A simple method of obtaining 11-keto-9β-estra-1,3,5(10)-trienes: Potential reactants for the synthesis of steroidal antigestagens

Full text of DOI:10.1023/A:1021857108579

Pharmaceutical Chemistry Journal
Vol. 36, No. 9, 2002
DRUG SYNTHESIS METHODS
AND MANUFACTURING TECHNOLOGY
A SIMPLE METHOD OF OBTAINING 11-KETO-9b-ESTRA-1,3,5(10)-
TRIENES: POTENTIAL REACTANTS FOR THE SYNTHESIS
OF STEROIDAL ANTIGESTAGENS
L. E. Golubovskaya,1 O. N. Minailova,1 and V. M. Rzheznikov1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 36, No. 9, pp. 47 – 49, September, 2002.
Original article submitted February 28, 2002.
In recent years there have been extensive investigations
into the chemistry and biology of 11-aryl-norsteroids known
to possess a broad spectrum of physiological properties, in
particular, antigestagen activity [1]. These compounds are
capable of competing with natural gestagens for binding to
receptors of the reproductive organs of females, thus violat-
ing normal development of the fetus. In contrast to tradi-
tional oral contraceptives, antigestagen preparations can not
only prevent but, owing to their abortive action, terminate
gestation.
first stage even for simple 17-analogs of estrone; attempts at
using relatively cheap and accessible chloranil instead of
DDB were unsuccessful [8 – 10].
CH3
R
CH3
O2NO
R
H
R'
H
R'
CÀN
H
H
OH
H
IIa, IIb
AcO
AcO
Ia, Ib
CH3
R
R'
Among the abortive contraceptives, most widely used is
the drug mifepristone (RU-486) reproduced in Russia as
pencroftone. RU-486 and its analogs are obtained by partial
syntheses from estrone. All variants of the synthesis, while
differing in the number of stages and/or the way of protect-
ing the 3-keto group, employ only estra-5,9-diene-3,17-dione
as the initial compound [2 – 4]. At the same tine, the synthe-
sis of related 11-alkyl-19-norsteroids was frequently per-
formed using 11-ketoestrogens, representing steroids with ar-
omatic ring A [5]. These compounds, albeit considered
among possible reactants in the synthesis of
11-aryl-19-norsteroids [6], were never used in practice – ap-
parently because of the lack of sufficiently economic and
technologically simple methods for their production.
H
O
NaOH
AcO
IIIa, IIIb
–
O
O
H
H
–
O
O
IVa, IVb
O
CH3
R
H
R'
H+
The known syntheses, for example, of 11-keto-9b-estro-
ne (compounds with the 9b configuration are most stable in
the series of 11-ketoestratrienes [7]), include three principal
stages: (i) dehydration with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDB), (ii) epoxidation with superacid, and
(iii) epoxide conversion into ketone under the action of
Lewis acid (BF3, Et2O, LiClO4) [7]. All these schemes pos-
sess drawbacks related to the difficulties in reproducing the
H
H
HO
Va, Vb
I – V: R + R¢ = O (a); R = b-OAc, R¢ = a-CºCH (b).
Below we describe a two-stage synthesis of 11-keto-9b-
estrone (Va) and its 17a-ethinyl analog (Vb). The latter com-
pound was selected because most active gestagens contain
1
Scientific Endocrinological Center, Russian Academy of Medical Sci-
ences, Moscow, Russia.
507
0091-150X/02/3609-0507$27.00 © 2002 Plenum Publishing Corporation

508
L. E. Golubovskaya et al.
EXPERIMENTAL PART
17a-substituents with CºC structure (e.g., RU-486 contains
a propyl radical).
The melting points were determined using a Boetius
heating table. The optical rotation was studied with a Pola-
mat A spectropolarimeter. The UV spectra were recorded on
a Specord UV-VIS spectrophotometer as ethanol solutions;
the IR spectra were measured on a Specord 75-IR spectro-
Taking into account the drawbacks of the aforemen-
tioned methods of obtaining 11-keto-9b-estrogens, we de-
cided to use an essentially different pathway for their synthe-
sis. Our synthesis is based on the reactivity of 11-substituted
nitrates of 9a,11b-dihydroxysteroids of types IIa and IIb
readily obtained through oxidation of estratrienes Ia and Ib
with cerium ammonium nitrate (CAN) [11]. A special feature
of 11-nitrates IIa and IIb is the easy elimination of HNO3 un-
der the action of alkalis. The elimination rate exceeds the rate
of hydrolysis of the 3-acetoxy group, as evidenced by the
synthesis of epoxides IIIa and IIIb at a nearly equimolar
amount of the alkali [12].
It could be expected that, with an excess of the alkali, the
hydrolysis of 3-acetoxy group in epoxides IIIa and IIIb might
lead to phenolates IVa and IVb. However, such compounds
are very unstable and several attempts [13 – 15] were unsuc-
cessful. Therefore, rupture of the mobile 9-C–O benzyl bond
can lead, via a pathway indicated in the scheme, to stable ke-
tones Va and Vb. Indeed, 11-nitrates IIa and IIb readily con-
vert into ketones Va and Vb within 2.5 – 3 h at room temper-
ature under the action of 4 – 5 mole-eq. NaOH in pyridine.
Ketones Va and Vb were isolated with a yield of 82 and 70%,
respectively. TLC monitoring showed that intermediate
epoxides IIIa and IIIb appear within 30 – 40 min upon mix-
ing the initial nitrates with the alkali.
As is known, nitroesters undergo the reaction of HNO2
a-elimination under the action of alkalis. An analogous reac-
tion was reported for steroids and well [16]. In the case of
11-nitrates IIa and IIb, this reaction could be expected to
yield the corresponding 9a-hydroxy-11-ketosteroids. How-
ever, possessing a sample of 9a-hydroxy-11-ketoestrone
[17], we established by HPLC that these compounds did not
appear in the reaction. Thus, a preferred reaction pathway for
the nitrates of vicinal diols II is the b-elimination of nitric
acid rather than the b-elimination process.
1
photometer in KBr pellets. The H NMR spectra were mea-
sured with Bruker Model 360 and Tesla BS-587A 80-MHz
instruments using CDCl3 as the solvent and TMS as the in-
ternal standard (unless otherwise indicated). The HPLC mea-
surements were performed on a Milikhrom-1 system
equipped with a UV detector tuned to 280 nm. A 80 ´ 2 mm
Silasorb C18 column was eluted with an acetonitrile – water
(7 : 3) mixture; peak retention times (RRT) were determined
in minutes. The compositions of reaction mixtures and the
purity of products were monitored by TLC on Silufol
UV-254 plates. The data of elemental analyses performed for
compounds IIb and IIc coincided with the results of analyti-
cal calculations.
General method for obtaining nitrates IIa and IIb. To
a solution of 1 mmole of compound Ia or Ib in 15 ml of ace-
tic acid was added dropwise a solution of 2.52 g (4.6 mmole)
of CAN in 2 ml of water. The orange solution was stirred for
2 h at room temperature, diluted by half with water, and ex-
tracted with chloroform or ethyl acetate. The extract was se-
quentially washed with saturated solutions of NaHCO3 and
NaCl and dried over MgSO4. The target products were iso-
lated by chromatography on silica gel (10 g sorbent per gram
mixture) eluted with an ethyl acetate – hexane (7 : 3) mix-
ture.
3,9a-Dihydroxy-11b-nitroxyestra-1,3,5(10)-trien-17-
one-3-acetate (IIa). Yield, 56%; m.p., 174 – 176°C; [a]D,
+103 ± 4° (c, 0.86; chloroform) (reported [13]: m.p.,
176.5 – 178°C; [a]D, +100°).
3,9a,17b-trihydroxy-11b-nitroxy-17a-ethinylestra-
1,3,5(10)-triene-3,17-diacetate (IIb). Yield, 44%; m.p.,
172 – 174°C (methanol); [a]D, –22 ± 2° (c, 0.95; chloro-
form); UV spectrum, lmax, nm (log e): 266 (2.75), 274
(2.70); IR spectrum (nmax, cm – 1): 3430 (OH), 3250 (CºCH),
1747 (3-OCOCH3), 1735 (17-OCOCH3), 1630, 1500 (C=C
arom.), 1240, 1030 (C–O); 1H NMR spectrum (d, ppm): 1.03
(s, 3H, 18-CH3), 2.04 (s, 3H, 17-OCOCH3), 2.27 (s, 3H,
3-OCOCH3), 2.7 (s, 1H, CºCH), 5.85 (t, 1H, J 3.0 Hz, 11-H),
6.88 (bs, 1H, 4-H), 6.92 (d, 1H, J 9.0 Hz, 2-H), 7.30 (d, 1H,
J 9.0 Hz, 1-H).
3-Hydroxy-9b-estra-1,3,5(10)-triene-11,17-dione-11-
keto-9b-estrone (Va). To a solution of 4.38 g (11.26 mmole)
of nitrate IIa in 80 ml of pyridine in an argon atmosphere was
added 8 ml of a 20% aqueous NaOH solution (40 mmole)
and the mixture was stirred at room temperature, whereby
the solution becomes yellow (15 min), then turns violet and
dark-violet (1.5 h), and NaNO3 is precipitated. After a 3-h
stirring, the reaction mixture was diluted by half with water,
acidified (on cooling) to pH 4 – 5 with a 10% aqueous HCl
Ketone Va appears as a crystalline, high-melting sub-
stance with physicochemical characteristics corresponding to
those reported in [11]. Ketone Vb was isolated in the form of
a foam, but the spectroscopic data confirmed the proposed
1
9b-11-ketone structure. In the H NMR spectrum of ketone
Vb (as well as in that of ketone Va), the signal from the equa-
torial 9-H proton is manifested as a broad doublet. The spin –
spin coupling constant is 3.5 Hz for Va and 4.3 Hz for Vb,
which corresponds to the electron-acceptor interaction with
8-H proton. Both ketones are characterized by a low-field
position of the signal from 1-H proton, caused by the
descreening effect of the 11-keto group. This group is mani-
fested in the IR spectra of ketones Va and Vb as an intense
absorption band at 1700 cm – 1 (Va) and 1680 cm – 1 (Vb).
It should be noted that the proposed synthesis of
11-keto-9b-estra-1,3,5(10)-trienes Va and Vb differs from
the known processes in that the number of stages is less, the
procedure is simpler, and no expensive reactants (such as
DDB) are involved.

A Simple Method of Obtaining 11-Keto-9b-estra-1,3,5(10)-trienes
509
solution, and extracted with ethyl acetate. The extract was
sequentially washed with a 10% aqueous HCl solution and a
saturated NaCl solution and dried over MgSO4. The ethyl ac-
etate was evaporated, the residue was dissolved in chloro-
form, and the chloroform solution was filtered through silica
gel (40 g), after which ketone Va was isolated; yield, 2.6 g
(82%); m.p., 199 – 204°C (methanol); [a]D, +259 ± 15° (c,
0.84; dioxane) (reported [11]: m.p., 194 – 198°C and 204 –
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1
OCOCH3), 1680 (CO), 1610, 1575, 1495 (C=C arom.). H
NMR spectrum in C5D5N (d, ppm): 0.98 (s, 3H, 18-CH3),
2.03 (s, 3H, OCOCH3), 2.39 (s, 1H, CºCH), 3.62 (bs, 1H, J
4.3 Hz, 9-H), 5.1 (bs, 1H, OH), 6.6 (d, 1H, J 9 Hz, 2-H), 6.62
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ACKNOWLEDGMENTS
This study was supported by the Russian Foundation for
Basic Research, project No. 00–03–32848.
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