1152
Facile and Efficient Synthesis of [18F]Fluoromisonidazole Using Novel 2-Nitroimidazole Derivatives
J. Braz. Chem. Soc.
Synthesis of 2-(tert-butyldimethylsilyloxy)-3-(2-nitro-1H-
imidazol-1-yl)propyl 4-methylbenzenesulfonate (5)
p-Toluenesulfonyl chloride (0.204 g, 1.065 mmol)
was added dropwise to a solution of compound 4 (0.21 g,
and pyridinium p-toluenesulfonate (0.05 g, 0.199 mmol)
in anhydrous CH2Cl2 (35 mL). The mixture was stirred at
room temperature for 4 h. The mixture was washed with
brine (20 mL) and extracted with ethyl acetate (20 mL).
The extract was dried over Na2SO4 and filtered. The
filtrate was concentrated under reduced pressure, and then
purified by flash column chromatography (EtOAc:hexane
= 1:1) on silica gel to yield compound 7 (0.17 g, 70.3%)
as a yellowish oil. 1H NMR (600 MHz, CDCl3) d 7.79 (d,
2H, J 8.4 Hz, Ar–H), 7.36 (d, 2H, J 7.8 Hz, Ar-H), 7.11
(d, 1H, J 6.6 Hz, Im–H), 7.09 (d, 1H, J 6.0 Hz, Im–H),
4.71-4.61 (dd, 2H, J 13.8, 3.6 Hz, CH2), 4.44-3.98 (m,
4H, 3CH2 and 1H, CH), 3.37-3.23 (m, 2H, CH and CH2),
2.45 (s, 3H, CH3), 1.09-0.94 (m, 6H, CH3); 13C NMR
(150 MHz, CDCl3) d 145.4, 144.9, 132.3, 130.2, 128.1,
128.0, 127.7, 101.3, 72.7, 68.7, 60.9, 50.9, 21.8, 19.5,
15.1; HRMS (ESI) calcd. for C17H24N3O7S [M + H]+:
414.1335; found: 414.1331.
o
1.12 mmol) in anhydrous pyridine (2 mL) at 0 C. The
mixture was stirred at room temperature for 6 h. Then
imidazole (0.3 g, 4.47 mmol) in CH2Cl2 (10 mL) was
added. After addition of tert-butyldimethylsilyl chloride
(0.51 g, 3.36 mmol) in CH2Cl2 (10 mL) to the mixture,
the mixture was stirred at room temperature for 2 h. The
mixture was extracted with ethyl acetate (20 mL) and the
extract was dried over Na2SO4 and filtered. The filtrate was
concentrated under reduced pressure, and residual crude
product was purified by flash column chromatography
(EtOAc:hexane = 1:2) on silica gel to yield compound 5
(0.334 g, 65.53%) as a white solid. 1H NMR (600 MHz,
CDCl3) d 7.71 (d, 2H, J 8.4 Hz, Ar–H), 7.28 (d, 2H,
J 7.8 Hz, Ar–H), 7.02 (s, 1H, Im–H), 6.98 (s, 1H, Im–H),
4.58 (dd, 1H, J 13.8, 3.0 Hz, CH2), 4.19 (dd, 1H, J 12.6,
7.2 Hz, CH2), 4.13-4.11 (m, 1H, CH), 3.92 (dd, 1H,
J 10.2, 3.6 Hz, CH2), 3.82 (dd, 1H, J 10.2, 5.4 Hz, CH2),
2.37 (s, 3H, CH3), 0.67 (s, 9H, CH3), –0.21(s, 3H, CH3),
–0.41(s, 3H, CH3); 13C NMR (150 MHz, CDCl3) d 145.5,
144.8, 132.3, 130.2, 128.2, 128.1, 127.7, 69.9, 68.6, 52.7,
25.6, 21.8, 17.8, –5.12, –5.66; HRMS (ESI) calcd. for
C19H30N3O6SSi [M + H]+: 456.1625; found: 456.1623.
Radiosynthesis of [18F]FMISO
Kryptofix222 (K222, 4,7,13,16,21,24-hexaoxa-1,10-
diazabicyclo[8.8.8]-hexacosane) (8 mg, 21.27 μmol)
and K2CO3 (1.5 mg, 10.87 μmol) were dissolved in
water (50 μL) and diluted in 150 μL of anhydrous
MeCN to form the phase transfer agent. A volume of
18
200 μL of no-carrier-added H2 O/18F– fluoride, obtained
Synthesis of 2-hydroxy-3-(2-nitro-1H-imidazol-1-yl)propyl
4-methylbenzenesulfonate (6)
from the cyclotron solution, was added to generate the
[18F]KF/K222 complex. Separately, FMISO precursors
(2.5-30 mg) were dissolved in 300 μL of anhydrous MeCN.
The [18F]KF/K222 complex was heated to 105 oC and held
at 105 oC for 3 min to evaporate the solvent. Subsequently,
one cycle of azeotropic distillation was performed by
adding 300 μL of MeCN to the dried residue, and the
reaction mixture was heated at 105 oC for 3 min.A volume
of 300 μL of FMISO precursors solution (7.43-48 μmol)
was transferred to the dried [18F]KF/K222 complex on the
reaction site at room temperature. The reaction mixture
p-Toluenesulfonyl chloride (0.37 g, 1.92 mmol) was
added to a solution of compound 4 (0.37 g, 1.96 mmol)
in anhydrous pyridine (3 mL). The mixture was stirred at
room temperature for 23 h. The mixture was washed with
brine (20 mL) and extracted with ethyl acetate (20 mL).
The extract was dried over Na2SO4 and filtered. The filtrate
was concentrated under reduced pressure, and then purified
by flash column chromatography (EtOAc:hexane = 1.5:1)
on silica gel to yield compound 6 (0.43 g, 65%) as a white
solid. 1H NMR (600 MHz, CD3OD) d 7.79 (d, 2H, J 8.4 Hz,
Ar–H), 7.44 (d, 2H, J 7.2 Hz, Ar–H), 7.36 (s, 1H, Im–H),
7.08 (s, 1H, Im–H), 4.61 (dd, 1H, J 13.8, 3.0 Hz, CH2),
4.32 (dd, 1H, J 13.8, 8.4 Hz, CH2), 4.09-4.00 (m, 3H, 2CH2
and 1H, CHOH), 2.45 (s, 3H, CH3); 13C NMR (150 MHz,
CD3OD) d 145.5, 132.6, 129.8, 127.8, 126.8, 70.8, 67.3,
51.6, 20.2; HRMS (ESI) calcd. for C13H16N3O6S [M + H]+:
342.0760; found: 342.0757.
o
was stirred at 120 C for each time point (5, 10, 15 and
20 min) to perform the fluorination reaction. Afterwards,
1 mL of 1 mol L-1 HCl was added to the crude intermediate
o
product, and the reaction mixture was stirred at 100 C
for 3 min for the hydrolysis reaction. After neutralization
with 2 mol L-1 NaOH, the reaction mixture was purified
by radio high performance liquid chromatography
(HPLC) with EtOH:H2O = 5:95. Radioactive thin layer
chromatography scanner (AR-2000 radio-TLC imaging
scanner, Bioscan, Inc) was used to analyze fluorination
efficiency. The TLC plate was developed in a chamber
containing 1:3 (v/v) hexane/ethyl acetate solvent
mixtures.
Synthesis of 2-(1-ethoxyethyl)-3-(2-nitro-1H-imidazol-1-yl)
propyl 4-methylbenzenesulfonate (7)
Ethyl vinyl ether (0.9 g, 12.5 mmol) was added
dropwise to a solution of compound 6 (0.2 g, 0.586 mmol)