Fluorine-18 labelled Ruppert-Prakash reagent ([18F]Me3SiCF3) for the synthesis of 18F-trifluoromethylated compounds

Article abstract of DOI:10.1039/d1cc01789f

This article describes the first synthesis and application of fluorine-18 labelled Ruppert-Prakash reagent [18F]Me3SiCF3. [18F]Me3SiCF3 was synthesized from [18F]fluoroform with radiochemical yields of 85-95% and radiochemical purities of >95% within 20 m

Full text of DOI:10.1039/d1cc01789f

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Fluorine-18 labelled Ruppert–Prakash reagent
([18F]Me3SiCF3) for the synthesis of
Cite this: DOI: 10.1039/d1cc01789f
18F-trifluoromethylated compounds†
Received 5th April 2021,
Accepted 23rd April 2021
a
c
a
Anna Pees,
Danielle J. Vugts
Maria J.W.D Vosjan,b Neil Vasdev,
Albert D. Windhorst
and
a
*
DOI: 10.1039/d1cc01789f
rsc.li/chemcomm
This article describes the first synthesis and application of fluorine-
Since trifluoromethyl moieties are so often found in modern
18 labelled Ruppert–Prakash reagent [18F]Me3SiCF3. [18F]Me3SiCF3 pharmaceuticals, much attention has been paid to the develop-
was synthesized from [18F]fluoroform with radiochemical yields of ment of synthesis strategies for introducing fluorine-18 labelled
85–95% and radiochemical purities of 495% within 20 minutes. trifluoromethyl groups into PET tracers. Aromatic [18F]trifluoro-
18F-trifluoromethylated compounds were successfully prepared by methylation is well established and multiple strategies have been
reaction of [18F]Me3SiCF3 with benzaldehydes, acetophenones and reported.14–18 However, the reported methodologies mainly rely
benzophenones.
on [18F]fluoroform as [18F]trifluoromethylation agent. In organic
chemistry, not many trifluoromethylation procedures report the
Positron emission tomography (PET) is a molecular imaging use of [19F]fluoroform, as alternative trifluoromethylation agents
technique that non-invasively visualizes biochemical processes are generally preferred. One of the most applied nucleophilic
in vivo.1–3 This highly sensitive technique is increasingly used trifluoromethylation agents is the Ruppert–Prakash reagent
for the diagnosis of diseases, evaluation of the efficacy of a drug (Me3SiCF3).9 It was first described in 1984 by Ruppert et al.19 and
treatment, and drug discovery.3 PET radiotracers incorporate found its first application in 1989 by Prakash et al.20 We therefore
positron-emitting radionuclides, the most frequently used envisioned that developing a synthesis strategy for 18F-labelled
nuclide being fluorine-18.4 Fluorine-18 has very favourable Ruppert–Prakash reagent would be very useful for the translation
characteristics for PET imaging, such as a convenient half-life of CF3 functionalization reactions that have been developed in
(109.7 minutes) and a low positron energy (Emax = 0.634 MeV), fluorine-19 chemistry to radiofluorination reactions and PET tracer
making it desirable for distribution to radiochemistry laboratories synthesis.21
and imaging centres thereby enabling multi-centre clinical
trials.5–7
To synthesize [18F]Me3SiCF3 we followed a procedure reported
by Prakash et al. that reacted fluoroform with trimethylsilyl
There is a tremendous interest in the use of fluorine-19 in chloride in presence of potassium hexamethyldisilazide (KHMDS)
drug development.8,9 This is reflected by recent Food and Drug as the base in toluene.22 Initial experiments using [18F]fluoroform
Administration (FDA) drug approvals: in 2018 almost 1/3 of the 1 synthesized according to our previously reported method18
new drugs approved contained one or more fluorine atoms.10 showed successful formation of the desired product [18F]Me3SiCF3
The trifluoromethyl group is a prevalent motif as it can positively 3, in addition to unreacted [18F]fluoroform 1 and formation of a
influence many characteristics of a given drug, e.g. metabolic side product which was identified as [18F]trimethylsilyl fluoride 4
stability, lipophilicity, and protein binding affinity.11–13
(see Scheme 1). To optimize the reaction towards full conversion
to [18F]Me3SiCF3 3 several reaction parameters were varied.
a Amsterdam UMC, VU University, Radiology and Nuclear medicine,
Radionuclide Center, De Boelelaan 1085c, Amsterdam, The Netherlands.
E-mail: d.vugts@amsterdamumc.nl
b BV Cyclotron VU, De Boelelaan 1081, 1081 HV Amsterdam, The Netherlands
c Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre,
Centre for Addiction and Mental Health & Department of Psychiatry,
University of Toronto, 250 College St., Toronto M5T-1R8, ON, Canada
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1cc01789f
Scheme 1 Formation of
18F]fluoroform 1.
[ 3 and side product 4 from
18F]Me3SiCF3
[
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Table 2 Optimization of the [18F]Me3SiCF3 distillation
The following reaction setup was used as a starting point:
[18F]fluoroform 118 was trapped in a solution of 0.6M Me3SiCl 2
and 0.5M KHMDS in 650 mL toluene at À80 1C (prepared
15 minutes before trapping [18F]fluoroform 1, analogous to
19F-chemistry).22 After complete distillation (B3 min) of
[18F]fluoroform 1, the trapping vial was either actively warmed
up to 20 1C or passively by removing it from the cooling bath.
[18F]Fluoroform was trapped well in the toluene solution
and comparable RCYs to those previously reported (trapping in
DMF) were obtained (up to 44 Æ 0% vs 44 Æ 1%, calculated
from dry [18F]fluoride). The conversion of [18F]fluoroform to
[18F]Me3SiCF3 was temperature sensitive and active warming to
20 1C resulted in complete conversion in less than 2.5 minutes,
while passive warming required 15 minutes to reach comple-
Flow mL minÀ1
Temp. 1C
RCYa Me3SiCF3
%
1
2
3
4
5
6
7
8
9
5
70
70
70
70
70
70
70
50
60
80
52 Æ 6
69 Æ 3
86 Æ 3
93 Æ 1
94 Æ 1
95 Æ 1
95 Æ 1
75 Æ 21b
88 Æ 6
95 Æ 1
10
20
30
40
50
70
50
50
50
10
Conditions: 1182 mmol Me3SiCl, 500 mmol KHMDS, 1 mL toluene.
a
b
Average Æ SD, dc, n = 3. Distillation blocked in 2 out of 3 reactions.
tion at these reagent concentrations. Trapping at around suggesting that precursor Me3SiCl (bp. 57 1C)23 and also solvent
À80 1C was crucial, since higher temperatures favoured the (toluene, bp. 111 1C) were co-distilled along with [18F]Me3SiCF3.
formation of the side product, [18F]Me3SiF.
Subsequently, we explored the possibility of further purification
Stirring of the precursor Me3SiCl together with the base by distillation over solid phase extraction (SPE) cartridges. Our
KHMDS before the trapping was not necessary for [18F]Me3 primary focus was on the removal of the precursor, Me3SiCl, to
SiCF3 formation, nor was stirring during the reaction. Increase avoid potential reaction with the subsequent [18F]trifluoro-
of the precursor concentration as well as the total amounts of methylation reaction. It was found that the silica plus long
precursor, base and solvent helped to push the reaction Sep-Paks was able to retain the precursor while almost all
towards completion and shorten the reaction time with passive [18F]Me3SiCF3 passed the SPE. The RCY of [18F]Me3SiCF3 was
warming up to 5 min (see Table 1).
comparable to distillation without SPE (86 Æ 1 vs. 88 Æ 6%).
After having established high-yielding reaction conditions However, the distillation time increased from 5 minutes to
for the formation of [18F]Me3SiCF3, we turned our attention to 10 minutes (see ESI† for more details). In summary,
the isolation of the product for its use in subsequent [18F]tri- [18F]Me3SiCF3 was readily synthesized from [18F]fluoroform
fluoromethylation reactions. As Me3SiCF3 has a low boiling and obtained as a solution in THF with radiochemical yields
point (54–55 1C)9 we investigated purification by distillation. of 85–95% and radiochemical purities of 495%.
Different distillation temperatures and flow rates were tested.
To explore the applicability of [18F]Me3SiCF3 as [18F]trifluor-
An overview of the conditions is given in Table 2. The distilla- omethylation reagent, we demonstrated its use by reaction
tion efficiency increased with higher flow (entry 1–7). At flow with aldehydes and ketones and adapted the procedure for
rates of 30 mL minÀ1 and higher, 490% of [18F]Me3SiCF3 could 19F-reactions reported by Prakash et al.20 In this procedure, the
be distilled into THF. Exploring different distillation tempera- aldehyde or ketone was reacted with Me3SiCF3 under addition
tures showed that temperatures Z70 1C led to the highest of catalytic amounts of TBAF in THF. After hydrolysis with
yields and at 50 1C the co-distilled precursor precipitated in aqueous HCl, the desired trifluoromethylated product was
the tubing and led to blockage during distillation (see entry 6, obtained. 4-Nitrobenzaldehyde 6g was selected as a model
8–10). The radiochemical purity of the distilled [18F]Me3SiCF3 substrate and the following reaction parameters were varied:
was determined and only minor impurities (0–2%) of reaction time and temperature, quantities of TBAF and pre-
[18F]Me3SiF were found.
cursor as well as the scale of the reaction. [18F]Me3SiCF3 was
At higher flow rates and higher temperatures we noted a found to readily react with 4-nitrobenzaldehyde: Reaction of an
significant decrease of the volume in the first reaction vessel aliquot of the [18F]Me3SiCF3 in THF (300 mL) with 100 mmol
and the formation of a precipitate in the second vessel 4-nitrobenzaldehyde 6g and 200 mmol TBAF for 5 minutes at
room temperature in a total of 0.5 mL THF resulted in 39 Æ 4%
RCY. [18F]CHF3 was formed as a side product, likely resulting
Table 1 Optimization of the [18F]Me3SiCF3 formation by variation of
precursor and base
from reaction of [18F]Me3SiCF3 with traces of water present in
THF or the TBAF solution. The 1M TBAF solution in THF was
therefore stored in small batches (10–20 mL) over molecular
sieves (3Å) to minimize the water content as much as
possible.23
Variation of reaction time (2.5–20 min) and temperature
(0–80 1C) did not have an effect on the radiochemical yield under
our conditions. The control of the TBAF concentration however
was important since low concentrations (r200 mM) resulted in
incomplete release of [18F]CF3À from [18F]Me3SiCF3 and therefore
lower yields, whereas high concentrations (Z600 mM) were not
Me3SiCl
mmol
KHMDS
mmol
Toluene
mL
RCY
CHF3
RCP
Me3SiCF3 %
a
b
%
1
2
3
4
5
394
788
1576
1182
1182
325
325
650
488
500
650
650
1300
975
n.d.
0 Æ 0
74 Æ 28
95 Æ 4
98 Æ 2
97 Æ 3
28 Æ 1
39 Æ 0
44 Æ 0
43 Æ 3
1000
Conditions: Trapping at À80 1C, passive warmup to rt in 5 min.
a
b
Isolated yield, average Æ SD, decay corrected (dc), n = 3. Determined
by HPLC, average Æ SD, dc, n = 3.
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beneficial for the reaction, and is likely attributed to increasing
amounts of water in the TBAF solution which is responsible for
promoting [18F]CHF3 formation.
Next, the effect of precursor concentration was investigated
and showed that the higher the concentration of precursor, the
higher the radiochemical yield (64 Æ 5% RCY with 400 mmol
precursor; see ESI† for details). To adapt the reaction for
relevance to PET tracer syntheses the scale of the reaction
was reduced compared to the initial conditions. It was observed
that scaling down the reaction to 250 mL and 125 mL total
volume resulted in comparable to even slightly higher radio-
chemical yields than the initial conditions (see Table S6 in
ESI†). Due to easier handling and abundance of the model
precursors we moved on to explore the substrate scope with
the following conditions: 250 mL THF, 200 mmol precursor,
100 mmol TBAF (ESI,† Table S6, entry 7).
Three different groups of substrates were investigated, ben-
zaldehydes, acetophenones and benzophenones, each with no
substituents, electron withdrawing (4-MeO-) and electron
donating (3-NO2-, 4-NO2-) substituents. An overview of all
products and the corresponding RCYs is shown in Scheme 2.
Two general trends were observed: 1. Electron withdrawing
groups had a positive influence on the RCY. 2. Benzaldehydes
reacted very well whereas benzophenones only resulted in low
RCYs (o10%). The first observation can be explained by the
electron density. The trifluoromethyl group attacks the posi-
tively polarised C atom of the carbonyl group. Electron with-
drawing groups reduce the electron density of the carbonyl C
atom and facilitate the nucleophilic attack whereas electron
donating groups exert the opposite effect. The second observa-
tion can be explained by the reaction kinetics. It has been
described that the rate constants of trifluoromethylation reac-
tions observe the following rank order: k(benzaldehyde) 4
k(acetophenone) 4 k(benzophenone); and a competing reac-
tion is the formation of fluoroform by reaction of Me3SiCF3
with trace amounts of water.24 The reaction with benzaldehydes
is likely fast enough to outcompete the [18F]fluoroform for-
mation whereas with benzophenones [18F]fluoroform for-
mation predominates.
Scheme 2 Reaction of
[
18F]Me3SiCF3 with aldehydes and ketones;
Reaction conditions: 200 mmol precursor, 250 mL THF, 5 min, rt, 100 mmol
TBAF or 80 mmol TBAT; RCY = average Æ SD, n = 3.
Attempts to increase the RCY of the benzophenone reactions
by further optimization of the previously varied reaction con- using [18F]fluoroform.16 Furthermore, the unsubstituted and
ditions (temperature, time, TBAF amount) were not fruitful. We methoxy-substituted benzaldehydes were [18F]trifluoromethy-
therefore turned our attention to alternative initiators. Based lated with decent to good yields (73 Æ 4% and 43 Æ 6%,
on work of Johnston et al.24 we chose two initiators, KOPh and respectively). Unsubstituted and methoxy-substituted acetophe-
TBAT. Reactions initiated by K+-containing initiators were nones and benzophenones still showed low yields (r10%). On
+
expected to have a faster turnover rate than with NH4 and the contrary to the nitro-substituted derivatives, these sub-
could improve the RCY of the slow-reacting benzophenones. strates are reported to react very well with [18F]fluoroform.
Anhydrous TBAT was reported to result in more reproducible
yields compared to TBAF, due to lower water content.
All optimization reactions were carried out using aliquots of
a [18F]Me3SiCF3 stock solution. To confirm that the [18F]tri-
Under our radiochemistry conditions KOPh resulted in very fluoromethylation reactions work using the full batch of
low yields for all substrate groups, and is likely due to poor [18F]Me3SiCF3 and to determine the overall RCY and molar
solubility of KOPh in THF. However, TBAT proved to be an activity (Am), [18F]Me3SiCF3 was synthesized from 5 GBq
excellent initiator (see Scheme 2). Reactions with nitro- [18F]fluoride. It was trapped after distillation in a reaction
substituted benzaldehydes and acetophenones resulted in vessel containing THF, TBAT and 4-nitrobenzaldehyde and
Z90% RCY of the corresponding products. It is noteworthy reacted for 5 min at rt after complete trapping. It was found
that three of these compounds previously failed to label that higher TBAT amounts (556 mmol) were required to fully
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À
release CF3 from [18F]Me3SiCF3, but the precursor amount Innovation, Ontario Research Fund and the Canada Research
could be kept at 200 mmol. The product was purified by Chairs Program as well as members of the CAMH Brain Health
preparative HPLC and the collected product fraction was mea- Imaging Centre for support.
sured for radioactivity and analysed by HPLC. The overall
radiochemical yield (with regard to aqueous [18F]fluoride) was
11 Æ 3% (dc) and the molar activity was 13 Æ 2 GBq/mmol
(n = 3). The molar activity compares well to the Am reported for
[18F]fluoroform18 at the same starting amount of [18F]fluoride.
The low overall yield is mainly due to losses during [18F]fluoro-
form formation. Details on the reaction procedure and molar
activity calculations can be found in the ESI.†
Conflicts of interest
There are no conflicts to declare.
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[
18F]Me3SiCF3
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The project is financially supported by the Dutch Research
Council (NWO) grant no. 731.015.413 and BV Cyclotron VU. We
also thank the Azrieli Foundation, Canada Foundation for
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Chem. Commun.
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