Wittig-Horner approach for the synthesis of tamoxifen

Article abstract of DOI:10.1080/00397910500290516

A stereoselective synthesis of Z-tamoxifen, a tetra-substituted alkene with antiestrogenic activity, is described. The Wittig-Horner reaction has been employed as the key step to establish the olefin stereochemistry. Copyright Taylor & Francis, Inc.

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Wittig–Horner Approach for the
Synthesis of Tamoxifen
Rajesh K. Pandey a , R. D. Wakharkar a & Pradeep
Kumar a
a Division of Organic Chemistry: Technology ,
National Chemical Laboratory , Pune, India
Published online: 22 Aug 2006.
To cite this article: Rajesh K. Pandey , R. D. Wakharkar & Pradeep Kumar (2005)
Wittig–Horner Approach for the Synthesis of Tamoxifen, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:21,
2795-2800
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Synthetic Communicationsw, 35: 2795–2800, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500290516
Wittig–Horner Approach for the
Synthesis of Tamoxifen
Rajesh K. Pandey, R. D. Wakharkar, and Pradeep Kumar
Division of Organic Chemistry: Technology, National Chemical
Laboratory, Pune, India
Abstract: A stereoselective synthesis of Z-tamoxifen, a tetra-substituted alkene with
antiestrogenic activity, is described. The Wittig–Horner reaction has been employed
as the key step to establish the olefin stereochemistry.
Keywords: Anticancer drug, phosphonate, stereoselectivity, tamoxifen, Wittig–
Horner reaction
INTRODUCTION
(Z)-Tamoxifen[1,2] (ICI-46,474, Nolvadex), a clinically useful triaryl ethylene,
is a synthetic antiestrogenic drug that elicits varied endrogenic effects (Fig. 1).
It is a powerful nonsteroidal agonist, useful for the treatment of hormone-
responsive human metastatic breast cancer as well as uterine, ovarian, and
prostatic neoplasm.[3] Tamoxifen first synthesized[1] in 1966 by Harper
et al., resulted in a mixture of E- and Z-isomers. The E-tamoxifen, usually
referred to as cis-tamoxifen (ICI-47, 699) 2, has no clinical uses and is an
estrogen agonist.
A variety of methods for the synthesis of this drug have been reported in
the literature.[4] Because majority of the synthetic approaches to tamoxifen
have been nonstereospecific, producing a mixture of Z- and E-isomers,
an efficient and highly stereospecific synthesis of this drug is still desirable.
As a part of our research interest in developing methodologies using
Received in India May 30, 2005
Address correspondence to Pradeep Kumar, Division of Organic Chemistry:
Technology, National Chemical Laboratory, Pune 411008, India. Fax: 0091-20-
25893614; E-mail: pk.tripathi@ncl.res.in
2795

2796
R. K. Pandey, R. D. Wakharkar, and P. Kumar
Figure 1. Structure of Z-tamoxifen 1 and E-tamoxifen 2.
phosphorus ylides and their subsequent application to biologically useful
compounds,[5] we became interested in developing a new and convenient
route for the synthesis of Z-tamoxifen. A recent report by Ando[6] about the
highly selective synthesis of Z-olefin using a variety of o-substituted aryl
phosphonates as a Horner–Emmons reagent prompted us to use this methodo-
logy for the stereoselective synthesis of Z-tamoxifen. We herein report the
synthesis of Z-tamoxifen using this protocol. The details of synthetic
strategy are depicted in Schemes 1 and 2.
RESULTS AND DISCUSSION
The synthesis began with the synthesis of starting materials for phosphonate 7,
one of the precursors of the Wittig–Horner reaction. Thus, 1-phenyl-1-
propanol 3 was treated with PBr3 in dichloromethane at room temperature
Scheme 1. Reagents and conditions: (a) PBr3, CH2Cl2, rt, overnight (95%); (b) rt to
reflux (95%); (c) i. 4, 130 8C, 5 days, ii 20% NaOH solution (45%); (d) Na, EtOH,
.
(CH3)2NCH2CH2Cl HCl, reflux, 24 h (90%).

Tamoxifen Synthesis
2797
Scheme 2. Reagents and conditions: (a) base, THF, 278 8C, 24 h (40%).
to give 1-bromo-1-phenylpropane 4 in 95% yield.[7] Another component for
the phosphonate 7 was prepared from o-cresol 5 which was treated with
PCl3 under reflux condition to give tritolylphosphite 6 in excellent yield.
The phosphite 6 on treatment with bromo compound 4 at 1308C for five
days afforded the corresponding adduct, which, on hydrolysis with aqueous
sodium hydroxide, furnished the desired phosphonate 7 in 45% yield
(Scheme 1). The ketone 9, another precursor for the Wittig–Horner
reaction, was prepared by the protection of hydroxyl group of
4-hydroxybenzophenone 8 using 2-(N,N-dimethylamino)ethyl chloride hydro-
chloride in the presence of sodium ethoxide to give [4-(2-dimethylamino-
ethoxy)-phenyl]-phenyl-methanone 9 in 90% yield.
The synthesis of Z-tamoxifen 1 was carried out employing the
Wittig–Horner reaction between ketone 9 and phosphonate 7 in the
presence of n-BuLi or NaHMDS at 2788C as shown in Scheme 2.
The product thus obtained was a mixture of Z- and E-isomer (7:3), and the
major product after separation by column chromatography was characterized
as the desired Z-tamoxifen. This reaction did not go to completion
and afforded only a low yield of the desired product (28%), probably
because of the poor reactivity of ketone in the reaction. However, the
starting material could be recovered and reused. The structure of
Z-tamoxifen was confirmed by comparing the physical and spectroscopic
data with the literature.[4c]
EXPERIMENTAL
Solvents were purified and dried by standard procedures before use; petroleum
ether of boiling range 60–80 8C was used. Infrared spectra were recor-
ded on ATI Mattson RS-1 FT-IR spectrometer. 1H NMR spectra were
recorded on a Bruker AC-200 spectrometer. The chemical shifts were
expressed in ppm (d) downfield from TMS with residual CDCl3 (d 7.27) as
internal standard. Mass spectra were obtained with TSQ 70, Finningen
MAT mass spectrometer.

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R. K. Pandey, R. D. Wakharkar, and P. Kumar
Synthesis of (1-Phenylpropyl)phosphonic Acid di-o-Tolyl Ester 7
A mixture of o-cresol 5 (20 g, 195.18 mmol) and PCl3 (8.10 g, 59.14 mmol)
was slowly heated to 1808C. When temperature became constant and
evolution of HCl was very slow (after 10 h), the excess o-cresol
was distilled out at reduced pressure and tritolyl phosphite (19.77 gm)
6 was obtained at 2008C at 0.10-mm pressure with 95% yield. Tritolyl
phosphite-1-phenyl-1-bromopropane adduct was formed by heating a
mixture of tritolyl phosphite
6 (10 g, 28.4 mmol) and 1-bromo-1-
phenylpropane 4 (5.65 g, 28.4 mmol) at 1308C for five days. Hydrolysis
of the adduct with 20% aqueous NaOH at room temperature, followed by
extraction with ethyl acetate and drying of the organic layer over
Na2SO4, afforded the crude product. Silica-gel column chromatography of
the crude product using petroleum ether as eluent gave phosphonate 7
(4.58 g, 45%) as a colorless viscous liquid. IR (neat): 2930, 1620, 1550,
1450 cm21
.
1H NMR (200 MHz, CDCl3): d ¼ 0.95 (t, J ¼ 6.6 Hz, 3H), 2.00–215
(m, 2H), 2.55 (s, 6H), 4.15 (t, J ¼ 6.6 Hz, 1H), 6.50–7.40 (m, 13H).
13C NMR (200 MHz, CDCl3): d ¼ 23.13, 26.36, 56.91, 130.43, 130.74,
134.49, 136.08, 136.72, 137.58, 138.28, 138.95, 139.22, 141.18, 154.88,
162.45. EIMS (m/z): Mþ380 (4), 344 (5), 315 (23), 226 (29), 197 (100),
165 (28), 152 (20), 115 (22), 91 (32). Anal. calc. for C23H25O3P: C, 72.62;
H, 6.62. Found: C, 72.30; H, 6.25.
Synthesis of 4-(2-Dimethylaminoethoxy)benzophenone 9
To a solution of sodium ethoxide in ethanol [prepared by adding sodium
metal (3.04 gm, 132 mmol) to absolute ethanol (150 ml)] was added
4-hydroxybenzophenone 8 (7.5 gm, 37.87 mmol) in absolute ethanol (150
ml). A solution of 2-(dimethylamino)ethyl chloride hydrochloride (10.83
gm, 75.75 mmol) in warm absolute ethanol (150 ml) was added to this
mixture in one portion. The resultant mixture was then refluxed for 24 h,
cooled to room temperature, poured into water and extracted with ether
(3 ꢀ 100 ml). The combined organic layers were washed with 5% sodium
hydroxide solution and brine, dried over anhydrous Na2SO4, and concentrated.
Silica-gel column chromatography of the crude product using chloroform:
methanol (9.5:0.5) as eluent gave compound 9 (9.17 g, 90%) as a viscous
pale yellow liquid. Bp 173–1798C/0.3 mmHg (lit.[4j] 174–1798C/
1
0.3 mmHg). IR (neat): 2930, 1720, 1620, 1540 cm21. H NMR (200 MHz,
CDCl3): d ¼ 2.49 (s, 6H), 2.95 (t, J ¼ 6.6 Hz, 2H), 4.25 (t, J ¼ 6.6 Hz, 2H),
6.98 (d, J ¼ 9.3 Hz, 2H), 7.35–7.65 (m, 3H), 7.75–7.80 (m, 2H), 8.85
(d, J ¼ 9.3 Hz, 2H). EIMS (m/z): Mþ 269 (3), 152 (2), 105 (7), 77 (14),
58 (100).

Tamoxifen Synthesis
2799
Synthesis of Z-Tamoxifen 11
A solution of phosphonate 7 (0.5 g, 1.32 mmol) in THF (20 ml) was treated
with n-butyllithium (0.561 ml, 15% solution in hexane, 1.32 mmol) or
NaHMDS (1.32 mmol) at 2788C for 1 h. A solution of ketone 9 in THF
(0.345 gm dissolved in 5 ml of THF, 1.316 mmol) was then added, and the
resulting mixture was stirred at 2788C for 48 h. The reaction was then
quenched with saturated NH4Cl and extracted with ethyl acetate
(3 ꢀ 20 ml). The combined extracts were washed with water (2 ꢀ 20 ml)
followed by brine, dried over anhydrous Na2SO4, and concentrated. The
crude product was purified by flash chromatography over a silica gel
column using chloroform:methanol (9.5:0.5) as eluent to furnish Z-
tamoxifen 1 (Rf value 0.20; 0.136 g, 28%) as white solid, mp 95–968C
(lit.[4c] mp 95–978C) along with E-tamoxifen 2 (Rf value 0.24; 0.058 g,
12%) and unreacted starting materials. The spectroscopic data for 1 are in
full accord with those described.[4c,4l]
CONCLUSION
In conclusion, we have synthesized Z-tamoxifen in a stereoselective manner
starting from commercially available starting materials and employing the
Wittig–Horner reaction as the key step.
ACKNOWLEDGMENTS
R.K.P. thanks CSIR, New Delhi, India, for the award of senior research
fellowship. We are grateful to M. K. Gurjar, Head, Organic Chemistry:
Technology Division for his constant encouragement and support. This is
NCL communication No. 6681.
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