédéric Dollé
CEA, Institut d’imagerie biomédicale, Service hospitalier Frédéric Joliot, 4 place du Général Leclerc, F-91401 Orsay, France
a r t i c l e i n f o
a b s t r a c t
A new flow-through system for the production of [1 C]phosgene, a versatile labelling agent in radiochem-
1
Article history:
Received 23 September 2009
Revised 27 October 2009
Accepted 3 November 2009
Available online 10 November 2009
11
11
istry for PET, is described. Cyclotron-produced [ C]CH
passing the mixture through an empty quartz tube at 510 °C. The outflow is directed through a Sb-filled
guard that takes out Cl and then, without intentional O addition, through a second empty quartz tube at
50 °C, giving rise to [ C]phosgene in 30–35% radiochemical yield.
Ó 2009 Elsevier Ltd. All rights reserved.
4 2 4
is mixed with Cl and converted into [ C]CCl by
2
2
1
1
7
Keywords:
Phosgene
Carbon-11
Radiolabelling
Positron emission tomography (PET) is a medical imaging tech-
nique that traces quantitatively substances, radiolabelled with a
short-lived positron-emitting radioisotope, administered to the pa-
for [11C]ureas and [11C]carbamates from [11C]CO
2
and [11C]CO have
3
6,37
been proposed
which may become more important in the
future although they may not have the same scope that offers
phosgene chemistry.
1
tient. Carbon-11 (20.4 min half-life) is one of the more important
radioisotopes in PET and [11C]phosgene has been for long a well-
recognized tool in radiochemical carbon-11 incorporation. It is par-
ticularly useful in the generation of carbonyl-labelled cyclic and
linear carbamates and ureas. Its high chemical reactivity, which of-
ten ensures almost instantaneous reaction, is an advantage in view
of the 20.4 min half-life of carbon-11.
Our original procedures of [11C]phosgene production based on
[11C]carbon monoxide
38,39
were replaced in 1987 by a method also
4
0
developed in our laboratory by Landais and Crouzel. In this pro-
1
1
cedure [ C]methane and chlorine gas are passed by way of a vec-
tor gas through hot cupric chloride on pumice stone giving
1
1
11
[
C]tetrachloromethane which is then converted into [ C]phos-
Since its first introduction in 1978 [11C]phosgene has been used
in a number of laboratories for the radiosynthesis of many tracers
for biomedical investigations, for example, the b-adrenoceptor li-
gene by passage through hot iron filings. Some dioxygen, added
to the inert vector gas, serves as an oxygen source for the latter
reaction (Scheme 1A). In 1997 we adopted a modification proposed
by Link et al. which replaces the cupric chloride catalyst by an
1
1
2–4
gand
[
(
[
C]CGP-12177,
the acetylcholinesterase inhibitor
1
1
5
11C]befloxatone
6,7
41
C]physostigmine, the MAO-A inhibitor
[
empty quartz tube at 560 °C ( Scheme 1B). In our experience
Fig. 1) and many others.8
–35
Recently some nonphosgene methods
and in that of others, however, the iron catalyst can give rise to
42
H C
3
CH3
CH3
OCH3
O
N
H
H
H C
H
3
1
1
N
O
OH
N
H C
C
11
O C
N11 O
3
N
OH
C
O
CH3
N
N
O
F3C
O
CH3
C]Physostigmine
H
[11
[11C]CGP-12177
[11C]Befloxatone
Figure 1. Three selected structures labelled with carbon-11 using [11C]phosgene.
*
Corresponding author. Tel.: + 33 (0)1 69 86 77 36; fax: + 33 (0)1 69 86 77 49.
E-mail address: dirk.roeda@cea.fr (D. Roeda).
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.011

3
14
Y. Bramoullé et al. / Tetrahedron Letters 51 (2010) 313–316
H
Cl
O
C
Cl , Δ
1
1
2
Cl 11C Cl
11
H C H
conditions
see below
conditions
see below
Cl
Cl
H
Cl
[11
C]methane
[11C]phosgene
Copper chloride (CuCl2)
on pumice stone, 380ºC
Iron filings (Fe)
Landais et al.
(JLCR, 1987)
A
B
C
O , 300ºC
2
Empty quartz tube
Iron filings (Fe)
290ºC
Link et al.
(JLCR, 1997)
560ºC
Empty quartz tube
10ºC
Empty quartz tube
750ºC
This work
5
Scheme 1. Conversion of [11C]methane into [11C]phosgene with reaction conditions of the various methods.
reproducibility problems related to the state of the iron. In the
present Letter we report on an innovation that disposes of the iron
catalyst in the second step and replaces it by an empty quartz tube
at 750 °C (Scheme 1C).
filled with phosphorus pentoxide, a U-shaped copper tube (T
filled with Porapak-Q, a second phosphorus pentoxide guard and
a second smaller U-shaped copper tube (T ) with Porapak-Q. The
units T , T and T
are cooled in liquid-argon bath (ꢀ186 °C). The
irradiated pressurized target gas is expanded through traps T /T
mol)
. Apart from [ C]methane the irradiation gives rise
to considerable amounts of ammonia comprising radioactive
1
),
2
0
1
2
The new manually remote-controlled flow-through system for
C]phosgene synthesis, placed in a 5 cm-lead shielded hot cell,
0
1
[11
(maximum flow rate: ꢁ500 mL/min). The [ C]methane (<1
11
l
1
1
comprises three stages arranged in series (stages 1–3, Fig. 2). The
vector gas for taking the radioactivity through the system is he-
is retained on T
1
1
1
13
lium. [ C]Methane is directly produced in a dedicated cyclotron
[ N]ammonia as well. Ammonia would interfere with the forma-
4
3
11
target holder.
The first stage aims at the isolation of cyclotron-produced no-
tion of [ C]phosgene and therefore trap T
0
4
freezes it out with
4
the phosphorus pentoxide guard as a backup. Any traces of water
are also intercepted by this system. [ N]Dinitrogen that is also
1
1
13
carrier-added [ C]methane from the irradiated matrix gases N
2
2
and H . It features an empty stainless steel coil (T
0
), a glass tube
formed in the target in large quantities, is not retained and ends
Cl2
FM
mv
mv
He
decay-lines
FM
5
10ºC
750ºC
Sb
empty
empty
v1
v2
v3
v4
v5
tube
tube
v6
v7
Target contents
1
1
[
C]CH
4
N + 5%H
2
2
T0
P2O5
liquid Ar
186ºC
M
-
1
1
[
C]CH4 - Cl2
R
mixing-chamber
T2
liquid Ar
liquid Ar
-186ºC
-
186ºC
T1
Porapak-Q
STAGE 1
STAGE 2
STAGE 3
Figure 2. Schematic outline of the [11C]phosgene synthesis apparatus. The components are interconnected by Teflon tubing (id: 1/16 ) via three-way valves (v1–v7,
00
Rheodyne 5301 and 5302; mv: manual valve). T
mesh, Waters), 4 mm id; T : 15 cm Porapak-Q-filled tube, 2 mm id; M: Vessel with screw-cap and septum with in- and outlet needles (h: 4.5 cm, V: 1.6 cm ); Heated quartz
tubes: (16.5 cm heated length, 7 mm id, 13 mm od); 13 cm Sb-filled tube, 8 mm id: 4 g of a 60/40 (w/w) mixture of Sb powder (Riedel-de-Haën) and 1 mm glass beads
Aldrich); R: Reaction vessel. Radioactivity is monitored with appropriately positioned miniature ionisation chamber probes.
0 2 5 1
: 50 cm empty coil, 4 mm id; P O -filled guards: 3 cm pathway, 10 mm id; T : 15 cm tube filled with Porapak-Q (80–100
3
2
(

Y. Bramoullé et al. / Tetrahedron Letters 51 (2010) 313–316
315
1
1
up as waste gas. Liquid-argon cooled Porapak-Q has a limited
soda lime trap. The first solution converts [ C]phosgene into a
11
11
0
11
capacity of methane retention; the
through the tube as in a gas chromatographic system. Therefore
our system has a relatively large trap T to initially collect
C]methane at high flow rate and a second smaller trap T to con-
centrate it in a small volume, which is important for an efficient
mixing with the chlorine in vessel M. Thus T is switched in series
with T and the vector gas (40 mL/min) is directed through the two
traps (outlet to waste at v4). T is lifted out of its cooling bath and
heated with a hot air jet which causes the [ C]methane to migrate
to T . The helium flow is now reduced to 15 mL/min and T is lifted
out of the cooling bath. The very moment that radioactivity begins
to leave T , the parts of the flow system representing the second
[
C]methane progresses
mixture of phenyl [ C]isocyanate and N,N -diphenyl[ C]urea
and traps all [ C]chloromethanes. It is analyzed with HPLC.
The CuCl/HCl solution traps [ C]carbon monoxide and the soda
1
1
50
1
1
1
1
1
11
[
2
lime intercepts any [ C]carbon dioxide.
Figure 3 shows the results of the experiments aimed at optimiza-
tion of the temperature of the second quartz tube. At the lowest
temperature of this series, 550 °C, most of the recovered radioactiv-
ity is [ C]tetrachloromethane (84%, confirmed by GC; [ C]trichlo-
romethane: 12%, [ C]dichloromethane: 4%). The radiochemical
yield of [ C]phosgene relative to [ C]methane has a maximum of
30–35% between 700 and 750 °C. With increasing temperature from
700 °C on, the amount of recovered radioactivity, all products in-
cluded, declines rapidly to reach only 12% at 900 °C. This decline
could possibly be due to carbonization on the hot quartz surface
on which the elemental carbon-11 would be retained. Above
2
1
1
1
11
1
11
11
1
1
11
2
2
2
and third stage are switched in line.
The second stage oxidizes [11C]methane with chlorine gas to
[11
C]tetrachloromethane and follows the procedure described by
4
1
11
11
Link and Krohn with a slight modification. The [ C]methane
arrives in a chlorine-filled vessel where it mixes with the chlorine.
Next a heated horizontal quartz tube assures the chlorination. In
ourhandsthemethodworkedbestwiththetubeat510 °C, atemper-
ature we maintained in the present work. Like in Link’s procedure,
dioxygen is not added intentionally. Probably traces of air sneaking
in during the filling of M with chlorine gas suffice as an oxygen
source or otherwise the hot quartz surface has also oxygen atoms
available. Before entering stage three the gases pass through a verti-
cal tube containing a mixture of antimony powder and 1 mm glass
beads (Aldrich), which eliminates excess of chlorine transforming
it into antimony tri- or pentachloride. The material, like in all other
tubes, is kept in place by quartz-wool plugs on either side.
600 °C the amount of surviving [ C]chloromethanes (mainly
C]tetrachloromethane) falls rapidly to reach practically zero at
750 °C. Around 750–800 °C [ C]phosgene, although declining in
absolute terms, accounts for 80% of the recovered activity. At
1
1
[
1
1
1
1
900 °C [ C]carbon monoxide, which is mounting gradually all along
1
1
the temperature stretch and possibly formed by [ C]phosgene
decomposition, is the only product present. Practically no [11C]car-
bon dioxide is found in the soda lime trap. The antimony guard is
placed in between the two tubes and not at the end because the pres-
1
1
2
ence of Cl in the second tube results in practically no [ C]phosgene
1
1
and lots of [ C]carbon monoxide.
This new method of [11C]phosgene production has been used
now for some time in our laboratory in the radiosynthesis of
C]befloxatone with yields and specific radioactivities (40–
mol, EOB decay corrected) comparable with the previ-
ous method and with good reproducibility. The main advantage
of the method is a gain in simplicity, as no catalyst at all is used,
avoiding at the same time potential problems related to this cata-
lyst. The whole process takes 12–13 min from the end of carbon-11
production.
The third stage converts [11C]tetrachloromethane into [11C]phos-
gene in an empty horizontal quartz tube, identical to the first, heated
at750 °C. Theoutletofthesystemcanbeconnectedtoa reactionves-
[
11
110 GBq/
l
6
,7
1
1
sel (R) in which the [ C]phosgene is passed through a solution for
further reaction and/or analyses.
All experiments were performed, after appropriate system
4
8
11
preparation, with a starting amount of [ C]methane of about
.85 GBq. The outflow of the first quartz tube was analyzed sepa-
1
49
rately (second oven off) with gas chromatography. The radio-
Acknowledgements
1
1
chemical yield of [ C]tetrachloromethane is around 60%. With
both ovens on, the final gaseous radioactive reaction mixture was
analyzed as follows: The outflow of the system is passed succes-
The authors wish to thank the cyclotron operators Mr Daniel
Gouel, Mr. Christophe Peronne and Mr. Christophe Lechêne for per-
forming the irradiations. This work was supported in part by the
EC—FP6-project DiMI (LSHB-CT-2005-512146) and EMIL (LSH-
sively through a solution of aniline (10
300
L) at room temperature,30 a solution of 0.45 M cuprous chlo-
ride in 6.5 N hydrogen chloride (33 mL) at room temperature and a
lL) in dichloromethane
(
l
2
004-503569).
References and notes
100
1
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9
8
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2
1
0
0
0
0
0
0
0
0
0
0
1
[
C]CH Cl
x
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1
[
C]CO
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1
Figure 3. Formation of [11C]phosgene, [11C]chloromethanes and [11C]carbon mon-
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C]methane ([11C]CH
4
) was
11
43. Radioisotope production: No-carrier-added
produced on an IBA Cyclone-18/9 cyclotron (18 MeV proton beam, IBA,
1
1
1
2
2
14
11
Louvain-la-Neuve, Belgium) via the
irradiation of a target consisting of an ultrapure mixture of dinitrogen and
dihydrogen (N /H , 95/5 (v:v), Air Liquide). The dedicated aluminium target
[ N(p,a) C] nuclear reaction by
2
2
holder (IBA, Louvain-la-Neuve, Belgium) contains the gas mixture at 20 bar
(beam off) in a volume of 50 mL. Typical production for the present work:
1
996, 23, 150.
11
2
2
2
2
2
2
2
2
2. Roeda, D.; Tavitian, B.; Coulon, C.; David, F.; Dollé, F.; Fuseau, C.; Jobert, A.;
ꢁ1.85 GBq of
4
[ C]CH at the end of bombardment for a 5 lA, 5 min
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44. To avoid1 [13N]ammonia one could make [11C]methane from [11C]carbon
4
11
45–47
2 2
dioxide ( N(p,a) C, N /O target) and dihydrogen catalyzed by nickel.
11
This dispenses from [ C]methane dedicated cyclotron targetry and the trap T
0
11
as no ammonia is produced. Also, [ C]carbon dioxide usually can be produced
in larger quantities than [11C]methane. On the other hand it introduces an
additional radiochemical transformation requiring an additional oven and
11
hydrogen gas manipulation.
specific radioactivity than [ C]carbon dioxide.
[
C]Methane often has
a somewhat higher
11
45. Dence, C. S.; Herrero, P.; Schwarz, S. W.; Mach, R. H.; Gropler, R. J.; Welch, M. J.
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1
1
48. System preparation before [ C]phosgene synthesis: Phosphorus pentoxide (1.5 g)
and antimony (4 g of a 60/40 (w/w) mixture of antimony powder and 1 mm
1
2, 3229.
glass beads) fillings are renewed before each synthesis. The Porapak-Q in T
and T can be reused an indefinite number of times. The system is thoroughly
flushed with helium while the ovens are heating the quartz tubes. The helium
flow is finally stopped and the helium in vessel M is replaced by chlorine gas
(99.99%, Air Liquide) by way of a 3 mL syringe. Vessel M is isolated from the
rest of the system by valves as is the system as a whole from the exterior.
1
3
3
3
3
3
3
3
0. Dollé, F.; Martarello, L.; Bramoullé, Y.; Bottlaender, M.; Gee, A. D. J. Label.
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2
49. Gas chromatography was performed using
a Delsi-Nermag DN 200 MC
0
0
apparatus; column: Hayesep-Q 80/100 mesh (2 m ꢂ 1/8 ); helium (15 mL/
min); catharometer and radioactivity detection. The retention times of the
11
11
4
various radioactive products were as follows: [ C]CO: 0.9 min, [ C]CH :
11 11 11
1.5 min, [ C]CO
[ C]CCl
4
2
: 2.8 min, [ C]CH
: 14.0 min.
50. High performance liquid chromatography (HPLC) was performed using
Waters 510 pump, a Shimadzu SPD10-AVP UV-multi-wavelength spectrometer
2 2 3
Cl : 8.5 min, [ C]CHCl : 10.8 min and
11
a
Ò
and a Geiger–Müller detector; column: semi-preparative Lichrosorb SiO
Merck (250 ꢂ 10 mm; porosity: m); solvents and conditions: isocratic
elution with CH Cl /EtOH/H O/EtNH : 990/9.6/0.2/0.2 (v:v:v:v); flow rate:
2
,
3
3
3
4
4
7. Kihlberg, T.; Karimi, F.; Långström, B. J. Org. Chem. 2002, 67, 3687.
8. Roeda, D.; Crouzel, C.; van Zanten, B. Radiochem. Radioanal. Lett. 1978, 33, 175.
9. Roeda, D.; Westera, G. Int. J. Appl. Radiat. Isot. 1981, 32, 931.
0. Landais, P.; Crouzel, C. Appl. Radiat. Isot. 1987, 38, 297.
1. Link, J. M.; Krohn, A. J. Label. Compd. Radiopharm. 1997, 40, 306.
7 l
2
2
2
2
8.0 mL/min; temperature: rt; absorbance detection at k = 254 nm. Capacity
0
factors: phenyl isocyanate: 6.45, N,N -diphenylurea: 1.73, chloromethanes:
1.00.