Synthesis of 11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(3-methyl-1-butynyl)-4,9-estra dien-3-one and 11β-(4-acetophenyl)-17β-hydroxy-17α-(3-methyl-1-butynyl)-4,9-estradien-3-one: Two new analogs of mifepristone (RU-486)

Article abstract of DOI:10.1016/S0039-128X(99)00097-5

From the structure activity relationship, two new analogs, 2 and 3, of the potent progesterone antagonist mifepristone 1 have been designed. The syntheses of these two analogs have been achieved in eleven steps through modified synthetic sequences and improved procedures starting from (+)-estrone. In comparison with mifepristone 1, the relative binding affinities of compound 2 for the progesterone receptor was found to be more, whereas that of compound 3 was less. Copyright (C) 2000 Elsevier Science Inc.

Full text of DOI:10.1016/S0039-128X(99)00097-5

Steroids 65 (2000) 157–162
Synthesis of 11␤-(4-dimethylaminophenyl)-17␤-hydroxy-17␣-
(3-methyl-1-butynyl)-4, 9-estradien-3-one and 11␤-(4-acetophenyl)-
17␤-hydroxy-17␣-(3-methyl-1-butynyl)-4, 9-estradien-3-one: two new
analogs of mifepristone (RU-486)૾,૾૾,૾૾૾
Braja G. Hazraa,*, Sourav Basua, Vandana S. Porea, Padmakar L. Joshia, Debnath Palb,
Pinak Chakrabartib
aOrganic Chemistry Synthesis Division, National Chemical Laboratory, Pune 411 008, India
bPhysical Chemistry Division, National Chemical Laboratory, Pune 411 008, India
Received 30 December 1998; received in revised form 23 September 1999; accepted 6 October 1999
Abstract
From the structure activity relationship, two new analogs, 2 and 3, of the potent progesterone antagonist mifepristone 1 have been
designed. The syntheses of these two analogs have been achieved in eleven steps through modified synthetic sequences and improved
procedures starting from (ϩ)-estrone. In comparison with mifepristone 1, the relative binding affinities of compound 2 for the progesterone
receptor was found to be more, whereas that of compound 3 was less. © 2000 Elsevier Science Inc. All rights reserved.
Keywords: Mifepristone analogs; Progesterone antagonist; Abortifacient; Antiglucocorticoid; Antiprogestin; 19-Norsteroids
1. Introduction
been synthesized [3–6] and were tested for their antipro-
gestin activity. Teutsch et al. [7] have synthesized a variety
of 11␤-substituted 19-norsteroids. Among these com-
pounds, 11␤-vinyl and 11␤-phenyl compounds showed a
high degree of binding affinity for the cytoplasmic uterine
progesterone receptor, whereas the 11␤-allyl and 11␤-ben-
zyl-19-norsteroids showed very low binding affinity. Thus,
shifting the unsaturation by one carbon atom practically
eliminates the receptor binding affinity. High binding affin-
ity of the 11␤-19-norsteroid led to the hypothesis that in the
region corresponding to the 11␤-position of the steroids, a
pocket exists in the progesterone receptor, where hydropho-
bic interactions are probably involved (Scheme 1).
In 1980, the French pharmaceutical company Roussel–
Uclaf announced the discovery [1,2] of RU-486, now
known by the generic name mifepristone (1). This was the
first antiprogestin to be developed. Mifepristone (1), when
used in combination with a prostaglandin, effectively and
safely terminates early pregnancies. It is already in use [1,2]
as an abortifacient in France, UK, Sweden, and China, has
passed the clinical trials in USA, and is under clinical trials
in India. It is also a potent antiglucocorticoid and shows
promising activity in treating estrogen-dependent gyneco-
logical disorders and hormone deficient tumors.
Over the years, a number of mifepristone analogs have
A very recent study by Spitz and Agranat [8] revealed
that the 17␣-substituent imparts higher binding affinity
for the receptor and the substituent at 11␤-position is
responsible for its antagonistic action. It has also been
reported [9] that replacement of the 11␤-(dimethylamino-
phenyl) substituent with the 11␤-(acetophenyl) moiety
increases the relative binding affinity for the progester-
one receptor in rat and lowers the relative binding affinity
for the glucocorticoid receptor than that of mifepristone
(1). In fact, the most active compound in this series, ORG
૾ The financial support from the Department of Science and Technol-
ogy, New Delhi (Grant No.SP/S1/G10/95) is gratefully acknowledged.
Two of the authors, S.B. and D.P. thank CSIR, New Delhi for the award of
SRF and JRF, respectively.
૾૾ This work originated at the National Chemical Laboratory, Pune
411 008, India.
૾૾૾ Dedicated to Prof. D. Nasipuri on his 75th birthday.
* Corresponding author. Tel.: ϩ91-20-5893153; fax: ϩ91-20-5893153.
E-mail address: hazra@ems.ncl.res.in (B.G. Hazra)
0039-128X/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved.
PII: S0039-128X(99)00097-5

158
B.G. Hazra et al. / Steroids 65 (2000) 157–162
Scheme 1.
33628, has been claimed to be 32ϫ as active as mife-
pristone in inducing abortions in rats, while being signif-
icantly less active as an antiglucocorticoid [8]. Com-
stored over KOH pellets. Reactions were monitored by TLC
using TLC aluminum sheets, silica gel 60F254 precoated,
Merck, Germany, and locating the spots spraying with eth-
anolic solution of phosphomolybdic acid followed by heat-
ing. Usual work-up means the organic extract was thor-
oughly washed with water and brine and finally dried over
anhydrous sodium sulfate. -IR: Perkin–Elmer 599B. -1H
NMR: Bruker AC 200 (200 MHz). For 1H NMR, CDCl3 as
solvent and TMS as an internal standard and J values are
given in Hz. -MS: Finnigan 1020C (70eV). -[␣]D: JASCO-
pound ORG 33628, is
a
17-spirofuran, 11␤-(4-
acetophenyl) analog of mifepristone.
In anticipation of changing the relative binding affin-
ity for the receptor, we planned to incorporate an isopro-
pyl group in place of methyl (e.g. 3-methyl-1-butynyl
side chain), at 17␣-position and successfully achieved the
synthesis of a new analog (2) of mifepristone (1). Fur-
thermore, with this new 17␣-alkynyl moiety in com-
pound (2), 4-acetophenyl group was introduced in the
11␤-position to afford another new analog (3) of mife-
pristone (1). Modification of both the active sites (at 17␣
and 11␤) are expected to bring about a cumulative effect
on the receptor binding affinity as well as antiglucocor-
ticoid activity of compound (3).
0
181 (4893 A). [␣]D values are given in 10Ϫ1 deg cm2/g,
m.p. (uncorrected): Yanaco Micro m.p. apparatus.
2.1. Estra-5 (10), 9( 11)-dien-3-one, 17␤-hydroxy-17␣-(3-
methyl-1-butynyl) cyclic 3-(1,2-ethanediyl acetal) (5)
In a 25-ml two-necked flask equipped with a septum and
a nitrogen assembly, 3-methyl-1, 1-dibromobut-1-en (0.454
g, 2 mmol) in dry THF (5 ml) was placed under nitrogen.
The solution was cooled to Ϫ78°C and to it was added
n-BuLi (2 ml, 2 M solution in hexane). The reaction mixture
was then slowly brought to Ϫ40°C and stirred at that tem-
perature for 2 h. After this period, it was again cooled to
Ϫ78°C and the 17-keto compound 4 (0.314 g, 1 mmol) in
THF (3 ml) was added dropwise to it and was stirred for a
further 8 h at 25°C. It was then quenched with ice-cold
saturated ammonium chloride solution and the mixture was
extracted with ethyl acetate (4 ϫ 50 ml). After usual work
up solvent was removed under vacuo to afford gum (0.432
g). Column chromatographic purification over silica gel by
using hexane/ethyl acetate (9:1) as eluent furnished com-
pound 5 as colorless foam (0.271 g, 71%), m.p. 56–58°C;
[␣]30 ϭ ϩ128.35° (c 0.79 in CHCl3); -IR (nujol) ␥ 3410
cmϪ1(OH); -1H NMR (CDCl3): ␦ ϭ 0.85 (s, 3H, 18-H3),
1.15 (d, 6H, J ϭ 6, isopropyl CH3), 2.46–2.75 (m, 2H,
Herein, we wish to report, the syntheses of two new
analogs, (2) and (3), of mifepristone (1), starting from (ϩ)-
estrone. Alteration of reported [6] synthetic sequences fur-
nished the target compounds (2) and (3) in higher overall
yields. Moreover, introduction of 3-methyl-1-butynyl moi-
ety at 17␣-position by nonhazardous modified method and a
highly chemoselective epoxidation of 5(10)-olefin with a
catalytic amount of hexafluoroacetone in H2O2 are the sa-
lient features of these syntheses. The structure of compound
(2) was confirmed by a single crystal X-ray.
2. Experimental
All solvents and reagents used were of commercial
grade. Dry tetrahydrofuran (THF) was freshly obtained by
taking the liquid to reflux under nitrogen, in a recirculation
still over sodium. Pyridine was purified by distillation and

B.G. Hazra et al. / Steroids 65 (2000) 157–162
159
4-H2), 4.0 (s, 4H, ketal -CH2), 5.65 (bd, 1H, 11-H); -MS (70
eV): m/z (%): 382 (Mϩ), 369, 332, 235, 159, 99 (100%);
-C25H34O3 (382.52): calculated C 78.5, H 8.96; Found C
78.7, H 8.8.
-CH), 2.90 (s, 6H, N, N-CH3), 3.96 (m, 4H, ketal -CH2),
4.26 (d, 1H, J ϭ 5, 11-H), 6.66 (d, 2H, J ϭ 10, Ar-H2), 7.05
(d, 2H, J ϭ 10, Ar-H2); -C33H45 NO4 (519.70): calculated C
76.26, H 8.73; Found C 76.43, H 8.6.
2.2. Estra-5␣,10␣-epoxy-9 (11)-en-3-one, 17␤-hydroxy-
17␣-(3-methyl-1-butynyl) cyclic 3-(1,2-ethanediyl acetal)
(6)
2.4. 11␤-[4-(N,N-dimethylamino)-phenyl]-17␣-(3-methyl-
1-butynyl)-estra-4, 9-dien-17␤-ol-3-one (2)]
The solution of the hydroxy ketal 7 (0.074 g, 0.142
mmol) in 70% AcOH (0.5 ml) was heated at 50°C for 2 h.
It then was cooled and neutralized with cold aqueous
NaHCO3. Usual work up followed by removal of solvent
under vacuo afforded a yellow gum (0.087 g) that was
chromatographed over silica gel by using hexane/ethyl ac-
etate (6:4) as an eluent to furnished 2 (0.045 g, 69%), as a
Compound 5 (0.095 g, 0.25 mmol) was dissolved in
CH2Cl2 (3 ml) and the solution was cooled to 0°C. Added
to it was Na2HPO4 (0.090 g, 0.63 mmol), followed by
hexafluoroacetone trihydrate (0.013 g, 0.059 mmol) and
44.6% H2O2 (0.0076 g, 0.225 mmol). The reaction mixture
was then slowly brought to 25°C and was stirred at that
temperature for 3 h. It was then diluted with CH2Cl2 and to
it was added 10% sodium thiosulphate solution (1 ml),
stirred for an additional 30 min. The reaction mixture was
extracted with CH2Cl2 (4 ϫ 25 ml), washed with water (3 ϫ
25 ml) and brine (2 ϫ 25 ml), and dried over anhydrous
sodium sulfate. Removal of solvent under vacuo afforded a
gum (0.102 g) that was chromatographed over silica gel by
using hexane/ethyl acetate (9:1) as eluent furnished com-
pound 6 (0.048 g, 49%) as colorless crystalline solid, m.p.
178°C (from hexane/ethyl acetate); [␣]32 ϭ Ϫ5.6 (c 0.56 in
CHCl3); -IR (nujol) ␥ 3410 cmϪ1 (OH); -1H NMR (CDCl3):
␦ ϭ 0.82 (s, 3H, 18-H3), 1.16 (d, 6H, J ϭ 6, isopropyl CH3),
2.41–2.65 (m, 2H, 4-H2), 3.95 (m, 6H, ketal -CH2), 6.1 (bd,
1H, 11-H); -MS (70 eV): m/z (%) 398 (Mϩ), 383 (Mϩ-
CH3), 337, 312, 297, 223, 141, 129, 59 (100%); -C25H34O4
(398.55): calculated C 75.34, H 8.6; Found C 75.5, H 8.9.
solid, m.p. 178°C (from hexane/diethyl ether); [␣]32
ϭ
ϩ126.25° (c 0.48 in CHCl3); -IR (nujol) ␥ cmϪ1 3415
(-OH), 1652 (-C ϭ O), 1517 (aromatic); 1H NMR (CDCl3)
␦ ϭ 0.56 (s, 3H, 18-H3), 1.22 (d, 6H, isopropyl -CH3), 2.95
(s, 6H, N, N-CH3) 4.37 (d, 1H, J ϭ 5, 11-H) 5.78 (s, 1H,
4-H), 6.67 (d, 2H, J ϭ 8, Ar-H2), 7.04 (d, 2H, J ϭ 8,
Ar-H2); -MS (70 eV): m/z (%) 457 (Mϩ), 439 (Mϩ-H2O),
121 (100%); -C31H39 NO2 (457.63): calculated C 81.36, H
8.59; Found C 81.3, H 8.7.
2.5. 11␤-[2-methyl-2-phenyl-1,3-dioxalan)-17␣-(3-methyl-
1-butynyl)-estra-9-en-5␣,17␤-diol-3-one, cyclic 1,2-
ethandiyl acetal (9)
In a two-necked flask equipped with a septum and a
nitrogen assembly, Mg (0.036 g, 1.5 mmol) was placed and
to it 2-methyl-2-(bromophenyl)-1, 3-dioxalan 8 (0.318 g,
1.5 mmol) in THF (1 ml) was introduced. The reaction
mixture was heated at 45 to 50°C for 2 h, and during this
time, all Mg disappeared, resulting in a dark-colored solu-
tion. In another flask, compound 6 (0.120 g, 0.3 mmol) and
CuI (0.0057 g, 0.03 mmol) in THF (4 ml) were placed under
nitrogen and cooled to 0°C. To it the dark-colored solution
of the Grignard reagent was added dropwise. The resulting
reaction mixture was slowly brought to 25°C and was
stirred at that temperature for a period of 6 h. It then was
quenched with cold saturated NH4Cl and extracted with
diethyl ether (4 ϫ 25 ml). Usual work up of the organic
extract and removal of solvent under reduced pressure af-
forded a gum (0.318 g) that on column chromatographic
purification over silica gel using ethyl acetate/hexane (2:8)
as an eluent afforded compound 9 as solid (0.130 g, 77%);
m.p. 173–174°C (from hexane/diethyl ether); [␣]28 ϭ Ϫ
46.1° (c 0.36 in CHCl3); -IR (nujol) ␥ cmϪ1 3400 (-OH); 1H
NMR (CDCl3) ␦ ϭ 0.52 (s, 3H, 18-H3), 1.2 (d, 6H, J ϭ 6,
isopropyl -CH3), 1.65 (s, 3H, acetophenyl CH3), 3.65–4.05
(m, 8H, ketal CH2), 4.3 (bd, 1H, J ϭ 5, 11H), 7.16 and 7.35
(AB pattern, J ϭ 10, Ar-H); -MS (70eV): m/z (%) 562
(Mϩ), 544 (100%), 434, 366, 191, 178, 133, 105; -C35H46
O6 (562.72): calculated C 74.7, H 8.24; Found C 74.3, H
8.35.
2.3. 11␤-[4-(N,N-dimethylamino)-phenyl]-17␣-(3-methyl-
1-butynyl)-estra-9-en-5␣,17␤-diol-3-one, cyclic 1,2-
ethandiyl acetal (7)
In a 25-ml two-necked flask equipped with a septum and
nitrogen assembly, Mg (0.053 g, 2.2 mmol) was placed and
to it 4-bromo-N,N-dimethylaniline (0.455 g, 2.27 mmol) in
THF (1 ml) was introduced with a syringe. The mixture was
heated at 45–50°C for 2 h, and during this period, all Mg
disappeared, resulting a yellowish solution. In another two-
necked flask, the ␣-epoxide 6 (0.074 g, 0.18 mmol) and CuI
(0.0095 g, 0.05 mmol) in THF (3 ml) were placed under
nitrogen and cooled to 0°C. To it the preformed Grignard
reagent was added dropwise. The resulting reaction mixture
was slowly brought to 25°C and was stirred at that temper-
ature for a period of 6 h. It was then quenched with cold
saturated NH4Cl solution and extracted with diethyl ether
(4 ϫ 25 ml). The ether extract was worked up in the usual
way. Removal of solvent under reduced pressure furnished
a gum (0.103 g) that was chromatographed over silica gel to
afford 7 (0.074 g, 77%) as a solid, m.p. 103°C (from
hexane/ethyl acetate); -IR (nujol) ␥ 3460 cmϪ1 (OH), 1510
(aromatic); -1H NMR (CDCl3): ␦ ϭ 0.59 (s, 3H, 18-H3),
1.19 (d, 6H, J ϭ 7, isopropyl CH3), 1.25 (m, 1H, isopropyl

160
B.G. Hazra et al. / Steroids 65 (2000) 157–162
Scheme 2.
2.6. 11␤-(4-acetophenyl)-17␣-(3-methyl-1-butynyl)-estra-
4, 9-dien-17␤-ol-3-one (3)
clic-3-(1,2-ethanediyl acetal) 4 [10,11] (Scheme 2). Intro-
duction of a 3-methyl-1-butynyl side chain at 17 ␣
orientation of compound 4 was tried with 3-methylbut-1-
yne [12] and n-butyl lithium in THF at temperatures ranging
from Ϫ78° to 25°C. The reaction furnished a complex
mixture of products from which we failed to isolate the
desired product 5. We then turned our attention at an effi-
cient procedure for the generation of 3-methyl-1-butynyl-
lithium in situ in the reaction mixture .This was accom-
plished by the reaction of 3-methyl-1, 1-dibromobut-1-en in
THF with 2 equivalents of n-BuLi in hexane. 3-methyl-1,
1-dibromobut-1-en was prepared by the reaction of CBr4
with isobutyraldehyde in the presence of triphenylphos-
phine by a reported [13] procedure. Alkynylation of 4 with
3-methyl-1-butynyl lithium proceeded smoothly to give the
17␣-alkynylated compound 5 in 71% yield as a foam. Che-
moselective epoxidation of the 5 [10] double bond of 5 was
achieved with H2O2 and a catalytic amount of hexafluoro-
acetone trihydrate to get a mixture of 5, 10␣-epoxide 6 and
5, 10␤-epoxide in good yield and in the ratio of 4:1. The
isomeric ratio was assigned from the integration of the 200
A solution of the hydroxy ketal 9 (0.038 g, 0.067 mmol)
in 70% AcOH (0.5 ml) was heated at 50 to 60°C for 2 h. The
solution was then cooled and neutralized with cold aqueous
NaHCO3 solution. The resultant gummy mass was extracted
with CH2Cl2 (3 ϫ 25 ml), washed thoroughly with water
(3 ϫ 25 ml) and brine (2 ϫ 25 ml), and was dried over
anhydrous sodium sulfate. Removal of solvent afforded a
yellowish gum (0.062 g) that was chromatographed over
silica gel to get pure compound 3 (0.026 g, 84%) as foam,
m.p. 97–100°C; [␣]30 ϭ ϩ86.25° (c 0.26 in CHCl3); -IR
1
(nujol) ␥ cmϪ1 3459 (-OH), 1665 (-C ϭ O); H NMR
(CDCl3) ␦ ϭ 0.49 (s, 3H, 18-H3), 1.2 (d, 6H, J 6, isopropyl
-CH3), 2.6 (s, 3H, acetophenyl CH3), 4.49 (bd, 1H, J ϭ 5,
11-H), 7.3 and 7.9 (AB pattern, 4H, J ϭ 10, Ar-H); -MS (70
eV): m/z (%) 439 (Mϩ-OH), 413, 395, 346, 236, 147, 91, 67
(100%); -C31H36 O3 (456.60): calculated C 81.54, H 7.95;
Found C 81.3, H 8.1.
1
MHz H NMR spectrum of the epoxides that showed two
signals at 6.1 and 5.9 ppm for the C-11 hydrogen of the ␣
and the ␤ isomer respectively. The combination of hexaflu-
oroacetone with H2O2 produces 2-hydroperoxyhexafluoro-
2-propanol, a reactive oxidizing agent [14] possessing con-
3. Results and discussion
Syntheses of our two new analogs 2 and 3 of mifepris-
tone 1 start from estra-5 (10), 9 (11)-dien-3,17-dione, cy-

B.G. Hazra et al. / Steroids 65 (2000) 157–162
161
Table 1
siderable selectivity, particularly in the oxidation of
Relative binding affinities of compounds 1, 2, and 3 for progesterone
receptors
strerically hindered olefins. Moreover, the byproduct of
epoxidation, 2-hydroxyhexafluoro-2-propanol, readily dis-
proportionates with H2O2 to regenerate 2-hydroperoxy-
hexafluoro-2-propanol, thereby implementing a simple cat-
alytic cycle. The required 5, 10␣-epoxide 6 was isolated by
column chromatography over silica gel in 49% yield as a
solid. The 11␤-(4-dimethenylaminophenyl) substituent was
introduced by SN2 opening of the oxirane ring of compound
6 with the Grignard reagent prepared from 4-bromo-N,N-
dimethyl aniline in presence of a catalytic amount of Cu (I)
iodide. The 11␤-substituted compound 7 was obtained as
solid in 77% yield. 4-Bromo-N,N-dimethyl aniline was pre-
pared [15] by the regioselective monobromination of N,N-
dimethylaniline with 2, 4, 4, 6-tetrabromo-2, 5-cyclohexa-
dien [16]. 11␤ Stereochemistry at C-11 is evident from the
large shielding effect in the proton resonance of the C-18
methyl group. In the 11-unsubstituted compound 6, the
18-methyl signal comes at 0.82 ppm whereas, introduction
of 11␤-aryl moiety, shields the 18-methyl signal to 0.59
ppm in compound 7. Deketalization and simultaneous de-
hydration of 7 with 70% AcOH gave the target compound 2
in 69% yield as a pale yellow crystalline solid. The structure
of compound 2 was finally confirmed by single crystal
X-ray analysis.
S. No.
Compound no.
Relative binding affinity (%)a
1.
2.
3.
4.
1 (Mifepristone)
2
3
103
175
35
Progesterone
100
a Values are mean of two separate experiments.
of compound 2. As compared to compound 1 i.e. mifepris-
tone, compound 2 is more active whereas compound 3 is
less active. The activity of progesterone is taken as 100%.
Acknowledgments
We are thankful to Dr C.M. Gupta, Director, Dr M.M.
Singh, Senior Scientist, and Dr Anila Dwivedi, Scientist,
Central Drug Research Institute Lucknow, for bioevaluation
of compounds 2 and 3. We thank Dr K.N. Ganesh, Head of
our Division, for encouragement.
References
For the synthesis of 11␤-(acetophenyl)-17␤-hydroxy-
17␣-(3-methyl-1-butynyl)-estra-4, 9-dien-3-one 3, the 5,
10␣-epoxide 6 was utilized (Scheme 2). 2-Methyl-2-(4-
bromophenyl)-1, 3-dioxalan 8 was prepared from 4-bro-
moacetophenone by ketalization with ethylene glycol in the
presence of catalytic amount of PTSA, which in turn was
prepared from bromobenzene by Fridel Craft acylation with
acetic anhydride [17]. The Grignard reagent prepared from
8 reacted with the 5, 10␣-epoxide 6 in SN2 mode, in pres-
ence of a catalytic amount of CuI, to furnish after column
chromatographic purification the 11␤-substituted steroid 9
in 72% yield as a solid. Deketalization of 9 and concomitant
dehydration with 70% AcOH afforded the 11␤-(4-acetophe-
nyl) substituted steroid 3 as a foam in 84% yield. This new
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Competitive binding assay for progesterone receptors
(PR) was performed using rabbit uterine cytosol and H
3
progesterone (radioligand) in the presence of unlabelled
cortisol at 4°C. Competitor dilutions were prepared in
DMF: Tris-HCl buffer pH 7.4 (1:1). Results calculated as
percent relative binding affinity for PR, revealed that com-
pound 2 was the most active. Compound 1 showed RBA
(103%) almost equivalent to that of progesterone (100%;
Table 1). Compound 2 showed an RBA of 175%. Com-
pound 3 showed 35% RBA that is approximately 1/5 of that
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