steroids 7 3 ( 2 0 0 8 ) 69–76
71
J = 9.9 Hz, 1H; 1-H). 13C NMR (100 MHz, CDCl3): ı 15.8, 17.8,
21.1, 24.2, 29.7, 29.8, 31.2, 33.9, 34.7, 39.7, 39.9, 48.2, 50.9, 55.2,
70.3, 90.7, 122.5, 127.9, 136.3, 155.9, 187.0, 203.2. Melting point:
237–239 ◦C. Analysis calculated for C22H30O4S: C, 67.66; H,
7.74; S, 8.21; found: C, 67.32; H, 7.49; S, 7.89.
6.28 (dd, J = 10.1 Hz, J = 1.9 Hz, 1H; 2-H), 7.27 (d, J = 10.1 Hz, 1H;
1-H), 7.46 (m, 2H; Ar–H), 7.60 (m, 1H; Ar–H), 7.96 (m, 2H; Ar–H).
13C NMR (100 MHz, CDCl3): ı 17.4, 21.1, 23.9, 31.2, 32.0, 33.9,
34.4, 36.6, 40.0, 44.1, 47.4, 51.3, 55.2, 70.3, 90.7, 122.4, 127.4,
127.8, 128.7, 133.9, 136.1, 156.23, 170.1, 186.6, 191.8, 205.7.
Melting point: 214–217 ◦C. Analysis calculated for C28H32O5S:
C, 69.97; H, 6.71; S, 6.67; found: C, 69.39; H, 6.43; S, 6.41.
21-(S)-Benzoylthio-9˛-fluoro-11ˇ,17˛-dihydroxy-16˛-methyl-
1,4-pregnadiene-3,20-dione 7. Yield: 75%. 1H NMR (400 MHz,
CDCl3): ı 0.96 (d, J = 7.3 Hz, 3H; 16␣-CH3), 1.07 (s, 3H; 18-CH3),
1.56 (s, 3H; 19-CH3), 4.03 (AB quartet, ꢀꢁ = 351 Hz, J = 16.8 Hz,
2H; CH2–SBz), 4.42 (m, 1H; 11␣-H), 6.13 (bs, 1H; 4-H), 6.35 (dd,
J = 9.9 Hz, J = 1.8 Hz, 1H; 2-H), 7.21 (d, J = 9.9 Hz, 1H; 1-H), 7.46
(m, 2H; Ar–H), 7.60 (m, 1H; Ar–H), 7.95 (m, 2H; Ar–H). 13C NMR
(100 MHz, CDCl3): ı 14.7, 16.2, 17.0, 19.5, 22.9 (d, J = 5.7 Hz),
27.3, 31.0, 32.4 (d, J = 19.5 Hz), 34.2, 35.6, 36.5, 37.3, 43.8, 48.0 (d,
J = 22.8 Hz), 72.3 (d, J = 38.5 Hz), 90.5, 91.8, 100.2 (d, J = 176.5 Hz),
111.1, 125.2, 127.4, 128.7, 129.9, 133.9, 136.0, 151.8, 166.4,
187.7, 205.3. Melting point: 184–188 ◦C. Analysis calculated for
21-Methylthio-9˛-fluoro-11ˇ,17˛-dihydroxy-16˛-methyl-1,4-
pregnadiene-3,20-dione 11. Yield: 82%. 1H NMR (400 MHz,
CDCl3): ı 0.96 (d, J = 7.3 Hz, 3H; 16␣-CH3), 1.06 (s, 3H; 18-CH3),
1.54 (s, 3H; 19-CH3), 2.08 (s, 3H; SCH3), 3.28 (AB quartet,
ꢀꢁ = 212 Hz, J = 12.8 Hz, 2H; –CH2–SMe), 4.35 (m, 1H; 11␣-H),
6.11 (bs, 1H; 4-H), 6.33 (dd, J = 9.9 Hz, J = 1.8 Hz, 1H; 2-H), 7.19
(d, J = 9.9 Hz, 1H; 1-H). 13C NMR (100 MHz, CDCl3): ı 14.6, 15.5,
17.3, 22.9 (d, J = 5.7 Hz), 27.3, 31.0, 32.3 (d, J = 19.4 Hz), 34.2,
35.9, 37.1, 39.1, 43.8, 48.3 (d, J = 22.8 Hz), 72.1 (d, J = 38.4 Hz),
90.7, 91.4, 100.2 (d, J = 176.5 Hz), 125.0, 129.7, 152.3, 166.4,
186.7, 205.5. Melting point: 176–180 ◦C. Analysis calculated for
C23H31FO4S: C, 65.38; H, 7.39; 15.15; S, 7.59; found: C, 65.11; H,
7.21; S, 7.24.
21-Methylthio-9˛-fluoro-16˛-17-O-isopropylidene-11ˇ,16˛,17˛-
trihydroxy-1,4-pregna-diene-3,20-dione 12. Yield: 74%. 1H NMR
(400 MHz, CDCl3): ı 0.96 (s, 3H; 18-CH3), 1.15 (s, 3H; CH3),
1.42 (s, 3H; CH3), 1.54 (s, 3H; 19-CH3), 2.19 (s, 3H; SCH3), 3.51
(AB quartet, ꢀꢁ = 23 Hz, J = 16.1 Hz, 2H; –CH2–SMe), 4.41 (m,
1H; 11␣-H), 5.02 (d, J = 5.8 Hz, 1H), 6.13 (bs, 1H; 4-H), 6.35 (dd,
J = 10.2 Hz, J = 1.8 Hz, 1H; 2-H), 7.17 (d, J = 10.2 Hz, 1H; 1-H). 13C
NMR (100 MHz, CDCl3): ı 16.1, 16.9, 22.9 (d, J = 5.7 Hz), 25.7,
26.5, 27.5, 30.9, 33.2 (d, J = 19.5 Hz), 37.6, 39.8, 43.1, 45.4, 48.1 (d,
J = 22.7 Hz), 72.5 (d, J = 38.6 Hz), 82.0, 98.4, 100.8 (d, J = 179.5 Hz),
111.1, 125.2, 129.9, 151.7, 166.0, 186.4, 204.7. Analysis calcu-
lated for C25H33FO5S: C, 64.63; H, 7.16; S, 6.90; found: C, 64.31;
H, 6.90; S, 6.57.
C
29H33FO5S: C, 67.95; H, 6.49; S, 6.26; found: C, 67.61; H, 6.06;
S, 5.98.
21-(S)-Benzoylthio-9˛-fluoro-16˛-17-O-isopropylidene-
11ˇ,16˛,17˛-trihydroxy-1,4-pregna-diene-3,20-dione 8. Yield:
82%. 1H NMR (400 MHz, CDCl3): ı 0.96 (s, 3H; 18-CH3), 1.22
(s, 3H; CH3), 1.46 (s, 3H; CH3), 1.56 (s, 3H; 19-CH3), 4.23 (AB
quartet, ꢀꢁ = 57 Hz, J = 18.3 Hz, 2H; –CH2–SBz), 4.47 (m, 1H;
11␣-H), 5.04 (d, J = 5.1 Hz, 1H), 6.14 (bs, 1H; 4-H), 6.36 (dd,
J = 10.2 Hz, J = 1.8 Hz, 1H; 2-H), 7.21 (d, J = 10.2 Hz, 1H; 1-H),
7.48 (m, 2H; Ar–H), 7.61 (m, 1H; Ar–H), 7.99 (m, 2H; Ar–H). 13C
NMR (100 MHz, CDCl3): ı 16.5, 16.9, 22.9 (d, J = 5.7 Hz), 25.7,
26.5, 27.5, 30.9, 33.2 (d, J = 19.6 Hz), 33.5, 38.1, 43.1, 45.3, 48.1
(d, J = 22.9 Hz), 72.0 (d, J = 38.4 Hz), 82.0, 100.0 (d, J = 176.6 Hz),
111.4, 125.2, 127.4, 128.7, 129.9, 133.9, 136.2, 151.8, 165.7, 186.4,
190.8, 203.8. Melting point: 230–234 ◦C. Analysis calculated for
2.3.
Radiochemistry
C
31H35FO6S: C, 67.13; H, 6.36; S, 5.78; found: C, 66.74; H, 6.02;
2.3.1. General
[
11C]CO2 was produced by the 14N(p,a)11C reaction on a IBA
S, 5.43.
CYCLONE 18/9 cyclotron. The synthesis was carried out in a
remotely controlled synthesis apparatus (Nuclear Interface,
Mu¨ nster, Germany). [11C]Methyl iodide was prepared accord-
ing to Crouzel et al. [20]. Semi-preparative HPLC-separation
and analytical HPLC were performed using a JASCO HPLC sys-
tem (JASCO, HPLC-pump PU-1580) equipped with a UV–vis
detector (JASCO UV-1575) and gamma detector (Raytest Gabi).
21-Methylthio-9˛-fluoro-16˛-17-O-isopropylidene-11ˇ,16˛,17˛-
2.2.2. General procedure for the synthesis of C-21
methylthioethers 9–12
S-Thiobenzoate 5–8 (0.2 mmol) was stirred in MeOH (5 ml) and
1 N NaOH (0.5 ml) at room temperature for 30 min. Then, MeI
(30 l) was added and the mixture was stirred for 3 h at room
temperature. Water (50 ml) was added and the mixture was
extracted with ethyl acetate. After evaporation of the sol-
vent the residue was purified by flash-chromatography (50%
EtOAc/petroleum ether).
trihydroxy-1,4-pregna-diene-3,20-dione
intermediate required for the methylation reaction was
generated 15 min prior to the distillation of
11C]methyl
iodide. stream
11C]Methyl iodide was transferred in
[
11C]12. The thiolate
21-Methylthio-11ˇ,17˛-dihydroxy-4-pregnene-3,20-dione
9.
[
Yield: 68%. 1H NMR (400 MHz, CDCl3): ı 1.00 (s, 3H; 18-CH3),
1.44 (s, 3H; 19-CH3), 2.11 (s, 3H; SCH3), 3.38 (AB quartet,
ꢀꢁ = 84 Hz, J = 13.5 Hz, 2H; –CH2–SMe), 4.46 (m, 1H; 11␣-H), 5.68
(bs, 1H; 4-H). 13C NMR (100 MHz, CDCl3): ı 15.8, 17.9, 21.0, 23.9,
29.7, 31.4, 32.0, 32.7, 33.8, 34.7, 39.2, 39.7, 39.9, 48.0, 51.5, 55.9,
68.4, 89.5, 122.3, 172.0, 199.5, 206.2. Melting point: 217–219 ◦C.
Analysis calculated for C22H32O4S: C, 67.31; H, 8.22; S, 8.17;
found: C, 66.93; H, 7.89; S, 7.82.
[
a
of nitrogen into the reaction vessel containing thioben-
zoate 8 (0.5 mg) in MeOH (400 l) and 5 N NaOH (30 l) at
room temperature. The formation of the corresponding
desmethyl precursor occurred in situ immediately after
the addition of NaOH to thiobenzoate 8 in MeOH at room
temperature. After completion of the
[
11C]methyl iodide
transfer, the reaction vessel was sealed and heated at 50 ◦C
for 5 min. The reaction mixture was diluted with eluent
(1 ml) and the mixture was transferred from the reaction
vessel onto a semi-preparative C-18 column (Phenomenex
Luna C18(2), 250 mm × 10 mm, 10 m) using CH3CN:H2O
(55:45) as the mobile phase at a flow rate of 9 ml/min. The
21-Methylthio-11ˇ,17˛-dihydroxy-1,4-pregnadiene-3,20-dione
10. Yield: 74%. 1H NMR (400 MHz, CDCl3): ı 1.02 (s, 3H; 18-CH3),
1.45 (s, 3H; 19-CH3), 2.11 (s, 3H; SCH3), 3.37 (AB quartet,
ꢀꢁ = 82 Hz, J = 13.5 Hz, 2H; –CH2–SMe), 4.49 (m, 1H; 11␣-H), 6.02
(bs, 1H; 4-H), 6.27 (dd, J = 9.9 Hz, J = 1.8 Hz, 1H; 2-H), 7.24 (d,