Efficient synthesis of [18F]trifluoromethane and its application in the synthesis of PET tracers

Article abstract of DOI:10.1039/c3cc37833k

A new strategy towards [¹⁸F]trifluoromethyl-containing compounds is developed. [¹⁸F]trifluoromethane is synthesised in a fast and efficient manner and subsequently used in the reaction with aldehydes and ketones forming [¹⁸

Full text of DOI:10.1039/c3cc37833k

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Efficient synthesis of [18F]trifluoromethane and its
application in the synthesis of PET tracers†
Dion van der Born,a J. (Koos) D. M. Herscheid,a Romano V. A. Orrub and
Danielle J. Vugts*ac
Cite this: Chem. Commun., 2013,
49, 4018
Received 29th October 2012,
Accepted 25th March 2013
DOI: 10.1039/c3cc37833k
www.rsc.org/chemcomm
A new strategy towards [18F]trifluoromethyl-containing compounds is prepare
[
18F]trifluoromethylated compounds have been
developed. [18F]trifluoromethane is synthesised in a fast and efficient reported.5,6 The published methods employ the direct reaction
manner and subsequently used in the reaction with aldehydes and of [18F]fluoride with electrophiles, like difluorobromomethyl-
ketones forming [18F]trifluoromethyl carbinols in good yields.
or gem-difluoroalkenyl containing compounds (Scheme 1).
These methods do generate the [18F]trifluoromethyl group in
Positron emission tomography (PET) is a powerful molecular a single synthetic step, but with limited success. Simple sub-
imaging technique that can visualise biological processes strates react in up to 93% yield, however, the labelling of more
in vivo.1 Today, PET has proven to be a valuable tool for the complex structures results in very low yields (o15%).5 More-
detection, characterisation and monitoring of diseases and for the over, precursors containing the difluorobromomethyl- or gem-
investigation of the efficacy of pharmaceuticals. Therefore, there difluoroalkenyl functional group are difficult to obtain using
is a continuous need for effective positron-emitting tracers that commercial sources or synthetic methods.
specifically interact in the biological processes of interest.2
A major limitation of the reaction with the gem-difluoroalkenyl
The development of a PET-tracer usually starts from a known group is that it actually yields a [18F]2,2,2-trifluoroethyl group.
biologically active compound by replacing one of the carbon, Trifluoromethyl aryls, for example, can therefore not be
nitrogen, oxygen or fluorine atoms by its radioactive isotope. Synth- obtained via this method.
esis of such compounds is challenging due to the short physical
half-life of these isotopes (11C t1/2 = 20 min, 13N t1/2 = 10 min,
15O t1/2 = 2 min, 18F t1/2 = 110 min). In general, the introduction of
the isotope and subsequent purification and analysis of the tracer
have to be finalized within 3 half-lives. Consequently, robust, reliable
and rapid chemical procedures are essential for success.3
Many pharmaceuticals contain a trifluoromethyl (CF3) func-
tional group. The CF3 group is incorporated into drug candi-
Scheme 1 Reported reactions of [18F]fluoride with: (a) difluorobromomethyl5
and (b) gem-difluoroalkenyl6 precursors.
dates to improve their binding selectivity, lipophilicity, and
metabolic stability.4 [18F]CF3-containing compounds are how-
ever rare because only limited synthetic approaches are avail-
able. Of the various fluorine-18 sources, only [18F]fluoride is
In this communication we present a novel approach to
available at most cyclotron sites, and therefore reactions using synthesise radiopharmaceuticals containing a CF3 group via
this fluorine-18 source are especially of interest. Albeit, only a nucleophilic trifluoromethylation using [18F]trifluoromethane.
handful of procedures using nucleophilic [18F]fluoride to
During initial studies, we discovered that the reaction of difluoro-
iodomethane with [18F]fluoride/kryptofix 2.2.2 in acetonitrile pro-
vided [18F]trifluoromethane in a satisfactory 60 Æ 15% yield in a
reaction time of 10 minutes at room temperature (Scheme 2).
[18F]trifluoromethane could be easily isolated by purging it
out of the reaction mixture using a flow of helium. The gaseous
[18F]trifluoromethane was separated from any gaseous difluoro-
iodomethane precursor by passing it through a silica column and
trapping the product in either DMF at À60 1C with a 88 Æ 8%
efficiency or in THF at À100 1C with a 96 Æ 3% efficiency in
a Department of Radiology and Nuclear Medicine, VU University Medical Center,
PO Box 7057, 1007MB, Amsterdam, The Netherlands. E-mail: d.vugts@vumc.nl
b Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for
Medicines and Systems, VU University, De Boelelaan 1083, 1081HV, Amsterdam,
The Netherlands
c Department of Otolaryngology/Head and Neck Surgery, VU University Medical
Center, PO Box 7057, 1007MB, Amsterdam, The Netherlands
† Electronic supplementary information (ESI) available: Synthesis and characterisation
of reference compounds and experimental details. See DOI: 10.1039/c3cc37833k
c
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Scheme 2 Synthesis of [18F]trifluoromethane.
3 minutes. HPLC analysis of the obtained [18F]trifluoromethane
solution showed no radioactive or UV-active impurities (see ESI†).
The time needed for the synthesis of [18F]trifluoromethane,
which includes azeotropic drying of [18F]fluoride/kryptofix 2.2.2
and subsequent reaction and purification, is about 30 minutes.
This provides enough time for a follow up reaction, and therefore
the applicability of [18F]trifluoromethane was further investigated.
In order to use [18F]trifluoromethane in nucleophilic trifluoro-
methylations, it needs to be deprotonated first. It is known that
deprotonation of ‘‘cold’’ trifluoromethane in THF yields a trifluoro-
methyl anion that decomposes to difluorocarbene and fluoride
(Scheme 3).7 Deprotonation in DMF, however, results in a trifluoro-
methyl anion stabilised as the corresponding gem-aminoalcoholate.
Using this method, aldehydes and ketones undergo reactions with
trifluoromethane to form the corresponding trifluorocarbinols in
high yields.7 The trifluoromethylation of a carbonyl group may
proceed via two distinct pathways (Scheme 3). Either the trifluoro-
methyl anion attacks directly the electrophilic carbonyl group, where
the gem-aminoalcoholate only acts as a temporary reservoir of the
trifluoromethyl anion, or the gem-aminoalcoholate formed in DMF
reacts with the carbonyl group.
Fig. 1 Analysis of the reaction of [18F]HCF3 with benzophenone using radio-
HPLC. (a) Investigation of the influence of the DMF concentration on the
formation of [18F]trifluorocarbinol 2a; (b) determination of the reaction products
in THF; (c) determination of the reaction products in THF with 10% DMF.
Scheme 4 Formation of [18F]fluoral hydrate in the HPLC eluent.
However, at low benzophenone concentrations, the yield of 2a
decreased and decomposition of the trifluoromethyl anion led to
the formation of [18F]fluoride. In this case, the presence of 50% of
DMF led to a tremendous increase in product yield. Apparently, the
direct reaction pathway I is very slow at these concentrations and
pathway II via the gem-aminoalcoholate comes more into play at
increasing DMF concentrations. In these reactions, [18F]fluoride was
also not found as a by-product, but [18F]fluoral hydrate was detected
instead. This can be attributed to protonation of the gem-amino-
alcoholate intermediate in the acidic HPLC eluent (Scheme 4) and
therefore can be used to quantify the amount of gem-aminoalcoho-
late present in the reaction mixture.
Scheme 3 Reaction pathways of the trifluoromethyl anion.
The absence of [18F]fluoride indicates that the gem-amino-
When fluorine-18 is used in a reaction the resulting products and alcoholate does not act as a trifluoromethyl anion reservoir, but
reactants can easily be monitored using HPLC and a radioactivity reacts directly in a concerted reaction with the substrate. If the
detector. With such an analytical set-up, reaction progress is easily gem-aminoalcoholate is in equilibrium with the trifluoromethyl
followed and we decided to investigate the mechanism of trifluoro- anion, at least some [18F]fluoride should have been formed.
methylation of carbonyls using [18F]trifluoromethane in more detail.
To investigate the scope of the [18F]trifluoromethylation
The reaction of [18F]trifluoromethane and benzophenone was reaction discussed above various benzaldehydes 1, aceto-
selected as a model reaction, because the initial experiments phenones 3 and benzophenones 5 (for R2 see Table 1–3)
showed that benzophenone reacts cleanly with the corresponding containing electron withdrawing and donating groups
[18F]trifluorocarbinol 2a. First the trifluoromethylation reaction (Scheme 5) were selected as the electrophilic reaction partners.
using [18F]trifluoromethane and KOtBu (100 mM) (5 min at 20 1C)
at various concentrations of benzophenone was investigated in THF expected products in excellent yields (Table 1). The synthesis of
that contained various percentages of DMF (Fig. 1a). Surprisingly, [18F]2b (R2 = 4-OMe), [18F]2e (R2 = 4-NO2) and [18F]2f (R2
Reaction with substituted benzophenones 1 provided the
=
the reaction in neat THF yielded the desired product 2a in up to 86%. 3-NO2) required although an increasing concentration of
However, to achieve this, a high concentration of benzophenone KOtBu. Under the low yielding reaction conditions, unreacted
(500 mM) was required. This demonstrates that the trifluoro- [18F]trifluoromethane was still present, because the substrates
methyl anion can react directly with benzophenone (pathway I). had degraded (as shown by UV-HPLC analysis).
c
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Scheme 6 Major by-product formation in the reaction of 5e with [18F]HCF3.
Scheme 5
[
18F]trifluoromethylation using [18F]HCF3.
In these reactions, also no radioactive by-products were
formed and in the synthesis of [18F]4e (R2 = 4-NO2) and [18F]4f
(R2 = 3-NO2) only unreacted [18F]trifluoromethane was observed.
Substrate degradation, as was observed using UV-HPLC, caused
by the strong basic conditions probably led to low yields.
Benzaldehydes 5 reacted in a moderate to high yield with
[18F]trifluoromethane (Table 3). Also here a positive effect of an
increasing KOtBu concentration on the product yield was
observed. Most reactions did not yield by-products, except for
the synthesis of [18F]6e. In this case not [18F]6e, but [18F]8 was
formed (Scheme 6). This may be explained by nucleophilic
attack of the tert-butoxide anion on the precursor 4-nitro-
benzaldehyde 5e (Scheme 6) resulting in 4-t-butoxy-benzaldehyde
7 which subsequently reacts with [18F]trifluoromethane to form
[18F]1-(4-(tert-butoxy)phenyl)-2,2,2-trifluoroethanol 8.
Table 1 Trifluoromethylation of benzophenones 1a
Substrate
(mmol)
KOtBu
(mmol)
Radiochemical
conversion (%)
Entry
R2
Product
1
2
3
4
5
6
7
8
9
H
10
10
10
10
10
10
10
10
10
20
20
30
20
20
20
50
20
50
[
[
[
[
[
[
[
[
[
18F]2a
18F]2b
18F]2b
18F]2c
18F]2d
18F]2e
18F]2e
18F]2f
18F]2f
>99
16
>99
99
>99
1
96
4-OMe
4-OMe
4-CF3
4-F
4-NO2
4-NO2
3-NO2
3-NO2
30
74
a
Reaction conditions: 1 mL DMF, 20 1C, 5 minutes.
In summary, [18F]trifluoromethane can be prepared in high yield
in a short synthesis time and undergoes smooth reaction with
various aromatic aldehydes and ketones to give [18F]trifluoromethyl-
carbinols in reasonable to good yields. Substrate stability seems to
be the most important factor to obtain high product yields.
We are currently investigating the use of [18F]trifluoro-
methane towards other products (trifluoromethylthioethers,
trifluoromethylarenes) and towards the synthesis of [18F]TMSCF3,
a milder reagent for trifluoromethylation reactions.
Table 2 Trifluoromethylation of acetophenones 3a
Substrate
(mmol)
KOtBu
(mmol)
Radiochemical
conversion (%)
Entry
R2
Product
1
2
3
4
5
6
H
100
100
100
100
100
100
150
150
150
150
150
150
[
[
[
[
[
[
18F]4a
18F]4b
18F]4c
18F]4d
18F]4e
18F]4f
41
44
22
36
0
4-OMe
4-CF3
4-F
4-NO2
3-NO2
0
a
Reaction conditions: 1 mL DMF, 80 1C, 5 minutes.
Notes and references
Table 3 Trifluoromethylation of benzaldehydes 5a
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Precursor
(mmol)
KOtBu
(mmol)
Radiochemical
conversion (%)
Entry
R2
Product
1
2
3
4
5
6
7
8
H
10
10
10
10
20
10
10
10
10
10
20
20
20
20
50
50
20
50
20
20
50
50
[
[
[
[
[
[
[
[
[
[
[
18F]6a
18F]6b
18F]6c
18F]6c
18F]6c
18F]6d
18F]6d
18F]6e
18F]6f
18F]6f
18F]6f
97
98
31
43
86
3
94
0b
2
4-OMe
4-CF3
4-CF3
4-CF3
4-F
4-F
4-NO2
3-NO2
3-NO2
3-NO2
9
10
11
26
90
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1990, 41, 823; (b) M. K. Das and J. Mukherjee, Appl. Radiat. Isot., 1993,
a
b
Reaction conditions: 1 mL DMF, 20 1C, 5 minutes. Increasing KOtBu
or precursor amounts did not lead to increased yield.
¨
44, 835; (c) P. Johnstrom and S. Stone-Elander, J. Labelled Compd.
High base concentrations probably led to faster deprotona-
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before degradation of the substrate occurred.
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´
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c
4020 Chem. Commun., 2013, 49, 4018--4020
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