J. M. Schmidt et al. / Bioorg. Med. Chem. 11 (2003) 1389–1396
1395
33.7 g (74.8%) of 6. 1H NMR (400 MHz, DMSO-d6) dH
1.34 (3H, d, CH3), 3.83 (3H, s, OCH3), 4.76 (1H, q,
CH), 6.67–7.96 (8H, ArH), 9.31 (1H, s, OH).
NCH2CH2), 2.78 (4H, m, NCH2CH2), 3.02 (2H, m,
NCH2CH2O), 4.03 (2H, t, OCH2), 6.42–7.87 (14H,
ArH), 9.19 (1H, br s, OH), 9.75 (1H, br s, OH).
1-(4-Methoxyphenyl)-2-(4-(2-chloroethoxy)phenyl)-1-pro-
panone (7a). Compound 6 (4.0 g, 15.6 mmol) was
dissolved in 1,2-dichloroethane (25 mL). Tetra-
butylammonium hydrogen sulfate (0.24 g, 0.7 mmol)
and 3M NaOH (20 mL) were added and the reaction
was refluxed for 21 h. The mixture was then extracted
with Et2O (2ꢃ30 mL) and washed with 1 M HCl (30
mL), and H2O (2ꢃ30 mL). The crude product was
chromatographed on silica gel with hexane/ethyl acetate
An alternative method useful for the preparation of
(E/Z)-9b is described below.
1-(4-Methoxyphenyl)-2-(4-(2-pyrrolidin-1-yl-ethoxy)-
phenyl)-1-propanone (7b). Compound 6 (7.2 g, 28
mmol) and K2CO3 (9.5 g, 69 mmol) were added to
DMF (50 mL) and heated to 100 ꢁC under Ar. 1-(2-
Chloroethyl)pyrrolidine hydrochloride (5.7 g, 33 mmol)
was added in portions over 10 min and the reaction
maintained at 100 ꢁC for 1.5 h. After cooling, the reac-
tion was filtered and the DMF removed from the filtrate
by evaporation. The residue was extracted with ethyl
acetate (2ꢃ100 mL) and added to the oil concentrated
from the filtrate, washed with brine and the solvent
evaporated. The crude product was chromatographed
on silica gel using 7% CH3OH/CH2Cl2 to yield 7.4 g
1
(5:1) to give 3.8 g (77%) 7a as a brown oil. H NMR
(400 MHz, CDCl3) dH 1.52 (3H, d, CH3), 3.80 (2H, m,
ClCH2), 3.85 (3H, s, OCH3), 4.20 (2H, t, CH2O), 4.63
(1H, q, CH), 6.88–7.97 (8H, ArH).
(E)-1-(4-Methoxyphenyl)-2-(4-(2-chloroethoxy)phenyl)-
1-(6-methoxynaphthalen-1-yl)propene (E-8a). 1-Iodo-6-
methoxy-naphthalene22 (3.8 g, 11.9 mmol) and n-butyl
lithium (7.8 mL, 12.5 mmol) were mixed in THF (50
mL) at ꢀ78 ꢁC. To this mixture was added 7a (3.38 g,
11.9 mmol) in THF (40 mL) was added and the mixture
stirred at ꢀ78 ꢁC for 2 h then at room temperature for
19 h. The reaction was quenched with saturated NH4Cl
(10 mL), washed with brine (60 mL) and water (2ꢃ60
mL). The crude product was chromatographed on silica
gel with hexane/ethyl acetate (10:1) to give 1.28 g
(23.4%) of (E)-8a as a white solid and 0.95 g (17.4%) of
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(75%) of 7b. H NMR (400 MHz, DMSO-d6) dH 1.36
(3H, d, CH3), 1.67 (4H, m NCH2CH2), 2.51 (4H, m
NCH2CH2), 2.76 (2H, t, NCH2CH2O), 3.81 (3H, s,
OCH3), 4.00 (2H, t, NCH2CH2O), 4.85 (1H, q, CH),
6.85–7.97 (8H, ArH).
(E/Z)-1-(4-Methoxyphenyl)-2-(4-(2-pyrrolidin-1-yl-
ethoxy)phenyl) - 1 - (6 - methoxynaphthalen - 1 - yl)propene
(E/Z-8b). 1-Iodo-6-methoxy-naphthalene (4.0 g, 14.2
mmol) and n-butyl lithium (0.9 g, 14.1 mmol) were
mixed in THF (20 mL) at ꢀ78 ꢁC. To this was added 7b
(5.0 g, 14.1 mmol) dissolved in THF (25 mL) and the
mixture stirred at ꢀ78 ꢁC for 1.5 h then at room tem-
perature for 5 days. The crude product was mixed with
30% HCl (20 mL) in ethanol (60 mL) and refluxed for 3
h to give 2.76 g (40%) of 8b as a mixture of E and Z
isomers. 1H NMR (400 MHz, CDCl3) dH (E)-Isomer
1.87 (3H, s, CH3), 1.89 (4H, m, NCH2CH2), 2.77 (4H,
m, NCH2CH2), 3.00 (2H, m, NCH2CH2O), 3.77 (3H, s,
OCH3), 3.96 (3H, s, OCH3), 4.18 (2H, t, OCH2), 6.56–
8.01 (14H, ArH). (Z)-isomer 1.87 (4H, m, NCH2CH2),
2.34 (3H, s, CH3), 2.72 (4H, m, NCH2CH2), 2.91 (2H,
m, NCH2CH2O), 3.80 (3H, s, OCH3), 3.89 (3H, s,
OCH3), 4.02 (2H, t, OCH2), 6.52–7.91 (14H, ArH).
1
a mixture of (E/Z)-8a. H NMR (400 MHz, CDCl3) dH
(E)-isomer 1.88 (3H, s, CH3), 3.71 (3H, s, OCH3), 3.85
(2H, t, ClCH2), 3.97 (3H, s, OCH3), 4.25 (2H, t, OCH2),
6.57–8.01 (14H, ArH). (Z)-isomer 2.35 (3H, s, CH3),
3.71(2H, t, ClCH2), 3.80 (3H, s, OCH3), 3.90 (3H, s,
OCH3), 4.07 (2H, t, OCH2), 6.52–7.91 (14H, ArH).
(E)-1-(4-Hydroxyphenyl)-2-(4-(2-chloroethoxy)phenyl)-1-
(6-hydroxynaphthalen-1-yl)propene (E-9a). The E/Z-8a
mixture (0.59 g, 1.3 mmol) was dissolved in CH2Cl2 (50
m) and cooled to ꢀ78 ꢁC under Ar. BBr3 in CH2Cl2
(1.0 M, 17.5 mL, 17.5 mmol) was slowly added to the
solution at ꢀ78 ꢁC under Ar. The reaction was stirred at
room temperature for 15 h and treated with water (5
mL). The aqueous layer was extracted with CH2Cl2
(2ꢃ30 mL), washed with 20% NaHCO3 and water (30
mL). The crude product was chromatographed on silica
gel with 3% MeOH/CH2Cl2) to give 0.07 g of (E)-9a
and 0.27 g of a mixture of (E/Z)-9a. 1H NMR
(400 MHz, CDCl3) dH (E)-isomer 1.88 (3H, s, CH3),
3.85 (2H, t, ClCH2), 4.25 (2H, t, OCH2), 6.49–8.00
(14H, ArH). (Z)-isomer 2.34 (3H, s, CH3), 3.72 (2H, t,
ClCH2), 4.06 (2H, t, OCH2), 6.52–7.90 (14H, ArH).
(E/Z)-1-(4-Hydroxyphenyl)-2-(4-(2-pyrrolidin-1-yl-
ethoxy)phenyl)-1-(6-hydroxynaphthalen-1-yl)propene (E/
Z-9b). The mixture of (E/Z)-8b (2.5 g, 5.0 mmol) was
dissolved in CH2Cl2 (200 mL) and cooled to ꢀ78 ꢁC
under Ar. BBr3 (8 mL, 79.8 mmol) was diluted with
CH2Cl2 and added slowly at ꢀ78 ꢁC under Ar. The
reaction was stirred at room temperature overnight and
then treated with water (250 mL). The crude product
was chromatographed on silica gel using 7% CH3OH/
CH2Cl2 to yield 2.0 g (72%) of 9b as a mixture of E and
Z isomers.
(E)-1-(4-Hydroxyphenyl)-2-(4-(2-(1-pyrrolidinyl)ethoxy)-
phenyl)-1-(6-hydroxynaphthalen-1-yl)propene
(E-9b).
(E)-9a (54 mg, 0.125 mmol) was dissolved in ethanol (2
mL) and mixed with of pyrrolidine (0.5 mL). The mix-
ture was sealed and heated to 105 ꢁC under stirring for
15 h. The solvents were removed and the residue
chromatographed on silica gel with 7% MeOH/CH2Cl2)
to give 40 mg (68%) of (E)-9b. H NMR (400 MHz,
DMSO-d6) dH 1.76 (3H, s, CH3), 1.86 (4H, m,
Computational docking
ERa co-crystallyzed with the antagonist raloxifene, was
taken from the PDB (1ERR) and after the removal of
raloxifene, the cis and trans isomers of neutral and pro-
tonated 9b were rigidly docked into the pocket using
1