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P.N. Rao et al. / Steroids 65 (2000) 395–400
sulfonic acid monohydrate (21.6 g, 0.11 mol) were added and
the mixture was stirred overnight at room temperature. Satu-
rated sodium bicarbonate solution (2150 ml) was added and
stirred for 10 min. The organic layer was washed with water
and brine. The aqueous washes were extracted with additional
dichloromethane and the combined extract was dried over
sodium sulfate. The solvent was evaporated in vacuo to afford
a thick syrup. While the flask was still attached to the rotary
evaporator, methanol (ϳ3 l), containing pyridine (0.5%), was
drawn into the flask to induce crystallization. After chilling the
flask to 4°C, the solid was filtered and washed with methanol
containing pyridine and dried in vacuo overnight to give 506.4
g (67.3%) of (4), m.p. ϭ 170–172°C. The above material was
homogenous by TLC (5% acetone/dichloromethane) and was
used without further purification in the following reaction.
NMR (CDCl3) ␦ 0.78 (s, C-18 Me), 1.37 (s, C-21 Me),
3.99 (m, ketals), 5.57 (br.s., C-11 H) ppm. Analysis calcu-
lated for C24H34O5: C 71.61, H 8.51; Found: C 71.53, H
8.50.
a Teflon paddle. Several crystals of iodine and 1.0 ml of
dibromoethane were added, followed by the addition of
THF (1000 ml). The mixture was stirred gently and a THF
(2000 ml) solution of p-bromo-N,N-dimethylaniline (597.5
g, 2.99 mol) was added at such a rate as to maintain a gentle
reflux. Upon completion of the addition, the mixture was
stirred for 1.5 h and allowed to come to room temperature.
Copper (I) chloride (29.5 g, 0.30 mol) was added and the
mixture was stirred for 30 min at room temperature. Epox-
ide (5) (250 g, 0.6 mol) in THF (1500 ml) was added over
ϳ30 min and the mixture was stirred for 1 h. Ammonium
chloride solution (800 g/4500 ml water) was added and
stirred for 30 min.
While stirring, air was bubbled through the solution until
the mixture turned blue, indicating the complete oxidation
of Cu(I) to Cu(II). The layers were separated and the or-
ganic layer was diluted with ether (4500 ml). The ether/THF
layer was washed with 2.0 N ammonium chloride solution
(5 ϫ 1000 ml), water, and brine. The organic extract was
percolated through sodium sulfate contained in a large fun-
nel and the filtrate evaporated in vacuo. The residue was
triturated with ether (1000 ml) and the resulting solid was
filtered, washed with ether, and dried in vacuo to afford
245.8 g (76%) of Grignard product (6), m.p. ϭ 236–240°C
dec.
2.4. 3,20-bis-Ethylenedioxy-17␣-hydroxy-5␣,10␣-epoxy-
19-norpregn-9(11)-ene (5)
Hexafluoroacetone trihydrate (266 g, 1.6 mol) was
weighed into a 3 neck, 12 l round bottom flask. Dichlo-
romethane (2500 ml) was added and the mixture was stirred
vigorously at 4°C. Sodium phosphate, dibasic (125 g, 0.88
mol) was added, followed by the addition of 30% hydrogen
peroxide (242 ml, 2.36 mol) and stirred for 20 min. A
dichloromethane (2500 ml) solution of (4) (439.7 g, 1.23
mol) was chilled to 0°C and added to the above mixture.
The mixture was stirred at 4°C for ϳ 7.5 h. TLC analysis
(25% ethyl acetate/dichloromethane) showed the reaction to
be complete. Sodium sulfite (10%) solution (3 l) was added
and the mixture was stirred for 30 min. The mixture was
extracted with dichloromethane (3ϫ), washed with water
(2 ϫ 3 l) and brine (1 ϫ 2 l), dried over sodium sulfate, and
concentrated in vacuo. The residue was triturated with ether
and the resulting solid was filtered and washed with ether to
afford 250.5 g (54.3%) of epoxide (5) m.p. ϭ 188.5–
191.5°C. NMR analysis showed none of the 5,10-epox-
ide to be present.
NMR (CDCl3) ␦ 0.42 (s, C-18 Me), 1.38 (s, C-21 Me),
2.9 (s, N(CH3)2), 3.97 (br. m, 3, 20-diketal), 4.2 (d, C-11 H),
6.65 and 7.08 (d, aromatic H) ppm. FTIR: max 3573, 3543,
3087, 2976, 2874, 1612, 1516, 1484, 1371, 1214, 1100
cmϪ1. MS(EI): m/z (relative intensity) 539(Mϩ, 83),
521(Mϩ-18, 57), 324(21), 238(26), 87(100). Analysis cal-
culated for C32H45NO6: C 71.21, H 8.40, N 2.60; Found: C
71.29, H 8.35, N 2.74.
2.6. 11-(4-N,N-dimethylaminophenyl)-17␣-hydroxy-19-
norpregna-4,9-diene-3,20-dione (7)
A mixture of ethanol (4450 ml) and sulfuric acid (8.5%,
445 ml) was sparged with argon for 10 min. Grignard
product (6) (244.4 g, 0.45 mol) was added as a solid with
stirring and the mixture was heated to reflux for 1 h. TLC
(10% acetone/dichloromethane) showed the reaction com-
plete. The mixture was cooled in an ice bath and neutralized
with saturated NaHCO3 solution. The solids were removed
by filtration and washed well with ethanol and discarded.
The filtrate was evaporated in vacuo, water was added, and
the aqueous mixture was extracted with dichloromethane.
The extract was washed with water and brine, dried over
Na2SO4, and evaporated to a stable foam. The product was
recrystallized from ether. A total of 172.5 g (88%) of (7)
was obtained in three crops. m.p. 125–128°C.
NMR (CDCl3) ␦ 0.79 (s, C-18 Me), 1.36 (s, C-21 Me),
3.92 (m, ketal), 6.03 (m, C-11 H of ␣-epoxide) ppm. FTIR:
max 3510(OH), 2947, 2887, 2669, 1649, 1469, 1438, 1220
cmϪ1. MS(EI) m/z (relative intensity) 418(Mϩ, 18),
400(Mϩ-18, 77), 293(35), 141(30), 131(92), 115(56),
87(100). Analysis calculated for C24H34O6: C 68.88, H
8.19; Found: C 68.70, H 8.09.
2.5. 3,20-bis-Ethylenedioxy-5␣,17␣-dihydroxy-11-(4-
N,N-dimethylaminophenyl)-19-norpregn-9-ene (6)
NMR ␦ 0.47 (s, C-18 Me), 2.26 (s, C-21 Me), 2.90 (s,
N(CH3)2), 4.38 (d, C-11 H), 5.77 (br.s., C-4 H), 6.65, and
Activated magnesium (72.5 g, 2.98 mol) was weighed
into a dry 12-l 3-neck flask that was subsequently fitted with
an argon inlet, reflux condenser, and a stir shaft fitted with
7.02 (d, aromatic H) ppm. FTIR:
3448(OH), 3074,
max
1709(C ϭ O), 1643, 1602(conjugated C ϭ O), 1560, 1519,
1440 cmϪ1. MS(EI) m/z (relative intensity): 433(Mϩ, 35),