M. G. C. Kahn et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3454–3458
3457
Table 2. Kinetic data
of microwave heating to the synthesis of fluoropyridyl
derivatives of [3,2-c]pyrazolo-corticosteroids will in-
crease the feasibility of producing fluorine-18 labeled
versions of these important glucocorticoids for imaging
of GR containing tissues using positron emission
tomography.
Isomer
Temp
(ꢁC)
kc · 103 minꢀ1
km · 103 minꢀ1
km/c
(rel rate)
6
4
7
8
150
150
130
110
13
48
3.7
2
2.7
0.6
3.5
5.4
3.7
5.7
6.2
1.6
c, conventional heating.
m, microwave heating.
Acknowledgments
This work was supported by National Institutes of
Health Grants GM08180 and GM08722 (to R.M.H.)
and CA37799 (to R.B.H.).
Table 3. Percent conversion to fluorinated product
Isomer Temp (ꢁC) Method Time (min) % conversion
6
4
7
8
150
150
Conventional
Microwave
60
60
12
33
References and notes
150
150
Conventional 120
Microwave 120
11
65
1. Hoyte, R. M.; Zhang, J.; Lerum, R.; Oluyemi, A.;
Persaud, P.; O’Connor, C.; Labaree, D. C.; Hochberg,
R. B. J. Med. Chem. 2002, 45, 5397.
2. Kilbourn, M. R. In Flourine-18 labelling of radiopharma-
ceuticals; National Academy Press: Washington, DC,
1990; pp 22–35.
130
130
Conventional 120
Microwave 120
7
47
110
110
Conventional 120
Microwave 120
19
51
3. Liveris, M.; Miller, J. J. Chem. Soc. 1963, 3486.
4. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
5. Dolce, F.; Dolle, F.; Jubeau, S.; Vaufrey, F.; Crouzel, C.
J. Labelled Compd. Radiopharm. 1999, 42, 975.
6. Dolle, F.; Dolce, F.; Valette, H.; Hinnen, F.; Vaufrey, F.;
Guenther, I.; Fuseau, C.; Coulon, C.; Bottlaender, M.;
Crouzel, C. J. Med. Chem. 1999, 42, 2251.
In addition to the kinetic experiments we collected data
from preparative runs over extended times to demon-
strate the extent of conversion to product under both
conventional and microwave-heating conditions. In con-
sideration of the goal of achieving significant conver-
sions at approximately one half-life of the isotope (t1/2
18F = 110 min), we present in Table 3 the degree of con-
version to fluorinated products under conventional and
microwave heating. The kinetic data and the conver-
sions observed in preparative experiments demonstrate
that microwave heating enhanced these halogen ex-
change reactions. The best enhancement was a 6.2-fold
increase observed for isomer 7, the precursor to fluoro-
pyridyl compound Ia. Significantly, Ia has been shown
to be a high affinity and highly active glucocorticoid
(Table 1). Rate enhancements were also demonstrated
(Tables 2 and 3) for isomers 6 and 4 leading to the other
active glucocorticoids Ib and II.
7. Kumar, P.; Wiebe, L. I.; Asikoglu, M.; Tandon, M.;
McEwan, A. J. Appl. Radiat. Isot. 2002, 57, 697.
8. Data for II: mp 139–144 ꢁC; UV kmax = 270 nm; 1H
NMR (400 MHz, CDCl3) d 8.27 (d, 1H, J = 5.6 Hz,
pyridine H-6), 7.50 (s, 1H, pyrazole-H), 7.44 (d, 1H,
J = 5.6 Hz, pyridine H-5), 7.15 (s, 1H, pyridine H-3),
6.27 (s, 1H, H-4), 4.51 (m, 1H, H-11a), 4.62 & 4.30 (AB
quartet, J = 19.9 Hz, 2H, H-21), 1.31 (s, 3H, H-19), 1.07
(s, 3H, H-18), 0.94 (d, 3H, J = 7.4 Hz, 16a-CH3);
HRMS (M+H) calcd for C28H34FN3O4: 495.2606,
found: 495.2602.
9. Wust, F.; Carlson, K. E.; Katzenellenbogen, J. A. Steroids
2003, 68, 177.
10. Fluorination reactions were carried out using 5 mg
(0.009 mmol) of chloropyridyl compound, 10 mg
(0.027 mmol) kryptofix-222, and 5.4 mg (0.093 mmol)
KF in 0.5 mL DMSO. In reactions studied using conven-
tional heating the reactants were mixed in a screw-capped
test tube that was closed and then heated with stirring in
an oil bath at the indicated temperature (Table 2).
Reaction progress was monitored by withdrawing small
aliquots, which were diluted in methanol and analyzed for
fluorinated product by high-performance liquid chroma-
tography (HPLC): Beckman System Gold (Model 126
modular pumps and Model 168 diode-array detector) with
32Karat Software using a 25 cm · 4.4 mm Ultrasphere-
ODS column eluted at 1 mL/min with 70% or 85%
methanol–water. UV detection was at 270 nm. In reac-
tions studied using microwave heating the reactants were
mixed in a 10 mL conical flask fitted with a condenser and
mounted in the cavity of a CEM Discover microwave
reactor. The reactor was operated with stirring in open-
vessel mode under constant temperature conditions. The
temperature was maintained by a combination of com-
pressed air cooling and applied microwave power. For
example, to maintain a temperature of 130 ꢁC, typically
required about 80 W with compressed air at 40 psi.
These results demonstrate that significant rate enhance-
ments in nucleophilic fluorination of pyridyl substitu-
ents by halogen exchange can be realized using
microwave heating compared to conventional-heating
methods. The applicability of these results to no-carri-
er-added radiochemical synthesis has not yet been eval-
uated. However, the very low concentrations of
[18F]fluoride under such conditions would be counter-
balanced by an excess of the substrate, which can be
expected to favor successful radiolabeling. Indeed, expe-
rience with similar nucleophilic fluorinations shows that
even faster rates are often observed under no-carrier-
added conditions compared to those of routine chemical
synthesis.11 Finally, as indicated in the above discussion
and in Scheme 1, a deprotection step is required in each
case to obtain the biologically active product. As we
have shown1 this can be accomplished efficiently in
15 min and will not add significant time to the synthesis
of the radiolabeled material. Therefore, the application