A simple and convenient synthetic route to Ulipristal acetate

Article abstract of DOI:10.1016/j.steroids.2013.09.009

We set out to describe a new and efficient route for preparing Ulipristal acetate with a good yield. The selected epoxidization conditions gave out 80% of 5α,10α-epoxide 2a in the two diastereoisomers which greatly improved the yield of 11β-substituted isomer 4a. And phenyl-sulfinyl compound 6 was synthesized from ketone 5 directly treated with phenylsulfenyl chloride in the presence of triethylamine. These synthetic procedures is only 8 steps, less than currently reported in the literature, but more suitable for industrial process.

Full text of DOI:10.1016/j.steroids.2013.09.009

Steroids 78 (2013) 1293–1297
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
A simple and convenient synthetic route to Ulipristal acetate
⇑
Yongguo Yu, Yun He, Yi Zhao, Li Hai, Yong Wu
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2013
Received in revised form 12 September 2013
Accepted 20 September 2013
Available online 2 October 2013
We set out to describe a new and efficient route for preparing Ulipristal acetate with a good yield. The
selected epoxidization conditions gave out 80% of 5a,10a-epoxide 2a in the two diastereoisomers which
greatly improved the yield of 11b-substituted isomer 4a. And phenyl–sulfinyl compound 6 was synthe-
sized from ketone 5 directly treated with phenylsulfenyl chloride in the presence of triethylamine. These
synthetic procedures is only 8 steps, less than currently reported in the literature, but more suitable for
industrial process.
Keywords:
Ó 2013 Elsevier Inc. All rights reserved.
Ulipristal acetate
Diastereoisomers
Synthesis
Industrial process
1
. Introduction
differences in their active metabolites. Compared with the most
commonly used emergency contraceptive levonorgestrel, its clini-
A great number of 11b-substituted norpregna compounds with
antiprogestational and/or antiglucocorticoid activity were synthe-
sized by Teutsch’s method [1–5]. Among them, 17 -acetoxy-11b-
4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione,
represented by formula I, is a well-known steroid and more specif-
ically 19-norprogesterone, which possesses appropriate antipro-
gestational and antiglucocorticoidal activity as progesterone
receptor blocker/antagonist [1].
cal applicability is wider, and more potential to prevent unwanted
pregnancies [6].
a
Cook CE, et al. [1] used 3-methoxy-19-norpregna-1,3,
5(10),17(20)-tetraene as the starting material, and processed about
9 steps to give Ulipristal acetate with total yield of about 0.62%.
However, this route introduced osmium tetroxide which is not
only expensive but also highly toxic and hazardous from the point
of environment protection. Thus this route is not suitable for
industrial process. Kim HK, et al. [7] used 3-ethylendioxy-17b-cya-
(
no-17a-hydroxy-5(10),9(11)-diene as the starting material via 7
steps yield about 12.5%. But the synthesis of the starting material
O
N
must use the highly toxic KCN or acetone cyanohydrin. Kim group.
OAc
[
8] started with 17a-hydroxy-19-norpregnen-4,9-diene-3,20-
dione to yield the total yield of about 19.5%. Unfortunately, the
starting material was expensive, in part because the synthesis of
the starting material must even use the highly toxic osmium
tetroxide or KCN or acetone cyanohydrins. Dancsi L, et al. [9] used
O
I
3
-(ethylene-dioxy)-estra-5(10),9(11)-diene-17-one as the starting
material. This route is 9 steps with 14% total yield. And the propor-
tion of the 5 ,10 and 5b,10b in the epoxidized biketal is about 55/
a
a
In 2010, the acetate form of Ulipristal was approved by FDA as
emergency contraceptive pill, with the trade name Ella to be used
for pregnancy prevention within 120 h after unprotected sex or
known or suspected contraceptive failure. As a selective progester-
one receptor modulator (SPRM), in vivo, Ulipristal has much weaker
45, which led to up to 45% waste of isomer.
The above four routes currently reported in the literature gave
unsatisfactory yield and relatively complex process. Therefore this
study aim at a simple and convenient synthetic route (Scheme 1)
3-Ethylenedioxy-estra-5(10),9(11)-diene-17-one 1 was epoxidized
with hydrogen peroxide to give two diastereoisomers, 3-ethylene-
antiglucocorticoid activity than mifepristone as
a result of
dioxy-estra-5
a,10a-epoxy-9(11)-ene-17-one 2a and 3-(ethylene-
⇑
Corresponding author. Tel.: +86 028 85503235.
E-mail address: wyong@scu.edu.cn (Y. Wu).
dioxy)-estra-5b,10b-epoxy-9(11)-ene-17-one 2b (2a/2b = 80/20)
0
039-128X/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2013.09.009

1
294
Y. Yu et al. / Steroids 78 (2013) 1293–1297
O
O
O
sodium acetylide
anhydrousTHF
2 2 3 2
H O , (F C) CO
O
O
+ O
O
O
Na HPO /CH Cl
2
4
2
2
o
O
o
O
0 C,100%
0
-5 C,100%
O
2a
2b
1
5
α,10α
:
5β,10β
8
0 : 20
HO
N
HO
OH
1
)
N
MgBr
C
CuCl, THF, 0 o
O
O
O
O
+
O
2
) NH
4
Cl, CH
2
Cl
2
/H
2
O,
O
3b
O
3a
50.4%
O
OH
4a
5
α,10α
:
5β,10β
20
8
0
:
N
O
N
O
OH
C
C
S
SCl
H
8
.5%H SO
2
4
3 3
CH ONa,CH OH
o
ethanol,70 C,95.2%
Et N, anhydrousTHF,
40 C,98.5%
3
o
trimethyl phosphite,
7
-
o
0 C, 88.1%
O
5
6
O
O
N
N
O
N
OCH3
OH
N HCl
CH OH, rt, 70%
OH
OAc
Ac O, HClO
1
2
4
o
CH
2
Cl
2
,-30 C, 93.4%
3
O
O
7
I
8
Scheme 1. Synthesis of Ulipristal acetate.
in dichloromethane. The above mixture without separation was re-
acted with sodium acetylide in anhydrous THF to afford 3-ethyl-
further purification. TLC was performed using precoated silica gel
GF254 (0.2 mm), while column chromatography was performed
using silica gel (100–200 mesh). The melting point was measured
on a YRT-3 melting point apparatus (Shantou Keyi instrument &
Equipment Co. Ltd., Shantou, China). IR spectra were obtained on
enedioxy-estra-5a,10a-epoxy-17a-ethynyl-17b-hydroxy-9(11)-ene
3
a and 3-(ethylene-dioxy)-estra-5b,10b-epoxy-17a-ethynyl-17b-
hydroxy -9(11)-ene 3b (3a/3b = 80/20). Both of them underwent
copper catalyzed Grignard addition to get out 3-ethylenedioxy-
1
a Perkin Elmer983 (Perkin Elmer, Norwalk, CT, USA). H NMR spec-
estra-5
a
-hydroxy-11b-(4-N,N-dimethylaminophenyl)-17
a
-ethy-
tra were taken on a Varian INOVA400 (Varian, Palo Alto, CA, USA)
nyl-17b-hydroxy-9-ene 4 at 0 °C. Treatment of this compound with
3 2
using CDCl , d-DMSO and D O as solvent. Chemical shifts are ex-
a 10:1 mixture of ethanol and 8.5 vol% sulfuric acid solution at
pressed in d (ppm), with tetramethylsilane (TMS) functioning as
the internal reference, and coupling constants (J) were expressed
in Hz. Mass spectra were recorded on an Agilent 1946B ESI–MS
instrument (Agilent, Palo Alto, CA, USA).
7
0 °C yielded 11b-(4-N,N-dimetnylaminophenyl)-17
a-ethynyl-
1
7b-hydroxy-estra-4,9-diene-3-one 5. The ketone 5 was then
reacted with phenylsulfenyl chloride in the presence of triethyl-
amine in anhydrous THF at À78 °C to form 11b-(4-N,N-dimetnyl-
aminophenyl)-21-(phenyl-sulfinyl)-19-norpregna-4,9,17(20),20-
tetraene-3-one 6. The compound 6 is coupled with sodium meth-
oxide in methanol, then treated with trimethyl phosphate at
2.1. 3-(ethylene-dioxy)-estra-5a,10a-epoxy-9(11)-ene-17-one(2a)
and 3-(ethylene-dioxy)-estra-5b,10b-epoxy-9(11)-ene-17-one(2b)
7
0 °C to provide 11b-(4-N,N-dimetnylaminophenyl)-17a-hydro-
xy-20-methoxy-19-norpregna-4,9,20-triene-3-one 7, which was
hydrolyzed in the presence of diluted HCl in methanol at room
temperature to give 11b-(4-N,N-dimetnylaminophenyl)-17a-hy-
droxy-19-norpregna-4,9-diene-3,20-dione 8. To the mixture of
acetic acid and perchloric acid, a solution of the above dione 8 in
methylene chloride is added with a slow speed at À30 °C to give
the desired Ulipristal Acetate I. All the route is about 8 steps and
the crude yield is about 27.2%.
Hexafluoroacetone (0.4 ml, 0.0032 mol) and 30% aqueous
hydrogen peroxide (1.6 ml 0.0541 mol) and sodium phosphate
dibasic dodecahydrate (11.5 g, 0.0321 mol) were added to a solu-
tion of 1 (10 g, 0.0318 mol) in methylene chloride (100 ml) at
0 °C. The reaction mixture was stirred for 18 h at the same temper-
ature. Then, it was poured into a mixture of methylene chloride
(140 ml) and ice (160 g). A solution of sodium thiosulphate
(31.6 g, 0.2 mol) in water (140 ml) was added dropwise to the mix-
ture to destroy the excess of hydrogen peroxide. After separation,
the organic fraction was washed with water (2 Â 100 ml) and dried
on sodium sulphate. The solvent was removed in vacuo to give
10.6 g (100%) of product, which was a 80:20 mixture of the
2
. Experimental
All reactions were carried out under a argon atmosphere. Most
chemicals and solvents were analytical grade and used without
5a,10a- and 5b,10b-epoxides showed by HPLC. The obtained crude

Y. Yu et al. / Steroids 78 (2013) 1293–1297
1295
mixture of epoxides was used in the next step without further
120–123 °C MS(m/z): 416.58 (M + H), Analysis calculated for
purification. (2a/2b) MS(m/z): 331.42 (M+H), Analysis calculated
C
28
H
33NO
2
: C 80.93, H 8.00, N 3.37; found: C 80.89, H 7.98, N
1
1
for C20H
26
O
4
: C 72.70, H 7.93; found: C 72.58, H 7.88. H NMR
3.35. H NMR {400 MHz, CDCl (TMS), d (ppm)}: 0.555 (s, 3H,
3
{
2
400 MHz, CDCl
3
(TMS), d (ppm)}: 0.874 (s, 3H, CH
.509 (m, 18H), 3.876–3.966 (m, 4H), 5b,10b: 5.860 (d, 1H,
,10 : 6.054 (d, 1H, J = 2.8,@CH).
3
), 1.214–
CH
2.937 (s, 6H, N–CH
6.669 (d, 2H, J = 7.6), 7.039 (d, 2H, J = 7.6).
3
), 0.789–2.778 (m, 16H), 2.636 (s, 1H, acetylenic hydrogen),
3
), 4.376 (d, 1H, J = 6.4), 5.760 (s, 1H, C@CH),
J = 2.8,@CH), 5
a
a
2
.2. 3-(ethylene-dioxy)-estra-5
hydroxy-9(11)-ene(3a) and 3-(ethylene-dioxy)-estra-5b,10b-epoxy-
-ethynyl-17b-hydroxy -9(11)-ene (3b)
a,10a-epoxy-17a-ethynyl-17b-
2
.5. 11b-(4-N,N-dimetnylaminophenyl)-21-(phenyl-sulfinyl)-19-
norpregna-4,9,17(20),20-tetr aene-3-one (6)
17a
To a suspension of compound 5 (6.34 g, 0.0152 mol), triethyl-
amine (8.8 ml, 0.0608 mol) in dry tetrahydrofuran (60 ml), a solu-
tion of phenylsulfenyl chloride (3.76 g, 0.026 mol) in dry
tetrahydrofuran (30 ml) was added dropwise while keeping the
temperature between À70 and À78 °C. The reaction mixture was
stirred for 2 h at À78 °C, then water (100 ml) and methanol
Under nitrogen the mixture of 2a and 2b (10.5 g, 0.031 mol)
was dissolved in dry tetrahydrofuran (160 ml) at 0 °C, and sodium
acetylide (3 g, 0.0636 mol) was added. The mixture was stirred for
h. Saturated ammonium chloride solution (75 ml) and water
200 ml) were added and the reaction mixture was stirred for
0 min. Then the reaction mixture was concentrated to a volume
of 200 ml. The residue was stirred for 3 h at 0 °C. The precipitated
crystals were filtered off and dried at 50 °C to yield 11.3 g (100%) of
1
(
1
(
50 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 70 ml), dried over
sodium sulfate, filtered, and concentrated in vacuo to give
the title compound. (3a/3b) MS(m/z): 379.48 (M+Na), Analysis cal-
1
culated for C22
H
28
O
4
: C 74.13, H 7.92; found: C 74.08, H 7.80.
H
7
.87 g(98.5%) of a reddish brown oil. MS(m/z): 546.78 (M+Na),
NMR {400 MHz, CDCl
3
(TMS), d (ppm)}: 0.846 (s, 3H, CH
.149–2.663 (m, 17H), 2.557 (s, 1H, acetylenic hydrogen), 3.878–
.943(m, 4H, O–CH ), 5b,10b: 5.574 (t, 1H, J = 5.27,@CH), 5 ,10
3
),
Analysis calculated for C34 S: C77.97, H 7.12, N 2.67, S
H
37NO
2
1
3
5
1
6
.12; found: C 77.95, H 7.05, N 2.70, S 6.08. H NMR {400 MHz,
2
a
a:
CDCl
3
3
(TMS), d (ppm)}: 0.618 (s, 3H, CH ), 0.828–2.816 (m, 16H),
.751 (t, 1H, J = 5.27,@CH).
2
6
7
.953 (s, 6H, N–CH ), 4.272 (d, 1H, J = 6.8), 5.753 (s, 1H, C@CH),
.152 (m, 1H), 6.695 (d, 2H, J = 7.6), 7.000 (d, 2H, J = 7.6), 7.475–
.576 (m, 3H), 7.644 (t, 2H, J = 7.6).
3
2
.3. 3-(ethylene-dioxy)-estra-5a-hydroxy-11b-(4-N,N-
dimethylaminophenyl)-17a-ethynyl-17b-hydroxy-9-ene(4a)
2
.6. 11b-(4-N,N-dimetnylaminophenyl)-17
a-hydroxy-20-methoxy-
Under anhydrous conditions, to the mixture of magnesium
3.1 g, 0.1272 mol) in dry tetrahydrofuran (10 ml), a portion
19-norpregna-4,9,20-triene -3-one(7)
(
(
0
4 ml) of
a solution of 4-bromo-N,N-dimethylaniline (22.3 g,
To a solution of sodium methoxide (0.75 g, 0.015 mol) in meth-
anol (70 ml), compound 6 (7.87 g, 0.015 mol) was added. The reac-
tion mixture was stirred at 70 °C for 1 h, then trimethyl phosphite
2.85 g, 0.0226 mol) was added and stirring was continued at 70 °C
for 2 h. The reaction mixture was cooled to 20 °C and poured into
water (200 ml), then extracted with methylene chloride
(3 Â 40 ml). The combined organic fractions were dried over so-
dium sulfate, filtered, and concentrated in vacuo to give 6.72 g
88.1%) of a reddish brown oil. The obtained crude product was
used in the next step without further purification. MS(m/z):
.1113 mol) in dry tetrahydrofuran (100 ml) and one crystal of io-
dine was added at 50 °C. After evidence of reaction was observed,
the entire amount of the reagent was added dropwise. The reaction
mixture was stirred for an additional 2 h while it was cooling to
room temperature. The mixture was then added dropwise to a sus-
pension of 3 (11.3 g, 0.03181 mol) and copper (I) chloride (0.96 g,
0
mixture was stirred for 1 h, and then, it was poured into 10%
ammonium chloride (70 ml) solution and extracted with methy-
lene chloride (3 Â 100 ml). The combined organic fractions were
washed with water (4 Â 70 ml), dried over sodium sulfate, filtered,
and concentrated in vacuo to give a black oil (31.2 g). Diisopropyl
ether was added to the residue, and the mixture was stirred for
(
°
.0032 mol) in dry tetrahydrofuran (110 ml) at 0 C. The reaction
(
4
8
48.62 (M + H), Analysis calculated for C29
H
37NO
3
: C77.82, H
.33, N 3.13; found: C 77.88, H 8.37, N 3.08. H NMR {400 MHz,
(TMS), d (ppm)}: 0.359 (s, 3H, CH ), 1.258–2.795 (m, 16H),
.913 (s, 6H, N–CH ), 2.919 (s, 1H, OH), 3.589 (s, 3H, O–CH ),
.045 (d, 1H, J = 2.8, C@CH ), 4.206 (d, 1H, J = 2.8, C@CH ), 4.327
1
CDCl
3
3
2
4
(
3
3
3
h at room temperature. The precipitated crystals were filtered
2
2
off and dried at 50 °C to yield light blue solid (14.4 g). The solid
was crystallized in n-hexane/dioxane (3:1) to give 7.66 g (50.4%)
of the title compound. mp: 181–183 C MS(m/z): 478.62 (M+H),
d, 1H, J = 6.8), 5.740 (s, 1H, C@CH), 6.665 (d, 2H, J = 7.6), 7.016
(d, 2H, J = 7.6).
°
Analysis calculated for C30
H
39NO
4
: C 75.44, H 8.23, N 2.93; found:
C 75.48, H 8.30, N 2.87. H NMR {400 MHz, CDCl (TMS), d (ppm)}:
.969 (s, 3H, CH ), 0.855–2.795 (m, 19H,), 2.475 (s, 1H, acetylenic
hydrogen), 2.928 (s, 6H, N–CH ), 3.688 (br, 1H, OH), 3.809–4.475
), 4.475 (d, 1H, J = 6.4), 6.758 (d, 2H, J = 8.4), 7.044
1
3
2.7. 11b-(4-N,N-dimetnylaminophenyl)-17a-hydroxy-19-norpregna-
0
3
4,9-diene-3,20-dione(8)
3
(
(
m, 4H, O–CH
d, 2H, J = 8.4).
2
A suspension of compound 7 (6.72 g) in a mixture of 1 N hydro-
chloric acid (3.3 ml) and methanol (60 ml) was stirred at room
temperature for 30 min, then ice water (200 ml) was added. After
neutralizing with saturated sodium bicarbonate, the precipitated
crystals were filtered off and dried at 50 °C to yield 6.05 g off-white
solid. Purification via column chromatography (petroleum ether–
ethyl acetate 10:1) gave 4.55 g (70%) off-white solid. mp: 124–
127 °C. HPLC: 99.1%; MS(m/z): 434.58 (M + H), Analysis calculated
2
.4. 11b-(4-N,N-dimetnylaminophenyl)-17
a-ethynyl-17b-hydroxy-
estra-4,9-diene-3-one(5)
8
.5% aqueous sulfuric acid (3.8 ml) was added to a solution of
compound 4 in ethanol (70 ml) under a nitrogen atmosphere.
The reaction mixture was stirred for 2 h at 70 °C. After neutralizing
with saturated sodium bicarbonate, the mixture was diluted with
water (200 ml). The precipitated crystals were filtered off and dried
at 50 °C to yield 6.34 g (95.2%) light white solid. The obtained crude
product was used in the next step without further purification. mp:
for C28
H
35NO
3
: C 77.56, H 8.14, N 3.23; found: C 77.52, H 8.11, N
3.18. H NMR {400 MHz, CDCl (TMS), d (ppm)}: 0.466 (s, 3H,
CH ), 0.827–2.785 (m, 16H), 2.259 (s, 3H, COCH ), 2.911 (s, 6H,
N–CH ), 4.376 (d, 1H, J = 6.4), 5.760 (s, 1H, C@CH), 6.669 (d, 2H,
J = 7.6), 7.039 (d, 2H, J = 7.6).
1
3
3
3
3

1
296
Y. Yu et al. / Steroids 78 (2013) 1293–1297
HO
over sodium sulfate and concentrated under reduced pressure to
give 4.66 g (93.4%) off-white syrupy. mp: 183–185 °C. HPLC:
8.9%; FTIR (KBr, diffuse reflectance): max 2941; 1733 and 1715
(–C@O); 1663 and 1659 (conjugated –C@O); 1565; 1520; 1438;
355; 1303; 1254; 1209; 1168; HRMS: calculated for C30
O
9
c
sodium acetylide,THF
O
O
O
0
C, 100%
1
H37NO
4
O
O
9
1
1
475.6191, found: 475.6189. H NMR {400 MHz, CDCl
ppm)}: 0.355 (s, 3H, CH ), 1.253–2.857 (m, 16H), 2.099 (s, 3H,
OCOCH ), 2.137 (s, 3H, COCH ), 2.913 (s, 6H, N–CH ), 3.086 (s,
H, OH), 4.365 (d, 1H, J = 7.2), 5.779 (s, 1H), 6.638 (d, 2H, J = 7.6),
3
(TMS), d
(
3
HO
HO
3
3
3
1
6
1
3
.982 (d, 2H, J = 7.6);
3
C NMR {400 MHz, CDCl (TMS), d
epoxidation
O
O
O
O
+
(
ppm)}:21.194; 24.096; 25.699; 26.767; 27.779; 30.160; 30.975;
O
3b
O
3a
36.681; 36.768; 38.255; 39.277; 40.489; 46.972; 50.844; 66.992;
9
1
6.110; 112.692; 122.859; 127.225; 129.199; 131.406; 145.543;
48.539; 156.487; 170.537; 199.421; 203.719.
5
0
5
0
Scheme 2. Synthesis of the intermediates 3a/3b.
3
. Discussion
The synthesis of the drug substance was based on the very effi-
cient 1,4-addition in the presence of copper(I) catalyst such as cop-
N
HO
HO
per (I) chloride (Scheme 1). To the best of our knowledge, when the
5a,10a-epoxide (3a) was presented a higher proportion, the 11b-
N
MgBr
O
O
3a
O
addition ingredient (4a) was provided in higher yield [11]. In order
to improve the ratio of 3a, the starting material was first reacted
with sodium acetylide to give the compound 9, and then processed
epoxidation to yield 3a/3b (Scheme 2). Unfortunately, it was found
CuCl, THF
O
O
OH
4
a
N
HO
the ratio of the 5
0:50. Even if hexachloroacetone was used as the catalyst, mCPBA
was used as epoxidation reagents, or lowering the reaction tem-
perature, the ratio of 5 ,10 -3a epoxide was still not improved.
At last, it was found if epoxidation firstly, the ketone 1 can give
out a 65:35 mixture of the 5 ,10 -(2a) and 5b,10b-(2b) epoxides.
And when the temperature was reduced to 0–5 °C and the reaction
time was prolonged for 24 h, the 5 ,10 -epoxide was up to 80%.
However, if the catalyst was changed to hexachloroacetone, the
,10 -epoxide was lowered to 55%. Even the temperature was
lowered, the ratio of 5 ,10 -epoxide was about 60% and the start-
a,10a-3a and 5b,10b-epoxides 3b was about
HO
5
N
MgBr
O
O
a
a
O
CuCl, THF
O
O
OH
3
b
a
a
4
b
Scheme 3. Synthesis of 11b(4a) and 11
a
(4b)-substituted isomers.
a
a
5a
a
2
.8. Ulipristal acetate (I)
a
a
ing materials was remained much. At last, the best optimized con-
dition was selected, using 30% hydrogen peroxide as epoxidation
reagent, hexafluoroacetone as catalyst at 0–5 °C for 24 h.
Acetic anhydride (9.9 ml, 0.105 mol) was cooled to À10 °C and
perchloric acid was added (1.5 ml, 0.0171 mol). The so obtained
solution was cooled to À30 °C and the solution of compound 8
The 5
a
,10
a
-isomer 3a got out 11b-substituted isomer (4a)
-substituted isomer
-substituted isomer
-3a and 5b,10b-epoxides 3b was at-
(
4.55 g, 0.0105 mol) in dichloromethane (50 ml) was added at such
while the 5b,10b-epoxide 3b afforded 11
4b) (Scheme 3). In order to remove the 11
4b), the mixture of 5 ,10
a
a
rate to keep the temperature between À20 and À30 °C, then the
reaction mixture was stirred at this temperature for 2 h. The mix-
ture was diluted with dichloromethane (100 ml) and poured into
water (100 ml) containing sodium acetate (1.4 g, 0.017 mol). The
organic layer was separated, washed with water (3 Â 30 ml), dried
(
(
a
a
tempted to recrystallize to remove the 5b,10b-epoxide, then
underwent Grignard addition to get out 11b-substituted isomer
(4a) only. But the yield of recrystallization of 3a and 3b was about
N
O
N
OH
C
C S
SCl
H
CH ONa,CH OH
3
3
O
O
trimethyl phosphite
O
N
OH
O
OH
4
1
0
O
N
O
OCH3
OH
OH
H
O
O
OH
8
1
1
Scheme 4. Synthesis of the intermediate 8.

Y. Yu et al. / Steroids 78 (2013) 1293–1297
1297
5
5%, and 62% of 4a was obtained after Grignard addition and puri-
Acknowledgements
fication. Thus, the total yield of 4a was about 34% after above pro-
cesses. It was well known that 5b,10b-epoxide reacted more slowly
The authors wish to thank the National Natural Science Founda-
tion of China (81072532) and (81102324).
than the 5
Grignard reagent(2.0 equiv) [10]. Therefore the obtained crude
mixture of 5 ,10 -(3a) and 5b,10b-(3b) epoxides was used in the
a,10a-isome, and required more copper (I) chloride,
a
a
References
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The reason was the existence of 17-hydroxyl group consumed
the Grignard (1.0 equiv). After the Grignard reagent was increased
to 3.5 equiv, the materials was completely reacted including the
[
[
[
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[
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At the beginning, we had tried to synthesize the compound 8
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1
(
from the compound 4 listed in Scheme 4. Firstly, diol 4 was directly
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3
4
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a
-
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a-
a
2
nyl-sulfinyl compound 6 was successfully synthesized from ketone
directly reacted with phenylsulfenyl chloride. These synthetic
5
procedures is only 8 steps, less than currently reported in the liter-
ature, but more suitable for industrial process.