Simple and Efficient Production of (Z)-4-Hydroxytamoxifen, a Potent Estrogen Receptor Modulator

Article abstract of DOI:10.1021/jo035164n

A McMurry coupling reaction and selective crystallization were used to develop a simple and efficient two-step synthesis of (Z)-4-hydroxytamoxifen (2a). This compound is an active metabolite of tamoxifen, a selective estrogen receptor (ER) modulator widely used to treat breast cancer. The synthesis employed 1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene (1) as a useful building block.

Full text of DOI:10.1021/jo035164n

Sim p le a n d Efficien t P r od u ction of
Z)-4-Hyd r oxyta m oxifen , a P oten t Estr ogen
Recep tor Mod u la tor
(
Donna D. Yu and Barry M. Forman*
Division of Molecular Medicine, The Beckman Research
Institute, The City of Hope National Medical Center, The
Gonda Diabetes & Genetic Research Center, Duarte,
California 91010
bmforman@earthlink.net
Received August 7, 2003
Abstr a ct: A McMurry coupling reaction and selective
crystallization were used to develop a simple and efficient
two-step synthesis of (Z)-4-hydroxytamoxifen (2a ). This
compound is an active metabolite of tamoxifen, a selective
estrogen receptor (ER) modulator widely used to treat breast
cancer. The synthesis employed 1,1-bis(4-hydroxyphenyl)-
F IGURE 1. Chemical structures of (Z)-tamoxifen, (Z)-4-
hydroxytamoxifen, and E .
2
SCHEME 1
2
-phenylbut-1-ene (1) as a useful building block.
1
Estrogen receptors (ER) are members of the super-
family of ligand-modulated nuclear receptors that medi-
ate the actions of steroid hormones, vitamin D, retinoids,
and thyroid hormones. ER is activated in vivo when
bound by naturally occurring estrogens such as 17â-
2
estradiol (E ) (Figure 1). Ligand binding results in a
conformation change that alters the transcriptional
activities of ER. This in turn leads to specific changes
in the activity of gene networks that regulate the female
reproductive system, bone mineral density, lipid homeo-
stasis, central nervous system, and cardiovascular func-
tion.2
7
higher affinity than tamoxifen. Only the Z isomer has
the required antiestrogenic activity; the (E)-4-hydroxy-
2
8
tamoxifen has only about 5% of its affinity for the ER.
Since (Z)-4-hydroxytamoxifen readily equilibrates into a
Z/E mixture, there is considerable need for the discovery
of a straightforward synthesis that produces high yields
8
In addition to regulating these physiological processes,
estrogen also plays a central role in stimulating breast
cancer growth. Therefore, the use of estrogen for its
positive physiological effects can result in deleterious side
of the pure Z isomer without loss by isomerization.
We reviewed numerous synthetic strategies including
stereoselective syntheses of tamoxifen and 4-hydroxy-
tamoxifen.9 Gust and co-workers synthesized 1,1-bis-
-14
7
3
effects. As a result, there is considerable interest in the
(
4-hydroxyphenyl)-2-phenylalkene analogues. The pub-
therapeutic profile of a unique class of drugs known as
selective ER modulators (SERMs).4 These drugs are
useful because they can prevent breast cancer growth by
acting as ER antagonists in the breast while maintaining
the therapeutic property of agonists in other tissues.
lished methods for the preparation of these compounds,
including 1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene (1),
are long and proceed in five steps7 starting with 1-(4-
methoxyphenyl)-2-phenylethan-1-one which is obtained
by a Friedel-Crafts acylation of phenylacetyl chloride
and anisole. The products were reacted with the ap-
propriate alkyl bromides under the influence of potas-
,5
,15
(
Z)-Tamoxifen ((Z)-2-[4-(1,2-diphenyl-1-butenyl)phe-
noxy]-N,N-dimethylethanamine) (Figure 1) is a first-
generation SERM that is currently approved by the Food
and Drug Administration and is widely used to treat
6
(7) Lubczyk, V.; Bachmann, H.; Gust, R. J . Med. Chem. 2002, 45,
estrogen-dependent breast cancers. An active metabolite
5
358.
8) Robertson, D. W.; Katzenellenbogen, J . A.; Long, D, J .; Rorke,
E. A.; Katzenellenbogen, B. S. J . Steroid Biochem. 1982, 16, 1.
of (Z)-tamoxifen is (Z)-4-hydroxytamoxifen ((Z)-1-[4-(2-
dimethylaminoethoxy)phenyl)]-1-(4-hydroxyphenyl)-2-
phenylbut-1-ene (Figure 1), which binds to ER with 8-fold
(
(
(
9) Al-Hassan, M. I. Synth. Commun. 1989, 19, 1619.
10) Gauthier, S.; Mailhot, J .; Labrie, F. J . Org. Chem. 1996, 61,
3
890.
(11) Detsi, A.; Koufaki, M.; Calogeropoulou, T. J . Org. Chem. 2002,
67, 4608.
(12) McCague, R. J . Chem. Res., Synop. 1986, 58.
(
1) Karnik, P. S.; Kulkarni, S.; Liu, X. P.; Budd, G. T.; Bukowski,
R. M. Cancer Res. 1994, 54, 349.
(
(
2) McCague, R.; Leclercq, G. J . Med. Chem. 1987, 30, 1761.
3) Cancer Facts and Figures; American Cancer Society: New York,
(13) Foster, A. B.; J arman, M.; Leung, O. T.; McCague, R.; Leclercq,
G.; Devleeschouwer, N. J . Med. Chem. 1985, 28, 1491.
(14) Olier-Reuchet, C.; Aitken, D. J .; Bucourt, R.; Husson, H, P.
Tetrahedron Lett. 1995, 36, 8221.
1
997.
(
95, 2380.
4) Katzenellenbogen, B. S.; Katzenellenbogen, J . A. Science 2002,
2
(
(
5) Shang, Y.; Myles, B. Science 2002, 295, 2465.
6) J ordan, V. C. J . Med. Chem. 2003, 46, 883.
(15) Dodds, E. C.; Golberg, L.; Lawson, W.; Robinson, R. Proc. R.
Soc. London Ser. B 1939, 127, 140.
1
0.1021/jo035164n CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/30/2003
J . Org. Chem. 2003, 68, 9489-9491
9489

SCHEME 2
sium tert-butyl alcoholate to obtain the C2-alkyl-substi-
tuted intermediates. These intermediates were reacted
with 4-methoxyphenylmagnesium bromide by the Grig-
nard reaction to yield the corresponding carbinols, which
were dehydrated by either phosphoric acid or hydrobro-
mic acid in THF. The methoxy groups were then con-
verted to hydroxyls substituted on the benzene rings with
In Scheme 2, we couple 1 directly with 2-(dimethyl-
amino)ethyl chloride hydrochloride using a known
method10 and obtain an equimolar mixture of the geo-
metrical isomers of 4-hydroxytamoxifen (2). In previous
strategies for the synthesis of 4-hydroxytamoxifen, sepa-
ration of the isomers was a difficult task involving
preparative TLC or HPLC. We explored the possibility
of using selective crystallization to simplify the separa-
tion. Several solvents were tested including methanol,
ethanol, 2-propanol, butanol, pentanol, and ethyl acetate.
We were ultimately able to separate the geometric
isomers as follows: (Z)-4-hydroxytamoxifen was crystal-
lized from hexanol (49% yield) and (E)-4-hydroxytamox-
ifen from methanol (41% yield). The geometry of (Z)-4-
BBr
alkenes.
The McMurry reaction has been used by several groups
as a key step in the stereoselective synthesis of (Z)-4-
3
to afford the 1,1-bis(4-hydroxyphenyl)-2-phenyl-
hydroxytamoxifen.1
0,11
This reaction is a version of tita-
-Zn
nium-mediated reductive coupling in which TiCl
4
serves as the reductant to completely remove oxygen with
the formation of an alkene.16 Gauthier et al. used the
McMurry reaction as the main step in their synthesis of
10
hydroxytamoxifen and (E)-4-hydroxytamoxifen was
1
confirmed by H NMR using CD
3
OD as a solvent. (Z)-4-
(
Z)-4-hydroxytamoxifen. They made the monopivaloate
Hydroxytamoxifen has upfield NMR signals of the 2-dim-
ethylaminoethoxy chain protons compared to the corre-
derivative of 4,4′-dihydroxybenzophenone and reacted it
with propiophenone under McMurry reaction conditions
to produce a 14:1 E/Z ratio in favor of the desired
triarylethylene. The unprotected phenol was then alkyl-
ated and the pivaloyl ester was removed as the final step.
More recently, Calogeroupoulou et al.11 employed benzyl
monoprotected 4,4′-dihydroxybenzophenone to couple
with propiophenone under McMurry conditions. The
resulting two isomeric triarylethylenes were converted
to corresponding perfluorotolyl ethers, which were sepa-
rated. These protective groups were then removed by
sodium methoxide in DMF, and the final step was a mild
debenzylation without E/Z isomerization.
We wanted to develop a more efficient procedure for
the synthesis of (Z)-4-hydroxytamoxifen by minimizing
the number of steps requiring protection groups. To do
so, we utilized 1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-
ene (1) as an efficient synthetic precursor and we
improved the yield of this precursor from inexpensive
starting materials. The successful synthetic route is
shown in Schemes 1 and 2.
sponding (E)-4-hydroxytamoxifen.10 Interestingly, if CDCl
3
is used as a solvent, the samples undergo a facile
isomerization to a mixture of (Z/E)-4-hydroxytamoxifen.
Presumably, the isomerization is caused by acid catalysis
or by a bimolecular oxidative-reductive reaction that
might result in a single bond rotation.1
7-19
Further
studies are required to confirm the mechanism underly-
ing this observation.
In summary, the above one-pot synthesis of 1,1-bis(4-
hydroxyphenyl)-2-phenylbut-1-ene (1) by the McMurry
reaction and coupling with 2-(dimethylamino)ethyl chlo-
ride hydrochloride gave a 1:1 Z/E ratio of 4-hydroxyta-
moxifen and the Z- and E-isomers were effectively
separated by selective crystallization. Thus, our novel
strategy allows for the efficient production of (Z)-4-
hydroxytamoxifen with two simple synthetic steps fol-
lowed by crystallization. While many other approaches
to 4-hydroxytamoxifen have been reported, our procedure
offers a simpler pathway suitable for large-scale indus-
trial production.
Scheme 1 consists of a McMurry reductive coupling
between 4,4′-dihydroxybenzophenone and propiophenone
in the presence of zinc and titanium tetrachloride in dry
THF under reflux conditions. This results in 91% yield
of 1,1-bis(4-hydroxyphenyl)-2-phenylbut-ene (1) in a small-
scale (0.5 g) synthesis. The same reaction expanded to a
Exp er im en ta l Section
Gen er a l P r oced u r es. Organic reagents were purchased from
commercial suppliers unless otherwise noted and were used
(17) Katzenellenbogen, J . A.; Carlson, K. E.; Katzenellenbogen B.
S. J . Steroid Biochem. 1985, 22, 589.
4
-g scale resulted in an 87% yield.
(18) Airy, S. C.; Sinsheimer, J . E. Steroids. 1981, 38, 593.
(
19) Winkler V. W.; Nyman, M. A.; Egan, R. S. Steroids. 1971, 17,
(16) McMurry, J . E.; Fleming, M. P. J . Org. Chem. 1976, 41, 896.
197.
9
490 J . Org. Chem., Vol. 68, No. 24, 2003

without further purification. All solvents were analytical or
reagent grade. All reactions were carried out in flame-dried
glassware under argon or nitrogen. Melting points were deter-
mined and reported automatically by an optoelectronic sensor
lamino)ethyl chloride hydrochloride (0.75 g, 0.005 mol) in a small
portion over a 15 min period and stirred for 1.5 h. After being
cooled to rt, the reaction mixture was poured into saturated
ammonium chloride (10 mL) and extracted with ethyl acetate
(4 × 10 mL). The combined organic phase was washed with brine
(4 × 10 mL), dried, and concentrated in vacuo. Flash chroma-
1
13
in open capillary tubes and were uncorrected. H NMR and
NMR spectra were measured at 500 and 125 MHz, respectively,
using CDCl or CD OD as the solvents and tetramethylsilane
Me Si) as the internal standard. Liquid column chromatography
C
3
3
2 2
tography (9:1 CH Cl /MeOH) afforded 2 (0.35 g, 64%); triturating
(
4
(petroleum ether-diethyl ether) afforded 2 as a white solid: mp
1
was carried out under moderate pressure by using columns of
an appropriate size packed and eluted with appropriate eluents.
All reactions were monitored by TLC on precoated plates (silica
gel HLF). TLC spots were visualized either by exposure to iodine
vapors or by irradiation with UV light. Organic solvents were
removed in a vacuum by rotary evaporator. Elemental analyses
were performed by Desert Analytics, Tucson, AZ.
143.3 °C, as a 1:1 mixture of (E)-2b/(Z)-2a isomers; H NMR
(CDCl ) δ 7.06-7.15 (m, 7H), 6.80 (d, 2H), 6.69 (d, 2H), 6.35 (d,
3
2H), 4.07 (t, 1H), 3.91 (t, 1H), 2.79 (t, 1H), 2.69 (t, 1H), 2.49 (q,
2H), 2.38 (s, 3H), 2.33 (s, 3H), 0.89 (t, 3H).
(Z)-1-[4-(2-Dim et h yla m in oet h oxy)p h en yl]-1-(4-h yd r ox-
yph en yl)-2-ph en ylbu t-1-en e ((Z)-4-Hydr oxytam oxifen ) (2a).
Crystallization of the white solid (2) with a 1:1 Z/E ratio (10
1
,1-Bis(4-h yd r oxyp h en yl)-2-p h en ylbu t-1-en e (1). To a
stirred suspension of zinc powder (2.0 g, 0.031 mol) in dry THF
20 mL) was added dropwise TiCl (1.5 mL, 0.014 mol) under
mg) from warm hexanol (0.1 mL) gave white crystals (2a ) (4.9
mg): mp 143.6 °C (lit.10 mp140-143 °C); H NMR (CD
1
OD) δ
3
(
4
7.08-7.01 (m, 5H), 7.02 (d, 2H), 6.96 (d, 2H), 6.71(d, 2H), 6.52
Ar, at -10 °C. When the addition was complete, the mixture
was warmed to room temperature and then refluxed for 2 h. To
the cooled suspension of the titanium reagent was added a
solution of 4,4′-hydroxybenzophenone (0.5 g, 0.0023 mol) and
propiophenone (1.0 g, 0.0074 mol) in dry THF (40 mL) at 0 °C,
and the mixture was refluxed in the dark for 2 h. After being
cooled to rt, the reaction mixture was quenched with 10%
aqueous potassium carbonate (30 mL) and extracted with EtOAc.
The organic layer was washed with brine, dried over MgSO ,
4
and concentrated in vacuo. Flash column chromatography (8:2
hexanes/EtOAc) afforded 1 (0.66 g, 91%) as a white solid: mp
00.6 °C; H NMR (CDCl
.75 (d, 2H), 6.49 (d, 2H), 4.65 (s, 1H), 4.43 (s, 1H), 2.49 (q, 2H),
.92 (t, 3H); C NMR (CDCl
36.0, 135.6, 132.6, 131.2, 130.5, 128.6, 126.0, 115.7, 115.0, 29.5,
3.8. Anal. Calcd for C22
3.23; H, 6.58.
(d, 2H), 3.91 (t, 2H), 2.66 (t, 2H), 2.44 (q, 2H), 2.25 (s, 6H), 0.87
(t, 3H); 13C NMR (CD
OD) δ 156.5, 155.4, 142.6, 139.7, 137.9,
136.0, 133.0, 131.6, 130.9, 128.8, 126.9,114.3, 64.5, 59.1, 45.7,
29.8, 13.8. Anal. Calcd for C26 : C, 80.59; H, 7.54; N, 3.61.
Found: C, 80.63; H, 7.52; N, 3.44.
3
H
29NO
2
(E)-1-[4-(2-Dim et h yla m in oet h oxy)p h en yl]-1-(4-h yd r ox-
yph en yl)-2-ph en ylbu t-1-en e ((E)-4-Hydr oxytam oxifen ) (2b).
Crystallization of the white solid (2) with a 1:1 Z/E ratio (10
mg) from warm methanol (0.1 mL) gave white crystals (2b) (4.1
mg): mp 157.8 °C (lit.10 mp155-157°C); 1H NMR (CD
OD) δ
3
7.08-7.05 (m, 7H), 6.89 (d, 2H), 6.58 (d, 2H), 6.35 (d, 2H), 4.07
1
13
2
6
0
1
1
8
3
) δ 7.17-7.10 (m, 7H), 6.86 (d, 2H),
(t, 2H), 2.75 (t, 2H), 2.42 (q, 2H), 2.32 (s, 6H), 0.85 (t, 3H);
NMR (CD OD) δ 158.9, 156.4, 144.1, 141.8, 139.7, 137.9, 135.9,
133.0, 131.6, 130.8, 128.8, 126.9, 115.1, 66.6, 59.1, 45.8, 29.8,
13.9. Anal. Calcd for C26 : C, 80.59; H, 7.54; N, 3.61.
Found: C, 80.90; H, 7.55; N, 3.87.
C
3
1
3
3
) δ 157.0, 156.2, 143.8, 141.0, 139.5,
H
29NO
2
20 2
H O : C, 83.51; H, 6.37. Found: C,
(
E,Z)- 1-[4-(2-Dim eth ylam in oeth oxy)ph en yl]-1-(4-h ydr ox-
Ack n ow led gm en t. We thank Michael Ho for tech-
1
3
yp h en yl)-2-p h en ylbu t-1-en e ((E,Z)-4-Hyd r oxyta m oxifen )
nical assistance, Weidong Hu for the C NMR experi-
ments, J ohn Termini for critical review, and the Gonda
family for support and encouragement.
(
(
(
2). A solution of 1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene (1)
0.45 g, 0.0014 mol) in DMF (5 mL) was treated with Cs CO
1.06 g, 0.0033 mol) and heated in an oil bath at 70-80 °C for
0 min. The resulting suspension was treated with 2-(dimethy-
2
3
1
J O035164N
J . Org. Chem, Vol. 68, No. 24, 2003 9491