4752 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21
Cushman et al.
was added, and the mixture was stirred at room temperature
for 3 h. The excess LAH was carefully quenched with methanol
(5 mL) and 10% NaOH (2 mL). The THF solution was
decanted, and the residue was washed with THF (20 mL). The
combined THF portion was stirred with 6 M HCl (50 mL) for
10 h. Evaporation of solvent from the organic layer, followed
by trituration of the crude product with ethyl acetate, gave
the pure compound 7 as a colorless solid (0.85 g, 62%); mp
2 H), 4.65 (s, 2 H), 3.60 (t, J ) 7.5 Hz, 1 H), 3.51 (s, 3 H), 3.37
(s, 3 H), 2.82 (m, 2 H), 2.30-1.10 (m, 13 H), 0.80 (s, 3 H). CIMS
(isobutane) m/z (relative intensity) 486 (MH+), 455, 425 (100%).
2-Iod oestr a d iol (13). Hydrochloric acid (6 M, 150 mL) was
added to a solution of 12 (8 g, 16.4 mmol) in THF (150 mL),
and the reaction mixture was stirred at room temperature for
10 h. It was poured into ice water (400 mL), extracted into
ethyl acetate (3 × 50 mL), washed with brine (100 mL), and
dried (Na2SO4). Removal of organic solvent gave 2-iodoestradiol
(13) as a fluffy solid (6.4 g, 98%); mp 150-152 °C (lit.44 mp
146-153 °C; lit.13mp 154-155 °C). 1H NMR (300 MHz,
CDCl3): δ 7.52 (s, 1 H), 6.71 (s, 1 H), 3.76-3.70 (t, J ) 7.5 Hz,
1 H), 2.80-2.76 (m, 2 H), 2.28-1.15 (m, 13 H), 0.81 (s, 3 H).
CIMS (isobutane) m/z (relative intensity) 399 (MH+), 381
(100%).
214-216 °C. IR (KBr): 3328, 2923, 1511 cm-1 1H NMR
.
(DMSO-d6): δ 8.4 (s, 1 H), 6.78 (s, 1 H), 6.45 (s, 1 H), 3.93-
3.89 (t, J ) 6 Hz, 2 H), 3.69-3.66 (t, J ) 6 Hz, 2 H), 3.54-
3.49 (t, J ) 6 Hz, 1 H), 2.63 (m, 2 H), 2.26-1.07 (m, 13 H),
0.66 (s, 3 H). Anal. (C20H28O4‚0.2CH3CO2CH2CH3) C, H.
2-(2′-N,N-Dim et h yla m in oet h ylim in o)est r a d iol (8). 2-
(Aminoethyl)dimethylamine (1.46 mL, 13.3 mmol) was added
to the aldehyde 2 (0.4 g, 1.33 mmol), and the suspension was
heated at reflux for 6 h. The excess amine was removed in
vacuo, and the crude product was recrystallized from ethyl
acetate-hexane (1:1) to give 8 (0.42 g, 85%) as a pale yellow
3,17-Bis-O-(ter t-bu tyldim eth ylsilyl)-2-iodo-estr adiol (14).
This compound was prepared according to the published
procedure.45
2-(P h en yleth yn yl)estr a d iol (15). Tri-n-butylphenyleth-
ynylstannane (0.589 g, 1.51 mmol) was added to a solution of
2-iodoestradiol 13 (0.3 g, 0.75 mmol) in dry THF (30 mL), Pd-
(PPh3)4 (0.087 g, 0.075 mmol) was added, and the reaction
mixture was maintained between 60 and 65 °C for 10 h under
argon. The solvent was removed, and the crude product (0.22
g, 79%) was purified by passing it through a column of silica
gel (230-420 mesh, 1:4 ethyl acetate-hexane); mp 156-158
solid; mp 138-140 °C. IR (KBr): 3206, 2946, 2864, 1630 cm-1
.
1H NMR (DMSO-d6): δ 13.17 (s, 1 H), 8.46 (s, 1 H), 7.29 (s, 1
H), 6.54 (s, 1 H), 4.50 (s, 1 H), 3.64-3.60 (t, J ) 6 Hz, 2 H),
3.54-3.49 (t, J ) 6 Hz, 1 H), 2.78-2.76 (m, 2 H), 2.52-2.47
(t, J ) 6 Hz, 2 H), 2.30-1.12 (m, 19 H), 0.65 (s, 3 H). CIMS
(isobutane) m/z (relative intensity) 371 (MH+, 100%). Anal.
(C23H34N2O2) C, H, N.
2-(2′-Hyd r oxyeth ylim in o)estr a d iol (9). Ethanolamine
(0.4 mL, 6.66 mmol) was added to the aldehyde 2 (0.4 g, 1.33
mmol), and the suspension was heated at 100 °C for 6 h. Most
of the excess ethanolamine was removed in vacuo, and the
crude product was purified by passing it through a column of
silica gel (230-420 mesh, ethyl acetate-methanol 2:8) to give
compound 9 as a yellow solid (0.42 g, 92%); mp 190-192 °C.
1
°C. H NMR (MeOH-d4): δ 7.53-7.50 (dd, J ) 6 and 3 Hz, 2
H), 7.36-7.29 (m, 3 H), 7.24 (s, 1 H), 6.55 (s, 1 H), 4.87 (s, 1
H, exchangeable with D2O), 3.66-3.61 (t, J ) 6 Hz, 1 H), 2.76
(m, 2 H), 2.29-2.25 (m, 1 H), 2.08-1.83 (m, 4 H), 1.68-1.25
(m, 8 H), 0.76 (s, 3 H). CIMS (isobutane) m/z (relative intensity)
373 (MH+, 100%), 355 (MH+-H2O). Anal. (C26H28O2‚0.3Et2O‚
0.5H2O) C, H.
1
IR (KBr): 3357, 2923, 2867, 1636 cm-1. H NMR (DMSO-d6):
3,17-Bis-O-(ter t-bu tyld im eth ylsilyl)-2-(1-eth yn yl)estr a -
d iol (16). A procedure similar to that for the preparation of
compound 17 was employed, and the product was obtained as
a pale yellow solid (0.321 g, 95%); mp 126-128 °C. IR (KBr):
δ 13.17 (s, 1 H), 8.43 (s, 1 H), 7.31 (s, 1 H), 6.55 (s, 1 H), 4.74
(m, 1 H), 4.50-4.49 (d, J ) 3 Hz, 1 H), 3.61 (s, 4 H), 3.55-
3.48 (m, 1 H), 2.79-2.76 (m, 2 H), 2.34-1.11 (m, 13 H), 0.66
(s, 3 H). CIMS (isobutane) m/z (relative intensity) 344 (MH+,
100%). Anal. (C21H29NO3) C, H, N.
1
3307, 2925, 2855, 2101, 1488, 1398 cm-1. H NMR (500 MHz,
CDCl3): δ 7.30 (s, 1 H), 6.49 (s, 1 H), 3.61 (t, J ) 6 Hz, 1 H),
3.10 (s, 1 H), 2.77-2.75 (m, 15 H), 0.96 (s, 9 H), 0.87 (s, 9 H),
0.71 (s, 3 H), 0.19 (s, 6 H), 0.05 (s, 6 H). Anal. (C32H52O2Si2) C,
H.
2-(â-3,4,5-Tr im eth oxyp h en yl)eth en ylestr a d iol (10). LH-
MDS (1 M, 4.64 mL) was added to a suspension of 3,4,5-
(trimethoxybenzyl)triphenylphosphonium chloride (1.59 g, 3.2
mmol) in dry THF (40 mL) at 0 °C, and the mixture was stirred
under argon for 15 min. A clear orange color developed.
Compound 2 (0.2 g, 0.66 mmol) in anhydrous THF (20 mL)
was added dropwise under argon, and the reaction mixture
was stirred for 8 h at room temperature. It was acidified to
pH 5, extracted with ether (3 × 40 mL), washed with brine (2
× 50 mL), and dried (Na2SO4). Evaporation of the filtrate
followed by column chromatographic purification (silica gel,
230-420 mesh; ethyl acetate-hexane, 1:1) gave compound 10
as a fluffy solid (0.24 g, 78%); mp 220-222 °C (ether). IR
(KBr): 3430, 2931, 1580, 1508 cm-1. 1H NMR (CDCl3): δ 7.43
(s, 1 H), 7.26-7.21(d, J ) 15 Hz, 1 H), 7.03-6.98 (d, J ) 15
Hz, 1 H), 6.74 (s, 2 H), 6.54 (s, 1 H), 5.2 (s, 1 H), 3.92 (s, 6 H),
3.85 (s, 3 H), 3.82-3.70 (m, 1 H), 2.80 (m, 2 H), 2.44-1.20 (m,
13 H), 0.80 (s, 3 H). PDMS m/z 464.4 (M+). Anal. (C29H36NO2)
C, H, N.
3,17-Bis-O-(ter t-bu tyldim eth ylsilyl)-2-(1-pr opyn yl)estr a-
d iol (17). Anhydrous ZnBr2 (0.289 g, 1.28 mmol) was dissolved
in dry THF (40 mL) under argon. A solution of 1-propynyl-
magnesium bromide (2.6 mL, 0.5 M) in THF was added, and
stirring was continued under argon as the solution became
turbid. After 10 min, Pd(PPh3)4 (0.074 g, 0.064 mmol) and iodo
compound 14 (0.4 g, 0.64 mmol) were added, and stirring was
continued for 6 h at room temperature. The reaction mixture
was poured over ice water (100 mL), extracted into ethyl
acetate (3 × 20 mL), washed with brine (50 mL), and dried
(Na2SO4). Removal of organic solvent followed by column
chromatographic purification (silica gel, 230-420 mesh, 5%
ethyl acetate in hexane) gave 0.28 g (82%) of pure compound
17 as a colorless solid; mp 192-194 °C. IR (KBr): 2934, 2844,
1
1493, 1462, 1297, 1247, 1131, 1091 cm-1. H NMR (300 MHz,
CDCl3): δ 7.22 (s, 1 H), 6.48 (s, 1 H), 3.62 (t, J ) 8.6 Hz, 1 H),
2.76 (m, 2 H), 2.25 (m, 1 H), 2.10 (m, 1 H), 2.04 (s, 3 H), 1.86
(m, 3 H), 1.70-1.10 (m, 8 H), 1.02 (s, 9 H), 0.89 (s, 9 H), 0.73
(s, 3 H), 0.20 (s, 6 H), 0.03 (s, 3 H), 0.02 (s, 3 H).
2-Iod o-3,17-bis-O-(m eth oxym eth yl)estr a d iol (12). A 1.3
M solution of sec-BuLi in cyclohexane (8.6 mL, 11.2 mmol) was
added dropwise to a solution of 3,17-bis-O-(methoxymethyl)-
estradiol (11)40 (1 g, 2.8 mmol) in anhydrous THF (25 mL) at
-78 °C, and the reaction mixture was stirred at the same
temperature under argon for 2 h. A solution of iodine (2.8 g,
11.1 mmol) in dry THF (30 mL) was added to the pale yellow
solution of the anion, and the reaction mixture was slowly
raised to room temperature and stirred overnight. It was
poured into ice water (100 mL). The crude product was
extracted into ethyl acetate (3 × 30 mL), washed with a
saturated solution of Na2S2O3 (2 × 20 mL), and dried (Na2-
SO4). The removal of organic solvent followed by trituration
of the crude product with methanol (30 mL) gave the pure iodo
compound 12 as a colorless solid (1.1 g, 78%); mp 94 °C. 1H
NMR (300 MHz, CDCl3): δ 7.65 (s, 1 H), 6.78 (s, 1 H), 5.18 (s,
2-Eth yn ylestr a d iol (18). A solution of compound 16 (0.5
g, 0.95 mmol) in TBAF (1 M in THF, 9.6 mL) was stirred under
argon at room temperature for 10 h. The reaction mixture was
then poured into an ice-cold 5% aqueous sodium bicarbonate
solution (50 mL). The crude product was extracted into ethyl
acetate (2 × 50 mL), washed with brine (50 mL), and dried
(Na2SO4). Removal of solvent followed by column chromato-
graphic purification (silica gel, 230-420 mesh, 1:4 ethyl
acetate-hexane) gave compound 18 (0.115 g, 41%); mp 102-
1
104 °C. H NMR (CDCl3): δ 7.29 (s, 1 H), 6.67 (s, 1 H), 3.72
(m, 1 H), 3.40 (s, 1 H), 2.84-2.80 (m, 2 H), 2.32-1.15 (m, 13
H), 0.78 (s, 3 H). CIMS (isobutane) m/z (relative intensity) 353