A simple and convenient synthesis of 2-methoxyestradiol from estrone

Article abstract of DOI:10.1016/j.steroids.2012.01.005

A simple and straightforward synthesis of 2-methoxyestradiol have been achieved in nine synthetic steps with 21% of overall yield. Being a convenient process, it can be upscaled to industrial process.

Full text of DOI:10.1016/j.steroids.2012.01.005

Steroids 77 (2012) 467–470
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Steroids
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A simple and convenient synthesis of 2-methoxyestradiol from estrone
⇑
A.P. Prakasham, Karuna Shanker, Arvind S. Negi
Chemical Sciences Division, Central Institute of Medicinal and Aromatic Plants (CIMAP–CSIR), P.O. CIMAP, Kukrail Picnic Spot Road, Lucknow, 226015 UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and straightforward synthesis of 2-methoxyestradiol have been achieved in nine synthetic steps
with 21% of overall yield. Being a convenient process, it can be upscaled to industrial process.
Ó 2012 Elsevier Inc. All rights reserved.
Received 21 November 2011
Received in revised form 24 December 2011
Accepted 6 January 2012
Available online 16 January 2012
Keywords:
2-Methoxyestradiol
Breast cancer
Total synthesis
1. Introduction
Rao et al. [11c] for introducing an acetyl group at 2-position of
estradiol by using ZrCl4. Chen et al. [11d] and Luo et al. [11e] both
Oestrogens play an important role in the physiology of female
[1]. They function as oestrogen action mediators in reproductive
tissues as well as cardiovascular, bone, brain and liver [2]. Hence,
they exhibit several interesting biological activities and have been
developed as pharmaceuticals for fertility regulation, osteoporosis,
breast cancer, inflammation etc. [3]. 2-Methoxyestradiol (1, 2ME2)
a potent anticancer agent, has shown antiproliferative activity
against breast cancer [4], prostate cancer and ovarian cancer [5]
in preclinical and clinical studies [6]. It exerts microtubule depoly-
merisation after binding to the colchicine binding site of tubulin
[7] and exhibits antiangiogenic and proapoptotic activity [8]. In a
recent study, 2-methoxyestradiol was found to be a promising
radiosensitizer in the treatment of radioresistant breast cancer
cells [9]. Some of its analogues like ENMD-1198 and STX140, have
shown impressive potency in reducing breast cancer induced oste-
olysis and tumour burden [10] and are under further evaluations.
Being an important anticancer drug candidate, several researchers
have put their efforts towards the synthesis of 2-methoxyestradiol
[11a–h].
In the recent past, eight different syntheses of 2-methoxyest-
radiol have been developed. Different strategies were adopted
to introduce a suitable group at 2-position of estradiol. Leese
et al. [11a] used BuLi as a superbase in the key step for introduc-
ing an aldehyde group at 2-position at À78 °C. In another method,
Kiuru et al. [11b] used superbase (LIDAKOR) for the insertion a
hydroxyl group directly at 2-position of substituted estradiol.
Fries rearrangement was a crucial step in the methodology by
synthesized 2-methoxyestradiol through 2-bromoestradiol. Wang
et al. [11f] transformed 2-formyl bis (MOM) ethers of estradiol to
2-methoxyestradiol in excellent yields. Xin et al. [11g] reported a
five step short synthesis of 2-methoxyestradiol, here cupric bro-
mide was used in the key step to introduce a bromo group at
2-position of estradiol unit. Very recently, Akselsen and Hansen
[11h] used MgCl2–Et3N along with paraformaldehyde to formy-
late 2-position of estradiol. In some of these methods either reac-
tion conditions were very harsh or overall yields were very low.
Most of these methodologies are hampered by problems and
are not easily adoptable for industrial production. Herein, we re-
port a simple and straight forward methodology for the prepara-
tion of 2-methoxyestradiol.
2. Experimental
2.1. General procedures
Estrone was procured from Sigma chemicals, USA. Melting
points were determined on E-Z Melt automated melting point
apparatus, Stanford Research System, USA and were uncorrected.
Reactions were monitored on Merck silica gel thin layer chroma-
tography (TLC, UV254 nm) aluminium sheets. TLC visualization was
accomplished by spraying with a solution of 2% ceric sulphate in
10% aqueous sulphuric acid and charring at 80–100 °C. Column
chromatography was carried out on silica gel (100–200 mesh, Tho-
mas Baker). Concentration and evaporation of the solvents after
reaction or extraction were carried out in rotavapour at reduced
pressure. Dry solvents were prepared as per standard methods.
NMR experiments (1H NMR, 13C NMR, DEPT etc.) were obtained
⇑
Corresponding author. Tel.: +91 522 2359632; fax: +91 522 2342666.
E-mail address: arvindcimap@rediffmail.com (A.S. Negi).
0039-128X/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2012.01.005

468
A.P. Prakasham et al. / Steroids 77 (2012) 467–470
on Bruker Avance-300 MHz instrument. Chemical shifts are given
in d ppm with tetramethylsilane (TMS) as an internal standard.
The abbreviations of signal patterns are as; s, singlet; d, doublet;
t, triplet, m, multiplet & bs, broad singlet. All the 1H and 13C spec-
tral data are reported. Electrospray ionization (ESI) mass spectra
were recorded on Shimadzu LC–MS after dissolving the com-
pounds in methanol. FT-IR spectra were recorded on Perkin–Elmer
SpectrumBX after making KBr pellets. Nomenclature of steroid
derivatives has been given as per the recommendations published
by the Joint Commission on the Biochemical Nomenclature (JCBN)
of IUPAC [12].
poured into crushed ice, acidified with dil. HCl (5%, 5 mL) and ex-
tracted with ethyl acetate (15mL Â 3). Organic layer was washed
with water, dried over anhydrous sodium sulphate and evaporated
to dryness. The residue thus obtained was recrystallised with chlo-
roform–hexane to get 7 as white crystalline solid (634 mg).
Yield 94%, m.p. 152–153 °C. 1H NMR (CDCl3, 300 MHz):d 0.84 (s,
3H, 18-CH3), 2.07 (s, 3H, 17-OAc), 1.20–2.41 (m, 13H, rest of the 5Â
CH2 and 3Â CH of steroidal ring), 2.38 (s, 3H, 3-OAc), 2.92 (bs, 2H,
6-CH2), 4.70 (t, 1H, 17-CH, J = 8.4 Hz), 6.87 (s, 1H, 4-CH), 7.77 (s,
1H, 1-CH), 10.1 (s, 1H, CHO). 13C NMR (CDCl3, 75 MHz): d 12.0,
20.8, 21.1, 23.2, 25.9, 26.6, 27.5, 29.8, 36.6, 37.9, 42.8, 43.6, 49.7,
82.5, 123.3, 125.5, 128.8, 138.9, 145.8, 149.0, 169.6, 171.2, 188.8
Electrospray mass (MeOH): 407 [M+Na]+; IR: 2941, 2877, 2765,
2.2. Chemical synthesis
1774, 1731, 1687, and 1490 cmÀ1
.
2.2.1. 2-Formyl, 3-methoxyestra-1,3,5(10)-trien-17-acetate (5)
To a stirred cold solution of Estra 1,3,5(10)-trien-3,17-diol-3-
methyl ether, 17-acetate (4), (1000 mg, 3.04 mmol) in dry dimeth-
ylformamide (5 mL, 64 mmol), phosphorus oxychloride (3 mL,
32 mmol) was added dropwise. It was kept at 0–10 °C temperature
for 1 h and then heated at 90–100 °C for 4 h. After completion, the
reaction mixture was poured into crushed ice and extracted with
ethyl acetate (3 Â 30 mL). The organic layer was washed with
water, dried over anhydrous sodium sulphate and concentrated
in vacuum. The residue thus obtained was purified through silica
gel (100–200 mesh) column by eluting with 5–6% ethyl acetate–
hexane. Compound 5 was recrystallised with hexane–chloroform
(4:1) to get a creamish white solid (652 mg).
2.2.4. 2-Hydroxy, estra-1,3,5(10)-trien-3,17-diacetate (8)
Compound 7 (500 mg, 1.30 mmol) was taken in dry dichloro-
methane (10 mL). The reaction mixture was stirred with cooling
(0–10 °C) for 15 min. To this stirred solution 1 mL saturated
Na2HPO4 and m-chloroperbenzoic acid (1000 mg, 70%, 4.1 mmol)
were added. The reaction mixture was further stirred overnight
at room temperature. On completion the solvent was evaporated.
The residue was dissolved in ethyl acetate (40 mL), washed with
10% sodium bicarbonate solution (20mL Â 2). Organic layer was
washed with water, dried over anhydrous sodium sulphate and
evaporated to dryness. The residue thus obtained was purified
through silica gel column and eluted with ethyl acetate-hexane
to get desired product 8 as white crystalline solid (386 mg).
Yield 80%, m.p. 164–165 °C. 1H NMR (CDCl3, 300 MHz):d 0.82
(s, 3H, 18-CH3), 2.06 (s, 3H, 17-OAc), 1.26–2.29 (m, 13H, rest of
the 5Â CH2 and 3Â CH of steroidal ring), 2.34 (s, 3H, 3-OAc),
2.78 (bs, 2H, 6-CH2), 4.69 (t, 1H, 17-CH, J = 8.1 Hz), 5.17 (bs, 1H,
exchangeable, 2-OH, phenolic), 6.71 (s, 1H, 4-CH), 6.95 (s, 1H,
1-CH). 13C NMR (CDCl3, 75 MHz): d 12.4, 21.3, 21.6, 23.6, 26.6,
27.5, 27.9, 29.4, 37.2, 38.6, 43.3, 44.1, 50.1, 83.2, 118.0, 119.6,
133.6, 136.0, 136.9, 144.9, 170.3, 171.9; ESIMS (MeOH): m/z =
395 [M+Na]+; IR: 3415, 2930, 2864, 1766, 1735, 1590, 1506,
Yield 60%, m.p. 177–178 °C. 1H NMR (CDCl3, 300 MHz): d 0.82
(s, 3H, 18-CH3), 2.05 (s, 3H, OAc), 1.20–2.39 (m, 13H, rest of the
5Â CH2 and 3Â CH of steroidal ring), 2.90 (bs, 2H, 6-CH2), 3.88
(s, 3H, OCH3), 4.67 (t, 1H, 17-CH, J = 8.40 Hz), 6.67 (s, 1H, 4-CH),
7.73 (s, 1H, 1-CH), 10.38 (s, 1H, CHO). 13C NMR (CDCl3, 75 MHz):
d 12.4, 21.6, 23.6, 26.4, 27.3, 27.9, 30.8, 37.1, 38.7, 43.2, 43.9,
50.1, 56.0, 83.0, 112.1, 123.1, 126.0, 133.4, 146.6, 160.2, 171.6,
190.1. Electrospray mass (MeOH): 357.0 [M+H]+, 379 [M+Na]+,
395 [M+K]+; Negative mode: 355 [MÀH]À; IR: 3006, 2932, 1729,
1673, 1607, 1494, 1270, and 1041 cmÀ1
.
and 1269 cmÀ1
.
2.2.2. 2-Formyl, 3-hydroxyestra-1,3,5(10)-trien-17-acetate (6)
Compound 5 (500 mg, 1.40 mmol) was dissolved in dry dichlo-
romethane (15 mL). To this stirred solution anhydrous aluminium
chloride (600 mg, 4.49 mmol) was added in portions. The reaction
mixture was further stirred for 4 h at room temperature. On com-
pletion the solvent was evaporated and quenched with dil. HCl (5%,
10 mL), extracted with ethyl acetate (20mL Â 3). Organic layer was
washed with water, dried over anhydrous sodium sulphate and
evaporated in vacuo. The residue thus obtained was charged on sil-
ica gel column and eluted with ethyl acetate-hexane to get desired
product 6 as white solid (378 mg). It was recrystallised with chlo-
roform–hexane (1:3).
2.2.5. 2-Methoxy, estra-1,3,5(10)-trien-3,17-diacetate (9)
Compound 8 (200 mg, 0.54 mmol) was taken in dry acetone
(20 mL). To this solution anhydrous potassium carbonate (1 g)
and dimethyl sulphate (0.2 mL, 2.1 mmol) were added. The reac-
tion mixture was refluxed for 1 h. On completion, solvent was fil-
tered and evaporated to dryness. The residue was dissolved in
ethyl acetate (30 mL), washed with water, dried over anhydrous
sodium sulphate and evaporated to dryness. The residue was
passed through a small silica gel column and eluted with ethyl ace-
tate-hexane. Compound 9 was obtained as oil (185 mg).
Yield 89%, m.p. oil. 1H NMR (CDCl3, 300 MHz):d 0.81 (s, 3H, 18-
CH3), 2.05 (s, 3H, 17-OAc), 1.25–2.29 (m, 13H, rest of the 5Â CH2
and 3Â CH of steroidal ring), 2.30 (s, 3H, 3-OAc), 2.83 (bs, 2H, 6-
CH2), 3.84 (s, 3H, OCH3), 4.68 (bs, 1H, 17-CH), 6.56 (s, 1H, 4-CH),
6.93 (s, 1H, 1-CH). 13C NMR (CDCl3, 75 MHz): d 12.4, 21.1, 21.6,
23.6, 26.5, 27.6, 27.9, 29.1, 37.2, 38.6, 43.3, 44.1, 50.1, 56.27,
83.1, 113.1, 120.1, 133.1, 135.55,137.9, 149.1, 169.9, 171.6; ESIMS
(MeOH): m/z = 387 [M+H]+, 409 [M+Na]+.
Yield 79%, m.p. 177–179 °C. 1H NMR (CDCl3, 300 MHz): d 0.84
(s, 3H, 18-CH3), 2.06 (s, 3H, OAc), 1.22–2.35 (m, 13H, rest of the
5Â CH2 and 3Â CH of steroidal ring), 2.89 (bs, 2H, 6-CH2), 4.70 (t,
1H, 17-CH, J = 8.4 Hz), 6.70 (s, 1H, 4-CH), 7.42 (s, 1H, 1-CH), 9.82
(s, 1H, CHO), 10.78 (s, 1H, exchangeable, OH phenolic). 13C NMR
(CDCl3, 75 MHz): d 12.0, 21.1, 23.2, 26.0, 26.7, 27.5, 30.1, 36.6,
38.1, 42.8, 43.2, 49.7, 82.5, 116.9, 118.9, 130.5, 132.5, 147.9,
159.2, 171.2, 196.1. Electrospray mass (MeOH): 343 [M+H]+, 365
[M+Na]+; IR: 3049, 2966, 2870, 1727, 1652, 1571, 1412, and
1253 cmÀ1
.
2.2.6. 2-Methoxy, estra-1,3,5(10)-trien-3,17-diol (10)
Compound 9 (100 mg, 0.26 mmol) was taken in 5% methanolic
KOH (10 mL). The reaction mixture was refluxed for 1 h. On com-
pletion the reaction mixture was acidified with 5% dil. HCl with
cooling. It was extracted with ethyl acetate (3 Â 20 mL), washed
with water, dried over anhydrous sodium sulphate and evaporated
in vacuo. The residue thus obtained was purified through silica gel
2.2.3. 2-Formyl, estra-1,3,5(10)-trien-3,17-diacetate (7)
Compound 6 (600 mg, 1.75 mmol) was dissolved in dry pyridine
(2 mL). To this solution acetic anhydride (0.5 mL, 5.29 mmol) was
added. The reaction mixture was left as such overnight (14–16 h)
at room temperature. On completion the reaction mixture was

A.P. Prakasham et al. / Steroids 77 (2012) 467–470
469
column by eluting with chloroform–hexane. Compound 10 was ob-
tained as white crystalline solid (64 mg).
afford estradiol 3-methyl ether, 17-ol (3). The 17-hydroxyl was
acetylated with acetic anhydride in dry pyridine to yield estradiol
3-methyl ether, 17-acetate (4). A formyl group was introduced at
2-position of 4 by applying Vilsmeier–Haack formylation reaction.
Compound 4 was treated with dry DMF-POCl3 system to get the 2-
formyl estradiol 3-methyl ether, 17-acetate (5) in 60% yield [13].
Aldehyde 5 was demethylated by stirring it with anhydrous alu-
minium chloride in dry dichloromethane (AlCl3–DCM) at room
temperature to get 2-formyl, estradiol 17-acetate (6) in 79% yield
[14]. The phenolic hydroxyl of 6 was protected as acetyl derivative
using dry pyridine-acetic anhydride combination at room temper-
ature to yield 2-formyl, estradiol 3,17-diacetate (7) in 94% yield.
Compound 7 underwent Baeyer–Villiger oxidation in presence of
m-chloroperbenzoic acid in the buffered solution of Na2HPO4-
dichloromethane to yield directly 2-hydroxy estradiol 3,17-diace-
tate (8) in 80% yield. This was a hydrolysed product of estradiol
3,17-diacetate 2-formate. Compound 8 was methylated to 2-meth-
oxy estradiol 3,17-diacetate (9) by using dimethyl sulphate in dry
acetone in anhydrous potassium carbonate. Compound 9, on alka-
line hydrolysis afforded the desired product 2-methoxyestradiol
(10) in 82% yield.
In the recent past, several methods were developed to synthe-
size 2ME2. Some of the methods are good but in most of these
either complex reagents or drastic reaction conditions were used.
Except one or two, in most of these methodologies total yield are
also low. We prepared 2ME2 through a straight forward and simple
route. Under the optimized reaction conditions, it was synthesized
in 21% of overall yield. In our methodology, there are nine syn-
thetic steps with no drastic reaction conditions. Most of the con-
versions are very efficient with an average yield of 85% and
overall yield of the 21%. The methodology is based on simple and
Yield 82%, mp 188–189 °C. 1H NMR (CDCl3, 300 MHz): d 0.78
(s, 3H, 18-CH3), 1.18–2.31(m, 13H, rest of the 5Â CH2 and 3Â CH
of steroidal ring), 2.77 (bs, 2H, 6-CH2), 3.73 (bs, 1H, 17-CH), 3.86
(s, 3H, 2-OCH3), 5.43 (s, 1H, exchangeable, Phenolic OH), 6.64
(s, 1H, 4-CH), 6.79 (s, 1H, 1-CH): 13C NMR (CDCl3, 75 MHz): d
11.5, 23.5, 27.0, 27.7, 29.4, 31.0, 37.1, 39.2, 43.7, 44.7, 50.4, 56.4
82.3, 108.5, 115.0, 129.9, 132.1, 143.9, 145.0: ESIMS (MeOH): 325
[M+Na]+, negative mode:301 [MÀH]À; IR: 3482, 3404, 2927,
1508, 1274,1207, and 1118 cmÀ1
.
2.3. HPLC analysis of 2-methoxyestradiol
The purity profile of synthesized 2-methoxyestradiol was
checked by reverse phase HPLC (Schimadzu) using C-18 (Phenom-
enex, 4.6 Â 250 mm , 5
lm) column and water:acetonitrile = 40:60
as mobile phase with flow rate of 1 mL/min. The 2-ME2 procured
from Sigma was used as standard. Retention time (tR) of 2ME2
was 6.09 min. The absorbance of the compound kmax was deter-
mined as 254 nm in PDA. The purity of the synthesized 2ME2
was found to be 91% (% area basis).
3. Results and discussion
A retrosynthetic plan is as depicted in Scheme 1. For total syn-
thesis (Scheme 2), estrone (1) was methylated to estrone 3-methyl
ether (2) by using dimethyl sulphate/anhydrous potassium carbon-
ate in dry acetone- chloroform (1:1) under reflux conditions. The
17-ketone of estrone 3-methyl ether (2) was reduced to alcohol
by using sodium borohydride in methanol-dichloroform (1:1) to
OH
OAc
OAc
O
H3CO
HO
OHC
HO
AcO
AcO
HO
10: 2-ME2
1: Estrone
Scheme 1. Retrosynthetic analysis of 2-methoxyestradiol 1.
O
O
OAc
OH
i
ii
iii
HO
93%
95%
H3CO
93%
H3CO
H3CO
1
: Estrone
2
4
3
iv
60%
OAc
OAc
OAc
OAc
v
OHC
vi
OHC
HO
vii
OHC
AcO
HO
AcO
H3CO
79%
94%
80%
5
6
7
8
89%
viii
OAc
OH
ix
H3CO
AcO
H3CO
HO
82%
9
10
Scheme 2. Reagents and conditions: (i) Me2SO4, anhyd. K2CO3, acetone:chloroform (1:1), reflux, 93%; (ii) NaBH4, MeOH–DCM (1:1), RT, 95%; (iii) pyridine, Ac2O, RT,
overnight, 93%; (iv) DMF-POCl3, 0–10 °C for 1 h, 90–100 °C for 4 h, 60%; (v) Anhydrous AlCl3–DCM, RT, 3 h, 79%; (vi) pyridine, Ac2O, RT, overnight, 94%; (vii) m-CPBA, DCM, sat.
Na2HPO4, 0 °C-RT, overnight, 80%; (viii) Me2SO4, anhydrous K2CO3, acetone, reflux, 1 h, 89%; (ix) 5% KOH in MeOH, reflux, 1 h, 82%.

470
A.P. Prakasham et al. / Steroids 77 (2012) 467–470
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cess. The purity of the final product was found to be 91% by RP-
HPLC.
In conclusion, a simple and straight forward synthesis of 2-
methoxyestradiol has been achieved starting from estrone with
an overall yield of 21% in nine steps. No drastic reaction condition
was used. This route might provide a new access to the synthesis of
new analogues of 2-methoxyestradiol as well which is presently in
process.
Methoxyestradiol,
a promising anticancer agent:antitumour activity of 2-
Acknowledgements
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The authors are thankful to Director CSIR-CIMAP for constant
help and support. This work was financially supported by CSIR.
CSIR Research Internship to AP Prakasham is duly acknowledged.
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.steroids.2012.01.005.
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