Direct fixation of [11C]-CO2 by amines: Formation of [11C-carbonyl]-methylcarbamates

Article abstract of DOI:10.1039/b916419g

[¹¹C-Carbonyl]-methylcarbamates can be synthesised directly from [¹¹C]-CO₂ and primary or secondary amines in a one-pot, two-step reaction. The use of either diazabicyclo[5.4.0]undec-7-ene (DBU) or 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) enables efficient trapping of [¹¹C]-CO₂ in small volumes of DMF as [¹¹C]-carbamate salts. Subsequent reaction with a variety of methylating agents rapidly generates the desired [ ¹¹C-carbonyl]-methylcarbamates in high radiochemical yields. The usefulness of the method is illustrated by the efficient radiosynthesis of a kappa opioid receptor imaging radiotracer, useful in positron emission tomography (PET).

Full text of DOI:10.1039/b916419g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Direct fixation of [11C]-CO2 by amines: formation
of [11C-carbonyl]-methylcarbamates†
Alan A. Wilson,* Armando Garcia, Sylvain Houle and Neil Vasdev
Received 11th August 2009, Accepted 5th October 2009
First published as an Advance Article on the web 18th November 2009
DOI: 10.1039/b916419g
[11C-Carbonyl]-methylcarbamates can be synthesised directly from [11C]-CO2 and primary or secondary
amines in a one-pot, two-step reaction. The use of either diazabicyclo[5.4.0]undec-7-ene (DBU) or
2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) enables
efficient trapping of [11C]-CO2 in small volumes of DMF as [11C]-carbamate salts. Subsequent reaction
with a variety of methylating agents rapidly generates the desired [11C-carbonyl]-methylcarbamates in
high radiochemical yields. The usefulness of the method is illustrated by the efficient radiosynthesis of a
kappa opioid receptor imaging radiotracer, useful in positron emission tomography (PET).
and guanidines.13 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in
Introduction
particular has been the subject of much study in this regard,14,15
and while its mechanism of action is still debatable,16 this amidine
seems particularly efficient as a CO2 fixation and transfer agent.
Indeed, during this work, an elegant study showed the utility of
DBU as an agent to prepare [11C]-benzylcarbamates directly from
[11C]-CO2 and amines.17
Positron emission tomography (PET) is a powerful biomedical
imaging technique, which continues to develop as a useful tool for
cancer imaging, drug development and basic research.1 PET relies
upon the supply of radiotracers, labelled with positron emitting
radionuclides; most commonly carbon-11 (half-life 20.4 min) or
fluorine-18 (half-life of 109.7 min).2 The short half-life of carbon-
11 severely restricts the type and number of chemical steps that
can be employed in the production of a target molecule.3 While
cyclotron-produced [11C]-CO2 is the starting material for the
radiosynthesis of the vast majority of [11C]-labelled radiotracers
used for PET, it is commonly transformed into other, more
versatile synthons such as [11C]-iodomethane4 or [11C]-methyl
triflate.5 These are then reacted with more complex substrates
(precursors) to generate the desired radiotracer.
Methods of direct reaction of [11C]-CO2 with amines have been
limited to a few examples of mainly esoteric interest. Pre-formed
N-silyl amines have been labelled with [11C]-CO2 and reduced to
[11C]-N-methylamines.6 However, the conditions were complex,
yields low, and products unisolated. Simple symmetrical [11C]-
labelled ureas have been reported by the low-temperature trapping
of [11C]-CO2 with amines followed by treatment with POCl3.7
Unsymmetrical [11C]-labelled ureas have been synthesised by the
sequential reaction of [11C]CO2 with phosphinimines followed by
treatment with amines, but only phenylureas were prepared by
this method.8 Recent interest in “green” chemistry has resulted
in significant advances in the direct fixation of carbon dioxide
into organic molecules.9 Specifically, the synthesis of carbamates
from amines, CO2 and an alkylating agent has been the subject
of much scrutiny, and reaction conditions have been developed
which allow efficient CO2 fixation.10 Catalysts studied for this
particular transformation include alkali carbonates,11 zeolites12
We report here the use of DBU and an even more
efficient fixation agent, 2-tert-butylimino-2-diethylamino-1,3-
dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP), to directly
trap [11C]-CO2 at ambient temperature and facilitate (a) the
fixation of [11C]-CO2 into solution from a dilute N2 gas stream
as carbamic acid salts 1 and (b) the rapid and efficient syn-
thesis of [11C]-methylcarbamates 3 from a variety of primary
and secondary amines (Scheme 1). The practical application of
this [11C-carbonyl]-carboxymethylation radiolabelling method to
complex functionalised molecules is demonstrated by the efficient
radiosynthesis of [11C-carbonyl]-GR103545, a positron-emitting
radiopharmaceutical developed for the PET imaging of kappa
opioid neuroreceptors.18
Scheme 1 Q = fixation agent, either DBU or BEMP.
Results and discussion
Efficiency of [11C]-CO2 trapping
PET Centre, Centre for Addiction and Mental Health and University of
Toronto, Toronto, Canada. E-mail: alan.wilson@camhpet.ca
† Electronic supplementary information (ESI) available: Full experi-
mental details on the radiosynthesis of [11C-carbonyl]-GR103545, [11C]-
CO2 gas–liquid partition data, and 1H and 13C NMR spectra of
4-(2-methoxyphenyl)-1-piperazinecarboxylic acid methyl ester. See DOI:
10.1039/b916419g
The abilities of DBU and BEMP to trap [11C]-CO2 in solution were
determined by measuring the equilibrium distribution of [11C]-CO2
between the gas and liquid phase of solutions of fixation agent in
DMF at various concentrations in a sealed container.19 In pure
DMF, the partition ratio [11C]-CO2 liquid–gas (PR) was 7.5, in
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Table 1 Synthesis of [11C-carbonyl]-methylcarbamates from [11C]-CO2
showed that (a) radiochemical yields were not increased by
increasing the reaction time of [11C]-CO2 with amine past 1 min
and (b) yields were not improved by increasing the reaction time
of the methylating agent to more than 10 s. That both reaction
steps are rapid bodes well for radiosyntheses with the short-lived
isotope carbon-11.
and primary or secondary amines using DBUa
Radiochemical yields of [11C]-methylcarbamates were good
to excellent for both primary and secondary aliphatic amines
(Table 1, entries 1–6), even for the sterically hindered N-benzyl-N-
isopropylamine (Table 1, entry 4). However, aromatic amines were
more problematic. Aniline gave variable results with yields varying
between 11–40% (Table 1, entry 7), while the even less nucleophilic
4-nitroaniline gave only 3–8% radiochemical yield (Table 1, entry
8, first 2 runs). Yields from aromatic amines could be improved
somewhat by doubling the amine concentration (Table 1, entries
8 and 9, last runs). Using the hydrochloride salts of amines as
opposed to the free base had little effect on the reaction (compare
Table 1, entries 1 and 2).
With 2-methoxyphenylpiperazine hydrochloride (MPP) as a
model amine, the effects of amine concentration, fixation agent,
and methylating agent on radiochemical yields were examined
(Table 2). It became immediately apparent that BEMP was supe-
rior to DBU in this reaction (compare Table 2, entries 1 vs. 2 and 3
vs. 4). Reducing the concentration of MPP had only a modest effect
on radiochemical yields; even at a concentration of only 0.5 mg
mL-1, radiochemcial yields were still moderate (Table 2, entry 12).
There was a more complex interplay between the stoichiometry of
the amine and the alkylating agent, which suggests that at lower
amine concentrations, too much methylating agent is deleterious
to the reaction (compare Table 2, entries 10 and 11). This, perhaps,
Entry
1
Amine substrate
Radiochemical yield (%)b
65–75 (n = 6)
2
80, 79
3
4
5
90, 95
76, 69
96, 91
6
7
85–90 (n = 3)
11, 23, 32, 40, 28
8
9
3, 8, 20c
22, 40, 55c
Table 2 A study of amine concentration, fixation agent, and methylating
agenta
a Standard conditions: amine (4.16 mmols) + DBU (42.4 mmols) in DMF
(80 mL) treated with [11C]-CO2 in N2 (10 mL min-1). Reaction at r.t.
for 1 min then treated with solution of DMS (52.8 mmols) in DMF
(400 mL). Reaction quenched with aq. NH3 after 10 s. b See experimental
for definition. c 8.32 mmols of amine used.
good agreement with literature values.20 PRs increased in a linear
manner with increasing concentrations for both fixation agents,
but the effect was much more dramatic for BEMP than DBU, e.g.
at 100 mM, the PR for DBU in DMF was 25, while for BEMP
in DMF it was over 250. Thus, while DBU is effective at trapping
CO2 in solution as previously reported, BEMP is even more so.
Fixation
Methylating Radiochemical
agent/mL
Entry [MPP]/mg mL-1 agent/mL
yield (%)b
1
2
3
4
5
6
7
10
10
10
10
10
10
5
DBU (6)
DMS (5)
79
93
39
75
10
48
87
94
96
60
90
45
79
78
0.7
33c
BEMP (6) DMS (5)
DBU (6) DMS (1)
BEMP (6) DMS (1)
DBU (1) DMS (5)
BEMP (1) DMS (5)
BEMP (6) DMS (5)
BEMP (3) DMS (5)
BEMP (6) DMS (1)
BEMP (6) DMS (5)
BEMP (1) DMS (1)
BEMP (6) DMS (2)
BEMP (6) MeI (2)
BEMP (6) MeOTs (2)
BEMP (6) TMOF (2)
BEMP (6) DMS (2)
[11C]-Carboxymethylation of model amines
8
9
5
5
Initial experiments were carried out using model primary and
secondary aliphatic and aromatic amine substrates (Table 1). Small
volume (80 mL) solutions of amine in DMF containing DBU were
used to trap cyclotron-produced [11C]-CO2 from a stream of N2 as
such a scale is practical for the synthesis of PET radiotracers for
imaging studies.
Trapping of radioactivity was essentially quantitative when
the [11C]-CO2 was bubbled through the amine solution at room
temperature at 10 mL min-1. Increasing the flow to 70 mL min-1
resulted in significant breakthrough (60%) of [11C]-CO2. A solution
of dimethylsulfate (DMS, 10 mL) in DMF (400 mL) was then added
and the reaction monitored by radio-HPLC. Control experiments
10
11
12
13
14
15
16
1
1
0.5
0.5
0.5
0.5
0.5
a A solution of MPP hydrochloride + fixation agent in DMF (80 mL)
treated with [11C]-CO2 in N2 (10 mL min-1). Reaction at r.t. for 1 min
then treated with solution of alkylating agent in DMF (400 mL). Reaction
quenched with aq. NH3 after 10 s. b See experimental for definition - average
of two runs. c 2 mL of water added to amine solution.
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is due to competing methylation of amine (Scheme 1, Path A) at
low amine concentrations.
Both methyl tosylate (MeOTs) and iodomethane (MeI) were
efficacious as methylating agents (Table 2, entries 13 and 14).
However, solutions of the former had to be freshly prepared, while
the latter might not be useful in the radiosynthesis of high specific
activity radiopharmaceuticals.21 Trimethylorthoformate (TMOF)
was ineffective as a methylation agent, reflecting its much lower
methylating ability (Table 2, entry 15). Anhydrous reagents were
used throughout here but the reaction proved quite tolerable to
the presence of water as addition of 2 mL (1.4 M) only reduced
radiochemical yields moderately (compare Table 2, entries 12
and 16).
Scheme 3 Q = fixating agent, either DBU or BEMP.
by addition of amine. Preliminary experiments of this type have
produced very low radiochemical yields (data not shown).
The reactivity of the carbonic acid salt to the methylating agent
is exceedingly high. This is apparent, not only from the very short
reaction time required, but also from the successful radiosynthesis
of [11C]-GR103545. This molecule contains a tertiary amine, yet
carboxymethylation competes well with methylation at this site.
Application of the method to the radiosynthesis of a PET
radiopharmaceutical
GR103545, a potent and selective agonist for the kappa opiod
receptor,22 is currently being used as PET imaging agent in non-
human primates.23 It has previously been labelled with carbon-
11 by a multi-step radiosynthesis involving the production and
coupling of [11C]-methylchloroformate to its norcarboxymethyl
amine precursor18 or by reacting [11C]MeI with CO2-saturated
solutions of said amine.24 Our [11C]-CO2 fixation approach was
applied to this radiosynthesis (Scheme 2) using a “loop” method,25
whereby the [11C]-CO2 is trapped in a loop of narrow-bore steel
tubing pre-coated with a solution the norcarboxymethylamine
precursor and BEMP in DMF. This technique provides a higher
surface area for interaction of [11C]-CO2 with the precursor
solution, promotes easy automation of the process, and enables
us to use only 0.1 mg of the norcarbomethoxy precursor while
producing high specific activity product in practical yields.
Experimental
A Scanditronix MC 17 cyclotron was used for radionuclide pro-
duction. [11C]-CO2, produced by the 14N(p,a)11C nuclear reaction,
was concentrated from the gas target in a stainless steel coil
◦
cooled to -178 C. Upon warming, the [11C]-CO2 in a stream
of N2 gas was passed through a NOx trapping column27 and a
drying column of P2O5 prior to use. Purifications and analyses of
radioactive mixtures were performed by high performance liquid
chromatography (HPLC) with an in-line UV (254 nm) detector in
series with a NaI crystal radioactivity detector (purifications) or a
Bioscan Flowcount coincidence radioactivity detector (analyses).
Isolated radiochemical yields were determined with a dose-
calibrator (Capintec CRC-712M). Proton and carbon-13 NMR
spectra were recorded at 25 ◦C on a Varian Mercury 400 MHz
spectrometer. Chemicals were obtained from Aldrich, Tocris, or
Fisher. Dimethylformamide (DMF) was distilled from barium
˚
oxide. DBU, BEMP, and DMF were stored over 4 A molecular
sieves prior to use. Automated radiosyntheses were controlled
by LabviewTM software. Unless stated otherwise, all radioactivity
measurements were normalised for radioactive decay.
Scheme 2
Cyclotron-produced [11C]-CO2 (24 GBq) was converted into
purified, formulated, sterile and pyrogen-free [11C-carbonyl]-
GR103545 (2.6–3.8 GBq) in only 23 min with radiochemical
purities >98% and specific activities of 108–162 GBq mmol-1 (all
values at end-of-synthesis).26
Synthesis of reference methylcarbamates
A solution of amine (see Table 1, 0.5 g) and triethylamine
(1 mL) in EtOAc (10 mL) was treated with methylchloroformate
(0.5 mL) and the mixture stirred until reaction was complete by
HPLC analysis (5 min to 16 h). Saturated aq. K2CO3 was added
(10 mL) and the mixture stirred for 15 min. The aqueous layer
was extracted with EtOAc, and the combined organic fractions
washed with water, aq. HCl (1 N) and brine, then dried (Na2SO4)
and filtered through a short plug of silica. Evaporation gave the
desired carbamates. With the exception of 4-(2-methoxyphenyl)-1-
piperazinecarboxylic acid methyl ester, all carbamates are known
compounds and had 1H NMR spectra in accord with their
structure.
Mechanism
The role of the CO2-fixation agent, DBU or BEMP, in the reaction
is still open to speculation. It is obvious that fixing the CO2 in
solution is essential but other aspects, such as providing a highly
polarisable soft counter-ion,13,15–17 could also play a significant
part in their effectiveness. The observation that the phosphazene,
BEMP, is superior to the amidine, DBU, does not allow a
distinction between the two plausible reaction pathways outlined
in Scheme 3. However, if Path X is significant then it ought to be
possible to reverse the order of addition of reagents i.e. trap [11C]-
CO2 in a solution of fixation agent containing CH3X, followed
4-(2-Methoxyphenyl)-1-piperazinecarboxylic acid, methyl ester.
Yield 67%. White crystals from diisopropyl ether; mp 66–69 ◦C.
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[11C]-CO2 partition experiments
expand the type and number of radiotracers available for PET
imaging and other radiotracer applications.
5 mL (nominal volume) conical vials were used. Each vial volume
was measured (by filling with water and weighing) and exactly
half-filled with solutions of carbon dioxide fixation agent (DBU
or BEMP) in DMF (ca. 2.5 mL). [11C]-CO2, was bubbled into the
vials (30–300 MBq), which were then septum-sealed and left to
stand at ambient temperature for 10 min. Control experiments
showed that equilibrium had been reached by this time. For each
vial, the total radioactivity was measured and 1 mL of the gas
phase above the solution removed with a gas-tight syringe, then
measured for radioactivity. The partition ratios (PR) of [11C]-CO2
between the liquid and gas phases were calculated as:
Acknowledgements
The authors thank Winston Stableford and Min Wong for
[11C]-CO2 productions, and Dr Oleg Sadovski for NMR data
acquisition.
Notes and references
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PR = [Activity in vial - (F ¥ Activity in syringe)]/[F ¥ Activity
in syringe]; where F = volume of gas phase (in mL).
[11C-carbonyl]-carboxymethylation reactions
[11C]-CO2 was bubbled (using a 2” ¥ 21G needle at 10 mL min-1)
into a solution of test amine and carbon dioxide fixation agent
(DBU or BEMP) in DMF (80 mL) in a septum-sealed 1 mL
conical vial. The vial was vented directly to a 3 mL syringe barrel
filled with silica-coated NaOH (AscariteTM) to trap any escaping
[11C]-CO2. Trapping of [11C]-CO2 was >95% in all cases. After
1 min, a solution of methylating agent in DMF (400 mL) was
added followed, after 10 s, by aq. ammonia (0.01 N, 0.5 mL).
Radioactivity in the vial and NaOH trap were measured and
aliquots of the reaction mixture analysed by HPLC and compared
to standards of methylcarbamates to determine conversion yields
to [11C]-methylcarbamates. Radiochemical yields were calculated
as:
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[Activity in vial/(Activity in vial + Activity in NaOH trap)] ¥
HPLC conversion yield.
Radiosynthesis of [11C-carbonyl]-GR103545
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Complete experimental details are given in the ESI section.†
Briefly, a ValcoTM 6-port, 2-position valve equipped with 1 mL
stainless steel sample loop and a 0.4 mL PTFE sample loop was
used. Before release of [11C]-CO2, the PTFE sample loop was
charged with a solution of degassed DMS (4 mL) in DMF. The
1 mL steel loop was charged with a solution of norcarbomethoxy
GR103545 (0.1 mg) and carbon dioxide fixation agent (DBU or
BEMP, 5 mL) in DMF (40 mL). [11C]-CO2was then swept through
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Conclusions
Sequential trapping of [11C]-CO2 in amine solutions followed by
reaction with methylating electrophiles provides [11C]-carbonyl]
methylcarbamates rapidly and in high radiochemical yields.
Biologically interesting molecules which contain carbamate
groups are relatively rare (nevertheless, for recent examples see
ref. 28) but it can be anticipated that their numbers will grow
as libraries of carbamates are easily accessible via combinatorial
techniques. The method described herein should be useful to
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