Organic Process Research & Development 2002, 6, 20−27
The Synthesis of 17r-Methyl-11â-arylestradiol: Large-Scale Application of the
Cerium (III)-Mediated Alkylation of a Ketone
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John Patrick Larkin, Christian Wehrey, Philippe Boffelli, Henri Lagraulet, Guy Lemaitre, Alban Nedelec, and
Denis Prat*,‡
AVentis Pharma, 102 Route de Noisy, 93235 RomainVille Cedex, France
Abstract:
7r-Methyl-11â-arylestradiol (17r-methyl-11â-(4-(2-(1-piperi-
bromide and acetic anhydride, (5) stereospecific alkylation
at the 17R-position by methylmagnesium chloride and cerium
trichloride at room temperature.
Although the synthesis itself was not changed during this
development work, the scaling-up of the aromatization
reaction and of the alkylation at the 17-position required
significant optimization work.
1
dinyl)ethoxy)phenyl)estra-1,3,5(10)-triene-3,17â-diol) is a new
molecule developed by Aventis Pharma for the treatment of
osteoporosis. It was produced on the pilot plant scale from the
norsteroid intermediate ethylene deltenone (3,3-ethylenedioxy-
estra-5(10)-9(11)-diene-17-one). Stereoselective epoxidation of
the 5(10)-olefin was performed by hydrogen peroxide and
hexachloroacetone, the most selective of the systems tested. The
Results
1
1â-aryl appendage was introduced as a cuprate generated
1. Epoxidation. Ethylene deltenone 1 was chosen as the
starting material of the synthesis. It is a well-known industrial
intermediate for norsteroids, particularly Trimegestone. The
catalytically from the related Grignard reagent. The A-ring was
aromatized by a mixture of acetyl bromide and acetic anhy-
dride. This reaction was optimized by a Design Of Experiments
carried out on an automated workstation. The advantages and
limits of this approach are discussed. The last step consisted of
the stereospecific alkylation of the 17-ketone by methylmagne-
sium bromide and dehydrated cerium trichloride. The drug
substance was crystallized as a hydrate (overall yield ) 23%).
2
introduction of the aromatic moiety at the 11â-position
requires an almost diastereomerically pure 5(10)-R-epoxide
2. As the previously described epoxidation of 1 using
3
hydrogen peroxide and hexachloroacetone or hexafluoro-
4
acetone is poorly stereoselective (R/â ≈ 2/1) as a result of
the lack of steric differentiation between both sides of the
substrate, we investigated alternative, recently described
5
-11
systems
(Table 1).
With all systems, the R-isomer was the major isomer
formed, but with different chemo- and regioselectivities
observed. We tested first the catalysis by other electron-
deficient ketones developed by Schering A.G., but we could
not reproduce the excellent diastereoselectivities described
Introduction
The treatment of osteoporosis is a key challenge of this
century. The decrease in bone mineral density after menopose
induces a risk of fractures (mainly hip and femur) in the
increasingly senior female population.
The main preventive treatment consists of the regular
intake of estradiol, which slows down the bone loss, but not
without side effects. The ideal drug would have the beneficial
effects of estradiol on bone without the side effects on the
other tissues.
5
(up to 9/1 with trifluoroacetophenone) (entry 3). Moreover,
(2) Crocq, V.; Masson, C.; Winter J.; Richard, C.; Lemaitre, G.; Lenay, J.;
Vivat, M.; Buendia, J.; Prat, D.; Org. Process. Res. DeV. 1997, 1, 2.
(
3) (a) Costerousse, G.; Teutsch, G.; EP 5100 (Roussel Uclaf). (b) Neef, G.;
Ast, G.; Michl, G.; Schwede, W.; Vierhufe, H. Tetrahedron Lett. 1994, 35,
8587. (c) Ottow, E.; Beier, S.; Elger, W.; Henderson, D. A.; Neef, G.;
Wiechert, R.; Steroids 1984, 44, 519. (d) Scholz, S.; Hofmeister, H.; Neef,
G.; Ottow, E.; Scheidges, C.; Wiechert, R.; Liebiegs Ann. Chem. 1989,
151. (e) Rao, P. N.; Taraporewala, I. B.; Steroids 1992, 57, 154.
17R-Methyl-11â-arylestradiol 6 is a new molecule de-
veloped by Hoechst Marion Roussel, now Aventis Pharma,
for the treatment of osteoporosis. Its steroid structure is an
advantage in terms of tolerance and specificity of action.
For the supply of the preclinical and phase I studies,
several batches of drug substance were prepared in the pilot
plant from the known norsteroid intermediate 1 (Scheme 1)
by a short sequence involving: (1) stereoselective epoxida-
tion by hydrogen peroxide catalyzed by hexachloroacetone,
(4) (a) Teutsch, G.; Belanger, A.; Philibert, D.; Tournemire, C. Steroids 1982,
39, 607. (b) Napolitano, E.; Fiachi, R.; Hanson, R. N. Gazz. Chim. Ital.
1
1990, 120, 323.
(
(
5) Nickisch, K.; Hanfried, A.; Rohde, R.; EP 298,020 (Schering A. G.).
6) (a) N e´ d e´ lec, L.; Bull. Soc. Chim. Fr. 1970, 2548. (b) Nemoto, H.; Nagai,
M.; Fukumoto, K.; Kametami, T.; J. Chem. Soc., Perkin Trans. 1 1986,
1621
(
7) (a) Herrmann, W. A.; Fischer, R. W.; Scherer, W.; Rauch, M. U. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1157. (b) Al-Ajlouni, A. M.; Espenson, J.
H. J. Org. Chem. 1996, 61, 3969. (c) Abu-Omar M. M.; Hansen, P. J.;
Espenson, J. H.; J. Am. Chem. Soc. 1996, 118, 4966. (d) Herrmann, W. A.;
Ding. H.; Kratzer, R. M.; K u¨ hn, F. E.; Haider, J. J.; Fischer, R. W. J.
Organomet. Chem. 1997, 549, 319. (e) Gisdakis, P.; Antonczak, S.;
K o¨ stlmeier, S.; Herrmann, W. A.; R o¨ sch, N. Angew. Chem., Int. Ed. 1998,
(2) protection of the 17-keto group as a silyl enol ether, (3)
stereospecific arylation at the 11-position by a cuprate
generated catalytically from the corresponding Grignard
reagent, (4) aromatization of the A-ring by a mixture of acetyl
3
7, 2211 and references therein.
8) Rudolph, J.; Reddy, K. L.; Chiang, J. P. J. Am. Chem. Soc. 1997, 119,
189.
(
6
†
Chemical Development, Aventis Pharma.
Process Development, Aventis Pharma.
(9) Herrmann, W. A.; Kratzer, R. M.; Ding, H.; Thiel, W. R.; Glas, H. J.
Organomet. Chem. 1998, 555, 293.
‡
(
1) Bouali, Y.; Nique, F.; Teutsch, G.; Van De Velde, P.; FR 2,757,519 (Roussel
Uclaf).
(10) Cop e´ ret, C.; Adolfsson, H.; Sharpless, K. B. Chem. Commun. 1997, 1565.
(11) Adam, W.; Mitchell, C. M. Ang. Chem., Int. Ed. Engl. 1996, 35, 533.
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Vol. 6, No. 1, 2002 / Organic Process Research & Development
10.1021/op010051w CCC: $22.00 © 2002 American Chemical Society and The Royal Society of Chemistry
Published on Web 12/14/2001