An environmentally friendly and cost effective synthesis of estradiol featuring two novel reagents: Si(0)/KF and PMHS/hexamethyldisiloxane/pTSA

Article abstract of DOI:10.1016/j.tetlet.2006.06.136

Si(0)/KF is introduced as a strong, inexpensive, environmentally friendly, and safe reagent for 'dissolving metal'-type reduction. PMHS/hexamethyldisiloxane/pTSA is introduced as an inexpensive substitute for Et₃SiH/TFA for 'ionic hydrogenation', where the hexamethyldisiloxane functions as a capping agent to block the oligomeric silicone by-product from cross-linking to a gel, rubber, or plastic. An environmentally friendly and cost effective synthesis of estradiol is described which showcases these new reagents.

Full text of DOI:10.1016/j.tetlet.2006.06.136

Tetrahedron Letters 47 (2006) 6417–6420
An environmentally friendly and cost effective synthesis of
estradiol featuring two novel reagents: Si(0)/KF and
PMHS/hexamethyldisiloxane/pTSA
Chongsoo Lim, Gerald N. Evenson, William R. Perrault and Bruce A. Pearlman*
Chemical Research and Development, 31073-091-201, Pfizer, Inc., 7000 Portage Road, Kalamazoo, MI 49001-0102, USA
Received 21 March 2006; revised 26 June 2006; accepted 26 June 2006
Abstract—Si(0)/KF is introduced as a strong, inexpensive, environmentally friendly, and safe reagent for ‘dissolving metal’-type
reduction. PMHS/hexamethyldisiloxane/pTSA is introduced as an inexpensive substitute for Et SiH/TFA for ‘ionic hydrogenation’,
3
where the hexamethyldisiloxane functions as a capping agent to block the oligomeric silicone by-product from cross-linking to a gel,
rubber, or plastic. An environmentally friendly and cost effective synthesis of estradiol is described which showcases these new
reagents.
Ó 2006 Elsevier Ltd. All rights reserved.
Estradiol-3-bis(2-chloroethyl)carbamate (estramustine)
is an antineoplastic agent used for treatment of prostate
cancer. Estradiol-3-benzoate and estradiol-17-cyclo-
tetralin (540–650 °C, 0.1–3 s) gives estrone in reported
yields of over 80% on laboratory scale, but co-formation
of tar and soot render scale up technically challenging
1
6
pentylpropionate are active pharmaceutical ingredients
(Scheme 1). Heating ADD-17-ethylene ketal with an al-
(
API’s) in hormone replacement treatments. Estradiol
kali metal (Li or Na) and an aromatic hydrocarbon
7
,8
itself is an ingredient in animal growth regulation prod-
ucts. To make these pharmaceuticals available to the
worldwide patient population, an efficient synthesis of
estradiol is needed.
(biphenyl, phenanthrene, etc.) in refluxing THF
2
8
affords estrone-17-ethylene ketal in 86% yield, but the
difficulties in running Birch-type reactions on commer-
5
c
cial scale have been discussed. Recently, it has been
reported that treatment of ADD with NaH Al(OCH -
2
2
A number of elegant total syntheses of estradiol have
been developed over the years.3,4 However, to obtain
estradiol in commercial quantity economically, pharma-
ceutical companies generally employ ‘semisynthetic’
CH OCH ) (to give the 3,17-diol) followed by 5 equiv
n-BuLi (PhMe, 100 °C) gives estradiol in 75% yield.
2 3 2
9
Androsta-1,4,9-triene-3,17-dione (ATD) is readily avail-
able from soy sterols by a short series of efficient micro-
routes that start from androsta-1,4-diene-3,17-dione
5
10
11
(
ADD) since ADD is available in one step by microbial
biological and chemical steps. In principle, ATD
should undergo methyl expulsion under milder condi-
tions than ADD because ATD contains a double bond
at 9(11) that is orthogonal to the C10–C19 bond. In-
deed, it has been reported that treatment of ATD with
5
c
degradation of soy sterols and can be converted into
estrone in one step (Scheme 1).
One drawback of the semisynthetic approach via ADD
is that cleavage of the C10–C19 carbon–carbon bond re-
quires harsh conditions. Controlled cracking of ADD in
1
2
the mild reducing agent zinc (pyridine/H O, D) gives
2
O
O
H3C
H
H3C
H
1
9
540 - 650 o
0.1-3 secs.
C
H3C
Keywords: Silicon(0); Potassium fluoride; PMHS/hexamethyldisilox-
ane/pTSA; ATD; Estradiol.
1
0
H
H
H
H
*
Corresponding author at present address: Schering-Plough Research
Institute, 1011 Morris Ave., U-3-2 2100, Union, NJ 07083, USA.
Tel.: +1 908 820 6106; fax: +1 908 820 6640; e-mail: bruce.
pearlman@spcorp.com
O
HO
ADD
Estrone (>80% on lab scale)
Scheme 1. Pyrolytic process for synthesis of estrone.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.136

6418
C. Lim et al. / Tetrahedron Letters 47 (2006) 6417–6420
O
O
In order to avoid the waste of electrons to hydrogen
H3C
H
H3C
H
1
1
formation as well as the formation of ‘silicate cement’,
fluoride was investigated as silicon activator under
anhydrous conditions. Fluoride increases the reduction
potential of silicon(0) only slightly less than hydroxide
H3C
77 equiv Zn, 6 equiv H2O
pyridine,Δ , 20 min.
9
H
H
O
HO
Δ9-Estrone (93.3%)
ATD
(
Table 1). Treatment of ATD with 5 equiv silicon pow-
der and 5 equiv potassium fluoride in 2/1 DEGME/
Scheme 2. Zinc/pyridine reduction of ATD.
1
8
EG (140 °C, 2 h) afforded, after extractive workup
9
9
and crystallization, D -estrone in 92.1% yield (Scheme
D -estrone in 93.3% yield without protection of the C17
ketone (Scheme 2). However, an extreme excess of
freshly activated zinc dust (77 equiv) is required. Such
a large amount of zinc dust is difficult to suspend in or-
ganic solvents without resorting to high dilution condi-
3
). The reaction mixture remained easily stirrable
throughout the course of the reaction.
The evolved gas from the reaction was collected and
analyzed by Raman spectroscopy. It was found to con-
sist of a mixture of hydrogen and methane (identified by
3
tions due to the high density of zinc metal (7.133 g/cm ).
ꢀ
1
characteristic peaks at 2917, 3020, and 3072 cm ). The
amounts were not quantitated. The source of the hydro-
gen atom that is abstracted by the expelled methyl group
to give methane was not determined.
Silicon(0) should be an ideal commercial scale reducing
agent because it is inexpensive (150 USD/kg for
1
3
ꢀ
325 mesh powder from Aldrich), safe to handle, gen-
erates silicate by-products of relatively low toxicity, has
3
a sufficiently low density (2.33 g/cm ) to be easily sus-
To complete the synthesis, first the C17 ketone was re-
duced with sodium borohydride. The reduction is conve-
niently carried out using commercially available 12%
pendable in organic solvents, and has a reduction poten-
tial (ꢀ0.8 V) more negative than that of zinc (ꢀ0.497 V)
so that, thermodynamically, silicon(0) is a stronger
1
4
NaBH /40% NaOH solution in methanolic caustic as
4
reducing agent than zinc (Table 1).
solvent, as these conditions are safer than using solid
sodium borohydride and permit higher throughput
On treatment of ATD with 5 equiv silicon(0)
ꢀ325 mesh powder) in 2/1 diethyleneglycol monoethyl
ether (‘DEGME’)/ethylene glycol (EG) at 120 °C for
h, no reaction occurred. Thus, just as zinc requires
(
(
Scheme 4). The reduction is highly stereoselective
0.9% 17-epi).
(
2
The final challenge was to reduce the 9(11) double bond
stereoselectively. In the final step of Torgov’s classic
activation by pyridine, silicon(0) requires activation to
function as a reducing agent. Ferrosilicon is inert to
water but reacts with 20% aqueous sodium hydroxide
8
synthesis of estradiol, D -estradiol is stereoselectively
1
5
reduced to estradiol by treatment with Et
3
SiH/TFA
at 100 °C to generate hydrogen gas at a rapid rate.
2
0
(PhH, rt, 3 h; 96% yield after workup with hydroxide).
Sodium hydroxide activates the ferrosilicon by increas-
ing its reduction potential (Table 1) and/or by dissolving
a silicon dioxide overlayer to expose surface silicon
However, one drawback of this process is that both tri-
ethylsilane and trifluoroacetic acid are relatively expen-
sive. Also triethylsilanol and silyl ether by-products
1
6
atoms. Our interest was to investigate whether the
electrons from the silicon(0) could be intercepted by
2
1
complicate product isolation/purification.
9
ATD to give D -estrone rather than reduce water to give
Although Et SiH/TFA is the ‘most frequently
3
hydrogen.
2
2
reported’ reagent used for ‘ionic hydrogenation’, poly-
methylhydrosiloxane (‘PMHS’; Me SiO(HSiMeO) -
3
n
Treatment of ATD with 5 equiv silicon(0) powder
SiMe , where n ꢁ 35) is ‘most economically favored
3
(
ꢀ325 mesh) and 5 equiv sodium hydroxide or potas-
sium carbonate in 2/1 DEGME/EG (120 °C, 2.5 h) gave
mainly hydrogen gas (identified by Raman spectro-
9
scopy) along with minor amounts of D -estrone. The
silicon clumped up during the reaction, presumably
O
O
H3C
H
H3C
H
H3C
5 equiv Si(0), 5 equiv KF
due to coating of its surface with sodium silicate (so-
1
7
H
/1 DEGME/EG, 140 oC, 2 h
H
2
called ‘silicate cement’ ). By including a small amount
of water (5 vol %) and doubling the amounts of silicon
and potassium carbonate, it was possible to attain a
O
HO
Δ9-Estrone (92.1% yield
corr for 97.8% purity])
ATD
9
[
yield of 52–53% of D -estrone, but clumping was still a
problem.
19
Scheme 3. ATD Si(0)/KF reduction protocol.
O
OH
H3C
H3C
H
1
4
Table 1. Reduction potentials of zinc and silicon
0
.5 equiv NaBH4, 4.2 equiv NaOH
H
Electrochemical equation
Reduction potential
aq. MeOH, 0 oC to rt, 30 min.;
add aq. HCl, filter (99.9%)
H
H
+
ꢀ
ꢀ
ZnO + 2H + 2e ꢀ Zn + H
2
O
ꢀ0.497 V
ꢀ0.8 V
HO
HO
+
SiO + 2H + 2e ꢀ Si + H
2
O
Δ9-Estradiol
ꢀ
2
ꢀ
ꢀ
Δ9-Estrone
SiF6 þ 4e ꢀ Si þ 6F
ꢀ1.24 V
ꢀ1.697 V
ꢀ
2
ꢀ
ꢀ
SiO3 þ 3H2O þ 4e ꢀ Si þ 6OH
Scheme 4. Borohydride reduction step.

C. Lim et al. / Tetrahedron Letters 47 (2006) 6417–6420
6419
for large-scale reductions’.22 Applications of PMHS in
(Me Si) O, which functions as a capping agent to block
3 2
2
3
organic synthesis have been reviewed. However, one
disadvantage of PMHS is that, under both acidic and
basic conditions, the oligomeric chains tend to cross-link
to form a polymer that separates from the reaction mix-
the oligomeric silicone by-product from cross-linking to
a gel, rubber, or plastic. The synthesis is environmen-
tally friendly because the silicon-containing by-products
have low toxicity.
2
3a,d,24
ture as a gel, rubber, or plastic.
This precipitate
could render a plant reactor inoperable or, at best, very
difficult to clean. This longstanding problem has limited
applications of PMHS on commercial scale.
Acknowledgements
9
The authors thank Dr. Thomas J. Thamann (Pfizer
Analytical Research and Development, Kalamazoo)
for analysis of the evolved gas and Dr. Douglas A.
Livingston for suggesting the concept of capping the
silicone by-product.
Attempted reduction of D -estradiol by treatment with
2
5
26
3
.0 equiv PMHS
and 4.0 equiv anhyd pTSA
(
CH Cl , MeOH, ꢀ20 °C!rt) gave estradiol cleanly,
2
2
but the silicone by-product formed a solid crust that
covered the surface of the reaction mixture. It is known
that (HSiMeO) equilibrates with (Me Si) O in the pres-
5
3
2
2
7
ence of acid to give the monomer (Me SiO) SiMeH.
Thus, it was speculated that, if the above D -estradiol
reduction experiment were run with added (Me Si) O,
3
2
9
References and notes
3
2
the silicone by-product would equilibrate to the mono-
mer (Me SiO) SiMeOMe, which would remain in
solution.
1
. (a) Niculescu-Duvaz, I.; Cambanis, A.; Tarnauceanu, E. J.
Med. Chem. 1967, 10, 172; (b) Fex, H. J.; Hogberg, K. B.;
Konyves, I.; Kneip, P. H. O. J.; U.S. Patent 3,299,104,
January 17, 1967.
3
2
9
Indeed, on treatment of D -estradiol with 3.0 equiv
2. Beermann, D. H. In Kirk-Othmer Encycl. Chem. Tech., 4th
ed.; Kroschwitz, J. I., Ed.; John Wiley and Sons: New
York, NY, 1994; Vol. 12, p 795.
PMHS and 4.0 equiv anhyd pTSA in the presence of
2
8
29
1
.1 equiv
(Me Si) O (CH Cl ,
6.1 equiv MeOH,
3
2
2
2
3
. Reviews: (a) Windholz, T. B.; Windholz, M. Angew.
Chem., Int. Ed. Engl. 1964, 3, 353; (b) Klimstra, P. D.;
Colton, F. B. In Contraception: The Chemical Control of
Fertility; Lednicer, D., Ed.; Marcel Dekker: New York,
NY, 1969; pp 69–159; (c) Taub, D. In The Total Synthesis
of Natural Products; ApSimom, J., Ed.; Wiley: New York,
NY, 1973; Vol. 2, p 641; (d) Eder, U. J. Steroid Biochem.
1979, 11, 55; (e) Kametani, T. Pure Appl. Chem. 1979, 11,
55; (f) Funk, R. L.; Vollhardt, K. P. C. Chem. Soc. Rev.
ꢀ
25 to 38 °C, 1 h), the double bond underwent smooth
reduction to give estradiol with high stereoselectivity
(
9a/b ꢁ 94/6). As the reaction progressed, the reaction
mixture divided into two liquid phases: a colorless upper
phase consisting of the neat silicone by-product (pre-
sumably (Me SiO) MeSiOMe and higher oligomers)
3
2
and a lower CH Cl /MeOH phase containing estradiol,
2
2
9
-epi-estradiol, and pTSA. When the reaction was com-
1
1
980, 9, 41; (g) Kametani, T.; Nemeto, H. Tetrahedron
981, 37, 3; (h) Quinkert, G.; Stark, H. Angew. Chem., Int.
plete, the reaction mixture was quenched into aq potas-
sium carbonate. This extracts the pTSA and essentially
all the methanol out of the CH Cl layer, thus reducing
Ed. Engl. 1983, 22, 637; (i) Vollhardt, K. P. C. Pure Appl.
Chem. 1985, 57, 1819.
2
2
the solubility of the estradiol, causing it to crystallize
out, leaving essentially all of the 9-epi-estradiol as well
as the silicone by-product in the filtrate. After recrystal-
lization from acetone/water, crystalline estradiol hemi-
hydrate was obtained in 72.8% yield (Scheme 5). The
4
. Recent total syntheses of estrone/estradiol: (a) Tietze, L.
F.; Nobel, T.; Spescha, M. J. Am. Chem. Soc. 1998, 120,
8
971; (b) Rigby, J. H.; Warshakoon, N. C.; Payen, A. J. J.
Am. Chem. Soc. 1999, 121, 8237; (c) Hu, Q.-Y.; Rege, P.
D.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 5984.
3
0,31
yield was 67.0% (overall from ATD).
5. Reviews on industrial synthesis of estrogenic steroids: (a)
Djerassi, C.; Rosenkranz, G.; Romo, J.; Kaufmann, S.;
Pataki, J. J. Am. Chem. Soc. 1950, 72, 4534; (b) Wiechert,
R. Angew. Chem., Int. Ed. Engl. 1970, 9, 321; (c) Djerassi,
C. Proc. Royal Soc. London B 1976, 195, 175; (d)
Wiechert, R. Angew. Chem., Int. Ed. Engl. 1977, 16, 506;
In summary, an environmentally friendly and cost effec-
tive synthesis of estradiol is described. The synthesis
starts with a readily available steroidal raw material
(
ATD). The C19 methyl group is expelled by treatment
(
e) Imada, Y. J. Synth. Org. Chem. Jpn. 1983, 41, 1008; (f)
with Si(0)/KF, the C17 ketone is reduced by treatment
Ray, S.; Lal, K. J. Sci. Ind. Res. 1984, 43, 133; (g)
Nagoshi, H.; Kinugasa, K. In Steroid Analysis in the
Pharmaceutical Industry; Gorog, S., Ed.; Ellis Horwood:
Chichester, UK, 1989; Chapter 4.2.
with NaBH , then the 9(11) double bond is reduced by
4
treatment with PMHS in the presence of pTSA and
6
. (a) Inhoffen, H. H. Angew. Chem. 1940, 53, 471; (b)
Inhoffen, H. H.; Zuhlsdorff, G. Ber. 1941, 74, 1911; (c)
Inhoffen, H. H. U.S. Patent 2,280,828, April 28, 1942; (d)
Inhoffen, H. H. Angew. Chem. 1947, 59, 207; (e) Buback,
M.; Hader, J.; Voegele, H.-P.; Al-Massri, Z. U.S. Patent
5,151,533, September 29, 1992.
OH
OH
H3C
H
H3C
H
1) 3.0 equiv PMHS, 1.1 equiv (Me3Si)2O
4.0 equiv anh pTSA, 6.1 equiv MeOH,
H
H
H
o
o
HO
CH2Cl2, -25 C to 38 C, 1 h;
add to aq. K2CO3, filter
HO
7. (a) Dyden, H. L., Jr.; Webber, G. M.; Wieczorek, J. J. J.
Am. Chem. Soc. 1964, 86, 742; (b) Dryden, H. L., Jr.;
Webber, G. M. U.S. Patent 3,274,182, September 20,
Δ9-Estradiol
Estradiol
2) recrystallize from acetone/water
7
9
2.8% yield (corr for
7.1% purity)
1
966.
9
Scheme 5. ‘Ionic hydrogenation’ of D -estradiol with PMHS/
8. Modderman, P. U.S. Patent 3,415,853, December 10,
1968.
3 2
(Me Si) O/pTSA.

6420
C. Lim et al. / Tetrahedron Letters 47 (2006) 6417–6420
9
. Vasiljeva, L. L.; Demin, P. M.; Kochev, D. M.; Lapits-
kaya, M. A.; Pivnitsky, K. K. Russ. Chem. Bull. 1999, 48,
93.
22. Arkles, B. In Kirk-Othmer Encycl. Chem. Tech., 4th ed.;
Kroschwitz, J. I., Ed.; John Wiley and Sons: New York,
NY, 1997; Vol. 22, p 38.
5
1
0. (a) Wovcha, M. G.; Antosz, F. J.; Knight, J. C.; Kominek,
23. Reviews: (a) Lipowitz, J.; Bowman, S. A. J. Org. Chem.
1973, 38, 162; (b) Lipowitz, J.; Bowman, S. A. Aldrichim.
Acta 1973, 6, 1; (c) Nagai, Y. Org. Prep. Proc. Intl. 1980,
12, 13; (d) Lawrence, N. J.; Drew, M. D.; Bushell, S. M. J.
Chem. Soc., Perkin Trans. 1 1999, 3381.
24. (a) Sauer, R. O.; Scheiber, W. J.; Brewer, S. D. J. Am.
Chem. Soc. 1946, 68, 962; (b) Laine, R. M.; Rahn, J. A.;
Youngdahl, K. A.; Babonneau, F.; Hoppe, M. L.; Zhang,
Z.-F.; Harrod, J. F. Chem. Mater. 1990, 2, 464; (c) Xin, S.;
Aitken, C.; Harrod, J. F.; Mu, Y.; Samuel, E. Can. J.
Chem. 1990, 68, 471; (d) Verdaguer, X.; Hansen, M. C.;
Berk, S. C.; Buchwald, S. L. J. Org. Chem. 1997, 62, 8522.
25. Dow Corning 1107.
L. A.; Pyke, T. R. Biochim. Biophys. Acta 1978, 531, 308;
(
b) Evans, T. W.; Kominek, L. A.; Wolf, H. J.; Hender-
son, S. L. U.S. Patent 4,749,649, June 7, 1988.
1
1
1. Beaton, J. M.; Huber, J. E.; Padilla, A. G.; Breuer, M. E.
U.S. Patent 4,127,596, November 28, 1978.
2. (a) Tsuda, K.; Ohki, E.; Nozoe, S.; Ikekawa, N. J. Org.
Chem. 1961, 26, 2614; (b) Tsuda, K.; Oki, E.; Nozoe, S.;
Okada, Y. U.S. Patent 3,040,036 and U.S. Patent
3,040,037, June 19, 1962; (c) Tsuda, K.; Ohki, E.; Nozoe,
S. J. Org. Chem. 1963, 28, 786.
1
3. Ferrosilicon (an inexpensive alloy of silicon and iron
used in the production of carbon steel) was once used by
the military to generate hydrogen gas to fill naval
26. Anhyd pTSA is commercially available from InterTrade
Organics, Inc. It is an intermediate in the synthesis of the
monohydrate and is thus cheaper. Although it contains
several minor impurities (typically 4% of the ortho isomer,
1.0% ‘sulfones’, 0.3% sulfuric acid, and <1.0% water), they
are innocuous. It is a sticky brown wax which liquifies at
approx. 50 °C. However, using jacketed totes, it can be
easily charged to a reactor as a melt. Since it is anhydrous,
1
5
balloons. Although not the most economical source
of hydrogen gas, ferrosilicon was used because it is non-
combustible and thus is safe enough to store and handle
aboard ship.
1
4. Vanysek, P. In Handbook of Chemistry and Physics,
7
1
6th ed.; Lide, D. R., Ed.; CRC Press: Boca Raton,
995; pp 8–21.
9
1
5. Weaver, E. R. J. Ind. Eng. Chem. 1920, 12, 232.
less methanol is required to dissolve the D -estradiol than
1
6. (a) Okamoto, M.; Suzuki, E.; Ono, Y. J. Catal. 1994, 145,
with the monohydrate, thus the reduction is faster.
27. Stober, M. R.; Musolf, M. C.; Speier, J. L. J. Org. Chem.
1965, 30, 1651.
537; (b) Okamoto, M.; Abe, H.; Kusama, Y.; Suzuki, E.;
Ono, Y. J. Organomet. Chem. 2000, 616, 74.
1
1
7. Gallagher, J. P. U.S. Patent 3,895,102, July 15, 1975.
8. A mixed solvent of DEGME and EG was chosen because
it was found to insure dispersability of both the silicon(0)
powder and the silicate by-products.
28. The amount of (Me Si) O required to prevent the gel/
3
2
rubber/plastic from forming was not determined.
29. To control emissions of CH Cl , the reactor vent may be
2
2
tied to a cryogenic condenser and/or thermal oxidizer.
9
1
9. Experimental procedure: A mixture of ATD (10.0 g,
30. Experimental procedure: To a mixture of D -estradiol (30 g,
3
4
1
5.4 mmol, 1 equiv), silicon(0) powder (ꢀ325 mesh;
.97 g, 177 mmol, 5 equiv), potassium fluoride (10.3 g,
77 mmol, 5 equiv), diethylene glycol monoethyl ether
0.111 mol, 1 equiv), hexamethyldisiloxane (HMDSO; 27 g,
0.13 mol,1.1 equiv),andpolymethylhydrosiloxane(PMHS;
20 g, 0.33 mol, 2.8 equiv) in methanol (12.8 mL, 0.316 mol,
3 equiv) and methylene chloride (120 mL) was added a
solution of anhyd pTSA (77 g, 0.45 mol, 4.0 equiv) in
methanol (12.3 mL, 0.30 mol, 2.7 equiv) and methylene
chloride (75 mL) while maintaining the pot temperature at
ꢀ30 to ꢀ25 °C. The pTSA solution was rinsed in with
methanol (2.5 mL, 0.063 mol, 0.56 equiv) and methylene
chloride (2.5 mL). The mixture was warmed to 38 °C and
stirred 1 h. The resulting two phase mixture was then added
to a mixture of potassium carbonate (44 g, 0.32 mol,
2.9 equiv) and water (300 mL), rinsing with 30 mL methyl-
ene chloride (30 mL). The resulting slurry was cooled to
15 °Candfiltered.Thecakewaswashedwithwater(320 mL)
and methylene chloride (142 mL) and dried to afford crude
estradiol (weight: 25.6 g). A portion of the solids (25.0 g,
(
140 mL) and ethylene glycol (70 mL) was heated to 90 °C,
at which point mild gas evolution began to occur. When
the temperature reached 120 °C, an exotherm to 140 °C
occurred. After 2 h, the reaction was judged complete by
TLC. The mixture was cooled to rt, poured into 1000 mL
1
N HCl (aq) and 500 mL THF, and the layers separated.
The organic layer was filtered through a pad of magnesol
on a glass frit (coarse porosity). The filtrate was concen-
trated to remove THF, causing solids to precipitate. The
slurry was filtered and the solids dried by nitrogen stream
overnight to give a solid identified as D -estrone by
NMR,
9
13
C
1
H NMR, HPLC retention time, and UV
(k
max = 263 nm) comparison with an authentic reference
standard. Weight: 8.95 g (92.1% yield [corrected for 97.8%
purity]). C NMR (100 MHz, pyridine-d ): d 220.4 (s);
1
3
9
from 0.108 mol D -estradiol) was dissolved in acetone
5
1
58.1 (s); 138.1 (s); 136.2 (s); 126.2 (s); 126.1 (d); 116.1 (d);
(275 mL) and water (6.25 mL) at 58 °C. The solution was
concentrated by atmospheric distillation to a volume of
137 mL. Water (21 mL) was added and the mixture was
concentrated by atmospheric distillation to a volume of
78 mL. The mixture was cooled to ꢀ12.5 °C and the solids
collected by vacuum filtration, washed with a cold (ꢀ8 °C)
mixture of acetone (23 mL), and water (23 mL), and dried to
116.0 (d); 115.0 (d); 47.9 (d); 46.3 (s); 38.6 (d); 36.3 (t); 34.4
1
(
t); 30.1 (t); 28.1 (t); 22.6 (t); 14.6 (q). H NMR (400 MHz,
pyridine-d ): d 7.71 (1H, d, J = 8.6 Hz); 7.12 (1H, dd,
J = 2.5 Hz, 8.6 Hz); 7.00 (1H, d, J = 2.0 Hz); 6.16 (1H, t,
J = 2.6 Hz); 5.18 (1H, br s); 2.84 (2H, m); 2.41 (2H, m);
2
J = 5.6 Hz, 12.7 Hz); 0.89 (3H, s). MS (CI, positive ion):
2
5
.20 (3H, m); 1.97 (2H, m); 1.52 (2H, m); 1.36 (1H, dd,
1
3
afford a solid identified as estradiol hemihydrate by
C
+
+
1
69 (P +H); MS (CI, negative ion): 267 (P ꢀH).
NMR and H NMR comparison with a reference standard.
The product contained 3.29% water by KF and was 97.1%
pure by quantitative HPLC comparison with a reference
standard. Weight: 22.8 g (22.0 g on anhydrous basis, 72.8%
yield [purity corrected]).
2
2
0. (a) Serebryakova, T. A.; Zakharychev, A. V.; Mol’gina,
M. A.; Ananchenko, S. N.; Torgov, I. V. Bull. Acad. Sci.
USSR 1973, 1872; (b) Serebryakova, T. A.; Zakharychev,
A. V.; Nekrasova, M. A.; Ananchenko, S. N.; Torgov, I.
V. U.S. Patent 3,761,497, September 25, 1973; (c) Kursa-
nov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974,
31. After the ionic hydrogenation procedure described
herein was developed, a group of our colleagues used
6
33.
1. Olah, G. A.; Wang, Q.; Prakash, G. K. S. Synlett 1992,
47.
it to reduce a nonsteroidal styrene: Gage, J. R.;
Perrault, W. R.; Poel, T.-J.; Thomas, R. C. Tetrahedron
Lett. 2000, 41, 4301.
6