Practical synthesis of 1-(2-Nitro-1H-imidazol-1-yl)-3-(tosyloxy) propan-2-yl acetate for the radiosynthesis of [18F]-FMISO

Article abstract of DOI:10.1002/bkcs.10107

Hypoxia is related with many tumors due to a decreased oxygen condition. Novel synthesis for 1-(2-nitro-1H-imidazol-1-yl)-3-(tosyloxy)propan-2-yl acetate for the radiosynthesis of the [¹⁸F]-Flouromisonidazole ([¹⁸F]-FMISO), a hypoxia imaging marker used in positron emission tomography, from the readily available starting material is described. In this approach, one-pot two-step syntheses were used for the preparation of the [¹⁸F]-FMISO precursors that contain acetyl group. The mild reaction conditions and easy treatments are attractive features in this synthesis. This new synthetic route provides alternative choices for the preparation of hypoxia imaging marker.

Full text of DOI:10.1002/bkcs.10107

Article
DOI: 10.1002/bkcs.10107
BULLETIN OF THE
Y.-D. Kwon et al.
KOREAN CHEMICAL SOCIETY
Practical Synthesis of 1-(2-Nitro-1H-imidazol-1-yl)-3-(tosyloxy)
propan-2-yl acetate for the Radiosynthesis of [18F]-FMISO
§
Young-Do Kwon,† Eun-taekSeol,‡ SeokTaeLim,† Myung-Hee Sohn,† Hee-KwonKim,†, YongjuJung,
*
and Seung Jae Lee‡
†Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Cyclotron
Research Center, Biomedical Research Institute, Chonbuk National University Medical School and Hospital,
Jeonju 561-712, Republic of Korea. *E-mail: hkkim717@jbnu.ac.kr
‡Department of Chemistry and Research Institute of Physics and Chemistry, Chonbuk National University,
Jeonju 561-756, Republic of Korea
§Department of Chemical Engineering, Korea University of Technology and Education (KOREATECH),
Cheonan 330-708, Republic of Korea
Received September 16, 2014, Accepted November 18, 2014, Published online January 20, 2015
Hypoxia is related with many tumors due to a decreased oxygen condition. Novel synthesis for 1-(2-nitro-
1H-imidazol-1-yl)-3-(tosyloxy)propan-2-yl acetate for the radiosynthesis of the [18F]-Flouromisonidazole
([18F]-FMISO), a hypoxia imaging marker used in positron emission tomography, from the readily available
starting material is described. In this approach, one-pot two-step syntheses were used for the preparation of
the [18F]-FMISO precursors that contain acetyl group. The mild reaction conditions and easy treatments are
attractive features in this synthesis. This new synthetic route provides alternative choices for the preparation
of hypoxia imaging marker.
Keywords: [18F]-FMISO, Positron emission tomography, Fluorine-18, Radiosynthesis, One-pot synthesis
Introduction
anion. This process is reversible in normoxic tissues, whereas
generating reactive intermediates in hypoxic tissues cova-
lently binds to cellular components. The trapping and accumu-
lation of bio-reductive species in cells are associated with
hypoxia andhavebeenused asa hypoxiaindicator, whichsug-
gests the presence of hypoxia in specific sites such as tumors
and myocardium.1,8
Hypoxia has been widely acknowledged as a feature of
many tumors, particularly solid tumors, because of oxygen
deficiency through a badly organize vasculature.1 Hypoxic
cells are related to malignant progression and the potential
metastasis and, resultantly, prevent radiotherapy and chemo-
therapy.2,3 Therefore, the verification and quantitative assess-
ment of tumor hypoxia is a significant factor to establish
proper therapeutic strategies for better clinical outputs.3
Hypoxia can be detected in hospitals using molecular ima-
ging techniques such as positron emission tomography (PET).
PET is commonly used in a noninvasive technique. Through
180ꢀ simultaneous detection of two gamma ray photons from
positron–electron annihilation, distributed radiolabeled mole-
cules provide crucial information about physiological and bio-
logical events.4,5 Particularly, with physical properties: a half-
life of110minandalow-energy positron of649KeV, 18F is an
ideal candidate for PET and produces molecular images with
high resolution. In addition, a carbon 18F covalent bond
formed from the introduction of 18F into organic molecules
by either electrophilic or nucleophilic ways is very stable
for the detection of biological events.4,6
Therefore, the various derivatives labeled with 18F such as
[18F]-FMISO, [18F]-FAZA, and [18F]-FETNIM have been
prepared.9–12 Among them, one of the widely studied radio-
pharmaceuticals for PET imaging is [18F]-FMISO. Therefore,
[1 F]-FMISO is an attractive target molecule for imaging
hypoxia conditions, and several research groups have devoted
efforts to develop efficient synthesis of [18F]-FMISO.2,13,14
The developed synthetic methods for [18F]-FMISO consists
of two types of reactions: general chemical synthesis of [18F]-
FMISO precursors and then radiochemical synthesis using
radio isotopes. One of precursors reported for the synthesis
of [18F]-FMISO is a precursor containing acetyl group. In this
study, we redesigned original synthetic method of [18F]-
FMISO and report an alternative synthetic route for new radio
synthesis of [18F]-FMISO (Figure 1).
In order to quantify the extent of hypoxia, PET radio tracers
containing 18F have been usually used in clinical study. One of
the most developed PET tracers is nitroimidazole derivatives.7
The nitro group of nitroimidazoles undergoes an enzyme-
mediated process that transfers single-electron to a free radical
Experimental
General. All chemicals were purchased from Sigma-Aldrich
(St. Louis, MO, USA) and used without further purification.
The 1H and 13C NMR spectra were recorded on a 600-MHz
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column chromatography (EtOAc:Hex = 1:1.5) on silica gel
to yield compound 4 (1.21 g, 47%) as a white solid.
1-(2-Nitro-1H-imidazol-1-yl)-3-(tosyloxy)propan-2-yl
acetate (5): 2-Nitroimidazole (0.23 g, 2.04 mmol) and cesium
carbonate (0.66 g, 2.04 mmol) were added to compound 4
(1 g, 2.26 mmol) in anhydrous DMF (7 mL) solvent in a round
bottom flask. The mixture was stirred at 110 ꢀC for 1 h and
then cooled. The mixture was extracted with ethyl acetate
(20 mL) and dried over with Na2SO4. The mixture was filtered
and evaporated. The residual was purified by flash column
chromatography (EtOAc:Hex = 1:1) on silica gel to yield
compound 5 (0.38 g, 48%) as a white solid. mp 100–103 ꢀC;
1H NMR (600 MHz, CDCl3) δ 7.77 (d, J = 9.0 Hz, 4H), 7.37
(d, J = 7.8 Hz, 4H), 7.10 (d, J = 2.8 Hz, 2H), 5.31 (m, 1H),
4.81 (t, J = 4.2 Hz, 1H), 4.50 (t, J = 4.2 Hz, 1H), 4.17 (s, J =
4.8 Hz, 2H), 2.45 (s, 3H), 1.92 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 169.3, 145.6, 131.8, 130.1, 129.9, 128.3, 127.8,
126.7, 68.7, 67.1, 49.3, 21.6, 20.3; ESI-MS m/z (M + H)+ calcd
for C15H17N3O7S = 383.08, found 384.09.
(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 4-methylben-
zenesulfonate (8): (2,2-Dimethyl-1,3-dioxolan-4-yl)methanol
(0.2 g, 1.97 mmol) and triethyl amine (0.6 g, 5.93 mmol) were
dissolved in anhydrous CH2Cl2 (2 mL). p-Methanesulfonyl
chloride (0.34 g, 2.96 mmol) was added dropwise to the mix-
ture. After the mixture was stirred at room temperature for
8 h, 2-nitroimidazole (0.35 g, 3.09 mmol), cesium carbonate
(1 g, 3.08 mmol), and anhydrous DMF (2 mL) were added
to the reaction mixture. The reaction mixture was stirred
at 110 ꢀC for 12 h. The crude was extracted with CH2Cl2
(20 mL) and dried over with Na2SO4. The solvent was removed
under reduced pressure and the residue was purified by flash
column chromatography (EtOAc:Hex = 1:1.5) on silica gel to
yield compound 8 (0.29 g, 65%) as a yellowish oil. 1H NMR
(600 MHz, CDCl3) δ 7.27 (s, 1H), 7.18 (s, 1H), 4.78 (dd, J =
11.4, 2.4 Hz, 1H), 4.62–4.51 (m, 1H), 4.44 (dd, J = 7.8, 5.4
Hz, 1H), 4.22 (dd, J = 7.2, 6.6 Hz, 1H), 3.73 (dd, J = 10.2,
5.4 Hz, 1H), 1.43 (s, 3H), 1.37 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 144.9, 128.2, 127.3, 110.4, 74.0, 66.4, 52.1, 26.6,
25.3; ESI-MS m/z (M + H)+ calcd for C9H13N3O4 = 227.09,
found 228.25.
Figure 1. The structure of [18F]-FMISO.
spectrometer at room temperature. The chemical shifts are
reported in δ units (ppm) relative to tetramethylsilane
(TMS) and the coupling constants (J) quoted in Hz. Reaction
progress was monitored by thin-layer chromatography (TLC)
analysis. TLC analysis was performed using an aluminum
plate with silica gel 60 F254 and TLC spots were visualized
by exposure to UV light (254 nm). Flash chromatography
was performed using 230–400 mesh silica gel and analytical
grade solvent. Mass spectrometry was performed by Mass
Spectrometry Service of Chonbuk National University.
Glycerol-1,3-ditosylate (3): p-Toluenesulfonyl chloride
(5.56 g, 29.2 mmol) was added dropwise to a stirred solution
of glycerol (1.35 g, 14.6 mmol) in anhydrous pyridine
(15 mL) at 0 ꢀC. The mixture was stirred at 0 ꢀC for 5 h and
then at room temperature for 3 h. The reaction mixture was
acidified by addition of concentrated HCl. The mixture was
extracted with CH2Cl2 (100 mL), dried over with Na2SO4,
and filtered. The filtrate was evaporated and the residual crude
product was purified by flash column chromatography
(EtOAc:Hex = 1:1.5) on silica gel to yield compound 3
(4.17 g, 71%) as a colorless oil. 1H NMR (600 MHz, CDCl3)
δ 7.73 (d, J = 8.4 Hz, 4H), 7.33 (d, J = 8.0 Hz, 4H), 4.02 (m,
4H), 3.35 (bs, 1H), 2.43 (s, 6H); 13C NMR (150 MHz, CDCl3)
δ 145.3, 130.2, 129.8, 127.9, 69.4, 67.2, 21.5.
Glycerol-1,3-ditosylate-2-O-acetylate (4): Acetyl chlo-
ride (0.25 g, 3.18 mmol) and triethylamine (0.45 g, 4.45
mmol) were added dropwise to a solution of compound 3
(0.85 g, 2.13 mmol) in CH2Cl2 (20 mL). The mixture was stir-
red at room temperature for 2 h. The reaction mixture was
extracted with CH2Cl2 (30 mL) and dried over with Na2SO4.
The residual was purified by flash column chromatography
(EtOAc:Hex = 1:1.5) on silica gel to yield compound 4
(0.82 g, 87%) as a white solid. mp 79–82 ꢀC; 1H NMR
(600 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 4H), 7.34 (d, J =
8.4 Hz, 4H), 5.05 (t, J = 4.8 Hz, 1H), 4.12 (s, J = 4.8 Hz,
4H), 2.43 (s, 6H), 1.91 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 170.2, 145.3, 130.5, 129.9, 127.9, 68.1, 66.7, 21.6, 20.5.
Preparation of compound 4 from compound 3: p-
Toluenesulfonyl chloride (2 g, 10.52 mmol) was added drop-
wise to a stirred solution of glycerol (0.53 g, 5.79 mmol) in
anhydrous pyridine (6 mL) at 0 ꢀC. The mixture was stirred
at room temperature for 5 h. Then triethylamine (2.94 g,
29.05 mmol) in CH2Cl2 (15 mL) was added. After addition
of acetyl chloride (1.82 g, 23.18 mmol) to CH2Cl2 (15 mL),
the mixture was stirred at room temperature for 1 h and 30
min. The mixture was extracted with CH2Cl2 (50 mL), dried
over with Na2SO4, and and filtered. The filtrate was evapo-
rated and the residual crude product was purified by flash
3-(2-Nitro-1H-imidazol-1-yl)propane-1,2-diol (9): Tri-
fluoroacetic acid (10 g, 87.7 mmol) was added to a solution
of 8 (1.99 g, 8.76 mmol) in anhydrous MeOH (20 mL) and
stirred at room temperature for 7 h. The solvent was removed
under reduced pressure. The residue was purified by flash
column chromatography (CH2Cl2:MeOH = 10:1) on silica
gel to give compound 9 (1.49 g, 91%) as a white solid. mp
1
110–112 ꢀC; H NMR (600 MHz, CDCl3) δ 7.47 (s, 1H),
7.15 (s, 1H), 4.77 (dd, J = 10.2, 3.6 Hz, 1H), 4.37 (dd, J =
10.2, 4.2 Hz, 1H), 4.01–3.95 (m, 1H), 3.61–3.55 (m, 2H);
13C NMR (150 MHz, CDCl3) δ 145.1, 128.0, 126.8, 70.3,
63.4, 52.3; ESI-MS m/z (M + H)+ calcd for C6H9N3O4 =
187.06, found 188.10.
2-Hydroxy-3-(2-nitro-1H-imidazol-1-yl)propyl 4-methyl-
benzenesulfonate (10): p-Toluenesulfonyl chloride (0.37 g,
1.92 mmol) was added to a solution of compound 9 (0.37 g,
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1.96 mmol) in anhydrous pyridine (3 mL) and stirred at room
temperature for 23 h. The mixture was washed with brine and
extracted with ethyl acetate (20 mL). The extracted was dried
over with Na2SO4 and filtered. The filtrate was evaporated
andthenpurifiedbyflashcolumnchromatography(EtOAc:Hex
= 1.5:1) on silica gel to yield compound 10 (0.43 g, 65%) as a
yellowish solid. mp 141–143 ꢀC; 1H NMR (600 MHz, CDCl3)
δ 7.80 (d, J = 7.8 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.36 (s, 1H),
7.08 (s, 1H), 4.6 (dd, J = 7.8, 3.6 Hz, 1H), 4.32 (dd, J = 5.4, 2.4
Hz, 1H), 4.11–4.00 (m, 3H), 2.45 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 145.5, 132.6, 129.8, 127.8, 126.8, 70.8, 67.3, 20.2;
ESI-MS (ESI) m/z (M + H)+ calcd for C13H15N3O6S = 341.07,
found 342.10.
Preparation of compound 5 from compound 10: Acetyl
chloride (0.066 g, 0.84 mmol) was added dropwise to a solu-
tion of compound 10 (0.14 g, 0.41 mmol) and triethylamine
(0.13 g, 1.27 mmol) in anhydrous CH2Cl2 (10 mL). The mix-
ture was stirred at room temperature for 1 h and 30 min. The
reaction mixture was extracted with CH2Cl2 (20 mL), dried
over with Na2SO4, and filtered. The filtrate was evaporated
and then purified by flash column chromatography (EtOAc:
Hex = 1:1) on silica gel to yield compound 5 (0.14 g, 90%)
as a white solid.
Preparation of compound 5 from compound 9: p-
Toluenesulfonyl chloride (0.29 g, 1.56 mmol) was added
dropwise to a stirred solution of compound 9 (0.31 g, 1.63
mmol) in anhydrous pyridine (4 mL) at 0 ꢀC. The mixture
was stirred at room temperature for 6 h. Then triethylamine
(0.5 g, 4.94 mmol) in CH2Cl2 (10 mL) was added. After addi-
tion ofacetyl chloride (0.38 g, 4.89 mmol) to CH2Cl2 (10 mL),
themixture wasstirred atroomtemperaturefor1 hand30 min.
The mixture was extracted with CH2Cl2 (20 mL), dried over
with Na2SO4, and filtered. The filtrate was evaporated and
the residual crude product was purified by flash column chro-
matography (EtOAc:Hex = 1:1.1) on silica gel to yield com-
pound 5 (0.34 g, 57%) as a white solid.
Results and Discussion
In this study, [18F]-FMISO precursor with acetyl group, com-
pound 5, was prepared by two synthetic methods.
It is well known that the syntheses of the precursor for [18F]-
FMISO from glycerol have been widely accepted and studied
its radiochemical synthesis to [18F]-FMISO, even though the
reported overall yield is low due to the limiting step to substi-
tute 2-nitroimidazole for tosylate in the ditosylate intermedi-
ate.2,13,14 Therefore, we utilized glycerol as a starting
material for our first synthetic approach of the precursor for
[18F]-FMISO (Scheme 1). Glycerol was treated with 2 equiv
of tosyl chloride in pyridine for 5 h to provide glycerol-1,3-
ditosylate, compound 3, in 71% yield which was a previously
reported procedure by Oh et al.13 A secondary alcohol of com-
pound 3 was protected by the treatment with acetyl chloride
and triethylamine in CH2Cl2. After checking each reaction
step separately, we introduced one-pot synthesis in the first
synthetic step because one-pot operation is a useful technique
for the performance of multiple transformations in a single
reaction vessel and is one of the most efficient methods for
the reduction of purification procedures and prevention of
chemical waste production. One-pot operation for the prepa-
ration of compound 4 was performed from compound 2 via
ditosylation of primary alcohols and acetylation of secondary
alcohol, and showed a 47% overall yield from compound 2.
And then one of the tosyl moieties of primary alcohol was
converted into 2-nitroimidazole group in the presence of
Cs2CO3 and 2-nitroimidazole in DMF according to the previ-
ously reported method.14
Even though compound 5 was successfully prepared from
glycerol in the first synthetic method, the yield in substitution
reactionof2-nitroimidazole groupledoverallyieldtobelower
like the other studies using glycerol. Thus, we considered
another synthetic method using a five-membered ring struc-
ture as a starting material. The second synthesis of [18F]-
Scheme 1. Synthesis of [18F]-FMISO precursor from glycerol (method A).
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Scheme 2. Synthesis of [18F]-FMISO precursor from (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (method B).
FMISO shown in Scheme 2 started with 2,2-dimethyl-1,3-
dioxolane-4-methanol, an inexpensive commercially availa-
ble compound.
gave compound 5, FMISO precursor, in 90% yield. In these
step, we also tried to perform one-pot synthesis of compound
5 fromcompound 9, whichconsist of tosylation andprotection
of secondary alcohol with acetyl group. This one-pot sequent
operation afforded compound 5 in 57% yield, and the second
synthesis of compound 5 from compound 6 was proceeded
with 34% yield.
The utilization of compound 5 prepared in this study was
investigated through performing radiosynthesis of [18F]-
FMISO (Scheme 3). The [18F]fluorination substitution reac-
tion was carried out with [18F]-fluoride and K2CO3/Krypto-
fix222 in MeCN at 120 ꢀC for 10 min, and deprotection
reaction of acetyl group by treatment with 1 M HCl in MeCN
was performed at 100 ꢀC for 5 min. After neutralization with
2 M NaOH, purified [18F]-FMISO was isolated using a reverse-
phase HPLC column. The final product was identified by com-
mercially available reference standard of [18F]-FMISO.
Initially, the treatment of 2,2-dimethyl-1,3-dioxolane-4-
methanol with methanesulfonyl chloride and triethylamine
in CH2Cl2 successfully resulted in the production of com-
pound 7, and then the SN2 reaction with 2-nitroimidazole at
110 ꢀC for 7 h was carried out to provide compound 8 in
74% yield. For these reaction steps, one-pot synthesis consist-
ing of mesylation of primary alcohol and nucleophilic reaction
of the mesylates with 2-nitroimidazole was performed for the
incorporation step of 2-nitroimidazole into the five-membered
ring structure. After one-pot operation, compound 8 was suc-
cessfully obtained in 65% yield.
Hydrolysis of compound 8 (Table 1) was carried out by the
treatment of acid. Inorder tofind the optimal condition of ring-
opening step, several acids were treated. The HCl treatment in
MeOH at 45 ꢀC for 5 h gave lower yield of diol compound 9.
Hydrolysis using of Dower 50WX4 for 4 h led to produce
compound 9 in 74% yield. When trifluoroacetic acid was uti-
lized in MeOH, the yield of product was increased to 91%.
Next, tosylated compound 10 was successfully prepared
in the present of p-toluenesulfonyl chloride and anhydrous
pyridine at room temperature for 23 h. Then the treatment with
acetyl chloride and triethylamine at room temperature for 8 h
Conclusion
In summary, new facile processes for the synthesis of 1-(2-
nitro-1H-imidazol-1-yl)-3-(tosyloxy)propan-2-yl acetate, the
precursor of hypoxia maker [18F]-FMISO, from two different
starting materials were developed. These synthetic routes
started with commercially available inexpensive materials
Bull. Korean Chem. Soc. 2015, Vol. 36, 559–563
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Table 1. Hydrolysis of compound 8.
Entry
Acid
Solvent
Temp. (ꢀC)
Isolation yield (%)
1a
2b
3c
HCl
Dower 50WX4
TFA
MeOH
H2O
MeOH
45
85
22
13
74
91
a Reaction runs for 5 h.
b Reaction runs for 4 h.
c Reaction runs for 7 h.
Scheme 3. Radiosynthesis of [18F]-FMISO from 1-(2-nitro-1H-imidazol-1-yl)-3-(tosyloxy)propan-2-yl acetate.
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Acknowledgment. Theworkwassupportedbyagrant[2014]
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