New fluorine-18 labeled benzaldehydes as precursors in the synthesis of radiopharmaceuticals for positron emission tomography

Article abstract of DOI:10.1007/s11172-016-1330-2

4,5-Bis(butoxy)-2-nitrobenzaldehyde and 4,5-bis(tert-butoxycarbonyloxy)-2-nitrobenzaldehyde, as well as their fluorine-18 labeled derivatives (the half-life of F¹⁸ is T_1/2 = 110 min) were synthesized for use as precursors in the synt

Full text of DOI:10.1007/s11172-016-1330-2

Russian Chemical Bulletin, International Edition, Vol. 65, No. 2, pp. 507—512, February, 2016
507
New fluorineꢀ18 labeled benzaldehydes as precursors in
the synthesis of radiopharmaceuticals for positron emission tomography*
V. V. Orlovskaja,a O. S. Fedorova,a,c E. P. Studentsov,b A. A. Golovina,b and R. N. Krasikovaa,c
aN. P. Bechtereva Institute of Human Brain, Russian Academy of Sciences,
9 ul. Akad. Pavlova, 197376 Saint Petersburg, Russian Federation.
Fax: +7 (812) 234 3247. Eꢀmail: raisa@ihb.spb.ru
bSaint Petersburg State Technological Institute (Technical University),
26 Moskovskii prosp., 190013 Saint Petersburg, Russian Federation.
Fax: +7 (812) 494 9306
cDepartment of Chemistry, Saint Petersburg State University,
7—9 Universitetskaya nab., 199034 Saint Petersburg, Russian Federation.
Fax: +7 (812) 328 2000
4,5ꢀBis(butoxy)ꢀ2ꢀnitrobenzaldehyde and 4,5ꢀbis(tertꢀbutoxycarbonyloxy)ꢀ2ꢀnitrobenzalꢀ
dehyde, as well as their fluorineꢀ18 labeled derivatives (the halfꢀlife of F18 is T1/2 = 110 min)
were synthesized for use as precursors in the synthesis of fluorineꢀ18 labeled catecholamines
and 6ꢀ[18F]fluoroꢀLꢀDOPA ((S)ꢀ3ꢀ[4,5ꢀdihydroxyꢀ2ꢀ[18F]fluorophenyl]ꢀ2ꢀaminopropionic
acid), important radiopharmaceutical agents (RPAs) for positron emission tomography. An
advantageous feature of the newly obtained substituted nitrobenzaldehydes is the presence of
labile protective groups which can be removed without using aggressive chemicals and severe
conditions, which is of fundamental importance for automation of the RPA synthesis in modern
synthesis apparatus. A high and stable radiofluorination yield achieved under the optimum
fluorination conditions (Kryptofix 222 [K/K2.2.2.]+[18F–], DMF, 140 °C, 10 min) using
4,5ꢀbis(butoxy)ꢀ2ꢀnitrobenzaldehyde as a substrate (83 6%, the number of experiments was
n = 15) makes this compound a precursor of choice for the radioactive synthesis.
Key words: fluorineꢀ18, 18F, radiopharmaceuticals, positron emission tomography, substiꢀ
tuted nitrobenzaldehydes, nucleophilic radiofluorination, fluorineꢀ18 labeled aromatic amino
acids.
Positron emission tomography (PET) is a rapidly deꢀ
veloping method of nuclear medicine allowing one to obꢀ
tain in vivo quantitative information on physiological and
biochemical processes forming the basis of different disꢀ
eases, mechanisms of drug actions, etc. The method conꢀ
templates the use of radiotracers (radiopharmaceutical
agents (RPAs)), bioactive compounds containing shortꢀ
lived radioactive isotopes, such as 15O, 13N, 11C, 18F, and
others, with positron decay. In clinical PET studies, the
RPAs based on the longestꢀlived isotope, fluorineꢀ18 (the
halfꢀlife is T1/2 = 110 min), whose nuclearꢀphysical charꢀ
acteristics are almost ideally suited for PET, have wideꢀ
spread application.
in automated synthesis apparatus. Modern medical cycloꢀ
trons provide up to 25 Ci of fluorineꢀ18 in the chemical
form of no carrier added [18F]fluoride,1 which is crucial
for PET studies. The nucleophilic radiofluorination using
[18F]fluoride is the most common method for the prepaꢀ
ration of different class RPAs for PET.2 The routine synꢀ
thesis of RPAs widely uses the direct nucleophilic substiꢀ
tution of a leaving group in the molecule of an aliphatic
substrate with [18F]fluoride in the presence of phaseꢀtransꢀ
fer catalysts (tetraalkylammonium salts, crown ethers, and
cryptands). This reaction provides a high radiochemical
yield (RCY).
It is more problematic to synthesize compounds conꢀ
taining fluorineꢀ18 in the aromatic ring, which is one of
the most common structural fragments of bioactive moleꢀ
cules (aromatic amino acids, neurotransmitters, drugs,
etc.). In the case of simple aromatic compounds (benzalꢀ
dehydes, benzonitriles, etc.) containing strong electronꢀ
withdrawing substituents (NO2, CHO, COR, CN, etc.) in
the orthoꢀ or paraꢀposition relative to the leaving group,3,4
A simple and reliable method for generation of 18F by
the 18O(p,n)18F nuclear reaction realized upon proton irꢀ
radiation of waterꢀ18O in an aqueous cyclotron target is an
exceptionally convenient for routine production of RPAs
* Dedicated to Academician of the Russian Academy of Sciences
N. S. Zefirov on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0507—0512, February, 2016.
1066ꢀ5285/16/6502ꢀ0507 © 2016 Springer Science+Business Media, Inc.

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Orlovskaja et al.
the direct nucleophilic aromatic radiofluorination provides
a high RCY. However, this method is not efficient if the
reactive center of nucleophilic attack in the benzene ring
forming a part of complex molecules is not activated. In
this case, fluorineꢀ18 can be introduced only through
a multistsep synthesis, whose automation requires solving
a number of problems.5
radiofluorination and the possibility for deprotection at
the final step of synthesis (step of hydrolysis, see Scheme 1)
under mild conditions. Hydroxy groups are usually proꢀ
tected by the methylene dioxy group as in 6ꢀnitroꢀ1,3ꢀ
benzodioxolꢀ5ꢀcarbaldehyde (1) (nitropiperonal or
4,5ꢀmethylenedioxyꢀ2ꢀnitrobenzaldehyde) or the methꢀ
oxy group as in 4,5ꢀbis(methoxy)ꢀ2ꢀnitrobenzaldehyde (2)
and 2ꢀformylꢀ4,5ꢀbis(methoxy)ꢀ2ꢀN,N,Nꢀtrimethylbenꢀ
zeneammonio trifluoromethanesulfonate (3). Note that
the removal of these protective groups requires aggressive
reagents and severe conditions (Table 1).10—13,15—19 The
deprotection step is the most difficult to be implemented
in automated synthesis apparatus, especially in the case,
when singleꢀuse reagent cassettes5 not tailored for appliꢀ
cation in aggressive media are used.
A classical example of the multistep process is the fiveꢀ
step synthesis of fluorineꢀ18 labeled fluorinated amino acid
analogs ([18F]FAA) starting from the nucleophilic radioꢀ
fluorination of a substituted benzaldehyde. Among
[18F]FAAs, 6ꢀ[18F]fluoroꢀLꢀDOPA ((S)ꢀ3ꢀ[4,5ꢀdihydrꢀ
oxyꢀ2ꢀ[18F]fluorophenyl]ꢀ2ꢀaminoprionic acid) is of parꢀ
ticular interest. This compound is a unique PET tracer
proposed first for assessment of the Parkinson disease6
and widely used in recent years in diagnostics (brain maꢀ
lignancies, neutroendocrine and other tumor types).7
Despite a great number of works on the synthesis of
6ꢀ[18F]fluoroꢀLꢀDOPA, the development of efficient synꢀ
thetic procedures based on the nucleophilic substitution
with [18F]fluoride, including automation of the producꢀ
tion of this radiotracer, continues to be of current conꢀ
cern.8 Enantiomerically pure [18F]FAAs are prepared usꢀ
ing asymmetric synthesis methods.9—13 In the case of corꢀ
rect selection of chiral reagents and reaction conditions,
these methods provide radiotracers with a high enantioꢀ
meric purity (higher than 95%) allowing their application
in PET. In the case of 6ꢀ[18F]fluoroꢀLꢀDOPA, the synꢀ
thesis includes several steps starting from the nucleophilic
substitution of the leaving group with [18F]fluoride in the
substituted benzaldehyde molecule where the hydroxy
functions have to be protected to avoid their oxidation in
subsequent steps. The resulting 18Fꢀfluorobenzaldehyde is
used in the direct condensation with an asymmetric chiral
The problem can be solved using more labile protective
groups that can be removed under mild conditions (aqueꢀ
ous solutions of weak acids). Recently, in the asymmetric
synthesis of (2S,3R)ꢀ2ꢀaminoꢀ3ꢀhydroxyꢀ3ꢀ(4,5ꢀdihydrꢀ
oxyꢀ2ꢀ[18F]fluorophenyl)propionic acid (6ꢀLꢀthreoꢀ
[
18F]FDOPS)20 we have applied for the first time
inductor,14 but it is more often transformed into the fluoꢀ
rineꢀ18 labeled benzyl halides, electrophilic alkylating
agents in the asymmetric alkylation9—13 (Scheme 1).
The main requirements for benzaldehydes used as preꢀ
cursors at the first step of nucleophilic synthesis of
6ꢀ[18F]fluoroꢀLꢀDOPA is the high radiochemical yield of
4,5ꢀbis(methoxymethoxy)ꢀ2ꢀnitrobenzaldehyde (4) with
readily removable MOM protections (1 M HCl, 50—
100 °C, 5 min). However, according to the preliminary
data19 the use of this benzaldehyde in the asymmetric synꢀ
thesis of 6ꢀ[18F]fluoroꢀLꢀDOPA by a known procedure12
was accompanied by a significant decrease in the yield of
Scheme 1
Fluorination, 18F–
Halogenation
Reduction
Hydrolysis
Asymmetric alkylation
LG is a leaving group.

New 18Fꢀlabeled benzaldehydes
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
509
Table 1. Conditions for deprotection of protecting groups for
the 4,5ꢀhydroxy functions in benzaldehydes 1—4 as
precursors of 6ꢀ[18F]fluoroꢀLꢀDOPA*
Benzaldehyde
Conditions
Reference
10, 12, 15
1
57% HI,
180 °C, 20 min
2
57% HI,
180 °C, 20 min
48% HBr, KI,
16
17
150 °C, 10 min
3
4
57% HI, red
phosphorus, 200 °C, 20 min
1 M HCl, 120 °C, 5 min
13, 18
19
Boc is C(O)OBut.
of removal of alkyl groups increases in the order: OMe <
—OCH(CH2)3, —OBn < —OBut, —OCH2OMe, and
Oꢀtetrahydropyranyl group.21
* See Scheme 1, hydrolysis step.
In the present work, the 4,5ꢀsubstituted benzaldehydes
5 and 6 were synthesized for the first time by alkylation of
4,5ꢀdihydroxyꢀ2ꢀnitrobenzaldehyde. The lastꢀmentioned
compound was obtained by ring opening of the 4,5ꢀmethꢀ
ylenedioxy derivative 1 according to a known procedure.22
The alkylating agents were nꢀbromobutane, di(tertꢀ
butyl)dicarbonate, and isobutylene. The acidꢀcatalyzed
alkylation with isobutylene gave no desired results. Comꢀ
pounds 5 and 6 were obtained in high yields and isolated
final product compared to the case, when the precursor
was the conventional benzaldehyde 1.
The aim of the present work was to search for
4,5ꢀsubstituted nitrobenzaldehydes with other labile proꢀ
tective groups for their use as precursors upon introducꢀ
tion of fluorineꢀ18 to the aromatic ring of complex moleꢀ
cules. The possibility for deprotection under mild condiꢀ
tions is essential for automation of the asymmetric nuꢀ
cleophilic synthesis of not only 6ꢀ[18F]fluoroꢀLꢀDOPA
(see Scheme 1), but also of the fluorineꢀ18 labeled cateꢀ
cholamines, viz., 6ꢀ[18F]fluoronorepinephrine (4ꢀ[(1R)ꢀ
2ꢀaminoꢀ1ꢀhydroxy]ꢀ5ꢀ[18F]fluoroꢀ1,2ꢀdihydroxyꢀ
benzene) and 6ꢀ[18F]fluorodopamine (2ꢀ(6ꢀ[18F]fluoroꢀ
3,4ꢀdihydroxyphenyl)ethylamine). Ding et al. in the work3
on the synthesis of fluorineꢀ18 labeled benzaldehydes
showed that the yields of radiofluorination correlate with
the chemical shifts in the 13C NMR spectra, which deꢀ
pend on the electron density at the site of nucleophilic
attack. This approach is used also in the present work in
the analysis of radiofluorination data of newly synthesized
benzaldehydes.
1
in pure form and their structures were confirmed by H
and 13C NMR spectroscopy. 4,5ꢀBis(methoxymethoxy)ꢀ
2ꢀnitrobenzaldehyde (4) was synthesized according to the
earlier proposed procedure.20 The protective groups in benꢀ
zaldehydes 4—6 are stable under alkaline conditions of
fluorination and, at the same time, can be removed under
mild conditions. As noted above, the MOM groups in
compound 4 are easily removed upon heating in aqueous
hydrochloric acid,19.20 whereas the butyl and tertꢀbutoxyꢀ
carbonyloxy protective groups are removed upon treatꢀ
ment with trifluoroacetic acid at room temperature.
Another essential requirement for precursors used in
the first step of a multistep radioactive synthesis is the
high efficiency of radiofluorination, which is defined by
the nature of leaving and protective groups and their muꢀ
tual arrangement in the molecule of a substituted benzalꢀ
dehyde.3 The corresponding radiofluorinated derivatives,
6ꢀ[18F]fluoroꢀ1,3ꢀbenzodioxolꢀ5ꢀcarbaldehyde (7),
4,5ꢀbis(methoxymethoxy)ꢀ2ꢀ[18F]fluorobenzaldehyde (8),
4,5ꢀbis(butoxy)ꢀ2ꢀ[18F]fluorobenzaldehyde (9), and
4,5ꢀbis(tertꢀbutoxycarbonyloxy)ꢀ2ꢀ[18F]fluorobenzaldeꢀ
hyde (10), are produced upon replacement of the nitro
group in benzaldehydes 1 and 4—6.
Results and Discussion
Traditionally, 4,5ꢀsubstituted benzaldehydes 1—3 are
used in the synthesis of 6ꢀ[18F]FluoroꢀLꢀDOPA.10,12,15—18
In the present work, we propose to use nitrobenzaldehydes
with different labile protective groups: the earlier20 introꢀ
duced 4,5ꢀbis(methoxymethoxy)ꢀ2ꢀnitrobenzaldehyde (4)
and two new compounds, i.e., 4,5ꢀbis(butoxy)ꢀ2ꢀnitrobenzꢀ
aldehyde (5) and 4,5ꢀbis(tertꢀbutoxycarboxy)ꢀ2ꢀnitrobenzꢀ
aldehyde (6).
It follows from the analysis of literature data that it is
the ether groups having long carbon chain and branched
structure, which are promising for use as protections. Such
protective groups are labile and their removal requires
milder conditions compared to the methylenedioxy group
in the molecule of 1 (see Table 1). It is known that the ease
The radiofluorination reactions of compounds 1 are
well studied. When performing the reaction in the presꢀ
ence of Kryptofix 2.2.2 (4,7,13,16,20,24ꢀhexaoxaꢀ
1,10ꢀdiazabicyclo[8.8.8]hexacosan) as the phaseꢀtransfer
catalyst and potassium carbonate (DMF, 140 °C, 10 min),
the efficiency of radiofluorination of aldehyde 1 reached
90%. These conditions were also used in the study of raꢀ
diofluorination of benzaldehydes 4—6 (Table 2).

510
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
Orlovskaja et al.
Scheme 2
the fluorineꢀ18 labeled pyrocatechol fragment, such as
6ꢀ[18F]fluoroꢀLꢀDOPA, allows deprotection under mild
conditions without using any aggressive chemicals. This is
of fundamental importance for automation of the syntheꢀ
sis processes in modern apparatus, where such automaꢀ
tion provides safety upon production of highly radioactive
PET radiotracers. The detected correlations between the
radiochemical yield and the chemical shift of the benzene
C(2) atom confirmed the data obtained earlier3 and are
also of interest for classical organic chemistry.
i. [K/K2.2.2]+[18F–], DMF, 140 °C, 10 min.
R + R = CH2 (1, 7), R = MeOCH2 (4, 8), Bu (5, 9), Boc (6, 10)
Table 2 also gives the 13C NMR spectral data for the
starting benzaldehydes 1 and 4—6. This method is quite
sensitive to determine the electron density on the aromatꢀ
ic carbon atoms taking into account the sp2ꢀ and sp3ꢀ
hybridization of ether carbon atoms.3 For a series of the
structurally similar substituted benzaldehydes 1 and 4—6,
there was a correlation between the radiofluorination effiꢀ
ciency and the chemical shift of the benzene C(2) atom,
the reactive center, where the fluorineꢀ18 atom is substiꢀ
tuted for the nitro group. The chemical shifts of the C(2)
atom in compounds 1, 4, and 5 are in the region of δ 143—
146 and correspond to high yields of radiofluorination.
However, in the case of aldehyde 6 the 13C NMR signal
for the C(2) atom is shifted upfield by 24 ppm, which
suggests an increase in the electron density on the reactive
center and corresponds to a decrease in the radiochemical
yield. These results can be explained by the difference in
the donorꢀacceptor effects of protective groups:
electronꢀdonating effect in compounds 1, 4, and 5 and
electronꢀwithdrawing effect in the Bocꢀsubstituted niꢀ
trobenzaldehyde 6. Higher and more stable yields of raꢀ
diofluorination of compounds 1 and 5 compared to aldeꢀ
hyde 4 are likely due to a specific solvation of 4 with DMF
in the presence of the Kryptofix phaseꢀtransfer catalyst.
Thus, among the studied substituted benzaldehydes 4—6
with labile protective groups, the highest and stable yield
of radiofluorination (83 6%, the number of experiments
was n = 15) was reached for compound 5. The use of
aldehyde 5 as the precursor in the synthesis of RPAs with
Experimental
The commercially available 6ꢀnitroꢀ1,3ꢀbenzodioxolꢀ5ꢀcarbꢀ
aldehyde (1) (Aldrich) was used. All reactions were performed
under the highꢀpurity argon in anhydrous solvents prepared imꢀ
mediately prior to use according to standard procedures. 1H and
13C NMR spectra were recorded on a Bruker WM spectrometer
(400.13 and 100.16 MHz, respectively). The chemical shifts (δ)
1
in the H NMR spectra were measured relative to the residual
signals of CHCl3 and the chemical shifts in the 13C NMR specꢀ
tra were measured relative to the signal of the carbon atom of
CDCl3. The individuality of synthesized compounds was proved
by thinꢀlayer chromatography on Merck Kieselgel 60 F254 plates.
Melting points were determined on a PTP instrument (Klin,
Russia).
Waterꢀ18O with 97 atom.% of 18O (Global Scientific Techꢀ
nologies, Sosnovy Bor, Russia), anhydrous acidꢀfree MeCN
(DNA grade), potassium carbonate, anhydrous DMF,
4,7,13,16,20,24ꢀhexaoxaꢀ1,10ꢀdiazabicyclo[8.8.8]hexacosan
(Kryptofix or K2.2.2) (Sigma Aldrich), and a SepꢀPak Light
Waters AccellTM Plus QMA anionꢀexchange cartridge (Waters)
were used in the work.
Radiochemical synthesis. A GE PETTrace 4 cyclotron (Sweꢀ
den, the proton energy was 16.5 MeV); a Von Gahlen hot cell
(Netherlands) for handling radioactive samples; a PTW Curieꢀ
mentorꢀ2 isotope calibrator (Germany); and a Minigita scanner
for thinꢀlayer radiochromatography (Raytest, Germany) were
used in the radiochemical synthesis. The synthesis was performed
on a remotely controlled semiꢀautomatic apparatus for nucleoꢀ
philic radiofluorination designed at the Institute of Human Brain
of the Russian Academy of Sciences. The apparatus was inꢀ
stalled in the hot cell and the control of valve switching, gas
Table 2. Chemical shifts of carbon atoms in the substituted pyrocatecholꢀ2ꢀnitrobenzaldehydes 1 and 4—6 and the efficiency of their
radiofluorination
Comꢀ
pound
13C NMR, δ
Efficiency of
radiofluorination*,** (%)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
Aldehyde
group
1
4
5
6
128.19
126.30
125.27
124.12
146.07
144.38
143.59
120.24
105.10
111.79
108.17
145.85
152.27
151.24
153.22
149.21
151.55
150.35
152.31
129.48
107.50
114.62
110.67
120.24
186.86
186.42
187.89
186.27
90 5 (n = 25)
45 12 (n = 17)
83 6 (n = 15)
3 1 (n = 3)
* According to the data from radioTLC.
** The number of experiments is given in parentheses.

New 18Fꢀlabeled benzaldehydes
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
511
flows, and temperature unit was carried out using an outer pushꢀ
button panel. This system does not allow operation at high raꢀ
dioactivity levels; therefore, the initial activity of fluorineꢀ18
was from 185 to 1100 MBq, which is sufficient to develop the
synthesis strategy and to analyze all products. The radiofluorinaꢀ
tion products were analyzed by radioTLC on plasticꢀcoated siliꢀ
ca gel plates with an UV 254 nm indicator (Sorbfil, Krasnodar,
Russia).
NMR (CDCl3), δ: 1.58 (m, 18 H, 2 But); 7.89 (s, 1 H, C(6)H);
8.16 (s, 1 H, C(3)H); 10.42 (s, 1 H, CHO).
Preparation of fluorineꢀ18 and its complex with a phaseꢀtransꢀ
fer catalyst. The fluorineꢀ18 radionuclide (the halfꢀlife is T1/2
=
= 110 min) in the form of [18F]fluoride was prepared by the
18O(p,n)18F nuclear reaction carried out by proton irradiation of
[18O]H2O in an aqueous niobium target of the cyclotron with
a volume of 2.3 mL. The irradiated water containing [18F]fluoride
was transferred by helium flow on a SepꢀPak Light Waters Acꢀ
cellTM Plus QMA anionꢀexchange cartridge activated by passing
0.5 M potassium carbonate (10 mL) and water (15 mL); the
cartridge was flushed with helium for 5—10 min to remove residꢀ
ual water. The 18F radionuclide was eluted with complexꢀcomꢀ
position solutions (2 mL) into a 5ꢀmL conical reaction vessel
placed to a heating unit. The eluent had the following composiꢀ
tion: K2.2.2. (9.8 mg), K2CO3 (2.1 mg), H2O (0.09 mL), and
MeCN (2 mL). The solvents were removed in the stream of
nitrogen for 4—6 min at 130 °C, MeCN (1 mL) was added, and
residual water was removed by azeotropic distillation. The reꢀ
sulting activated complex [K/K2.2.2.]+[18F]– was used in raꢀ
diofluorination.
4,5ꢀBis(butoxy)ꢀ2ꢀnitrobenzaldehyde (5). To a solution of
pure aluminum chloride (11 g, 82.4 mmol) in anhydrous
1,2ꢀdichloroethane (25 mL) prepared under the argon atmoꢀ
sphere and cooled to –5 °C, a solution of compound 1 (5 g,
25.6 mmol) in anhydrous 1,2ꢀdichloroethane (20 mL) was added
dropwise with stirring. The reaction was continued for 2 h mainꢀ
taining the temperature from –5 °C to 5 °C until compound 1
disappeared. To complete the reaction, the mixture was poured
into 48% HBr (60 mL) and stirred for 48 h at room temperature
(~20 °C) until the intermediate chloromethyl ether disappeared
(TLC control). The reaction mixture was diluted with water
(60 mL), extracted with ethyl acetate (3×50 mL), and dried over
magnesium sulfate. The solvent was evaporated and the residue
was treated with hot hexane. The treatment of the crude product
with hot dichloromethane (50 mL) yielded 4,5ꢀdihydroxyꢀ
2ꢀnitrobenzaldehyde (4.3 g, 90%), which was recrystallized from
water (100 mL) to yield the chromatographically homogeneous
product (1.79 g) as yellow crystals, m.p. 202—203 °C, Rf 0.25
Synthesis 6ꢀ[18F]fluoroꢀ1,3ꢀbenzodioxolꢀ5ꢀcarbaldehyde (7),
4,5ꢀbis(methoxymethoxy)ꢀ2ꢀ[18F]fluorobenzaldehyde
(8),
4,5ꢀbis(butoxy)ꢀ2ꢀ[18F]fluorobenzaldehyde (9), and 4,5ꢀbis(tertꢀ
butoxycarbonyloxy)ꢀ2ꢀ[18F]fluorobenzaldehyde (10). A solution
of the substituted benzaldehyde 1, 4, 5, or 6 (5—8 mg) in DMF
(0.6 mL) was added to the activated fluorineꢀ18ꢀcontaining comꢀ
plex. The mixture was stirred in the stream of nitrogen and heatꢀ
ed in a closed vessel for 10 min at 140 °C. The efficiency
of radiofluorination was determined by the radioTLC control of
a reaction aliquot using dichloromethane as the eluent. The spot
positions of nonradioactive compounds were determined in the
UV light (254 nm); the radioactivity distribution was detected by
radiometry using a radioTLC scanner. The retention factors (Rf)
were 0.20 for [18F]fluoride, 0.32 for compound 7, 0.18 for comꢀ
pound 8, 0.30 for compound 9, and 0.20 for compound 10. The
efficiency of radiofluorination was determined by radioTLC as
the ratio between the peak area of product and the total area of
all peaks detected on the radioTLC chromatogram.
1
(acetone—hexane, 1 : 2). H NMR (CDCl3), δ: 7.21 (s, 1 H,
C(6)H); 7.50 (s, 1 H, C(3)H); 10.14 (s, 1 H, CHO); 10.85 (s, 2 H,
2 OH). To a solution of 4,5ꢀdihydroxyꢀ2ꢀnitrobenzaldehyde (0.5 g,
2.7 mmol) in DMF, the anhydrous finely powdered potassium
carbonate (0.94 g, 6.8 mmol) and nꢀbromobutane (1.1 g, 8.1 mmol)
were added with stirring in the argon stream with moisture proꢀ
tection. The resulting mixture was heated for 15 h at 60 °C,
diluted with water, and extracted with diethyl ether (3×50 mL).
The extract was dried with MgSO4 and the solvent was evaporatꢀ
ed. The residue was recrystallized from diethyl ether to yield the
chromatographically homogeneous compound 5 (0.66 g, 83%)
as a crystalline powder, m.p. 80—85 °C, Rf 0.62 (acetone—hexꢀ
ane, 1 : 2). Found (%): C, 61.04; H, 7.20; N, 5.71. C15H21NO5.
Calculated (%): C, 61.00; H, 7.17; N, 4.74. 1H NMR (CDCl3),
δ: 0.98—1.03 (m, 6 H, 2 CH3); 1.47—1.58 (m, 4 H, 2 CH2);
1.82—1.91 (m, 4 H, 2 CH2); 4.13—4.16 (m, 4 H, 2 CH2); 7.38
(s, 1 H, C(6)H); 7.58 (s, 1 H, C(3)H); 10.43 (s, 1 H, CHO).
4,5ꢀBis(tertꢀbutoxycarbonyloxy)ꢀ2ꢀnitrobenzaldehyde (6). To
a solution of 4,5ꢀdihydroxyꢀ2ꢀnitrobenzaldehyde (1 g, 5.46 mmol)
in DMF (10 mL) and triethylamine (1.1 mL, 0.8 g, 7.93 mmol),
a solution of di(tertꢀbutyl)dicarbonate (4.3 g, 19.70 mmol) in
DMF (5 mL) was added dropwise at room temperature (~20 °C).
After stirring for 24 h, the reaction mixture was diluted with ethyl
acetate (75 mL) and washed with brine (50 mL). The aqueous layer
was separated and extracted with ethyl acetate (2×30 mL). The
organic layer was washed with brine (2×50 mL) and distilled
water (3×50 mL). The combined organic extracts were dried
over sodium sulfate. After evaporation of the solvent, compound
6 (3.13 g) was obtained as a syrup. A solution of the product in
Et2O (7 mL) was passed through a Kieselgel 60 column and the
first fraction was collected. The solvent was evaporated to afford
the chromatographically homogeneous compound 6 (1.7 g, 85%)
as lightꢀyellow amorphous crystals, m.p. 50 °C; Rf 0.49 (aceꢀ
tone—hexane, 1 : 2). Found (%): C, 53.32; H, 5.51; N, 3.67.
C17H21NO9. Calculated (%): C, 53.29; H, 5.48; N, 3.65. 1H
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 14ꢀ03ꢀ31492).
References
1. S. Eberl, T. Eriksson, O. Svedberg, Appl. Radiat. Isot., 2012,
70, 922.
2. L. Cai, S. Lu, V. W. Pike, Eur. J. Org. Chem., 2008, 2853.
3. Y.ꢀS. Ding, C.ꢀY. Shiue, J. S. Fowler, A. P. Wolf, A. Pleꢀ
nevaux, J. Fluorine Chem., 1990, 48, 189.
4. M. Attina, F. Cacace, A. P. Wolf, J. Label. Compd. Radioꢀ
pharm., 1983, 20, 501.
5. R. Krasikova, Curr. Org. Chem., 2013, 17, 2097.
6. E. S. Garnett, G. Firnau, C. Nahmias, Nature, 1983, 305,
137.
7. H. Minn, S. Kauhanen, M. Seppanen, P. Nuutila, J. Nucl.
Med., 2009, 50, 1915.
8. M. Pretze, C. Wängler, B. Wängler, BioMed Res. Int., 2014,
Article ID 674063; Doi 10.1155/2014/674063.
9. C. Lemaire, in PET studies on Amino Acid Metabolism and
Protein Synthesis. Developments in Nuclear Medicine, Eds

512
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 2, February, 2016
Orlovskaja et al.
B. M. Mazoyer, W. D. Heiss, D. Comar, Springer, Dorꢀ
drecht, 1993, p. 89.
16. C. Lemaire, A. Plenevaux, R. Cantineau, Appl. Radiat. Isot.,
1993, 44, 737.
10. R. N. Krasikova, O. F. Kuznetsova, O. S. Fedorova, I. K.
Mosevich, V. I. Maleev, Yu. N. Belokon´, T. F. Savel´eva,
A. S. Sagiyan, S. A. Dadayan, A. A. Petrosyan, Radiochem.
(Engl. Transl.), 2007, 49, 512 [Radiokhimiya, 2007, 49, 449].
11. C. Lemaire, S. Gillet, S. Guillouet, A. Plenevaux, J. Aerts,
A. Luxen, Eur. J. Org. Chem., 2004, 2899.
12. R. N. Krasikova, V. V. Zaitsev, S. M. Ametamey, O. F.
Kuznetsova, O. S. Fedorova, I. K. Mosevich, Yu. N. Beꢀ
lokon, Р. Vyskocil, S. V. Shatik, M. Nader, P. A. Schubiger,
J. Nucl. Med. Biol., 2004, 31, 597.
13. C. Libert, X. Franci, A. R. Plenevaux, T. Ooi, K. Maruoka,
A. J. Luxen, C. F. Lemaire, J. Nucl. Med., 2013, 54, 1154.
14. A. Horti, D. E. Redmond, R. Soufer, J. Label. Compd. Raꢀ
diopharm., 1995, 36, 409.
15. С. Lemaire, P. Damhaut, A. Plenevaux, D. Comar, J. Nucl.
Med., 1994, 35, 1996.
17. B. Shen, W. Ehrlichmann, M. Uebele, H.ꢀJ. Machulla,
G. Reischl, Appl. Radiat. Isot., 2009, 67, 1650.
18. L. Zhang, G. Tang, D. Yin, X. Tang, Y. Wang, Appl. Radiat.
Isot., 2002, 57, 145.
19. R. Krasikova, V. Orlovskaja, O. Fedorova, V. Maleev,
T. Savelieva, Yu. Belokon, Quart. J. Nucl. Med. Mol. Imagꢀ
ing, 2014, 58, 63.
20. O. S. Fedorova, V. V. Orlovskaya, V. I. Maleev, Yu. N. Beꢀ
lokon´, T. F. Savel´eva, Ch. V. Chang, Ch. L. Chen, R. Sh.
Liu, R. N. Krasikova, Russ. Chem. Bull. (Int. Ed.), 2014, 63,
1169 [Izv. Akad. Nauk, Ser. Khim., 2014, 1169].
21. Protective Groups in Organic Chemistry, Ed. J. F. W. McOmie,
Plenum Press, New York, 1973.
22. B. P. Murphy, J. Org. Chem., 1985, 50, 5873.
Received April 30, 2015;
in revised form November 26, 2015