Efficient DBU accelerated synthesis of 18F-labelled trifluoroacetamides

Article abstract of DOI:10.1039/c6cc08535k

Nucleophilic ¹⁸F-fluorination of bromodifluoromethyl derivatives was performed using [¹⁸F]Bu₄NF in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). This novel procedure provided a diverse set of [¹⁸F]trifluoroacetamides in good to excellent radiochemical conversions. A mechanism where DBU acts as organomediator in this transformation is proposed.

Full text of DOI:10.1039/c6cc08535k

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Efficient DBU accelerated synthesis of 18F-labelled
trifluoroacetamides
Antonio Bermejo Gómez,a,b,c Miguel A. Cortés González,b,c Marvin Lübcke,b,c Magnus J. Johansson,d
Christer Halldinc,e Kálmán J. Szabó*b,c and Magnus Schou*a,c,e
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Nucleophilic 18F-fluorination of bromodifluoromethyl derivatives 1).7-12 Traditionally, these transformations have been thermally
was performed using [18F]Bu4NF in the presence of DBU (1,8- activated, but more recently metal salts were successfully used
diazabicyclo[5.4.0]undec-7-ene). This novel procedure provided a as activators.11 The second approach comprises a two-step
diverse set of
[
18F]trifluoroacetamides in good to excellent procedure in which the [18F]CF3 functionality is incorporated
radiochemical conversions. A mechanism where DBU acts as into aromatic substrates via [18F]CuCF3 species.8-10,13
organomediator in this transformation is proposed.
[
18F-]
- LG-
18F
F
R
LG
F
R
F
F
Due to the favourable properties of fluorine, approximately
one fifth of newly registered small drug molecules are
organofluorine compounds.1 Moreover, the artificial isotope
18F (t1/2 109.8 min) has suitable nuclear properties for in vivo
imaging in human subjects using positron emission
tomography (PET).2 Hence, there is a large demand for
efficient fluorination methodologies in both medicinal3 and
radiosynthetic chemistry. 4
Scheme
displacement of a leaving group.
1
General synthesis of 18F-CF3 moieties by
We
started
investigating
the
transformation
of
difluorobromoacetamide 1a into the corresponding 18F-
trifluoromethyl analog [18F]2a using [18F]Bu4NF in a set of
solvents with varying temperatures (Table 1, entries 1-5). The
reaction proceeded with low to modest radiochemical
conversion (RCC; the fraction of radioactivity incorporated into
the desired product) in all examined solvents, including DCE
(entry 1) acetonitrile (entry 2) and DMSO (entry 3). The highest
RCC (35%) was observed in DMF. There was no obvious
difference between kryptofix/K18F and [18F]Bu4NF as the
fluorinating species (entries 5 vs 4). Interestingly, the use of
metal salts as additives did not lead to improvements in the
RCC either (entries 6-8). In light of these results where
reported methods failed, we turned our attention to nitrogen
based nucleophilic organic activators for the 18F-fluorination.14
Thus, the transformation of 1a into [18F]2a was investigated in
Despite the remarkable developments in PET radiochemistry
during the past decade,4 lack of efficient radiochemical
methodology may still be a bottleneck in drug discovery and
development. It is particularly rate-limiting for microdosing
studies, in which the distribution of the radiolabeled drug
molecule, previously developed without the intent to be
radiolabeled, is studied during the PET measurement.5 In view
of our long-term objective to facilitate PET studies during drug
discovery and development, we turned our attention to the
development of a new method for introducing fluorine-18 into
trifluoroacetamide (-NCOCF3) groups. Although these groups
are important motifs in medicinal chemistry,6 their
radiolabelling has so far been remarkably neglected in the
literature. On the other hand, more attention has been
directed to the development of methods for the installation of
[18F]CF3 groups into other type of motifs and two distinct
approaches have been taken for this purpose. The first
proceeds via direct substitution of a leaving group in the
appropriate difluoromethyl analog with 18F-fluoride (Scheme
o
DMF at 100 C using 1 equiv. of activator. Though DABCO and
DBN did not provide an improvement in RCC (entries 9 and 12
vs 4), gratifyingly, DMAP and pyridine increased the RCC to
59% and 68%, respectively (entries 10 and 11). A further
increase in RCC to 71%, twice compared to control conditions
without activator (c.f. entries 4 and 13), was obtained using
DBU. When two further guanidine derivatives were used, TBD
and MTBD, an even higher RCC was observed (entries 15 and
16, respectively). However, when the reactions with TBD and
MTBD were repeated in the cold lab (using 19F-containing
TBAF) extensive hydrodebromination of the starting material
1a was also detected. Because formation of this by-product
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would complicate the purification and isolation of [18F]2a and apparent insensitivity of the protocol to thiol functionalities.
since the reaction with DBU proceeded with a high RCC Next, substrate 1l, with an additional amide function, and 1m
without hydrodebromination (or other side reactions), DBU 1o, with some important nitrogen containing heterocycles
-
was selected as the activator in the further studies.
commonly used in medicinal chemistry, were converted
smoothly into trifluoromethyl derivatives [18F]2l
2o in
-
Table 1 18F-labelling of 2a under various conditions.
excellent RCCs (77, 90, 75 and 80%, respectively). Finally, we
focused our attention to the more challenging secondary
bromodifluoroacetamide substrates 1p and 1r. As expected,
[18F]2p and [18F]2r were obtained in substantially lower RCCs
than the tertiary amide derivatives using direct DBU-mediated
fluorination. Considering that the introduction of a benzyl
group into 1r provided a threefold increase in RCC (cf. [18F]2e
vs [18F]2r) we decided to explore a protecting group strategy
for the secondary amide substrates. However, much to our
disappointment, N-Boc (tert-butoxycarbonyl) protection was
not a viable solution for this purpose as it provided only
marginal improvement, or even a reduction, in the RCC for
[18F]2q and [18F]2s
.
In an effort to improve the yields for this important class of
compounds, the protocol was modified to include an 18F-
labelled ester as intermediate (Scheme 3).15 Because of the
basic radiofluorination reaction media, extensive hydrolysis
was observed during the synthesis of ester [18F]4a and the
resulting RCC was only 2%. Gratifyingly, however, the more
stable menthol ester [18F]4b could be obtained in a 64% RCC
and further converted, without intermediate purification, into
the desired secondary amides [18F]2p and [18F]2r with high
RCCs (76% and 72% respectively). To evaluate the utility of the
current methodology for the labelling of druglike molecules it
was applied to the 18F-labelling of [18F]2t (AZD5423), a
nonsteroidal glucocorticoid agonist developed for the
treatment of respiratory diseases.12,16 Because [18F]2t is a
secondary amide, direct labelling in the presence of DBU
proceeded with only a modest RCC (7%, Scheme 2) and
starting from the N-Boc protected derivative 1u failed.
However, when using the above sequence (Scheme 3), with
[18F]4b as a key intermediate, we obtained the target molecule
in a 12% RCC under non-optimized conditions.
[a] Unless otherwise noted: 1a (0.06 mmol, 19 mg), solvent 0.4
mL, additive 0.06 mmol (1 equiv.). [b] DMF
= N,N-
dimethylformamide; DCM = dichloromethane; DCE = 1,2-
dichloroethane. [c] DMAP = 4-dimethylaminopyridine; DABCO
=
(1,4-diazabicyclo[2.2.2]octane);
DBN
=
1,5-
1,8-
diazabicyclo[4.3.0]non-5-ene;
diazabicyclo[5.4.0]undec-7-ene;
DBU
TBD
=
In a preparative run, starting from 762 MBq of [18F]Bu4NF,
[18F]2a was isolated by semi-preparative HPLC in a 44%
radiochemical yield (RCY, not corrected for decay) with a
specific activity (S.A. = radioactivity per molar amount of
product) of 0.10 GBq/µmol. Although an S.A. of 0.1 GBq/µmol
is useful for PET microdosing studies, it is insufficient for
examining drug-target engagement.17 Accordingly, a more
general application of the methodology for PET studies require
an increase of the S.A of the product. In control experiments
when [18F]Bu4NF was omitted from the reaction mixture, it was
found that the formation of [19F]2a was largely dependent on
the amount of 1a used in the reaction.9 This indicates that 19F
=
1,5,7-
triazabicyclo[4.4.0]dec-5-ene
;
MTBD
=
7-methyl-1,5,7-
triazabicyclo[4.4.0]dec-5-ene. [d] Estimated by radio-HPLC. [e]
Using KF[18F]/K2.2.2. [f] 2 equiv
With the improved conditions in hand, we explored the scope
of the DBU-mediated reaction with different tertiary (1a
and secondary (1p and 1r) bromodifluoroacetamides (Scheme
2). Substrates with cyclic or linear alkyl chains (1a 1b), or
including alkene functionalities (1c), gave the labelled amides
[18F]2a
2c in good to excellent RCC (71, 68 and 84%,
respectively). The benzylic derivatives 1d 1f and the
morpholine, oxetane, proline and ketal derivatives 1g 1j could
also be conveniently transformed with [18F]TBAF in the
presence of DBU to [18F]2d
2j (61-92% RCC). In metal
catalyzed/mediated reactions, sulfur has tendency to
-1o)
-
-
-
from the CF2Br group of 1a assists in the formation of [19F]2a
,
-
which lowers the S.A. of the product. This problem can be
circumvented by lowering the concentration of 1a in the
reaction mixture. Indeed, by a 100-fold reduction in the
amount of 1a (from 60 to 0.6 µmol, see ESI) and starting from
7.16 GBq of [18F]Bu4NF, [18F]2a (284 MBq, 4% RCY) was
obtained with an 84-fold improved specific radioactivity (8.4
-
a
coordinate to the metal atom and thus inhibit the reaction.
With the current methodology, thioether derivative [18F]2k
was obtained in excellent RCC (84%), thus suggesting an
2 | J. Name., 2012, 00, 1-3
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GBq/µmol). Compared to literature examples,7,11 this is a trifluoroacetamides. RCCs estimated by radio-HPLC. Boc = tert-
decent level of S.A. for a [18F]CF3 species, which inherently butoxycarbonyl.
suffers from low S.A. Furthermore, since we observed that the neither the RCY nor the S.A. can be increased by increasing the
formation of cold 2a was unaffected by the radioactivity used amount of DBU (1 equivalent) in the reaction mixture.
in the reaction, the S.A. of [18F]2a is expected to be
proportional also to the starting radioactivity. Thus, we
A very interesting feature of the above study is the
envisage that the S.A. could be easily increased further under acceleration effect of DBU in the bromide-18F exchange
automated conditions when a full cyclotron production may be process (c.f. Table 1 entries 4 and 13). In order to rationalize
used for the radiofluorination.18 This would provide a product this effect, we monitored the reaction of 1a with DBU using 13
with a S.A. useful also for drug-target engagement studies. NMR spectroscopy (Scheme 4). The 13C NMR spectra of
C
According to our studies
isolated 1a and DBU are given in Schemes 4b-c. When 1a and
DBU was mixed in DMF-d7 and heated at 100°C (simulating the
reaction conditions according to Table 1, entry 4), the 13C NMR
signals of DBU underwent systematic changes (Scheme 4a).
The signal at 46.5 ppm (assigned to C11) was shifted to 40.5
ppm and substantially broadened. The 13C signal at 38.1 ppm
(assigned to C6) also underwent a similar change shifting to
33.6 ppm. The shift of the 13C NMR signals clearly shows that
chemical enviroment of the above carbon atoms in DBU is
significantly changed on addition of 1a. Most probably DBU
displaces the bromide of 1a to form intermediate
4). The broadening of the shifts at 40.0 and 33.6 ppm may
indicate C F coupling and/or hindered rotation along the
C(F2) N bond in
. The 13C NMR spectrum of the mixture of
7 (Scheme
−
−
7
DBU+1a (Scheme 4a) remained unchanged in the temperature
range of 85-100 oC. When the reaction mixture of DBU+1a was
cooled to room temperature intermediate
7 decomposed to
is reversible14
DBU and 1a. This indicates that formation of
o
and its formation requires heating to at least to 85 C. Based
7
on the above, we suggest that DBU and CF2Br precursors
form intermediates such as prior to the reaction with
[18F]TBAF. In
two quaternary centers forms a strained
1
7
7
C(F2)
C(F2)
−
−
N bond, which is probably easier to cleave than the
Br bond. The behaviour of DBU as a nuclephilic catalyst
is known in the literature.14 However, this is the first study,
when DBU is applied for mediating the displacement of
bromide from CF2Br group and application for 18F labelling.
In summary, we have shown for the first time that 18F-
labelled trifluoroacetamides can be efficiently synthesized
from easily accessible CF2Br derivatives and [18F]TBAF in the
presence of DBU (or analogues). The 18F-labelled tertiary
trifluoroacetamide products are typically formed with high
RCC. For 18F-labelling of secondary trifluoroacetamides, we
propose a modified work-flow via synthesis of an 18F-labelled
ester reagent, which undergo transesterification with the
corresponding amine. The radiosynthetic utility of the method
was demonstrated by 18F-labelling of the druglike substance
[18F]2t (AZD5423). The preparative scale experiments show
that this method is suitable to produce 18F-labelled
trifluoroacetamides with sufficiently high specific activity for
PET microdosing studies and with slight modification even for
drug-target engagement studies (8.4 GBq/µmol for [18F]2a).
Mechanistic studies suggest that DBU has an activating effect
on the displacement of bromide from the CF2Br group of the
Scheme 2 Substrate scope in the 18F-labelling mediated by
precursor 1. This study broadens the radiosynthetic scope of
[18F]CF3 derivatives and assists in the development of new
DBU.
1a-1u
:
bromodifluoroacetamides,
2a-2u:
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Br
O
O
O
DBU
N
N
F
6
18F- 18F
F
Br
F
N
N
N
DMF-d7
F
F
F
100 o
C
1a
7
2a
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25.
,
o
intermediate
7.
13C NMR spectra (125 MHz) at 100 C in DMF-
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.
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The authors like to thank the members of the PET group at
Karolinska Institutet. Support from AstraZeneca, Stockholm
Brain Institute, the Swedish Research Council, the Knut and
Alice Wallenberg Foundation are gratefully acknowledged.
A.B.G. is grateful to the AstraZeneca Postdoctoral Programme
for funding a postdoctoral contract.
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4 | J. Name., 2012, 00, 1-3
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Table of contents:
Nucleophilic 18F-fluorination of bromodifluoroacetamides was performed in the presence of DBU. A
mechanism where DBU acts as organomediator is proposed.
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