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H. Ali et al. / Steroids 65 (2000) 74–84
3-OCOCH3), 5.59 (brs, 1 H, 16-H), 6.79, 6.84 (2 H, 2 and
4-CH), 7.23 (d, 7.8 Hz, 1 H, 1-CH); MS m/z (rel int) 368 (8,
Mϩ), 339 (30, Mϩ Ϫ CHO), 326 (25, Mϩ Ϫ CH2CO), 297
(100, Mϩ Ϫ C3H2O2), 255 (70). HRMS calculated for
C23H28O4 368.1987. Found: 368.1980.
1 H, 1-CH); MS m/z (rel int) 362, 364 (100, Mϩ). HRMS
calculated for C19H23BrO2 362.0881. Found: 362.0877.
2.9. 16-Bromo-18-methyl-estra-1,3,5(10)-trien-17-one (9)
A mixture of the 16␣-bromoestrogen (7) (140 mg, 0.38
mmol) and LiBr (140 mg) in 1 ml of 2-butanone was heated
for 0.5 h at reflux. The reaction mixture was poured into 20
ml of water and extracted with EtOAc, washed with water,
dried over sodium sulfate (anhydrous), and evaporated to
dryness. The purple residue was filtered over a silica gel
column to furnish a yellow residue that was purified by
HPLC to gave 16-bromo-18-methyl-estra-1,3,5(10)-trien-
17-one (9) (37%): m.p. 187–190°C; HPLC (70:30 MeOH/
2.6. 3-Acetoxy-18-methyl-estra-1,3,5(10)-trien-17-one (4)
(283 mg, 0.87 mmol; 32%): m.p. 155–157°C (lit [44].
156–158°C); 1H NMR (CDCl3) ␦ 0.79 (t, J ϭ 7.5 Hz, 3 H,
13-CH2CH3), 2.28 (s, 3 H, 3-OCOCH3), 6.80 (d, J ϭ 2.2
Hz, 1 H, 4-CH), 6.85 (dd, J ϭ 2.2 and 9.2 Hz, 1 H, 2-CH),
7.29 (d, J ϭ 9.2 Hz, 1-CH); MS m/z (rel int) 326 (18, Mϩ),
284 (100, Mϩ Ϫ CH2CO). HRMS calculated for C21H26O3
326.1882. Found: 326.1872.
1
H2O) tr ϭ 27 min; H NMR (CDCl3) ␦ 0.85 (t, J ϭ 7 Hz,
3 H, 13-CH2CH3), 4.12 (t, J ϭ 8.5 Hz, 1 H, 16␣-H), 6.57
(d, J ϭ 3 Hz, 1 H, 4-CH), 6.63 (dd, J ϭ 2 and 8.5 Hz, 1 H,
2-CH), 7.13 (d, J ϭ 8.5 Hz, 1 H, 1-CH); MS m/z (rel int)
362, 364 (100, Mϩ), 228 (100). HRMS calculated for
C19H23BrO2 362.0881. Found: 362.0877.
2.7. 16␣-Bromo-3-acetoxy-18-methyl-estra-1,3,5(10)-trien-
17-one (6)
3,17-Diacetoxy-18-methyl-estra-1,3,5(10),16-tetraene
(5) (550 mg, 1.5 mmol) was dissolved in ether (10 ml) and
acetate buffer (200 mg of potassium acetate in 4 ml of 85%
acetic acid) was added. The mixture was cooled to 0°C and
1.6 ml of bromine solution was added (0.2 ml of Br2 in 6.5
ml of acetic acid glacial) until the orange color persisted,
whereafter the solution was stirred for an additional 20 min.
The reaction was terminated by the addition of water and
the organic phase was washed with water, 5% sodium thio-
sulfate and 5% aqueous sodium bicarbonate, dried over
sodium sulfate (anhydrous), filtered and evaporated to dry-
ness to afford 16␣-bromo-3-acetoxy-18-methyl-estra-
1,3,5(10)-trien-17-one (6) in a quantitative yield: m.p.
2.10. 16-Bromo-18-methyl-estra-1,3,5(10)-trien-3,17-
diol (10)
A solution of NaBH4 (105 mg, 2.8 mmol) in ethanol (6.6
ml) was added to 16-bromo-18-methyl-estra-1,3,5(10)-
trien-17-one (9) (122 mg, 0.33 mmol) in ethanol (6.6 ml).
The mixture was stirred at room temperature for one hour.
Excess NaBH4 was destroyed with acetone and the reaction
mixture was poured into water, extracted with ethyl acetate,
washed with water, dried over sodium sulfate (anhydrous),
and evaporated to dryness to furnished the crude product
(119 mg). The residue was purified by column chromatog-
raphy over silica gel. Elution with 5% CH3CN in CHCl3
1
133°C; H NMR (CDCl3) ␦ 0.79 (t, J ϭ 7 Hz, 3 H, 13-
CH2CH3), 2.28 (s, 3 H, 3-OCOCH3), 4.60 (dd, J ϭ 7.5 Hz,
1 H, 16-H), 6.81 (d, J ϭ 2 Hz, 1 H, 4-CH), 6.85 (dd, J ϭ
2.5 and 8 Hz, 1 H, 2-CH), 7.29 (1 H, 1-CH); MS m/z (rel int)
404, 406 (15, Mϩ), 364, 366 (100, Mϩ Ϫ CH2CO). HRMS
calculated for C21H25BrO3 404.0987. Found: 404.0980.
furnished
16-bromo-18-methyl-estra-1,3,5(10)-trien-
3,17-diol (10) (36 mg, 0.1 mmol, 34%): m.p. 195–199°C;
HPLC (70: 30 MeOH/H2O) tr ϭ 29 min; 1H NMR (CDCl3)
␦ 1.01 (t, J ϭ 7.5 Hz, 3 H, 13-CH2CH3), 3.50 (t, J ϭ 8.5
Hz, 1 H, 17␣-H), 4.68 (td, J ϭ 8 Hz, 1 H, 16␣-H), 6.56 (d,
J ϭ 3 Hz, 1 H, 4-CH), 6.63 (dd, J ϭ 3 and 8.5 Hz, 1 H,
2-CH), 7.14 (d, J ϭ 8 Hz, 1 H, 1-CH); MS m/z (rel int) 364,
366 (30, Mϩ), 284 (90, Mϩ-Br), 159 (100). HRMS calcu-
lated for C19H25BrO2 364.1038. Found: 364.1033.
2.8. 16␣-Bromo-18-methyl-estra-1,3,5(10)-trien-17-one (7)
16␣-Bromo-3-acetoxy-18-methyl-estra-1,3,5(10)-trien-
17-one (6) (603 mg, 1.5 mmol) was hydrolyzed by treat-
ment with concentrated sulfuric acid (0.3 ml) in ethanol (30
ml) at room temperature. Water was added and the com-
pound was extracted with CHCl3 and the organic phase was
dried over sodium sulfate (anhydrous), filtered, and concen-
trated under reduced pressure. The residue was purified by
column chromatography over silica gel. Elution with 8%
EtOAc in hexane furnished 16␣-bromo-18-methyl-estra-
1,3,5(10)-trien-17-one (7) (460 mg, 1.3 mmol; 85%): m.p.
97–98°C; HPLC (70:30 MeOH/H2O) tr ϭ 25 min; 1H NMR
(CDCl3) ␦ 0.79 (t, J ϭ 7 Hz, 3 H, 13-CH2CH3), 4.61 (dd,
J ϭ 7.5 Hz, 1 H, 16-H), 6.57 (d, J ϭ 3 Hz, 1 H, 4-CH),
6.63 (dd, J ϭ 3 and 8 Hz, 1 H, 2-CH), 7.13 (d, J ϭ 8 Hz,
2.11. 16␣-Bromo-18-methyl-estra-1,3,5(10)-trien-3,17-
diol (8)
A solution of NaBH4 (18 mg, 0.5 mmol) in ethanol (1
ml) was added to 16-bromo-18-methyl-estra-1,3,5(10)-
trien-17-one (7) (20 mg, 0.05 mmol) in ethanol (2 ml). The
mixture was stirred at room temperature for 2 h. Excess
NaBH4 was destroyed with acetone and the reaction mixture
was poured into water, extracted with ethyl acetate, washed
with water, dried over sodium sulfate (anhydrous), and
evaporated to dryness to furnish a crude product (19 mg).
The residue was purified by HPLC to furnish 16␣-bromo-