(6). This result was obtained with the use of an iterative,
two-stage reaction response surface analysis facilitating a
practical solution to the difficulties occurring in the course
of chemical processes.
acetone (120 mL). This gave a precipitate which was filtered
and dried (1 mmHg, rt, 6 h), affording the diene (3) as an
off-white solid (36.43 g, 84.5%): mp; 165-169 °C; [R]D )
-155 ° (20 °C, c ) 1, CHCl3); 1H NMR (CDCl3, 200 MHz)
δ 5.77 (1H, d, 2.2 Hz), 5.47 (1H, bt, 2.6 Hz), 4.62 (1H, dd,
9.2, 7.3 Hz), 2.45 (1H, m), 2.13 (3H, s, AcO), 2.05 (3H, s,
AcO), 0.82 (3H, s, 18-Me); 13C NMR (CDCl3) δ 171.2,
169.2, 148.6, 134.5, 123.6, 117.5, 82.7, 50.2, 43.4, 42.5, 40.5,
36.5, 36.4, 30.8, 27.9, 27.4, 27.1, 26.2, 23.2, 21.1, 21.0, 11.9.
Synthesis of 17â-Acetoxy-4,6-estradien-3-one (4) from
3,17â-Diacetoxy-3,5-estradiene (3). Compound 3 (155.5 g,
0.434 mol) was placed under nitrogen in a three-necked, 2
L flask, equipped with a thermometer, a dropping funnel,
and a reflux condenser. Dimethylformamide (Fluka no.
40228; 1 L) was added, followed by H2O (30 mL). The
mixture was stirred, and the flask was immersed in an ice-
water cooling bath. When the temperature dropped to 0 °C,
NBS (Aldrich no. B8,125-5; 82 g, 0.46 mol) was added in
10 identical portions, with vigorous stirring, over 35 min.
Care was taken to avoid overheating the reaction mixture
above +7 °C. After stirring for another 45 min, LiBr (Fluka
no. 62463; 75 g) was added, followed by Li2CO3 (Riedel-
de-Hahn no. 13010; 152 g). The mixture was stirred under
nitrogen, the cooling bath was replaced with a heating mantle,
and the reaction mixture was allowed to reach 110 °C over
40 min. This temperature was maintained for another 45 min,
then the mixture was cooled to 20 °C and poured into water
(6 L) containing AcOH (500 mL). The mixture was stirred
for 15 min. The product precipitated in the form of a gummy
solid, which was filtered and dissolved in dichloromethane
(270 mL), and the remainder of water was removed in a
separatory funnel. The organic phase was flash-chromato-
graphed on a silica gel column (10.5 cm o.d.; 230-400 mesh,
1 kg, 25% EtOAc/hexane). Eluting the column with 30%
EtOAc-10% CH2Cl2-60% hexane afforded a yellow solid
(121 g), which crystallized from hot diisopropyl ether (250
mL) to give dienone (4) (95.9 g; 70.3%). On standing, the
mother liquors afforded a second crop of 17â-acetoxy-4,6-
estradien-3-one crystals (10.7 g), bringing the yield of
compound 4 to 78.2%: mp; 104-106 °C; [R]D ) -39° (20
°C, c ) 1, CHCl3); 1H NMR (CDCl3, 200 MHz) δ 6.18 (2H,
bs), 5.78 (1H, bt, 1.0 Hz), 4.65 (1H, dd, 9.1, 7.5 Hz), 2.55
(1H, m), 2.06 (3H, s, AcO), 0.88 (3H, s, 18-Me); 13C NMR
(CDCl3, 50 MHz) δ 200.0, 171.1, 158.8, 141.4, 128.8, 124.4,
82.1, 47.7, 45.9, 43.4, 41.1, 40.8, 37.7, 36.4, 27.3, 26.9, 25.0,
22.9, 21.1, 11.8.
Experimental Section
General Procedures. The reagents and solvents used
were of the specified grade. The progress of reactions and
the purity of compounds were determined using TLC plates
from Merck, art. no. 105549; spots were visualized with UV
light and by heating the plates moistened with 8% sulfuric
acid/water. Column flash chromatography was performed on
silica gel 60 (Merck, art. no. 1.09385 or 1.09390), using the
solvents indicated. Analytical high performance liquid chro-
matography (HPLC) was performed on a Phenomenex
Synergy MAX RP 80A, 150 × 4.6 mm2 column (4 micron
ODS packing; 1.0 mL/min of 65% CH3CN-35% H2O; UV
detection at 235 nm and 275 nm; retention time of compound
1, 3.3 min; retention time of compound 6, 3.6 min). HPLC
results (not shown) paralleled the results presented in the
tables. All optimization experiments were run on a conve-
nient laboratory scale (ca. 1 g of the substrate 4), substrate
4 was crystalline and of high purity, and product 1 was
purified by crystallization and carefully dried. Masses of the
substrate and of the pure, crystalline product were carefully
determined on a certified analytical balance (Mettler Toledo
AB104-S, readability 0.1 mg).
Infrared (IR) spectra were recorded on a Perkin-Elmer
model 1725X FT-IR spectrometer in KBr tablets. Ultraviolet
(UV) spectra were recorded on a Shimadzu model 160A
UV-vis spectrometer. Nuclear magnetic resonance (NMR)
spectra were recorded on a Varian Gemini 200 MHz and a
Bruker AM 500 MHz spectrometer. TMS was used as the
internal standard. Mass spectra (MS) were recorded on an
AMD Intectra GmbH model 604 spectrometer, in the EI
mode at 70 eV. Optical rotations were determined on a
Perkin-Elmer model 241 polarimeter. Melting points were
measured on a Bu¨chi model 535 capillary instrument and
are uncorrected. Tap water was used in experiments, unless
otherwise stated.
Synthesis of 3,17â-Diacetoxy-3,5-estradiene (3) from
19-Nortestosterone (2). 19-Nortestosterone (2) (33.0 g, 0.12
mol) was placed in a 1 L round-bottom flask and dried under
vacuum (1 mmHg, 40 °C, 1 h). EtOAc (100 mL) was then
added, and the mixture was vigorously stirred under nitrogen
until a milky suspension formed. The flask was immersed
in a water bath (18 °C), and Ac2O (Fluka no. 45830; 300
mL) was added, immediately followed by 70% aqueous
HClO4 (0.35 mL). Vigorous stirring was maintained for 8
h. Afterwards, finely powdered NaHCO3 (2.5 g) was added
in one portion, and the mixture was stirred for another 2 h.
The reaction mixture was then filtered. The filtrate was
concentrated in vacuo (10 mmHg, t ) 65 °C) to a viscous
solid, which was dried in vacuo (0.5 mmHg, rt, 12 h). The
crude product thus obtained was crystallized from hot acetone
(Polish Chemical Reagents POCh, analytical grade; 150 mL).
The crystallizing solution was set aside at +4 °C for 4 h.
The product was filtered through a large diameter no. 3
sintered glass funnel. The precipitate was recrystallized from
Synthesis of 17â-Hydroxy-7R-methyl-4-estren-3-one
(7R-Methylnortestosterone) (1) under Optimized Condi-
tions. Copper(I) iodide (Fluka; 3.63 g, 19.06 mmol) was
placed in a dry, 200 mL round-bottom flask. Anhydrous THF
(21 mL) was added, and the mixture was cooled, under N2,
to 0 °C. With vigorous stirring, a 3.1 M solution of MeLi in
diethoxymethane (Chemetall; 12.3 mL, 38.2 mol) was slowly
added. CAUTION: the rate of MeLi addition should be such
that the temperature of the reaction mixture does not exceed
+10 °C. The resulting mixture was stirred and cooled at 0
°C, after which a solution of 17â-acetoxy-4,6-estradien-3-
one (4) (0.976 g, 3.10 mmol) in anhydrous THF (5 mL) was
850
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Vol. 8, No. 6, 2004 / Organic Process Research & Development