Paper
Organic & Biomolecular Chemistry
cooled to room temperature and concentrated in vacuo to yield 270.2 Hz), 105.7 (q, 2JC–F = 33.4 Hz), 85.9, 83.0, 73.9, 63.6, 38.5,
the crude product as a pink solid. This was used directly in the 20.7, 20.4; 19F NMR (500 MHz, CDCl3): δF = −63.5; HRMS (ES+)
next step with no further purification (1.1 g, 100%). The data calculated 403.0831 for C14H15F3N2O7Na, observed 403.0815
were in agreement with the published values for this struc- [M + Na]+.
ture.46 1H NMR (500 MHz, CDCl3): δH = 7.34–7.33 (m, 2H),
5-Trifluoromethyl-2′-deoxyuridine (TFT). To a solution of 4
7.32–7.31 (m, 2H), 6.89–6.88 (m, 2H), 6.87–6.86 (m, 2H), 6.12 (60 mg, 0.16 mmol) in MeOH (3.2 mL) at 0 °C was added 7N
(s, 1H), 3.80 (s, 6H); 13C NMR (126 MHz, CDCl3): δC = 159.3, NH3 in MeOH (6.2 mL, 43.6 mmol) and the reaction mixture
133.5, 129.0, 113.8, 64.2, 55.3; HRMS (ES+) no ionisation.
was stirred at room temperature for 16 hours. The reaction
(N3-para-(Methylene)bis(methoxybenzene))-5-iodo-2′-deoxy- mixture was concentrated in vacuo and the crude material puri-
uridine-3′,5′-diacetate (3). To a solution of 2 (1.2 g, 2.7 mmol) fied using flash silica column chromatography (0–10% MeOH
in DMF (20 mL) at −60 °C was added NaH (60%) (159 mg, in CH2Cl2) to yield the product as a white solid (40 mg, 84%).
4.0 mmol) and the resulting solution stirred for 30 minutes at The data were in agreement with the published values for this
this temperature. TBAI (100 mg, 0.3 mmol) was added followed structure.34 1H NMR (500 MHz, MeOD): δH = 8.80 (br. s, 1H),
by Mbh-Cl (1.1 g, 4.2 mmol) in DMF (6.5 mL) and the solution 6.25 (t, J = 6.2 Hz, 1H), 4.42 (dt, J = 6.2 Hz, J = 4.0 Hz, 1H), 3.97
was warmed to room temperature and stirred for 16 hours. (dd, J = 6.2 Hz, J = 2.9 Hz, 1H), 3.84 (dd, J = 11.9 Hz, J = 2.9 Hz,
The reaction mixture was quenched with H2O (200 mL) and 1H), 3.75 (dd, J = 11.9 Hz, J = 2.9 Hz, 1H), 2.37 (ddd, J = 13.7,
extracted with EtOAc (200 mL). The organic layer was washed J = 6.2 Hz, J = 4.3 Hz, 1H), 2.27 (dt, J = 13.7 Hz, J = 6.2 Hz, 1H);
3
with H2O : brine (1 : 1, 2 × 200 mL), dried over MgSO4 and con- 13C NMR (126 MHz, MeOD): δC = 161.4, 151.5, 144.0 (q, JC–F
=
2
centrated in vacuo. The crude material was purified using flash 6.0 Hz), 124.1 (q, JC–F = 268.8 Hz), 105.5 (q, JC–F = 32.9 Hz),
silica column chromatography (20–50% EtOAc in cyclohexane) 89.5, 87.7, 71.9, 62.3, 42.3; HRMS (ES+) calculated 319.0509 for
to yield the product as a white foam (1.6 g, 92%). 1H NMR C10H11F3N2O5Na, observed 319.0492 [M + Na]+.
(500 MHz, CDCl3): δH = 7.98 (s, 1H), 7.31–7.29 (m, 4H), 7.26
(s, 1H), 6.86–6.83 (m, 4H), 6.24 (dd, J = 8.2 Hz, J = 5.6 Hz, 1H),
5.19 (dt, J = 6.5 Hz, J = 2.3 Hz, 1H), 4.38 (dd, J = 12.3 Hz, J =
3.3 Hz, 1H), 4.32 (dd, J = 12.3 Hz, J = 3.0 Hz, 1H), 4.26 (dd,
J = 6.5 Hz, J = 3.0 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 2.50 (ddd,
Radiochemistry
General methods. [18F]Fluoride was produced by a GE
PETrace cyclotron by 16 MeV irradiation of enriched [18O]H2O
target, supplied by Alliance Medical Radiopharmacy Ltd
(Warwick, UK) and delivered to a dispensing hot cell in
approximately 2 mL of water. [18F]Fluoride was used without
further purification. The automated radiosynthesis platform
used in the study was the Trasis AllInOne (Trasis, Belgium).
Analytical and semi-preparative RP-HPLC were carried out on
an Agilent 1260 quaternary pump system (Agilent
Technologies) equipped with a Lablogic radioTLC/HPLC detec-
tor and a Lablogic NaI/PMT radiodetector. Oasis HLB SPE car-
tridges were purchased from Waters (Elstree, UK) and were
conditioned using CH3CN (6 mL) and water (10 mL).
Radioactivity was measured in a CRC -55tR dose calibrator
(Capintec, Inc). Product identity and radiochemical (RC) purity
were determined using radio-HPLC. RCY was derived from the
crude reaction mixture unless stated otherwise (after quench-
ing the reaction), and accounted for radiochemical purity. All
RCYs quoted are decay-corrected to the activity of the aqueous
[18F]fluoride used at the start of the reaction.
J = 14.2 Hz, J = 5.6 Hz, J = 2.1 Hz, 1H), 2.20 (s, 3H), 2.12–2.07
(m, 1H), 2.07 (s, 3H); 13C NMR (126 MHz, CDCl3): δC = 170.5,
170.4, 159.8, 159.1, 150.2, 142.4, 130.2, 113.8, 86.3, 82.7,
74.3, 69.2, 64.0, 60.6, 55.5, 38.6, 21.4, 21.0. Note: Two carbon
signals are overlapping; HRMS (ES+) calculated 687.0810 for
C28H29IN2O9Na, observed 687.0803 [M + Na]+.
5-Trifluoromethyl-2′-deoxyuridine-3′,5′-diacetate (4). To
a
solution of 3 (300 mg, 0.45 mmol), CuI (103 mg, 0.54 mmol)
and KF (39 mg, 0.68 mmol) in DMF (0.9 mL) at room tempera-
ture was added TMS-CF3 (80 µL, 0.54 mmol). After stirring for
16 hours at 60 °C, the reaction mixture was poured into H2O
(20 mL) and extracted into EtOAc (2 × 20 mL). The combined
organic layers were dried over MgSO4 and concentrated
in vacuo. The crude residue was purified by flash silica column
chromatography (20–40% EtOAc in cyclohexane). To the
residue (a mixture of trifluoromethyl-5 and iodo-3) was added
CH2Cl2 (5.4 mL) and TFA (0.6 mL), and the reaction mixture
was stirred at room temperature for 16 hours. The reaction
mixture was concentrated in vacuo and purified by flash silica
column chromatography (30–40% EtOAc in cyclohexane) to
yield the product as a brown foam (63 mg, 37%). The depro-
tected iodonucleoside analogue 2 was also recovered (40 mg,
20%). The data were in agreement with the published values
ꢀ
ꢁ
decay‐corrected activity after quench of the reaction
RCY % ¼
activity used at the start of the reaction
ꢀ 100 ꢀ RC purity of the crude reaction mixture
HPLC conditions. Intermediate [18F]-4 was analysed on a
for structure 4.47 1H NMR (500 MHz, CDCl3): δH = 8.76 (br. s, Luna C18 column, 4.6 × 150 mm, 5 µM (Phenomenex) using
1H), 8.09 (s, 1H), 6.27 (dd, J = 8.1 Hz, J = 5.6 Hz, 1H), 5.23 (dt, isocratic method 1: eluant A H2O, 65%; eluant B CH3CN, 35%;
J = 6.5 Hz, J = 2.1 Hz, 1H), 4.43 (dd, J = 11.8 Hz, J = 2.6 Hz, 1H), flow rate 1 mL per minute. [18F]TFT was analysed using the
4.35–4.30 (m, 2H), 2.63 (ddd, J = 14.3 Hz, J = 5.6 Hz, J = 2.1 Hz, same column type and isocratic method 2: eluant A H2O, 90%;
1H), 2.17 (ddd, J = 14.4 Hz, J = 8.1 Hz, J = 6.5 Hz, 1H), 2.12 (s, eluant B EtOH, 10%; flow rate 1 mL per minute. [18F]TFT was
3H), 2.10 (s, 3H); 13C NMR (126 MHz, CDCl3): δC = 170.2, purified by semi-preparative RP-HPLC using an Ultracarb™
3
170.0, 157.9, 149.0, 139.9 (q, JC–F = 5.9 Hz), 121.6 (q, JC–F
=
ODS(30) C18 column, 10 × 250 mm, 7 µM (Phenomenex) and
Org. Biomol. Chem.
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