Base-catalysed 18F-labelling of trifluoromethyl ketones. Application to the synthesis of 18F-labelled neutrophil elastase inhibitors

Article abstract of DOI:10.1039/d1cc03624f

A new method for the fluorine-18 labelling of trifluoromethyl ketones has been developed. This method is based on the conversion of a-COCF3 functional group to a difluoro enol silyl ether followed by halogenation and fluorine-18 labelling. The utility of this new method was demonstrated by the synthesis of fluorine-18 labelled neutrophil elastase inhibitors, which are potentially useful for detection of inflammatory disorders.

Full text of DOI:10.1039/d1cc03624f

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Base-catalysed F-labelling of trifluoromethyl
ketones. Application to the synthesis
of F-labelled neutrophil elastase inhibitors†
Cite this: DOI: 10.1039/d1cc03624f
18
Received 6th July 2021,
Accepted 30th July 2021
Denise N. Meyer, ‡a Miguel A. Cortes Gonzalez, ‡a Xingguo Jiang,‡a
´
´
Linus Johansson-Holm,a Monireh Pourghasemi Lati,a Mathias Elgland,b
a
Patrik Nordeman,b Gunnar Antonib and Kalman J. Szabo
*
DOI: 10.1039/d1cc03624f
´
´
´
rsc.li/chemcomm
A new method for the fluorine-18 labelling of trifluoromethyl using nanomolar amounts of fluorine-18 precursors available for
ketones has been developed. This method is based on the conver- the radiosynthesis. Trifluoromethyl ketones (and analogues) are
sion of a–COCF3 functional group to a difluoro enol silyl ether very important pharmacophores in many enzyme inhibitors
followed by halogenation and fluorine-18 labelling. The utility of (Fig. 1).6
this new method was demonstrated by the synthesis of fluorine-18
A particularly important serine protease, neutrophil elastase
labelled neutrophil elastase inhibitors, which are potentially useful (NE), can be efficiently inhibited by COCF3-containing drugs
for detection of inflammatory disorders.
(1a–c). The main action of this functional group is forming
covalent hemiketal type adducts with the hydroxy group of the
Introduction of fluorine into organic compounds can be used to serine moieties in the active site of the enzyme.6a,7 This ability of
control the physicochemical properties and the bioactivity of the carbonyl group arises from the strong electron-withdrawing
small molecules.1 Typical application areas of organofluorine character of the CF3 moiety.8 NE is an important biomarker of
compounds are the pharmaceutical industry,1c,2 agrochemistry3 serious inflammatory disorders, which are causing fibrosis and
and medical diagnostics.4 The high metabolic stability of the
organofluorine species is also an attractive feature for applications
in life-science related areas.1c Although the C–F bond is the
strongest single bond that carbon may form, neighbouring func-
tional groups may induce cleavage of the C–F bond via, for
example, anomeric effects or hyperconjugation.1b Another possi-
ble complication can be the effects of the biological environment
(such as high calcium or magnesium ion concentrations), which
may lead to degradation of organofluorines.1c In drug substances
and imaging tracers for Positron Emission Tomography (PET),
mono-fluorination mainly occurs in aromatic species4c This is
because the C(sp2)–F bond is very strong preventing both oxidative
degradation and C–F bond cleavage via CaF2 formation or related
processes.1c In the case of alkyl fluorides, application of CF3 or
perfluoroalkyl groups are preferred due to the increased C–F bond
strength. Installation of fluorine-18 labelled CF3 groups is still a
formidable challenge in the synthesis of PET imaging tracers.5
The main difficulty is associated with the downscaling of the
synthetic methodologies used for the construction of CF3 groups
a Department of Organic Chemistry, Stockholm University, SE-106 91, Sweden.
E-mail: kalman.j.szabo@su.se; Web: http://www.organ.su.se/ks/
b Department of Medicinal Chemistry, Uppsala University, SE-751 23, Sweden
† Electronic supplementary information (ESI) available: Experimental proce-
Fig. 1 Bioactive molecules with fluoroalkyl ketone pharmacophores.
dures, characterization data and radiochemistry. See DOI: 10.1039/d1cc03624f
NE = neutrophil elastase.
‡ Contributed equally.
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Table 1 Labelling of 2,2,2-[18F]trifluoroacetophenonea
Fig. 2 Circular defluorination–fluorination sequence for fluorine-18
labelling of trifluoromethyl ketones.
Entry
Additiveb
Temperature [1C]
RCYc [%]
1
2
3
4
5d
6
7
8
—
100
100
100
75
75
75
5
organ failure. Examples of such disorders are chronic obstructive
pulmonary disease9 (COPD) and abdominal aortic aneurysm10
(AAA). In addition, neutrophil elastase (NE) is a key enzyme in
the formation of so-called neutrophil extracellular traps (NETs).11
Excessive formation of NETs have been identified as the major
cause of acute respiratory distress syndrome (ARDS),12 which is the
leading death cause in case of COVID-19.
DBU
TBD
TBD
TBD
MTBD
TBD
TBD
65 Æ 9 (n = 2)
92 Æ 3 (n = 2)
90 Æ 1 (n = 2)
90 Æ 1 (n = 2)
73 Æ 13 (n = 2)
84 Æ 1 (n = 2)
74 Æ 1 (n = 2)
50
RT
a
Unless otherwise stated, a solution of the precursor (60 mmol, 14 mg)
and the additive (60 mmol) in DMF (150 mL) was mixed with a solution of
As
a part of our synthetic organofluorine chemistry
18F]Bu4NF in DMF (150 mL). The reaction was stirred at the indicated
program5b,13 we decided to develop a new methodology for
the construction of fluorine-18 labelled COCF3 groups targeting
[
b
temperature for 10 min. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene;
TBD
= 1,5,7-triazabicyclo-[4.4.0]dec-5-ene; MTBD = 7-methyl-1,5,
c
new potential PET imaging tracers for the detection of NE. Our 7-triazabicyclo[4.4.0]dec-5-ene. RCY was estimated by radio-HPLC
analysis of the crude reaction mixture. Using [18F]KF/K222
.
d
approach (Fig. 2) is based on the defluorination of the natural
isotope (1) of the trifluoromethyl ketone to be labelled afford-
ing its difluoro enol silyl ether. This conversion can be carried
out by using Mg and TMSCl under dry conditions.14 Difluoro lower radiochemical yield of [18F]1g. In most of the further
enol silyl ethers are highly reactive nucleophilic species, which studies we employed the optimal conditions, which are given in
can be used for the synthesis of various organohalogen and other entry 4 of Table 1.
species.15 Bromination or iodination of these compounds14b,15a
With the optimized reaction conditions in hand, we
leads to stable halodifluoromethyl ketones (2), which can be used explored the substrate scope of this transformation (Fig. 3).
as precursors for fluorine-18 labelling5a,b (Fig. 2). A potential Similarly, to [18F]1g, para-phenyl substituted analogue [18F]1h
advantage of this circular defluorination–fluorination sequence, was obtained in 90% RCY. The radiochemical yield of
1 - [18F]1, is the easy access to suitable precursors for tracer 1-naphthyl derivative [18F]1i was similarly high (92%), whereas
development for bioactive small molecules, such as 1a–c. Difluoro 2-naphthyl substituted [18F]1j gave a somewhat lower RCY of
enol silyl ethers have been used as precursors for fluorine-18 84%. The radiosynthesis could easily be extended to [18F]tri-
labelling using [18F]F2 with F2 carrier gas by Prakash, Olah and fluoroacetophenones bearing electron-donating substituents,
their co-workers.16 By the above method (Fig. 2) based on bromi- such as 4-methyl ([18F]1k, 71% RCY) and 4-methoxy ([18F]1l,
nation/iodination of 2 the cumbersome handling of [18F]F2 and 93% RCY) derivatives. Similarly, [18F]trifluoroacetophenones
application of F2 as carrier gas can be avoided.
We started the development of the above-mentioned circular high radiochemical yields. Thus, 4-fluoro ([18F]1m) and 3,
approach by fluorination of 2-bromo-2,2-difluoro acetophenone 5-difluoro ([18F]1n) substituted 18F]trifluoroacetophenones
bearing electron-withdrawing substituents were obtained in
[
3g with [18F]Bu4NF targeting fluorine-18 labelled 2,2,2-trifluoro were labelled in 90% and 92% radiochemical yields, respec-
acetophenone [18F]1g (Table 1). The reaction proceeded with a tively. In the presence of electron-withdrawing substituents on
low but encouraging radiochemical yield (RCY) of 5% at 100 1C the aromatic ring, the air-stability of the difluoro enol silyl
in DMF (entry 1). Our earlier studies for the construction of ethers (2) were somewhat lowered. Thioether-containing [18F]1o
fluorine-18 labelled trifluoromethyl compounds showed that was obtained in only 20% radiochemical yield. A possible
nitrogen-containing bases facilitate the halogen exchange of explanation is instability under the applied reaction conditions
the CF2X groups.5b When we performed the fluorine-18 label- due to the presence of the SEt group. Labelled conjugated vinyl
ling reaction in the presence of DBU, [18F]1g was obtained in ketones [18F]1p and [18F]1q could also be obtained, albeit
65% RCY (entry 2). Our previous results5b indicated an excellent the RCY (51% and 67%) were lower than for aryl derivatives
performance of guanidine-like bases in these type of labelling
studies. Indeed, application of TBD in place of DBU afforded increased to 67% by elevating the temperature to 100 1C.
18F]1g in 92% RCY at 100 1C (entry 3). Furthermore, the However, the increase of the reaction temperature led to a drop
[
18F]1g–n. The RCY for thiophene derivative [18F]1p could be
[
temperature could be reduced to 75 1C without significant of RCY for the naphthyl derivative [18F]1q. The labelling was not
decrease in the radiochemical yield (90%, entry 4). When limited to C(sp2)–COCF3 derivatives. Aliphatic derivative [18F]1r
[18F]KF/K222 was used instead of [18F]Bu4NF, we found the could be prepared with 51% RCY. This is an important finding
reaction to proceed with similar RCY (entry 5). The use of indicating that the reaction proceeds with satisfactory yield
MTBD, which is structurally similar to TBD (entry 6) or further even in the presence of an a-proton in the precursor. When TBD
reduction of the reaction temperature (entries 7 and 8) led to a was replaced with DIPEA the RCY was slightly increased to 64%.
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Fig. 4 18F-Labelling of NE inhibitor 1a to obtain fluorine-18 NE ligand
[
18F]1a.
using [18F]Bu4NF without any additive. Thus, we obtained
[
18F]1a in 15 Æ 12% RCY (Fig. 4). In addition, a preparative
run starting from 3.6 GBq [18F]Bu4NF afforded an activity yield
(AY) of 2% and a molar activity of 0.41 GBq mmolÀ1 70 minutes
after the end of the bombardment. The obtained molar activity
was relatively low probably due to fluorine-18–fluorine-19
isotopic exchange, which is a well-known problem for labelling
trifluoroalkyl groups.5a
Fig. 3 Substrate scope in the 18F-labelling of trifluoromethyl ketones. RCY
was estimated by radio-HPLC or radio-TLC analysis of the crude reaction
mixture. aThe reaction was performed at 100 1C. bDIPEA (1.0 equiv.) was used
instead of TBD. cWith [18F]KF/K222. No additive was used.
The pharmacological properties of these NE inhibitors can
be varied without substantial alteration of the inhibitory con-
stant (Ki) by changing the substituent on the pyridone group.6a
This can be exploited for the development of radiosynthesis of
We have also studied the labelling of an analogue of 1a with fluorine-18 labelled NE inhibitors analogous to [18F]1a. We
a valine unit attached to the COCF3 functionality. The attempts have found that the carbamate moiety of 4a can be hydrolysed
using [18F]Bu4NF failed to give labelled product [18F]1s. How- by trifluoromethanesulfonic acid in the presence of anisole,
ever, when the fluorine source was changed to [18F]KF/K222 in affording 4t (Fig. 5). Subsequently, the amino group could be
the absence of base, [18F]1s was obtained in 55% RCY.
sulfonated by methanesulfonyl chloride in the presence of base
To demonstrate the synthetic utility of the above-described and DMAP. This resulted in a new precursor, 4b, for fluorine-18
method we prepared a NE PET imaging tracer candidate based labelling. Fluorine-18 labelled NE inhibitor [18F]1b could
on the known6a NE inhibitor 1a (Fig. 4). We started the synthesis by be isolated with 30% RCY, 0.5% AY and a molar activity of
defluorination of NE inhibitor 1a6a to the corresponding difluoro 1.3 GBq mmolÀ1 (Fig. 5). Starting from 4a, this synthesis sequence
enol silyl ether 2a under dry conditions. Halogenation of 2a was can be exploited for a modular approach for radiosynthesis of a
performed without further purification because of the poor air and broad variety of fluorine-18 labelled NE inhibitors.
moisture stability of this reaction intermediate. Using Br2, we could
In summary, we have developed a new method for the
obtain the corresponding COCF2Br derivative from this enol silyl fluorine-18 labelling of trifluoromethyl ketones based on a
ether. However, this bromodifluoromethylated precursor could not circular defluorination–fluorination sequence. The reactions
be converted to the targeted [18F]1a. The low reactivity of the took place in a short reaction time at 75–100 1C, affording
COCF2Br derivative was somewhat surprising as the valine analo- radiochemical yields of up to 93%. We have demonstrated the
gue [18F]1s could be obtained from the corresponding bromo radiosynthetic utility of this fluorine-18 labelling method for
derivative 3s. A possible explanation was that the fluorine-18 the preparation of [18F]1a–b, which are based on NE inhibitors
reagent was deactivated under the applied reaction conditions.
1a–b. The methodology can be extended to a modular
After extensive studies (see ESI†) we have found that the iodo approach, for synthesis of a large variety of fluorine-18 labelled
derivative 4a is sufficiently reactive for the synthesis of [18F]1a NE inhibitors.
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Conflicts of interest
There are no conflicts to declare.
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