Recent developments in the synthesis of 11β-aryl-estrone derivatives

Article abstract of DOI:10.1016/j.tetlet.2003.11.028

An industrial synthesis of 11β-aryl-estrone derivatives is described, based on the 1,4-addition of the aryl side-chain, as a cuprate, on to a mixture of allylic 5(10) alpha and beta epoxides, followed by hydrolysis and subsequent aromatization.

Full text of DOI:10.1016/j.tetlet.2003.11.028

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 765–768
Recent developments in the synthesis of 11b-aryl-estrone derivatives
Denis Prat,* Franßcoise Benedetti, Lahlou Nait Bouda and Gilles Franc Girard
Aventis Pharma, Chemical/Process Development, 102, route de Noisy, 93235 Romainville Cedex, France
Received 6 October 2003; revised 3 November 2003; accepted 10 November 2003
Abstract—An industrial synthesis of 11b-aryl-estrone derivatives is described, based on the 1,4-addition of the aryl side-chain, as a
cuprate, on to a mixture of allylic 5(10) alpha and beta epoxides, followed by hydrolysis and subsequent aromatization.
Ó 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Observations during the pilot-scale synthesis
Substitution of estradiol derivatives with 11b-aryl
groups is a way of modulating their affinity for estrogen
receptors.1 Recently, we described the synthesis of a
17a-methyl-11b-aryl estradiol derivative.2
Apart from this initial moderate selectivity, the strategy
of this synthesis is sound. Ethylene deltenone 1, which is
an industrial intermediate for norsteroids, particularly
trimegestone,6 is an appropriate starting material for the
synthesis. Epoxide 2a is crystalline, in contrast to parent
epoxides bearing other functions at C-17. The intro-
duction of the pre-formed aryl side-chain results in a
convergent route.
These drug substances are generally prepared from 11b-
aryl-estrone intermediates, the synthesis of which is
based on the very efficient 1,4-addition3 of the aryl side-
chain, as a catalytically generated cuprate, on an allylic
5a,10a-epoxide such as 2a or 3a (Scheme 1). When a 17-
keto group was present, this arylation was best per-
formed on the silyl enol ether,4 resulting in higher yield,
and use of lower amounts of copper(I) chloride and
Grignard reagent.2
Silylation was carried out using LDA as the base
(1.2 equiv) and TMSCl (1.4 equiv) as the silylating agent,
at 0 °C in THF. To the toluene solution of 3a was added
0.1 equiv of copper chloride and 1.3 equiv of the Grig-
nard reagent 4,7 at 0 °C. Aqueous work-up of the aryl-
ation mixture (aq NH4Cl, dichloromethane) gave the
11b-aryl,5a-alcohol 5b, the acidic hydrolysis of which
afforded a mixture of 11b-aryl-dienone 6b with minor
amounts (5–10%) of the deconjugated dienone 6c,8
which was oily and easily removed by crystallizing 6b
from diisopropyl ether (yield: ca. 74%, lab and pilot
scale).9
Though this strategy was satisfactory for the prepara-
tion of batches of drug substances devoted to phase 1
and 2 clinical trial studies, the low diastereoselectivity of
the initial epoxidation5 of the 5,10-olefinic double bond
of the dienone 1 was an issue to address in further scale-
up studies. Using our best conditions (1.7 equiv of 50%
hydrogen peroxide, 0.1 equiv of hexafluoroacetone,
dichloromethane, 18 h, 20–25 °C), the a-epoxide 2a was
isolated in 49% yield after crystallization from ethyl
acetate. Using hexachloroacetone as the catalyst, the
yield was 43%.2
The b-epoxide 3b reacted more slowly than the a-iso-
mer, thus requiring more copper(I) chloride (0.2 equiv),
higher temperatures (20 °C), and more Grignard reagent
(2 equiv). An 11a-aryl,5b-alcohol 5a was obtained, the
hydrolysis of which gave a ca. 9/1 mixture (estimated by
NMR) of the deconjugated dienone 6c and the expected
11a-aryl-dienone 6a (Scheme 2). The dienone 6c is
unstable and mainly decomposed during chromatogra-
phy (isolated yield: 6%).10 The 11a-aryl-dienone 6a was
isolated in 3% yield after chromatography.11 These
results were at first glance of little synthetic interest.
Keywords: Estrone derivatives; Industrial synthesis; Aromatization;
11-b-Aryl estrogen.
* Corresponding author. Tel.: +33-15893-8262; fax: +33-15893-8274;
e-mail: denis.prat@aventis.com
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.028

766
D. Prat et al. / Tetrahedron Letters 45 (2004) 765–768
O
O
OSiMe3
H2O2, (F3C)2CO
LDA, TMSCl,
°
°
THF, 0 C
CH2Cl2, 20-25 C
O
O
O
O
O
O
O
O
1
4
49%
2a
beta epoxide 2b
3a
O
Et N
1)
2
X
X
MgBr ,
HCl, CH2Cl2-water,
°
CuCl, THF, 0 C
OSiMe3
O
AcBr, Ac2O
CH2Cl2, 20-25 C
°
0-5 C
°
°
O
2) NH4Cl, CH2Cl2-water, 10-15 C
O
O
OH
6c
74%
6b
5b
X
O
O
Et2N
Et2N
O
1) KOH, MeOH
0-5 C
O
O
°
2) HCl, CH2Cl2
AcO
HO
, HCl
O
6c
7b
8b
79%
Scheme 1. Preparative synthesis of 11b-aryl-estrones (X ¼ Et2NCH2CH2O).
X
O
X
OSiMe3
OSiMe3
6c
O
1) HCl, CH2Cl2-water,
°
1) 4, CuCl, THF, 20 C
°
0-5 C
O
O
+
O
2) NH4Cl, CH2Cl2-water
2) Aq. NaHCO3
X
O
O
OH
5a
°
10-15 C
3b
O
O
6a
Scheme 2. Arylation at the 11a-position (X ¼ Et2NCH2CH2O).
Aromatization of 6b was carried out using a mixture of
acetyl bromide (2.5 equiv) and acetic anhydride
(1 equiv), in dichloromethane at 20–25 °C.12 An estrone
acetate 7b was formed, which required saponification
(1.5 equiv of KOH, MeOH, 0–5 °C). Aryl-estrone
hydrochloride 8b was crystallized from methyl ethyl
ketone in good yield (ca. 79% from 6b), in the lab and in
the pilot plant.13
dominant product: only ca. 0.5% of the 11a-aryl isomer
was detected by HPLC in the crude mixture after aro-
matization and saponification.
3. Design of the industrial synthesis
The study of the aromatization reaction also gave
unexpected results. During its optimization,2 we
observed that the starting 11b-dienone 6b rapidly
disappeared from the reaction mixture, giving an inter-
mediate, which slowly rearranged into 11b-aryl-estrone
acetate 7b. According to LC–MS it had the same
molecular mass as the aryl-estrone acetate, and we
proposed the structure 7d for this intermediate (Scheme
3). Later we succeeded in isolating it, and to our sur-
prise, it was not 7d but the isomeric trienol acetate 7c.
Compound 7d probably formed as a transient interme-
diate. It was interesting to note that the 11-aryl group
was no longer b in 7c, but it recovered the b configu-
ration after isomerization, thus giving 7b as the pre-
These observations paved the way to the synthetic
exploitation of the hitherto ÔundesiredÕ b-epoxide 2b.
The deconjugated dienone 6c was the main product of
arylation of 3b, and we expected 7c to be the kinetic
product in the aromatization of 6c, and that 7c would
then transform into the b-aryl product 7b in the same
way. It would be tempting to submit the crude mixture
of epoxides (a=b ꢀ 65=35) to the sequence arylation,
aromatization, and saponification, as the final product
should be 8b. Moreover, this should permit the use of
the small amount of dienone 6c, which was formed from
3a (Scheme 1), and which was previously lost during the
purification of 6b. Of course, to transform a preliminary
experiment into an industrial process took some time.

D. Prat et al. / Tetrahedron Letters 45 (2004) 765–768
767
X
O
X
X
O
O
AcO
7c
X
O
AcO
O
6b
7d
AcO
7b
Scheme 3. Proposed mechanism of A-ring aromatization (conditions: AcBr, Ac2O, CH2Cl2, rt).
The crude mixture of isomers (a=b ꢀ 2=1) was crystal-
lized from diisopropyl ether, leaving minor impurities in
the mother liquors. The yield was higher using hexa-
chloroacetone (85%) than hexafluoroacetone (80%).
Although the latter catalyst was slightly more stereo-
selective, it gave more side products.
as the batches of Drug Substances derived from it were
used in clinical trials.
These results were confirmed, using different mixtures of
epoxides containing from 50% to 75% of the b-isomer:
the overall yield (2a/b to 8b) was always in the range 55–
65%.
Arylation was carried out using 1.8 equiv of Grignard
reagent 4 and 0.15 equiv of copper(I) chloride, at 20 °C.
Work-up (aqueous ammonium chloride) and acidic
hydrolysis gave a mixture of aryl-dienones 6b, 6c, and 6a
(Scheme 4; the ratio of enones was estimated by NMR
spectroscopy). As mentioned above, 6c is not stable;
therefore, this mixture was rapidly submitted to aro-
matization (2.5 equiv of acetyl bromide, 1 equiv of acetic
anhydride, dichloromethane, rt), giving after 4–5 h 11b-
aryl-estrone acetate 7b as the main product. Again, it
was not isolated,14 but saponified to give the 11b-aryl-
estrone, which was crystallized as the hydrochloride 8b.
The yield from the mixture of epoxides was ca. 68%.
Only ca. 1% of the 11a-aryl isomer was detected in the
crude reaction mixture after saponification, and 0.15%
in the crystallized aryl-estrone hydrochloride. The purity
of 8b thus obtained (95%) was only slightly lower than
the purity (98%) of the previous batches starting from
95% pure a-epoxide. To keep the same profile of
impurities in this key intermediate was very important,
Thus, as expected, the deconjugated aryl-dienone 6c was
mainly transformed into 11b-aryl-estrone acetate 7b. On
the other hand, the fate of the small amount of 11a-
dienone 6a is less clear. As the amount of 8a in the crude
reaction mixture (1%) was lower than the initial pro-
portion of 6a in the mixture of dienones (2–3%), we
suggest that aromatization of the a-isomer also involved
the trienol acetate 7c as the kinetic product.
In conclusion, observation, and careful analysis of
secondary reactions permitted a breakthrough in a
classical sequence of reactions. Though we were unable
to achieve good stereoselectivity in the initial epoxida-
tion, we found a way to transform both epoxides at the
same time, thus doubling the overall yield. The com-
plete synthesis of the drug substance will be published
elsewhere.15 Again, despite all the knowledge accumu-
lated on norsteroids, they still reveal surprises to the
chemist.
O
O
O
°
1) LDA, TMSCl, THF, 0 C
H2O2, (Cl3C)2CO
°
2) 4, CuCl, THF, 0 C
°
CH2Cl2, 20-25 C
O
O
O
O
O
+
85%
°
3) aq. NH4Cl, CH2Cl2, 10 C
O
O
O
°
4) aq. HCl, CH2Cl2, 0-5 C
1
2a
2 : 1
2b
X
X
X
X
O
1) AcBr, Ac2O
CH2Cl2, 20-25 C
O
O
O
°
+
+
2) KOH, MeOH
O
°
0-5 C
O
O
3) HCl, CH2Cl2
HO
, HCl
6b (70-75%)
6c (20-25%)
6a (2-3%)
68%
8b
Scheme 4. Industrial synthesis of 11b-aryl-estrones.

768
D. Prat et al. / Tetrahedron Letters 45 (2004) 765–768
7. The Grignard reagent was prepared in two steps from 4-
Acknowledgements
bromo-phenol, 2-chloroethyl diethylamine hydrochloride,
and magnesium turnings, as described in Ref. 2 with the
parent piperidine derivative.
We would like to thank particularly Franßcois Nique,
Christian Moratille, and John Larkin, for fruitful dis-
cussions. Among the many colleagues involved in this
development work at the Romainville Research Center,
€
Marie Fenneteau (trainee), Joelle Bousquet and Pascal
Caboche are recognized for their contribution.
8. This type of dienone has been described by F. Nique,
Ref. 1b.
9. Analytical data for 6b: 11b-(4-(2-(diethylamino)ethoxy)-
phenyl)-estra-4,9-diene-3,17-dione: C30H39NO3, MW:
461.6, mp ¼ 188 °C; IR (CHCl3, cmꢁ1): 1735, 1658, 1609,
1581, 1509; 1H NMR (250 MHz, CDCl3, ppm): 0.56 (s,
3H), 1.06 (t, J ¼ 7 Hz, 6H), 2.63 (q, J ¼ 7 Hz, 4H), 2.85 (t,
J ¼ 6 Hz, 2H), 4.01 (t, J ¼ 6 Hz, 2H), 4.38 (d, J ¼ 7 Hz,
1H), 5.80 (s, 1H), 6.82 and 7.07 (AA0BB0, 4H); MS (EI,
m=z): 461 (Mþ).
References and notes
1. (a) Teutsch, G.; Belanger, A.; Philibert, D. Steroids 1981,
ꢀ
10. Analytical data for 6c: 11-(4-(2-(diethylamino)ethoxy)-
37, 361; (b) Nique, F.; Van de Velde, P.; Bremaud, J.;
Hardy, M.; Philibert, D.; Teutsch, G. J. Steroid Biochem.
Mol. Biol. 1994, 50, 21; (c) Van de Velde, P.; Nique, F.;
phenyl)-estra-5(10),9(11)-diene-3,17-dione:
C30H39NO3,
MW: 461.6; IR (CHCl3, cmꢁ1): 1733, 1712, 1607, 1568,
1508; 1H NMR (250 MHz, CDCl3, ppm): 1.03 (s, 3H),
1.12 (t, J ¼ 7 Hz, 6H), 2.72 (q, J ¼ 7 Hz, 4H), 2.94 (t,
J ¼ 6 Hz, 2H), 4.09 (t, J ¼ 6 Hz, 2H), 6.82 and 7.07
(AA0BB0, 4H); MS (EI, m=z): 461 (Mþ), 100.
ꢀ
Bouchoux, F.; Bremaud, J.; Hameau, M. C.; Lucas, D.;
Moratille, C.; Viet, S.; Philibert, D.; Teutsch, G. J. Steroid
Biochem. Mol. Biol. 1994, 48, 187; (d) Jin, L.; Borras, M.;
Lacroix, M.; Legros, N.; Leclercq, G. Steroids 1995, 60,
512; (e) Aliau, S.; Delettre, G.; Mattras, H.; El Garrouj,
D.; Nique, F.; Teutsch, G.; Borgna, J. L. J. Med. Chem.
2000, 43, 613.
11. Analytical data for 6a: 11a-(4-(2-(diethylamino)ethoxy)-
phenyl)-estra-4,9-diene-3,17-dione: C30H39NO3, MW:
461.6; 1H NMR (250 MHz, CDCl3, ppm): 1.02 (s, 3H),
1.12 (t, J ¼ 7 Hz, 6H), 2.69 (q, J ¼ 7 Hz, 4H), 2.91 (t,
J ¼ 7 Hz, 2H), 4.05 (m, 3H), 5.72 (s, 1H), 6.79 and 6.95
(AA0BB0, 4H); MS (ESP, m=z): 462 (MHþ).
2. Larkin, J. P.; Wehrey, C.; Boffelli, P.; Lagraulet, H.;
Lemaitre, G.; Nedelec, A.; Prat, D. Org. Process. Res.
Dev. 2002, 6, 20.
12. (a) Danishefsky, S.; Cain, P.; Nagel, A. J. Am. Chem. Soc.
1975, 97, 380; (b) Danishefsky, S.; Cain, P. J. Am. Chem.
Soc. 1975, 97, 5282; (c) Joly, R.; Joly, J. FR 81840, 1962
(Roussel Uclaf); Chem. Abstr. 1964, 60, 14566.
13. Analytical data for 8b: 11b-(4-(2-(diethylamino)ethoxy)-
phenyl)-estra-1,3,5(10)-trien-3-ol-17-one hydrochloride:
C30H40ClNO3, MW: 498.1, mp ¼ 189 °C; IR (CHCl3,
cmꢁ1): 3601, 2456, 1733, 1610, 1584, 1511; 1H NMR
(250 MHz, CDCl3, ppm): 0.42 (s, 3H), 1.31 (m, 6H), 3.16
(m, 4H), 3.31 (m, 2H), 3.96 (t, J ¼ 6 Hz, 1H), 4.17 (m, 2H),
6.51 (m, 1H), 6.68 (m, 1H), 6.73 (m, 1H), 6.51 and 6.95
(AA0BB0, 4H), 11.36 (s, 1H); MS (EI, m=z): 461 (Mþ), 446,
362, 86, 38, and 36 (HCl).
14. Variable amounts of 8b (as base) were formed during the
aqueous work-up after aromatization. Isolation of 7b
would thus have resulted in some loss of this intermediate.
15. Prat, D.; Benedetti, F.; Franc Girard, G.; Nait Bouda, L.;
Larkin, J.; Wehrey, C.; Lenay, J. Org. Process. Res. Dev.,
submitted.
3. (a) Teutsch, G.; Belanger, A. Tetrahedron Lett. 1979, 20,
2051; (b) Rao, P. N.; Taraporewala, I. B. Steroids 1992,
57, 154; (c) Scholz, S.; Hofmeister, H.; Neef, G.; Ottow,
E.; Scheidges, C.; Wiechert, R. Lieb. Ann. Chem. 1989,
151; (d) Napolitano, E.; Fiachi, R.; Hanson, R. N. Gazz.
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Duchesne, M. J.; Auzou, G.; Pons, M.; Nique, F.;
Teutsch, G.; Borgna, J. L. J. Med. Chem. 1997, 40, 2217.
4. (a) Greene, T. W.; Wuts, P. G. Protective Groups in
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G.; Heberle, J. Silylating Agents; Fluka Chemica, Fluka
Chemie AG: Buchs, Switzerland, 1995; (c) Lipshutz, B. H.;
Wood, M. R.; Lindsley, C. W. Tetrahedron Lett. 1995, 36,
4385.
5. Costerousse, G.; Teutsch, G. EP 5100, 1979 (Roussel Uclaf).
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G.; Lenay, J.; Vivat, M.; Buendia, J.; Prat, D. Org.
Process. Res. Dev. 1997, 1, 2.