Photochemical synthesis of N-arylbenzophenanthridine selective estrogen receptor modulators (SERMs)

Article abstract of DOI:10.1021/jm0101601

Selective estrogen receptor modulators are an emerging class of pharmaceutically important molecules. Many compounds in this class contain an aminoethoxyaryl moiety attached to a polycyclic framework at an asymmetric carbon atom. To assess whether this ca

Full text of DOI:10.1021/jm0101601

J . Med. Chem. 2001, 44, 2857-2860
2857
Brief Articles
P h otoch em ica l Syn th esis of N-Ar ylben zop h en a n th r id in e Selective Estr ogen
Recep tor Mod u la tor s (SERMs)
Timothy A. Grese,* M. Dee Adrian, D. Lynn Phillips, Pamela K. Shetler, Lorri L. Short,
Andrew L. Glasebrook, and Henry U. Bryant
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285
Received April 6, 2001
Selective estrogen receptor modulators are an emerging class of pharmaceutically important
molecules. Many compounds in this class contain an aminoethoxyaryl moiety attached to a
polycyclic framework at an asymmetric carbon atom. To assess whether this carbon atom can
be replaced by nitrogen, we have employed a Ninomiya enamide photocyclization for the rapid
synthesis of a novel N-arylbenzophenanthridine framework, 4. Further elaboration of 4 into a
new structural class of achiral, nonsteroidal estrogen receptor modulators is described.
In tr od u ction
Ch em istr y
Nonsteroidal compounds that interact with the es-
trogen receptor (ER) have long been investigated as
contraceptives and for the treatment of breast cancer,
uterine dysfunction, and other disorders of the female
reproductive system.1 More recently, the recognition
that some of these compounds can exert their effects in
a tissue specific manner has led to the development of
selective estrogen receptor modulators (SERMs). SERMs,
which fully antagonize the effects of estrogen on uterine
and mammary tissue while mimicking the effects of
estrogen on bone and the cardiovascular system, have
been investigated as a possible alternative to hormone
replacement therapy in postmenopausal women.2
Retrosynthetic analysis of targets 4a -d led to the
recognition of the N-aryldihydrobenzophenanthridone
8 as a key intermediate for the preparation of multiple
analogues at different oxidation states of the benzo-
phenathridine ring system (Figure 1). The key discon-
nection of the aryl substituent at the â-position of the
enamide functionality led to considerable simplification
and allowed for the convergent assembly of a variety of
precursor molecules 7a -e. Thus, O-protection of the
imine derived from 6-methoxy-1-tetralone and 4-hy-
droxyaniline, followed by acylation with benzoyl chlo-
rides 6a ,c,e, led to a variety of enamides, which could
be optionally halogenated at the â-position (Scheme 1).
Although a variety of radical- and metal-mediated
cyclization protocols were unable to effect the transfor-
mation of 7a -d to 8, photocyclization of 7e under
nonoxidative conditions8 provided 8 in 21-26% yield,
along with varying amounts of rearranged product 9.9
Solvent degassing reduced the formation of 9 substan-
tially; however, additional efforts to optimize the yield
by changing reaction conditions and solvents were
unsuccessful. The photocyclization was found to be
somewhat concentration dependent, with optimum yields
obtained at concentrations below 0.1 M.
We have recently described a novel series of highly
potent SERMs based upon tetracyclic naphtho-, benzo-
thieno-, or benzofuranobenzopyran scaffolds 1-3.3 In
each case, the required aminoalkoxyaryl side chain is
attached to the scaffold via a tertiary, asymmetric
carbon atom and the compounds were tested as racemic
mixtures. The nonplanar orientation of this side chain
is believed to be important for maintaining the observed
profile of tissue-specificity.4 We hypothesized that ni-
trogen for carbon replacement, as in N-arylbenzophenan-
thridines 4a -d , could potentially provide a similar side
chain orientation without the introduction of chirality.
Although many methods for the preparation of N-
alkylbenzophenanthridines are known,5 only a single
example of N-arylbenzophenanthridine synthesis, as an
undesired side product of an intermolecular benzyne
cycloaddition, has been described.6 Herein, we describe
the rapid synthesis of this novel framework, 4, via a
Ninomiya enamide photocyclization,7 and its further
elaboration to a new structural class of achiral, nonste-
roidal SERMs.
Conversion of 8 to target molecule 4a was effected
by sequential desilylation, Mitsunobu alkylation with
hydroxyethylpiperidine to give 10a , and phenolic de-
methylation. Alternatively, dehydrogenation of 8 with
DDQ followed by a similar reaction sequence provided
the N-arylbenzophenanthridone 4b. Reduction of 4a
with lithium aluminum hydride provided unstable 4c
in low yield. On the other hand, reduction of 10a ,b gave
the corresponding benzophenanthridine analogues 10c,d
in good yields. Demethylation of 10d then led to target
molecule 4d , which was substantially more stable than
its dihydro analogue.
* Phone: (317)276-1356. Fax: (317)276-2441. E-mail: grese@lilly.com.
10.1021/jm0101601 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/24/2001

2858 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 17
Brief Articles
F igu r e 1. Retrosynthetic analysis of N-arylbenzophenanthridine SERMs.
Sch em e 1a
a
Reagents: (a) 180 °C; (b) TBDMSCl, Et3N, CH2Cl2:THF; (c) Et3N, CH2Cl2, ∆; (d) NBS, CCl4; (e) hν, benzene; (f) HF‚pyridine, CH3CN:
CH2Cl2; (g) 1-(2-hydroxyethyl)piperidine, PPh3, DEAD, THF; (h) LAH, THF, ∆; (i) DDQ, DCE, ∆; (j) AlCl3, EtSH, CH2Cl2.
Biologica l Testin g
Resu lts a n d Discu ssion
As expected, the benzophenanthridine analogues in
which the phenolic moieties were blocked by methoxy
(10b-d ) showed relatively weak affinity for ER(MCF-7
lysate). Interestingly, the phenolic lactam analogues 4a
and 4b also demonstrated low affinity. In both series,
antagonist potency in the MCF-7 cell line roughly
paralleled binding affinity, and similar maximal efficacy
(80-90% inhibition) was observed for all active com-
pounds. The comparison of the dihydrobenzophenan-
thridine skeleton to the benzophenanthridine skeleton
was frustrated by the instability of 4c. However, for the
dimethoxy analogues, a substantial improvement in
ER binding affinities were determined by displace-
ment of bound H-17â-estradiol from MCF-7 cell lysate
3
and are reported in Table 1.10 Antagonism of estrogen
action in a mammary tumor cell line was assayed via
inhibition of MCF-7 cell proliferation stimulated by
10-11 M 17â-estradiol, and IC50 values are also included
in Table 1.11 Compound 4d was further evaluated in the
immature rat model of estrogen antagonist activity in
the uterus and in the ovariectomized rat model of tissue-
specific estrogen agonist effects on serum cholesterol
and uterine stimulation.3

Brief Articles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 17 2859
Ta ble 1. ER Binding and Inhibition of MCF-7 Cell
Proliferation by SERMs
Exp er im en ta l Section
General experimental procedures have been recently pub-
lished.13 The abbreviations THF, DMF, DCE, DMSO, DDQ,
TBAF, and DEAD refer to tetrahydrofuran, dimethylforma-
mide, 1,2-dichloroethane, dimethyl sulfoxide, 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, tetra-N-butylammonium fluoride,
and diethyl azodicarboxylate, respectively. All spectra were
recorded in acetone-d6 unless otherwise indicated. Elemental
analyses were carried out by the Physical Chemistry Depart-
ment of Lilly Research Laboratories.
6-Meth oxy-1-[(4-h yd r oxy)p h en yl]im in o-1,2,3,4-tetr a h y-
d r on a p h th a len e (5). A mixture of 6-methoxytetralone (25 g,
142 mmol) and 4-hydroxyaniline (16.3 g, 149 mmol) was heated
to 180 °C under a nitrogen stream for 2 h. After cooling to
ambient temperature, the solid mass was recrystallized from
toluene/methanol to provide 21.6 g (57%) of the title com-
pound: 1H NMR (300 MHz) δ 8.15 (d, J ) 9.7 Hz, 1H), 6.5-
7.9 (m, 6H), 3.80 (s, 3H), 2.84 (t, J ) 7.3 Hz, 2H), 2.51 (t, J )
6.8 Hz, 2H), 1.85 (m, 2H).
no.
ER RBAa,b
MCF-7 inhib. IC50 (nM)c
estradiol
1.00
0.36
0.34
0.22
NA
0.01
0.01
0.01
0.01
0.24
NAd
0.5
0.2
0.4
NA
287
19
128
NA
1
4-OH-tamoxifene
raloxifene
3
10b
10c
10d
4a
4b
4d
RBA ) relative binding affinity by competition with 3H-17â-
estradiol in MCF-7 cell lysate. b Average of at least two determina-
tions. Values are (10%. c Dose required for 50% inhibition of a
maximally effective (10-11) dose of 17â-estradiol. Average of at
a
d
least three determinations. Values are (10%. NA ) not active
at the doses tested. e 4-Hydroxytamoxifen.
6-Meth oxy-1-[N-[[4-(ter t-bu tyldim eth ylsilyl)oxy]ph en yl]-
N-(2,5-d im et h oxyb en zoyl)]a m in o-3,4-d ih yd r on a p h t h a -
len e (7e): (a ) Imine 5 (46 g, 172 mmol) was slurried in 1:1
CH2Cl2:THF (400 mL) and treated with triethylamine (52 g,
72 mL, 513 mmol) and tert-butyldimethylsilyl chloride (51.5
g, 342 mmol). The mixture was stirred overnight then diluted
with ether (1 L), filtered, and concentrated. The residue was
purified by chromatography (10:1 hexane:ethyl acetate) to give
46.3 g (71%) of the O-protected imine as a yellow foam: 1H
NMR (300 MHz, CDCl3) δ 8.32 (d, J ) 9.7 Hz, 1H), 6.86 (m,
3H), 6.73 (m, 3H), 3.92 (t, J ) 5.8 Hz, 2H), 2.57 (t, J ) 6.8 Hz,
2H), 1.96 (m, 2H), 1.05 (s, 9H), 0.26 (s, 6H).
antagonist potency was seen in going from 10c to 10d .
In both the phenolic and methoxy series, reduction of
the lactam was critical for antagonist potency. Only
compound 4d (ki ) 0.28 nM) bound ER(MCF-7 lysate)
with affinity comparable to the reference compounds
and potently inhibited MCF-7 proliferation. Preliminary
in vivo data from the immature rat model indicate that
this compound functions as a partial estrogen antago-
nist in the uterus at doses of 1 and 10 mg/kg, p.o. In
the ovariectomized rat model, 4d lowered serum cho-
lesterol at doses of 0.1-10 mg/kg, p.o., with minimal
stimulation of the uterus.
(b) The imine (46.3 g, 121 mmol) was dissolved in CH2Cl2
(400 mL), cooled to 0 °C, and treated with triethylamine (23.3
g, 32 mL, 230 mmol) followed by a solution of 2,5-dimethoxy-
benzoyl chloride (42.5 g, 212 mmol) in CH2Cl2 (100 mL),
dropwise. The mixture was warmed to reflux for 60 h, then
concentrated in vacuo. The residue was dissolved in ether (1
L), washed with brine (1 L), dried (Na2SO4), and concentrated.
Purification of the residue by chromatography (9:1-4:1 hex-
ane:ethyl acetate) provided 48.7 g of the title compound as a
white foam: 1H NMR (300 MHz, CDCl3) δ 6.4-7.6 (br m, 11H),
5.83 (br s, 1H), 3.4-3.8 (br m, 9H), 1.9-3.0 (br m, 4H), 0.95 (2
The importance of phenolic moieties for ER binding
is well documented.12 The poor affinity of the lactam
analogues in this series most likely relates to the known
preference of ER for molecules with a highly hydropho-
bic core structure.12 The addition of an electronegative
oxygen to the core benzophanthridine structure greatly
inhibits its ability to bind. Compound 4d , like tamoxifen,
demonstrates partial antagonist activity on uterine
tissue in contrast to compound 2 which appears to be a
full antagonist in this tissue and induces no uterine
stimulation in ovariectomized animals.3 We have previ-
ously postulated that the orthogonal orientation of the
side chains in raloxifene and 2 is responsible for their
tissue selectivity relative to tamoxifen, in which the side
chain is constrained to lie within the plane of the
stilbene moiety.4 Apparently, subtle changes in the
conformational properties of these molecules can induce
substantial differences in their biological properties.
Alternatively, biological oxidation of 4d could yield an
N-arylbenzophanthridinium species in which the side
chain would adopt a coplanar orientation. Further
studies to discriminate these possibilities are ongoing.
br s, 9H), 0.14 (2 br s, 6H); IR (CHCl3) 1651, 1607, 1507 cm-1
;
MS (FD) m/e 545 (M+); Anal. C32H39NO5Si: C, H, N.
2,8-Dim e t h oxy-5-[4-[(t er t -b u t yld im e t h ylsilyl)oxy]-
ph en yl]-11,12-dih ydr o-6H-ben zo[c]ph en an th r id-6-on e (8).
A solution of the product of 7e (2.73 g, 5 mmol) in benzene
(250 mL) was degassed via three freeze/pump/thaw cycles and
irradiated with a 450 W internal mercury lamp in a quartz
immersion well under nitrogen. After 22 h, the mixture was
concentrated, and the residue was purified by chromatography
(20:1 toluene:ether) to provide 675 mg (26%) of the title
compound as a yellow foam. An analytical sample was obtained
by crystallization from hexane/ether as light yellow crystals,
mp 194-95 °C: 1H NMR (300 MHz, CDCl3) δ 7.94 (d, 2.8 Hz,
1H), 7.73 (d, 8.9 Hz, 1H), 7.32 (dd, J ) 8.9, 2.8 Hz, 1H), 7.17
(d, J ) 8.7 Hz, 2H), 6.84 (d, J ) 8.7 Hz, 2H), 6.76 (d, J ) 2.6
Hz, 1H), 6.67, (d, J ) 8.8 Hz, 1H), 6.35 (dd, J ) 8.8, 2.7 Hz,
1H), 3.94 (s, 3H), 3.75 (s, 3H), 2.90 (s, 4H), 0.99 (s, 9H), 0.21
(s, 6H); MS (FD+) m/e 513 (M+); Anal. C31H35NO4Si: C, H, N.
In some runs, substantial amounts of compound 9 were also
isolated as a viscous, yellow oil: 1H NMR (300 MHz, CDCl3) δ
13.02 (s, 1H), 7.17 (d, 6.1 Hz, 1H), 6.85 (m, 5H), 6.70 (m, 3H),
3.80 (s, 9H), 2.69 (t, J ) 7.4 Hz, 2H), 2.33 (t, J ) 7.4 Hz, 2H),
0.98 (s, 9H), 0.18 (s, 6H); MS (FD) m/e 545 (M+).
2,8-Dim et h oxy-5-[4-[2-(1-p ip er id in yl)et h oxy]p h en yl]-
6H-ben zo[c]p h en a n th r id -6-on e (10b): (a ) A mixture of 8
(7.3 g, 14.2 mmol) and DDQ (2.9 g, 12.9 mmol) in DCE (10
mL) was heated at reflux for 2 h, inducing the formation of a
precipitate. The mixture was cooled to room temperature,
filtered, and concentrated. The remnant was recrystallized
from hexane:ethyl acetate to provide 6.9 g (95%) of the silylated
benzophenanrthridone as a white solid, mp 211-213 °C: 1H
NMR (300 MHz, CDCl3) δ 8.21 (d, J ) 9.0 Hz, 1H), 8.16 (d, J
In conclusion, the ability to rapidly assemble sub-
strate molecules such as 7e allowed for an efficient
synthesis of the target N-arylbenzophenanthridine scaf-
fold 8 via the Ninomya photocyclization, even though
the yield of the photocyclization was modest. The
convergent nature of the assembly of 7e bodes well for
additional analogue synthesis. A number of the com-
pounds bound ER(MCF-7 lysate) and inhibited MCF-7
cell proliferation. In particular, compound 4d demon-
strated a selective estrogen receptor modulator profile
of biological activity similar to that which has previously
been described for tamoxifen.13

2860 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 17
Brief Articles
) 8.9 Hz, 1H), 7.95 (d, J ) 2.8 Hz, 1H), 7.60 (d, J ) 8.8 Hz,
1H), 7.37 (dd, J ) 9.0, 2.8 Hz, 1H), 7.25 (d, J ) 9.7 Hz, 1H),
7.21 (d, J ) 8.7 Hz, 2H), 7.08 (d, J ) 2.7 Hz, 1H), 6.93 (d, J )
8.7 Hz, 2H), 6.66 (dd, J ) 9.7, 2.8 Hz, 1H), 3.94 (s, 3H), 3.87
(s, 3H), 1.02 (s, 9H), 0.25 (s, 6H); MS (FD) m/e 511 (M+).
6.73 (m, 5H), 3.92 (t, J ) 5.9 Hz, 2H), 2.57 (t, J ) 5.9 Hz, 2H),
2.38 (m, 4H), 1.4-1.5 (m, 4H), 1.3-1.4 (m, 2H); IR (KBr) 3560,
3490 cm-1; MS (FD+) m/e 466 (M+); Anal. C30H30N2O3‚
0.5H2O: C, H, N.
Biologica l Assa ys. Methods utilized for the ER binding,
MCF-7 proliferation, OVX rat, and immature rat assays have
been recently described.13,14
(b) The product (6.8 g, 13.3 mmol) of part a, above, was
dissolved in 1:1 acetonitrile:CH2Cl2 (200 mL) and treated with
hydrogen fluoride-pyridine (80 mL) for 1 h. The mixture was
diluted with brine (500 mL) and extracted with THF (3 × 300
mL). The combined organic layers were neutralized with
saturated NaHCO3, and the resulting aqueous layer was
washed with THF (2 × 500 mL). All aqueous layers were then
combined and washed with THF (500 mL), the combined
organic layers were dried (Na2SO4) and concentrated, and the
solid residue was washed with acetone to provide 5.27 g (100%)
of the phenol as an off-white powder, mp 310 °C: 1H NMR
(300 MHz, DMSO-d6) δ 9.79 (bs, 1H), 8.52 (d, J ) 9.0 Hz, 1H),
8.42 (d, J ) 9.0 Hz, 1H), 7.72 (m, 2H), 7.47 (dd, J ) 8.7, 2.3
Hz, 1H), 7.31 (d, 2.1 Hz, 1H), 7.21 (d, J ) 9.6 Hz, 1H), 7.07 (d,
J ) 8.4 Hz, 2H), 6.82 (d, J ) 8.3 Hz, 2H), 6.68 (dd, J ) 9.3,
2.6 Hz, 1H), 3.87 (s, 3H), 3.79 (s, 3H); MS (FD) m/e 397 (M+).
(c) A mixture of the crude product obtained above (4.8 g,
12.1 mmol), triphenylphosphine (6.3 g, 24.2 mmol), and 1-(2-
hydroxyethyl)piperidine in THF (100 mL) was treated with
DEAD (4.2 g, 24.2 mmol), and the mixture was stirred at
ambient temperature for 72 h. After concentation in vacuo,
chromatography (1:1 hexane:ethyl acetate, 5-20% methanol,
0.1% NH4OH) and recrystallization from ethyl acetate provided
5.14 g (84%) of the title compound as a white solid, mp 176
°C: 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J ) 9.1 Hz, 1H),
8.21 (d, J ) 8.8 Hz, 1H), 7.96 (d, J ) 2.8 Hz, 1H), 7.64 (d, J )
8.8 Hz, 1H), 7.40 (dd, J ) 9.0, 2.8 Hz, 1H), 7.31 (d, J ) 9.7 Hz,
1H), 7.26 (d, J ) 8.8 Hz, 2H), 7.10 (d, J ) 2.7 Hz, 1H), 6.99 (d,
J ) 8.9 Hz, 2H), 6.70 (dd, J ) 9.6, 2.7 Hz, 1H), 4.16 (t, J ) 6.0
Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 2.81 (t, J ) 6.0 hz, 2H),
2.53 (m, 4H), 1.5-1.7 (m, 4H), 1.4-1.5 (m, 2H); MS (FD) m/e
508 (M+); Anal. C32H32N2O4: C, H, N.
Su p p or tin g In for m a tion Ava ila ble: Detailed procedures
for the syntheses of compounds 4a , 4c, 10a , and 10c. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Refer en ces
(1) For a recent reviews, see: Magarian, R. A.; Overacre, L. B.;
Singh, S.; Meyer, K. L. The medicinal chemistry of nonsteroidal
antiestrogens. Curr. Med. Chem. 1994, 1, 61-104.
(2) For a recent review, see: Grese, T. A.; Dodge, J . A. Selective
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(3) Grese, T. A.; Pennington, L. D.; Sluka, J . P.; Adrian, M. D.; Cole,
H. W.; Fuson, T. R.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.;
Shetler, P. K.; Short, L. L.; Venugopalan, M.; Yang, N. N.; Sato,
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(4) Grese, T. A.; Sluka, J . P.; Bryant, H. U.; Cullinan, G, J .;
Glasebrook, A. L.; J ones, C. D.; Matsumoto, K.; Palkowitz, A.
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new access to benzo[c]phenanthridine alkaloids, synthesis of
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(8) Ninomiya, I.; Naito, T.; Ishii, H.; Ishida, T.; Ueda, M.; Harada,
K. Synthesis of dihydro-derivatives of the benzo[c]phenanthri-
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2,8-Dim et h oxy-5-[4-[2-(1-p ip er id in yl)et h oxy]p h en yl]-
6H-ben zo[c]p h en a n th r id in e (10d ). A solution of 10b (3.82
g, 7.51 mmol) in THF (250 mL) was treated with lithium
aluminum hydride (1.43 g, 37.5 mmol) resulting in a moderate
exotherm. After the exotherm ceased, the mixture was warmed
to reflux overnight, cooled to room temperature, and quenched
cautiously with ethyl acetate (200 mL) followed by 1 N NaOH
(200 mL). The layers were separated, the aqueous layer was
extracted with ethyl acetate (2 × 200 mL), and the combined
organic layers were washed with brine (200 mL), dried (Na2-
SO4), and concentrated. The residue was recrystallized from
hexane:ethyl acetate to provide 3.24 g (87%) of the title
compound as an off-white solid, mp 136-137: 1H NMR (300
MHz, CDCl3) δ 7.91 (d, J ) 8.6 Hz, 1H), 7.74 (d, J ) 8.8 Hz,
2H), 7.61 (d, J ) 8.6 Hz, 1H), 7.12 (d, J ) 2.5 Hz, 1H), 6.95
(dd, J ) 9.2, 2.6, 1H), 6.91 (dd, J ) 8.5, 2.6 Hz, 1H), 6.6-6.8
(m, 5H), 4.75 (s, 2H), 3.95 (t, J ) 6.1 Hz, 2H), 3.90 (s, 3H),
3.79 (s, 3H), 2.68 (t, J ) 6.1 Hz, 2H), 2.44 (m, 4H), 1.5-1.7
(m, 4H), 1.4-1.5 (m, 2H); MS (FD) m/e 494 (M+); Anal.
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Martin, G. R.; Dickson, R. B.; Lippman, M. E. Differential growth
and invasiveness of MCF-7 breast cancer cells by antiestrogens.
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C
32H34N2O3: C, H, N.
(12) Anstead, G. M.; Carlson, K. E.; Katzenellenbogen, J . A. The
estradiol pharmacophore: ligand structure-estrogen receptor
binding affinity relationships and a model for the receptor
binding site. Steroids 1997, 62, 268-303.
(13) Grese, T. A.; Cho, S.; Finley, D. R.; Godfrey, A. G.; J ones, C. D.;
Lugar, C. W.; Martin, M. J .; Matsumoto, K.; Pennington, L. D.;
Winter, M. A.; Adrian, M. D.; Cole, H. W.; Magee, D. E.; Phillips,
D. L.; Rowley, E. R.; Short, L. L.; Glasebrook, A. L.; Bryant, H.
U. Structure-activity relationships of selective estrogen receptor
modulators: modifications to the 2-arylbenzothiophene core of
raloxifene. J . Med. Chem. 1997, 40, 146-167.
(14) Palkowitz, A. D.; Glasebrook, A. L.; Thrasher, K. J .; Hauser, K.
L.; Short, L. L.; Phillips, D. L.; Muehl, B. S.; Sato, M.; Shetler,
P. K.; Cullinan, G. J .; Pell, T. R.; Bryant, H. U. Discovery and
synthesis of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-
2-(4-hydroxyphenyl)]benzo[b]thiophene: A novel, highly potent,
selective estrogen receptor modulator. J . Med. Chem. 1997, 10,
11407-1416.
2,8-Dih yd r oxy-5-[4-[2-(1-p ip er id in yl)et h oxy]p h en yl]-
6H-ben zo[c]p h en a n th r id in e (4d ). A solution of 10d (3.2 g,
6.4 mmol) in CH2Cl2 (150 mL) was treated with ethanethiol
(3.2 g, 3.6 mL, 51 mmol) and aluminum chloride (5.1 g, 38.2
mmol). After being stirred for 4 h at ambient temperature,
the mixture was quenched carefully with THF (150 mL) and
saturated NaHCO3 (150 mL). The layers were separated, the
aqueous layer was extracted with THF (150 mL), and the
combined organic layers were dried (Na2SO4) and concen-
trated. The residue was purified by chromatography (1:1
hexane:ethyl acetate, 10-20% methanol, 0.1% NH4OH) and
then recrystallized from methanol to provide 2.7 g (90%) of
the title compound as an off-white powder, mp 260-270 °C:
1H NMR (300 MHz, DMF-d7) δ 9.92 (br s, 1H), 9.74 (br s, 1H),
7.99 (d, J ) 8.8 Hz, 1H), 7.78 (d, J ) 8.5 Hz, 1H), 7.69 (d, J )
9.0 Hz, 1H), 7.63 (d, J ) 8.7 Hz, 1H), 7.23 (d, J ) 2.0 Hz, 1H),
6.98 (dd, J ) 9.0, 2.1 Hz, 1H), 6.84 (dd, J ) 8.4, 2.1 Hz, 1H),
J M0101601