8
Y. Zhao et al. / Steroids 95 (2015) 7–16
spectra were recorded on an Agilent 1946B ESI-MS instrument (Agi-
lent, Palo Alto, CA, USA).
of the reagent was added dropwise. The reaction mixture was stir-
red for an additional 2 h while it was cooling to room temperature.
The mixture was then added dropwise to a suspension of 3b (7.0 g,
0.02 mol) and copper (I) chloride (0.6 g, 0.002 mol) in dry tetrahy-
drofuran (70 mL) at 0 °C. The reaction mixture was stirred for 1 h,
then, it was poured into 10% ammonium chloride (70 mL) solution
and extracted with methylene chloride (3 Â 50 mL). The combined
organic fractions were washed with water (4 Â 50 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo to give a black
oil (21.1 g). The oil was purified via column chromatography
(petroleum ether–ethyl acetate 10:1) to yield 5.23 g (55%) light
blue solid. mp: 162–164 °C, MS (m/z): 478.62 [M + H]+, Analysis
calculated for C30H39NO4: C 75.44, H 8.23, N 2.93; found: C
75.55, H 8.28, N 2.75. 1H NMR {400 MHz, CDCl3 (TMS), d (ppm)}:
0.970 (s, 3H, CH3), 0.842–2.332 (m, 18H), 2.474 (s, 1H, acetylenic
hydrogen), 2.923 (s, 6H, NACH3), 3.716 (t, 1H, J = 6.4, CH), 3.820–
4.022(m, 4H, OACH2), 6.680(d, 2H, J = 8.4, ArAH), 7.048 (d, 2H,
J = 8.4, ArAH).
(1) Synthesis of the key intermediate 5:
2.1. 3,3-(Ethylene-dioxy)-5b,10b-epoxyestr-9(11)-ene-17-one(2b)
Hexachloroacetone (14.5 mL, 0.0954 mol), 30% aqueous hydro-
gen peroxide (14.1 mL, 0.477 mol) and sodium phosphate dibasic
dodecahydrate (34.5 g, 0.0964 mol) were added to methylene chlo-
ride (300 mL) at 0 °C. The mixture was stirred for 1 h at the same
temperature. The material 1 (30 g, 0.0954 mol) was added to above
mixture. The reaction mixture was stirred for another 18 h at the
same temperature. Then, it was poured into a mixture of methy-
lene chloride (200 mL) and ice (160 g). A solution of sodium thio-
sulfate (79 g, 0.5 mol) in water (300 mL) was added dropwise to
the mixture to destroy the excess of hydrogen peroxide. After sep-
aration, the organic fraction was washed with water (2 Â 100 mL)
and dried on sodium sulfate. The solvent was removed in vacuo to
give 32 g (100%) of product, which was a 65:35 mixture of the
2.4. 11a-(4-N,N-dimethylaminophenyl)-17a-ethynyl-17b-
5a,10a- and 5b,10b-epoxides showed by HPLC. The obtained crude
hydroxyestr-4,9-diene-3-one(5)
mixture of epoxides was recrystallized with petroleum ether/ethyl
acetate (5:1) to get 12.8 g (40%) white solid 2a. The filtrate was
concentrated in vacuo to yield 19.2 g (60%) of a 42:58 mixture of
To a solution of potassium bisulfate (3.7 g, 0.027 mol) in water
(50 mL) was added compound 4b (5 g, 0.01 mol) at 0 °C. The mix-
ture was stirred for 5 h and almost became clear. Then, saturated
sodium bicarbonate was added to the above mixture to adjust
pH to 7–8. The precipitated crystals were filtered off and dried at
50 °C to yield 2.7 g (65%) of the title compound 5. mp: 134–
136 °C, MS (m/z): 416.58 [M + H]+, Analysis calculated for
the 5a,10a- and 5b,10b-epoxides. Then the mixture was purified
via column chromatography (petroleum ether/ethyl acetate 10:1)
to give 6.91 g (36%) white solid 2b. mp: 158–160 °C, MS (m/z):
331.42 [M + H]+, Analysis calculated for C20H26O4: C 72.70, H
7.93; found: C 72.80, H 7.89. 1H NMR {400 MHz, CDCl3 (TMS), d
(ppm)}: 0.861 (s, 3H, CH3), 1.201–2.511 (m, 18H), 3.796–3.961
(m, 4H, OACH2), 5.851 (d, 1H, J = 2.8, @CH).
C
28H33NO2: C 80.93, H 8.00, N 3.37; found: C 80.85, H 8.18,
N3.28. 1H NMR {400 MHz, CDCl3 (TMS), d (ppm)}: 1.005 (s, 3H,
CH3), 1.396–2.628 (m, 16H), 2.476 (s, 1H, acetylenic hydrogen),
2.920 (s, 6H, NACH3), 3.899 (t, 1H, J = 8.8, CH), 5.664 (s, 1H,
@CH), 6.680 (d, 2H, J = 8.4, ArAH), 6.952 (d, 2H, J = 8.4, ArAH).
2.2. 3,3-(Ethylene-dioxy)-17a-ethynyl-17b-hydroxy-5b,10b-
epoxyestr-9(11)-ene (3b)
Under argon, 2b (6.8 g, 0.02 mol) was dissolved in dry tetrahy-
drofuran (70 mL) at 0 °C, and sodium acetylide (1.9 g, 0.04 mol)
was added. The mixture was stirred for 1 h. Saturated ammonium
chloride solution (50 mL) and water (50 mL) were added, then, the
reaction mixture was stirred for 10 min. Then the reaction mixture
was concentrated to a volume of 80 mL. The residue was stirred for
3 h at 0 °C. The precipitated crystals were filtered off and dried at
50 °C to yield 7.3 g (100%) of the title compound 3b, mp:
154–156 °C, MS (m/z): 379.48 [M + Na]+, Analysis calculated for
(2) Synthesis of 11
a,17a-isomer I:
2.5. 11 -(4-N,N-dimethylaminophenyl)-21-(phenyl-sulfinyl)-19-
a
norpregna-4,9,17(20),20-tetraene-3-one (6)
To a suspension of compound 5 (1.5 g, 0.0036 mol), triethyl-
amine (2.2 mL, 0.0152 mol) in dry tetrahydrofuran (20 mL), a solu-
tion of phenylsulfenyl chloride (0.9 g, 0.0062 mol) in dry
tetrahydrofuran (15 mL) was added dropwise while keeping the
temperature between À70 and À78 °C. The reaction mixture was
stirred for 4 h at À78 °C, then water (20 mL) and methanol
(20 mL) was added. The reaction mixture was stirred for 10 min
and extracted with methylene chloride (3 Â 40 mL). The combined
organic fractions were washed with water (4 Â 20 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo to get 2.5 g of a
reddish brown oil. The oil was purified via column chromatogra-
phy (petroleum ether–ethyl acetate 5:1) to yield 1.18 g (62.5%) of
white solid. mp: 151–155 °C. MS (m/z): 546.78 [M + Na]+, Analysis
calculated for C34H37NO2S: C77.97, H 7.12, N 2.67, S 6.12; found: C
77.84, H 7.21, N 2.75, S 6.18. 1H NMR {400 MHz, CDCl3 (TMS), d
(ppm)}: 1.042 (s, 3H, CH3), 1.213–2.767 (m, 16H), 2.900 (s, 6H,
NACH3), 3.967 (t, 1H, J = 8.8, CH), 5.681 (s, 1H, @CH), 6.075 (s,
1H, @CH), 6.634 (d, 2H, J = 8.4, ArAH), 6.888 (d, 2H, J = 8.4, ArAH),
7.460–7.539 (m, 3H, ArAH), 7.626 (d, 2H, J = 7.2, ArAH).
C
22H28O4: C 74.13, H 7.92; found: C 74.21, H 7.89. 1H NMR
{400 MHz, CDCl3 (TMS), d (ppm)}: 0.825 (s, 3H, CH3), 1.081–
2.627 (m, 18H), 2.557 (s, 1H, acetylenic hydrogen), 3.867–
3.946(m, 4H, OACH2), 5.890 (t, 1H, J = 4.4, @CH).
2.3. 3,3-(Ethylene-dioxy)-5b,17b-dihydroxy-11
a-(4-N,N-
dimethylaminophenyl)-19-nor-17 -pregn-9-ene-21-ethyne(4b)
a
Under anhydrous conditions, a portion (2 mL) of a solution of
4-bromo-N,N-dimethylaniline (12 g, 0.06 mol) in dry tetrahydrofu-
ran (50 mL) and one crystal of iodine was added to the mixture of
magnesium (1.7 g, 0.07 mol) in dry tetrahydrofuran (5 mL) at
50 °C. After evidence of reaction was observed, the entire amount
N
O
2.6. 11a-(4-N,N-dimethylaminophenyl)-17a-hydroxy-19-norpregna-
OAc
4,9-diene-3,20-dione(7)
Compound 6 (1.1 g, 0.0021 mol) was added to a solution of
sodium methoxide (0.11 g, 0.0021 mol) in methanol (20 mL). The
reaction mixture was stirred at 50 °C for 1 h, then trimethyl
O
Fig. 1. The structures of Ulipristal acetate.