490
steroids 7 3 ( 2 0 0 8 ) 488–494
1.57–1.66 (m), 1.24–1.43 (m), 0.90 (s, 3H). IR (KBr pellet) ꢀ 3563,
2.2.4. Synthesis of 17˛-ethinyl-17-hydroxy-3-
3388, 3277, 2965, 2945, 2891, 2865, 1664, 1607, 1498, 1385, 1311,
methoxyestra-1,3,5(10)-triene-6-one
(8)
1259, 1215, 1178, 1133, 1045 cm−1
.
A mixture consisting of 7 (4.34 g, 14 mmol), anhydrous potas-
sium carbonate (6.36 g, 46 mmol), methyl iodide (6 mL, 13.7 g,
97 mmol), and acetone (40 mL) was stirred at room temper-
ature for 36 h then refluxed for 6 h. The reaction mixture
was allowed to cool to room temperature and poured into
water (150 mL). The mixture was extracted with ethyl acetate
(80 mL 4×) and the combined organic phase was dried over
Na2SO4. After evaporation to remove solvent, the crude prod-
uct was purified by column chromatography on silica gel with
petroleum ether/ethyl acetate (2:1, v/v) as eluent or by recrys-
tallization from methylene dichloride/hexane to give 8 (4.3 g,
95%) as pale yellow needles, mp 161.8–162.5 ◦C (Ref. [1] value:
162–163 ◦C from ether), Rf 0.57 (petroleum ether/ethyl acetate,
2:1, v/v). 1H NMR (CDCl3) ı 7.57 (d, J = 2.9 Hz, 1H), 7.36 (d,
J = 8.6 Hz, 1H), 7.12 (dd, J = 8.6 and 2.9 Hz, 1H), 3.85 (s, 3H), 2.75
(dd, J = 16.9 and 3.3 Hz, 1H), 2.63 (s, 1H), 2.23–2.57 (m), 1.72–2.05
(m), 1.56–1.66 (m), 1.26–1.49 (m), 0.90 (s, 3H). 13C NMR (CDCl3)
ı 197.8 (C O), 158.2 (3-C), 139.5 (10-C), 133.4 (5-C), 126.6 (1-C),
121.6 (2-C), 109.7 (4-C), 87.2 (21-C), 79.6 (17-C), 74.4 (22-C), 55.5
(OCH3), 49.3 (13-C), 46.9 (14-C), 44.0 (9-C), 42.6 (7-C), 40.7 (8-
C), 38.9 (16-C), 32.4 (12-C), 25.7 (11-C), 22.5 (15-C), 12.5 (CH3).
IR (KBr pellet) ꢀ 3523, 3275, 2946, 1674, 1605, 1493, 1327, 1286,
1246, 1224, 1038 cm−1. MS (EI, 70 eV): m/z (%) 324 (M+, 77), 256
(50), 241 (68), 227 (12), 214 (15), 200 (60), 188 (100), 174 (19), 161
(23), 145 (10), 128 (12), 115 (18), 103 (11), 91 (11), 77 (13).
2.2.2. Synthesis of
19-norpregna-1,3,5(10)-triene-20-yne-3,6˛,17ˇ-triol (1) and
19-norpregna-1,3,5(10)-triene-20-yne-3,6ˇ,17ˇ-triol (3)
Compound 7 (4.97 g, 16 mmol) was dissolved in methanol
(70 mL). The solution was cooled in ice-water bath and sodium
borohydride (0.73 g, 19.3 mmol) was added in portions. After
the mixture was stirred for 12 h at room temperature the
excess sodium borohydride was destroyed by the addition of
acetone. The reaction mixture was concentrated at reduced
pressure then ethyl acetate (120 mL) and dilute hydrochlo-
ric acid (1N, 60 mL) were added to the residue. The organic
layer was separated and the aqueous phase was extracted
with ethyl acetate (40 mL 3×). The organic phases were com-
bined and washed with water and brine then dried over
MgSO4. After evaporation to remove solvent, the crude prod-
uct was purified by column chromatography on silica gel with
ethyl acetate/petroleum ether (1:1, v/v) to afford 1 (3.20 g,
64%) as pale yellow powder, mp 160–161 ◦C (Ref. [18] value:
158–161 ◦C), Rf 0.29 (petroleum ether/ethyl acetate, 1:1, v/v).
1H NMR (CDCl3) ı 7.17 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H),
6.72 (dd, J = 8.5 and 2.7 Hz, 1H), 4.80 (s, 1H), 4.10 (t, J = 7.1 Hz, 1H),
2.60 (s, 1H), 2.23–2.40 (m), 1.68–2.05 (m), 1.21–1.53 (m), 0.90 (s,
3H). IR (KBr pellet) ꢀ 3289, 2935, 2870, 1612, 1499, 1448, 1377,
1290, 1255, 1066, 1047, 1018 cm−1. MS (EI, 70 eV): m/z (%) 312
(M+, 25), 295 (17), 294 (70), 237 (10), 229 (35), 227 (13), 226 (36),
224 (25), 213 (13), 212 (19), 211 (100), 209 (17), 208 (11), 207 (16),
198 (10), 197 (23), 195 (12), 185 (10), 184 (12), 183 (19), 182 (10),
181 (12), 174 (13), 173 (11), 171 (18), 170 (20), 167 (15), 165 (13),
161 (11), 160 (10), 159 (31), 158 (51), 157 (68), 153 (10), 149 (11),
147 (15), 145 (18), 144 (20), 137 (14), 135 (10), 133 (15), 132 (10),
131 (19), 129 (11), 128 (15), 127 (12), 125 (10), 124 (19), 123 (12),
121 (11), 119 (10), 115 (15), 111 (15), 107 (20), 105 (17), 98 (23), 97
(24), 96 (10), 95 (22), 91 (22), 85 (15), 83 (24), 82 (11), 81 (21), 79
(14), 77 (20), 71 (20), 70 (11), 69 (26), 67 (16), 57 (27), 55 (32), 53
(13), 44 (27), 43 (41), 41 (21).
2.2.5. Synthesis of
17˛-ethinyl-3-methoxyestra-1,3,5(10)-triene-6˛,17ˇ-diol (2)
Treatment of 8 with sodium borohydride in a manner simi-
lar to reduction of 7 gave compound 5 as white solid, yield
95%, mp 144.2–145.6 ◦C (Ref. [18] value: 144–146 ◦C), Rf 0.38
(petroleum ether/ethyl acetate, 2:1, v/v). 1H NMR (CDCl3) ı
7.21 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 2.7 Hz, 1H), 6.80 (dd, J = 8.6
and 2.8 Hz, 1H), 4.84 (t, 1H), 3.83 (s, 3H), 2.60 (s, 1H), 2.25–2.38
(m), 1.99–2.08 (m), 1.89–1.93 (m), 1.71–1.85(m), 1.51–1.58 (m),
1.32–1.48 (m), 1.24–1.28 (m), 0.90 (s, 3H). IR (KBr pellet) ꢀ 3412,
2931, 2870, 1610, 1497, 1465, 1383, 1280, 1237, 1090, 1067,
Compound 3 (1.01 g, 20%) was obtained as pale yellow solid
as the minor product, mp 119–120 ◦C (Ref. [18] value: 120 ◦C),
Rf 0.44 (petroleum ether/ethyl acetate, 1:1, v/v).
1038 cm−1
.
2.2.6. Synthesis of
6ˇ,17ˇ-dihydroxy-19-norpregna-1,3,5(10)-triene-20-yne
6-(4-nitrobenzoate) (12)
2.2.3. Synthesis of
3,17ˇ-dihydroxy-19-norpregna-1,3,5(10),6-tetraene-20-yne
(5)
A
solution of diethyl azodicarboxylate (DEAD, 2.40 g,
13.8 mmol) in dry tetrahydrofuran (THF, 10 mL) was added
dropwise to a stirred solution containing 2 (1.80 g, 5.5 mmol),
triphenylphosphine (1.45 g, 5.5 mmol), and 4-nitrobenzoic
acid (2.30 g, 13.8 mmol) in dry THF (30 mL) maintained in
ice-water bath under nitrogen atmosphere. The mixture was
stirred at room temperature overnight. After evaporation
under reduced pressure the residue was chromatographed
on a silica gel column. Upon elution with 50% petroleum
ether in dichloromethane, a fore running yellow coloration
was removed. Further elution with 10% petroleum ether in
dichloromethane gave the desired 4-nitrobenzoate derivative
12 (2.5 g, 95%) as pale yellow solid, mp 86.5–88.0 ◦C, Rf 0.67
(petroleum ether/ethyl acetate, 2:1, v/v). 1H NMR (CDCl3) ı
8.19 (d, J = 8.6 Hz, 2H), 8.11 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.3 Hz,
A mixture consisting of 1 and 3 (1.72 g, 5.5 mmol) was heated
to 230 ◦C then was allowed to cool to room temperature. The
residue was dissolved in ethyl acetate and the solution was
dried over MgSO4. After evaporation to remove solvent, the
crude product was purified by column chromatography on sil-
ica gel with petroleum ether/ethyl acetate (3:1, v/v) as eluent
to give 5 (0.99 g, 61%) as pale yellow solid, mp 181.8–183.7 ◦C, Rf
0.64 (petroleum ether/ethyl acetate, 2:1, v/v). 1H NMR (CDCl3)
ı 7.05 (d, J = 7.8 Hz, 1H), 6.66 (dd, J = 8.2 and 2.6 Hz, 1H), 6.51 (d,
J = 2.7 Hz, 1H), 6.35 (dd, J = 9.5 and 2.8 Hz, 1H), 5.91 (dd, J = 9.6
and 1.6 Hz, 1H), 2.54 (s, 1H), 0.82 (s, 3H). IR (KBr pellet) ꢀ 3268,
2923, 2855, 1631, 1606, 1574, 1449, 1381, 1328, 1263, 1191, 1136,
1051, 1015, 798 cm−1
.