Organic Process Research & Development
Article
and 365 nm). Flash column chromatography was performed on
silica gel (200−300 mesh). H NMR spectra were recorded
mixture was cooled to room temperature and then poured into
ice-cold 2 N HCl (1 L). The solid was filtered and recrystallized
from ethyl acetate/petroleum ether to afford compound 6 as a
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with a Bruker Avance III 400 MHz NMR spectrometer at room
temperature. Chemical shifts (in ppm) were recorded as parts
per million (ppm) downfield to tetramethylsilane (TMS). The
following abbreviations are used for multiplicity of NMR
signals: (s) singlet, (d) doublet, (t) triplet, (q) quartet, (m)
multiplet, (dd) double doublet, (dt) double triplet, (dq) double
quartet, (br) broad. 13C NMR or 13C attached-proton-test (13C-
Apt) spectra were recorded with Bruker Avance III 400 MHz
NMR spectrometer (100 MHz) and calibrated with CDCl3 (δ
= 77.23 ppm). High-resolution mass spectra were recorded
with a Waters LCT Premier XE mass spectrometer.
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white solid (41.00 g, yield 89%), mp 149−151 °C. H NMR
(CDCl3, ppm): δ 7.21−7.23 (d, 1H), 6.72−6.75 (dd, 1H),
6.65−6.66 (dd, 1H), 3.80 (s, 3H), 2.85−2.92 (m, 2H), 2.70−
2.77 (dt, 2H), 2.25−2.39 (m, 5H), 1.89−2.00 (m, 4H), 1.64−
1.71 (m, 1H), 1.45−1.55 (m, 5H), 0.79 (s, 3H). 13C NMR
(DEPT, CDCl3, ppm): δ 126.30 (C-1), 113.83 (C-4), 111.51
(C-2), 55.22 (OMe), 49.61 (C-14), 43.37 (C-9), 38.65 (C-8),
33.61 (C-16), 30.38 (C-12), 29.84 (C-6), 27.96 (C-21), 27.86
(C-7), 26.11 (C-11), 23.75 (C-15), 15.57 (C-18).
20,20-(Ethylenedioxy)-3-methoxy-17α-hydroxy-19-
norpregna-1,3,5(10)-triene (7). To a 500 mL round bottle
was added DCM (300 mL), compound 6 (40.00 g, 0.12 mol),
p-TSA (2.00 g, 0.012 mol), ethylene glycol (36.00 g, 0.58 mol),
and trimethyl orthoformate (50.00 g, 0.47 mol). The reaction
was stirred at room temperature for 2 h and then poured into
water. The organic phase was separated, washed with brine, and
dried over Na2SO4. The solid was removed, and the solution
was concentrated to dryness. The crude product was
recrystallized from methanol to afford compound 7 as a
white solid (39.00 g, yield 88%, HPLC > 98%), mp 125−126
3-Methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17β-ol
(4). 3-Methoxy-19-norpregna-1,3,5(10)- trien-20-yn-17β-ol was
prepared according to a modified procedure of Wong et al.34
Estrone (100.00 g, 0.37 mol), acetone (500 mL), and 5 N
NaOH (75 mL) was added to a three-neck 1-L round bottle.
To the reaction mixture under stirring was added Me2SO4
(47.00 g, 0.37 mol) portionwise. The reaction was heated to
reflux for 2 h and cooled to room temperature; the solid was
filtered off and concentrated to dryness. The crude product was
crystallized from ethyl acetate/petroleum ether to give estrone-
3-methyl ether as a white solid product 3 (103.00 g, yield 98%,
HPLC > 98%), mp 167−169 °C (172−174 °C in ref 39).
Compound 3 (100.00 g, 0.35 mol), THF (1000 mL), and
potassium tert-butoxide (55.00 g, 1.40 mol) were added to a 2-
L four-neck round bottle and was stirred vigorously while
acetylene gas was bubbled to the bottom at 0−20 °C for 2−2.5
h. The reaction mixture was poured into ice−water (2 L), and
the solid was filtered, washed with water, and dried to afford
17α-ethinyl-17β-hydroxy analogue 4 as a white solid (107 g,
yield 98%, HPLC > 97%), mp 154−155 °C (151−154 °C in
reference 39).
3-Methoxy-21-(phenylsulfinyl)-19-norpregna-1(2),3-
(4),5(10),17(20),20-pentaene (5). To a 2-L round bottle was
added 4 (100.00 g, 0.32 mol), DCM (1 L), and triethylamine
(140 mL). The mixture was stirred until dissolution, phenyl-
sulfenyl chloride (55.00 g, 0.38 mol) was added at 0 °C, and the
reaction mixture was stirred at that temperature for 2 h. The
mixture was poured into water (1 L), and the organic phase was
separated, washed with saturated NaCl aqueous solution, and
dried with Na2SO4. The solid was filtered off, and the solution
was concentrated in vacuo to give an oily crude product that
was recrystallized from ethyl acetate/petroleum ether to give a
white solid product 5 (95.00 g, yield 71%), mp 267−270 °C.
1H NMR (CDCl3, ppm): δ 7.67−7.69 (dd, 2H), 7.49−7.58 (m,
3H), 7.20−7.22 (d, 1H), 6.72−6.75 (dd, 1H), 6.65−6.66 (d,
1H), 6.17−6.19 (t, 1H), 3.80 (s, 3H), 2.88−2.92 (m, 2H),
2.74−2.80 (m, 1H), 2.57−2.64 (m, 1H), 2.34−2.38 (m, 1H),
2.23−2.27 (br, 1H), 1.93−1.95 (m, 2H), 1.73−1.79 (m, 2H),
1.41−1.57 (m, 5H), 0.95 (s, 3H). 13C NMR (DEPT, CDCl3,
ppm): δ 130.70 (para-C of SOPh), 129.14 (2 ortho-Cs of
SOPh), 126.26 (C-1), 124.40 (meta-Cs of SOPh), 113.82 (C-
4), 111.58 (C-2), 104.89 (C-21), 55.22 (OMe), 54.43 (C-14),
43.74 (C-9), 38.74 (C-8), 35.86 (C-16), 29.77 (C-6), 27.78 (C-
12), 27.73 (C-7), 26.55 (C-11), 24.62 (C-15), 18.81 (C-18).
3-Methoxy-17α-hydroxy-19-norpregna-1,3,5(10)-
trien-20-one (6). To a 2-L round bottle was added methanol
(1 L), sodium methoxide (4.00 g, 0.074 mol), and 5 (60.00 g,
0.14 mol). The mixture was stirred and heated to reflux for 2−3
h; then trimethylphosphite (19.00 g, 0.15 mol) was added, and
the reaction was stirred at reflux for an additional 2 h. The
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°C. H NMR (CDCl3, ppm): δ 7.22−7.24 (d, 1H), 6.72−6.74
(d, 1H), 6.66 (s, 1H), 4.07−4.10 (m, 2H), 3.89−3.97 (m, 2H),
3.80 (s, 3H), 2.87−2.91 (m, 2H), 2.24−2.34 (m, 4H), 1.76−
2.10 (m, 5H), 1.43−1.54 (m, 7H), 1.26−1.31 (m, 1H), 0.88 (s,
3H). 13C NMR (DEPT, CDCl3, ppm): δ 126.29 (C-1), 113.78
(C-4), 111.41 (C-2), 66.21 (OCH2−), 63.53 (−CH2O), 55.22
(OMe), 49.85 (C-14), 43.35 (C-9), 38.51 (C-8), 32.79 (C-16),
31.55 (C-12), 29.94 (C-6), 27.72 (C-7), 26.31 (C-11), 22.70
(C-15), 21.09 (C-21), 14.66 (C-18).
17α-Hydroxy-19-norpregna-4-ene-3,20-dione (8).
Under nitrogen and at −60 °C, ammonia gas was bubbled
into a 2-L bottle until about 1000 mL of liquid ammonia was
collected. Sodium (16.00 g, 0.67 mol) was added, and the
solution was stirred at −60 °C for 20 min. A solution of 7
(25.00 g, 0.067 mol) in THF (500 mL) was added dropwise.
Then tert-butanol (100 mL) and ethanol (200 mL) were added,
and the reaction was stirred at −60 °C until the complete
disappearance of the raw material. Ethanol (200 mL) was
added to quench the reaction, and the solution was left to warm
to room temperature with a gas trap to collect the evaporated
ammonia. The remaining solvent was concentrated, and the
residue was added to a solution of THF (200 mL) and 1.3 N
HCl (40 mL) and stirred at 60 °C for 20 min. The solvent was
concentrated, and the residue was poured into water. The solid
was collected by filtration and dried to give 8 (18.60 g, yield
1
87.7%, HPLC > 98%), mp 214−216 °C. H NMR (CDCl3,
ppm): δ 5.80 (s, 1H), 2.64−2.67 (m, 2H), 2.30−2.50 (m, 2H),
2.22−2.26 (m, 4H), 2.05−2.15 (m, 1H), 1.71−1.78 (m, 5H),
1.54−1.58 (m, 4H), 1.34−1.37 (m, 2H), 1.15−1.25 (m, 3H),
0.89−0.91 (m, 1H), 0.75 (s, 3H). 13C NMR (DEPT, CDCl3,
ppm): δ 124.63 (C-4), 49.28 (C-14), 49.01 (C-9), 42.46 (C-
10), 40.27 (C-8), 36.49 (C-1), 35.49 (C-2), 33.46 (C-16),
31.16 (C-12), 30.09 (C-6), 26.59 (C-7), 25.96 (C-11), 23.74
(C-15), 15.43 (C-18).
17α-Acetoxy-19-norpregna-4-ene-3,20-dione (9). To a
100 mL reaction bottle was added intermediate 8 (14.00 g,
0.044 mol), acetic anhydride (52.00 g, 0.51 mol), and p-TSA
(0.30 g, 1.4 mmol). The reaction was stirred at room
temperature for 24 h and then poured into water (200 mL).
The solid was filtered and recrystallized from ethanol to give a
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dx.doi.org/10.1021/op4003533 | Org. Process Res. Dev. 2014, 18, 431−436