Steroids 95 (2015) 7–16

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Steroids
journal homepage: www.elsevier.com/locate/steroids

First synthesis and characterization for the stereoisomers of Ulipristal

acetate
Yi Zhao a, Xiaolong Li a, Hong Liu b, Yongguo Yu a, Li Hai a, Li Guo a,⇑, Yong Wu a,⇑
a
Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China
b
West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China

a r t i c l e i n f o a b s t r a c t

Article history: The three stereoisomers, 11a,17a-isomer I, 11a,17b-isomer II and 11b,17b-isomer III are related
Received 15 June 2014 substances of the selective progesterone receptor modulator Ulipristal acetate. Herein, we presented
Received in revised form 29 October 2014 an efficient and practical synthesis approach to deliver these three stereoisomers for the first time, and
Accepted 12 December 2014
also confirmed the structure of the key intermediate 5a by single-crystal X-ray analysis. Our research will
Available online 30 December 2014
be of immense help for organic chemists to study the impurity profile of Ulipristal acetate.
Ó 2014 Elsevier Inc. All rights reserved.
Keywords:
Ulipristal acetate
Stereoisomer
Synthesis
X-ray structure
Impurity

1. Introduction
The presence of impurities, especially chiral impurities in an
active pharmaceutical ingredient (API) has a significant impact
on the quality and safety of the drug products. Therefore, it is nec-
essary to study the impurity profiles of any API and try to control it
during the manufacturing of a drug product. As per the Interna-
tional Conference on Harmonization (ICH) guidelines any impuri-
ties, which are forming at a level of P0.10% with respect to the
API, should be identified, synthesized and characterized thor-
oughly [1,2].
17a-Acetoxy-11b-(4-N,N-dimethylaminophenyl)-19-norpregna-
4,9-diene-3,20-dione (Ulipristal, EllaÒ, VA-2914 or CDB-2914, Fig. 1)
is a well-known, more specific 19-norprogesterone and a selective
progesterone receptor modulator (SPRM) which efficiently binds
and inhibits progesterone receptor (PR) in progesterone target tissues
[3]. Ulipristal acetate is well characterized for its anti-fertility
potency in several of in vivo and in vitro assays. Different from the
active metabolites, Ulipristal acetate expresses less antiglucocorti-
coid activity compared with the most well-known SPRM and mifepri-
stone Besides, it also exhibits benefits for endometriosis treatment, as
well as ovarian and breast cancer therapies [4].
⇑ Corresponding authors. Tel.: +86 028 85503235 (Y. Wu), +86 028 85503777
(L. Guo).
E-mail addresses: guoli@scu.edu.cn (L. Guo), wyong@scu.edu.cn (Y. Wu).
Therefore, several methods have been developed so far for the
synthesis of Ulipristal acetate [5–9]. However, two chiral centers
in the Ulipristal acetate molecule from the starting materials can
give rise to four stereoisomers including Ulipristal acetate (Fig. 2)
[5,8,9]. Thus, the synthesis of the final product with the required
stereochemistry is a significant challenge. Furthermore, these ster-
eoisomers play essential roles for the preparation of Ulipristal ace-
tate and also for the quality control of bulk drugs and drug
formulations. In this report, we have designed and synthesized
the stereoisomers of Ulipristal acetate. More importantly, the con-
figuration of each isomer was also confirmed.
2. Experimental
All reactions were carried out under an argon atmosphere. Most
chemicals and solvents were analytical grade and used without fur-
ther 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 an YRT-3 melting point apparatus (Shantou Keyi instrument &
Equipment Co. Ltd., Shantou, China). IR spectra were obtained on a
Perkin Elmer 983 (Perkin Elmer, Norwalk, CT, USA). 1H NMR spectra
were taken on a Varian INOVA 400 (Varian, Palo Alto, CA, USA) using
CDCl3, d-DMSO and D2O as solvent. Chemical shifts are expressed in
d (ppm), with tetramethylsilane (TMS) functioning as the internal
reference, and coupling constants (J) were expressed in Hz. Mass

http://dx.doi.org/10.1016/j.steroids.2014.12.009
0039-128X/Ó 2014 Elsevier Inc. All rights reserved.
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).
(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  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
5a,10a- and 5b,10b-epoxides showed by HPLC. The obtained crude
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
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).
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
C22H28O4: 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-11a-(4-N,N-
dimethylaminophenyl)-19-nor-17a-pregn-9-ene-21-ethyne(4b)
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
OAc
O
Fig. 1. The structures of Ulipristal acetate.
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  50 mL). The combined
organic fractions were washed with water (4  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).
2.4. 11a-(4-N,N-dimethylaminophenyl)-17a-ethynyl-17b-
hydroxyestr-4,9-diene-3-one(5)
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
C28H33NO2: 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) Synthesis of 11a,17a-isomer I:
2.5. 11a-(4-N,N-dimethylaminophenyl)-21-(phenyl-sulfinyl)-19-
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 70 and 78 °C. The reaction mixture was
stirred for 4 h at 78 °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  40 mL). The combined
organic fractions were washed with water (4  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).
2.6. 11a-(4-N,N-dimethylaminophenyl)-17a-hydroxy-19-norpregna-
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
 Y. Zhao et al. / Steroids 95 (2015) 7–16 9

N N N
O O O
OAc OAc OAc

O O O
I II III

Fig. 2. The stereoisomers of Ulipristal acetate.

O O O

1) recrystallization
H 2O2, (Cl 3C)2CO 2) Column chromatography
O O O + O O
Na2HPO 4/CH 2Cl2
O O 2a O 2b 21.6%
rt, 12h, 100%
1
5α,10α : 5β,10β
65 : 35
N
HO 1) N
HO
MgBr
sodium acetylide CuCl, THF, 0 oC, 5h
2b
THF, 0oC, 4h, 100% O O 2) NH 4Cl, CH2Cl2/H2O,
rt, 55% O
O 3b
O OH
4b

N
HO

KHSO4 /H2 O,0o C, 4h

65%

O
5

Scheme 1. Synthesis of the key intermediate 5 [5,9].

O
N HC S
C
SCl
1)P(OCH 3)3 /NaOCH 3/CH 3OH
5
triethylamine/THF/-78 oC 2)1.0 M HCl/CH3OH, 0.5h, 54.8%
4h, 62.5% 6
O

N O N
HO O

Ac2O/HClO 4 OAc

CH 2Cl2, -20 oC,

3h, 86%
O O
7 I

Scheme 2. Synthesis of 11a,17a-isomer I [9].

phosphite (0.4 g, 0.0032 mol) was added and stirring was contin-
ued at 70 °C for 2 h. The reaction mixture was cooled to 20 °C
and poured into water (25 mL), then extracted with methylene
chloride (3  30 mL). The combined organic fractions were dried
over sodium sulfate, filtered, and concentrated in vacuo to give
2.12 g of reddish brown oil. The oil was dissolved in a mixture of
1 N hydrochloric acid (1.3 mL) and methanol (20 mL), then stirred
at room temperature for 30 min. Ice water (200 mL) was added to
the mixture. After neutralizing with saturated sodium bicarbonate,
the mixture was extracted with methylene chloride (3  20 mL).
The combined organic fractions were washed with water
(2  20 mL), dried over sodium sulfate, filtered, and concentrated
in vacuo to get 1.6 g of reddish brown oil. The obtained crude prod-
uct was purified via column chromatography (petroleum ether–
ethyl acetate 10:1) to yield 0.5 g (54.8%) off-white syrupy. MS
(m/z): 434.58 [M + H]+, Analysis calculated for C28H35NO3: C
77.56, H 8.14, N 3.23; found: C 77.62, H 8.21, N 3.28. 1H NMR
{400 MHz, CDCl3 (TMS), d (ppm)}: 0.881(s, 3H, CH3), 1.232–2.787
10 Y. Zhao et al. / Steroids 95 (2015) 7–16
(m, 16H), 2.258 (s, 3H, COCH3), 2.914 (s, 6H, NACH3), 3.867 (t, 1H,
J = 9.2, CH), 5.663 (s, 1H, @CH), 6.673 (d, 2H, J = 8.4, ArAH), 6.934
(d, 2H, J = 8.4, ArAH).
2.7. 11a,17a-Isomer I
Perchloric acid (0.1 mL, 0.0011 mol) was added to acetic anhy-
dride (0.5 mL, 0.0053 mol) by dropwise at 10 °C. The obtained
solution was stirred for an additional 1 h, then, cooled to 20 °C
and the solution of compound 7 (0.2 g, 0.0005 mol) in dry dichloro-
methane (10 mL) was added at such rate to keep the temperature
between 10 and 20 °C, then the reaction mixture was stirred at
this temperature for 3 h. The mixture was diluted with dichloro-
methane (10 mL) and poured into water (10 mL) containing
sodium acetate (1.4 g, 0.017 mol). The organic layer was separated,
washed with water (3  10 mL), dried over sodium sulfate and
concentrated under reduced pressure to give 0.22 g of slightly yel-
low syrupy. The syrupy was purified via column chromatography
(petroleum ether–ethyl acetate 15:1) to yield 0.19 g (86%) of
slightly yellow syrupy. FTIR (KBr, diffuse reflectance): cmax 2923;
1721 and 1718 (AC@O); 1673 and 1662 (conjugated AC@O);
1575; 1528; 1448; 1362; 1313; 1259; 1212; 1178; HRMS: calcu-
lated for C30H37NO4 475.6191, found: 475.6165. 1H NMR
{400 MHz, CDCl3 (TMS), d (ppm)}: 0.797 (s, 3H, CH3), 1.256–
2.658 (m, 16H), 2.024 (s, 6H, COCH3), 2.945 (s, 6H, NACH3),
3.905 (t, 1H, J = 9.2, CH), 5.686 (s, 1H, @CH), 6.710 (d, 2H, J = 8.4,
ArAH), 6.982 (d, 2H, J = 8.4, ArAH); 13C NMR {400 MHz, CDCl3
(TMS), d (ppm)}: 21.181; 24.075; 25.668; 26.761; 27.780; 30.165;
30.951; 36.688; 36.748; 38.268; 39.281; 40.479; 46.951; 50.839;
66.989; 96.110; 112.678; 122.851; 127.214; 129.195; 131.398;
145.525; 148.534; 156.481; 170.517; 199.425; 203.732.
(3) Synthesis of 11a,17b-isomer II:
2.8. 11a-(4-N,N-dimethylaminophenyl)-17b-hydroxy-19-norpregna-
4,9-diene-3,20-dione(8)
Compound 5 (1.2 g, 0.0029 mol) was dissolved in a mixture of
acetic acid-H2O-30% sulfuric acid (40:8:1, 10 mL), then, mercuric
sulfate (0.085 g, 0.0003 mol) was added to above mixture. The reac-
tion mixture was stirred for 5 h at 60 °C. After neutralizing with sat-
urated sodium bicarbonate, the mixture was extracted with
methylene chloride (3  20 mL). The organic layer was separated,
dried over sodium sulfate and concentrated under reduced pressure
to give 1.0 g of brown oil. The oil was purified via column chroma-
tography (petroleum ether–ethyl acetate 15:1) to yield 0.82 g
(65.2%) of a slightly yellow syrupy. MS (m/z): 434.58 [M + H]+, Anal-
ysis calculated for C28H35NO3: C 77.56, H 8.14, N 3.23; found: C
77.48, H 8.01, N 3.18. 1H NMR {400 MHz, CDCl3 (TMS), d (ppm)}:
0.901 (s, 3H, CH3), 1.079 (s, 3H, COCH3), 1.242–2.689 (m, 16H),
2.926 (s, 6H, NACH3), 3.811 (t, 1H, J = 7.2, CH), 5.704 (s, 1H, @CH),
6.676 (d, 2H, J = 8.4, ArAH), 7.016 (d, 2H, J = 8.4, ArAH).
N O
HO
HgSO4/H 2SO 4
5
CH 3COOH/H 2O, 60oC
5h, 65.2% O
8 II
Scheme 3. Synthesis of 11a,17b-isomer II [9,10].
2.9. 11a,17b-Isomer II (Scheme 3)
Perchloric acid (0.4 mL, 0.0044 mol) was added to acetic anhy-
dride (2 mL, 0.0212 mol) by dropwise at 10 °C. The obtained solu-
tion was stirred for an additional 1 h, then cooled to 30 °C and the
solution of compound 8 (0.8 g, 0.002 mol) in dry dichloromethane
(20 mL) was added at such rate to keep the temperature between
10 °C and 20 °C, then the reaction mixture was stirred at this
temperature for 3 h. The mixture was diluted with dichlorometh-
ane (20 mL) and poured into water (20 mL) containing sodium ace-
tate (5.6 g, 0.068 mol). The organic layer was separated, washed
with water (3  10 mL), dried over sodium sulfate and concen-
trated under reduced pressure to give 1.12 g of slightly yellow syr-
upy. The syrupy was purified via column chromatography
(petroleum ether–ethyl acetate 15:1) to yield 0.84 g (86%) of
slightly yellow syrupy. FTIR (KBr, diffuse reflectance): cmax 2933;
1731 and 1722(AC@O); 1669 and 1658 (conjugated AC@O);
1568; 1531; 1455; 1371; 1332; 1262; 1222; 1171; HRMS: calcu-
lated for C30H37NO4 475.6191, found: 475.6178. 1H NMR
{400 MHz, CDCl3 (TMS), d (ppm)}: 0.979 (s, 3H, CH3), 1.193–
2.683 (m, 16H), 1.609 (s, 3H, COCH3), 2.072 (s, 3H, COCH3), 2.917
(s, 6H, NACH3), 3.850 (t, 1H, J = 8.0), 5.687 (s, 1H, CH), 6.666 (d,
2H, J = 8.4, ArAH), 6.989 (d, 2H, J = 8.4, ArAH); 13C NMR
{400 MHz, CDCl3 (TMS), d (ppm)}:21.195; 24.087; 25.684;
26.754; 27.789; 30.168; 30.998; 36.676; 36.789; 38.257; 39.268;
40.485; 46.981; 50.848; 66.986; 96.120; 112.689; 122.845;
127.228; 129.187; 131.420; 145.548; 148.528; 156.496; 170.541;
199.431; 203.722.
(4) Synthesis of 11b,17b-isomer III:
2.10. 3,3-(Ethylene-dioxy)-17a-ethynyl-17b-hydroxyestr-5(10),9(11)-
diene (9)
Compound 1 (20 g, 0.0636 mol) was dissolved in dry tetrahy-
drofuran (200 mL) at 0 °C. The mixture was stirred for 0.5 h, and
sodium acetylide (6.0 g, 0.1272 mol) was added. After that, the
reaction mixture was stirred for another 1 h. Saturated ammonium
chloride solution (200 mL) and water (200 mL) were added and the
mixture was stirred for 10 min. Then the reaction mixture was
concentrated to a volume of 350 mL. The residue was stirred for
3 h at 0 °C. The precipitated crystals were filtered off and dried at
50 °C to yield 20.6 g (95%) of the title compound 9. mp: 145–
148 °C, MS (m/z): 340.21 [M + H]+, Analysis calculated for
C22H28O3: C 77.61, H 8.29; found: C 77.68, H 8.35. 1H NMR
{400 MHz, CDCl3 (TMS), d (ppm)}: 0.891(s, 3H, CH3), 1.134–2.662
(m, 18H), 2.579 (s, 1H, acetylenic hydrogen), 3.881–3.998 (m, 4H,
OACH2), 5.678 (t, 1H, J = 5.6, @CH).
2.11. 17a-Ethynyl-17b-hydroxyestra-4,9-diene-3-one(10)
To a solution of compound 9 (20 g, 0.059 mol) in acetic acid
(200 mL), perchloric acid (10.7 mL, 0.118 mol) was added
dropwise. The reaction mixture was stirred for 0.5 h at room
N
O
OAc
Ac2O/HClO4
CH 2Cl2, -20oC
3h, 88% O
 Y. Zhao et al. / Steroids 95 (2015) 7–16 11

O O
OH OH HO

sodium acetylide CH3COOH HgSO4 /H2 SO4

O
THF,0o C,1h O HClO4 ,rt, 0.5h
THF/H2O, 60o C, 5h
O 95% 87% O O
1 O 9 10 79% 11

O O O
HO O HO O HO O
ethylene glycol,
p-toluenesulfonic acid (CF3 )2 CO/H2 O2
O O + O O
triethyl orthoformate O
CH2Cl2 /Na2 HPO4,0o C,18h
CH2Cl2 ,rt, 3h 85.6% O O O
100%
12 13b
13a
5α,10α : 5β,10β
75 : 25

N O N
HO O
1) N MgBr / CuCl/THF,0oC,3h Ac 2O/HClO 4 OAc

2) Saturated NH4Cl/CH2Cl2 ,0oC CH2 Cl 2,

o
-20oC, 4h,
3) ethanol/ 8.5%H2 SO4,0 C, 2h,64% O O
86.9% III
14

Scheme 4. Synthesis of 11b,17b-isomer III [5,9,10].

temperature, then, poured into water (500 mL). The precipitated
crystals were filtered off and dried at 50 °C to give 15.21 g (87%)
off-white solid. mp: 181–185 °C, MS (m/z): 297.18 [M + H]+, Anal-
ysis calculated for C20H24O2: C 81.04, H 8.16; found: C 80.95, H
8.11; 1H NMR {400 MHz, CDCl3 (TMS), d (ppm)}: 0.879 (s, 3H,
CH3), 1.202–2.658 (m, 18H), 2.587 (s, 1H, acetylenic hydrogen),
5.682 (s, 1H, @CH).
2.12. 17b-Hydroxy-19-norpregna-4,9-diene-3,20-dione (11)
Compound 10 (15.0 g, 0.0506 mol) was dissolved in tetrahydro-
furan (150 mL), then, 30% sulfuric acid (50 mL), mercuric sulfate
(1.44 g, 0.0051 mol) was added to the above mixture. The reaction
mixture was stirred for 5 h at 60 °C. After neutralizing with satu-
rated sodium bicarbonate, the mixture was extracted with methy-
lene chloride (3  50 mL). The organic layer was separated, dried
over sodium sulfate and concentrated under reduced pressure to
give brown oil. The oil was purified via column chromatography
(petroleum ether–ethyl acetate 10:1) to yield 12.57 g (79%) white
solid. mp: 195–196 °C, MS (m/z): 315.19 [M + H]+, Analysis calcu-
lated for C20H26O3: C 76.40, H 8.33; found: C 76.45, H 8.41; 1H
NMR {400 MHz, CDCl3 (TMS), d (ppm)}: 0.877(s, 3H, CH3), 1.239
(s, 3H, CH3), 1.363–2.945 (m, 18H), 5.688 (s, 1H, @CH).
2.13. 3,3,20,20-Bis(ethylene-dioxy)-17b-hydroxy-19-norpregna-
5(10),9(11)-diene (12)
To a solution of compound 11 (12 g, 0.0382 mol) in methylene
chloride (120 mL), ethylene glycol (21.3 mL, 0.382 mol), trimethyl
orthoformate (41.7 mL, 0.382 mol) and p-toluenesulfonic acid
(3.3 g, 0.0191 mol) were added. The reaction mixture was stirred
at room temperature for 3 h, then saturated sodium bicarbonate
was added to adjust pH to 7–8. The organic layer was separated,
and the water-course was extracted with methylene chloride
(3  50 mL). The combined organic fractions were dried over
sodium sulfate and concentrated under reduced pressure to give
slightly brown oil. The oil was purified via column chromatography
(petroleum ether–ethyl acetate 20:1) to yield 13.1 g (85.6%) white
solid. mp: 185–190 °C, MS (m/z): 403.24 [M + H]+; Analysis calcu-
lated for C24H34O5: C 71.61, H 8.51; found: C 71.55, H 8.59; 1H
NMR {400 MHz, CDCl3 (TMS), d (ppm)}: 0.905 (s, 3H, CH3), 1.090
(s, 3H, CH3), 1.173–2.665 (m, 18H), 2.261 (s, 1H, OH), 3.746–
3.819 (m, 1H, AOCH2), 3.933–4.013 (m, 6H, AOCH2), 4.067–4.119
(m, 1H, AOCH2), 5.588 (t, 1H, J = 5.6, @CH).
2.14. 3,3,20,20-Bis(ethylene-dioxy)-17b-hydroxy-5a,10a-epoxy-19-
norpregna-9(11)-ene (13a) and 3,3,20,20-bis(ethylene-dioxy)-17b-
hydroxy-5b,10b-epoxy-19-norpregna-9(11)-ene (13b)
Under nitrogen, 30% aqueous hydrogen peroxide (4.4 mL,
0.15 mol) and sodium phosphate dibasic dodecahydrate (11.7 g,
0.033 mol) were added to a solution of hexafluoroacetone
(3.75 mL, 0.03 mol) in methylene chloride (120 mL). The mixture
was stirred for 1 h at 0 °C. Compound 12 (12 g, 0.03 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
methylene chloride (100 mL) and ice (6 g). A solution of sodium
thiosulphate (23.7 g, 0.15 mol) in water (150 mL) was added drop-
wise to the mixture to destroy the excess of hydrogen peroxide.
After separation, the organic fraction was washed with water
(2  50 mL) and dried over sodium sulfate. The solvent was
removed in vacuo to give 12.6 g (100%) of product, which was a
75:25 mixture of the 5a,10a- and 5b,10b-epoxides showed by HPLC.
The obtained crude mixture of epoxides was used in the next step
without further purification. MS (m/z): 419.24 [M + H]+; Analysis
calculated for C24H34O6: C 68.87, H 8.19; found: C 68.95, H 8.31;
1
H NMR {400 MHz, CDCl3 (TMS), d (ppm)}: 0.885 (s, 3H, CH3),
1.042 (s, 3H, CH3), 1.073–2.641 (m, 18H), 3.751–3.811 (m, 1H,
AOCH2), 3.852–4.003(m, 6H, AOCH2), 4.060–4.112 (m, 1H, AOCH2),
5a,10a: 5.830 (t, 1H, J = 6.0, @CH), 5b,10b: (t, 1H, J = 6.0, @CH).
2.15. 11b-(4-N,N-dimethylaminophenyl)-17b-hydroxy-19-norpregna-
4, 9-diene-3, 20-dione(14)
Under anhydrous conditions, a portion (4 mL) of a solution
of 4-bromo-N,N-dimethylaniline (21 g, 0.105 mol) in dry
12 Y. Zhao et al. / Steroids 95 (2015) 7–16

tetrahydrofuran (100 mL) and one crystal of iodine was added to the
mixture of magnesium (2.92 g, 0.12 mol) in dry tetrahydrofuran
(10 mL) 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 tem-
perature. The mixture was then added dropwise to a suspension of
13a and 13b (12.6 g, 0.03 mol) and copper (I) chloride (0.9 g,
0.003 mol) in dry tetrahydrofuran (130 mL) at 0 °C. The reaction
mixture was stirred for 3 h, then, poured into 10% ammonium chlo-
ride (70 mL) solution and extracted with methylene chloride
(3  100 mL). The combined organic fractions were washed with
water (4  50 mL), dried over sodium sulfate, filtered, and concen-
trated in vacuo to give black oil (28.5 g). The obtained oil was dis-
solved in ethanol (200 mL) under a nitrogen atmosphere, and 8.5%
aqueous sulfuric acid (8.9 mL) was added. The reaction mixture
was stirred for 2 h at 70 °C. After neutralizing with saturated sodium
bicarbonate, the mixture was diluted with water (300 mL), and
extracted with methylene chloride (3  100 mL). The combined
organic fractions were dried over sodium sulfate and concentrated
under reduced pressure to give brown oil. The oil was purified via
column chromatography (petroleum ether–ethyl acetate 15:1) to
yield 8.3 g (64%) of a light blue syrupy. MS (m/z): 434.26 [M + H]+,
Analysis calculated for C28H35NO3: C 77.56, H 8.14, N 3.23; found:
C 77.48, H 8.24, N 3.17; 1H NMR {400 MHz, CDCl3 (TMS), d
(ppm)}: 0.394 (s, 3H, CH3), 0.858–3.042 (m, 16H,), 1.241 (s, 3H,
COCH3), 3.916(s, 6H, NACH3), 4.364 (d, 1H, J = 5.2, CH), 5.767 (s,
1H, @CH), 6.667 (d, 2H, J = 8.0, ArAH), 7.020 (d, 2H, J = 8.0, ArAH).
2.16. 11b,17b-Isomer III (Scheme 4)
Perchloric acid (2.3 mL, 0.025 mol) was added to acetic anhy-
dride (11.8 mL, 0.125 mol) by dropwise at 10 °C. The obtained
solution was stirred for an additional 1 h, then, cooled to 30 °C
and the solution of compound 14 (5 g, 0.0125 mol) in dry dichloro-
methane (50 mL) was added at such rate to keep the temperature
between 10 °C and 20 °C, then the reaction mixture was stirred
at this temperature for 4 h. The mixture was diluted with dichloro-
methane (50 mL) and poured into water (50 mL) containing
sodium acetate (35 g, 0.425 mol). The organic layer was separated,
washed with water (3  10 mL), dried over sodium sulfate and
concentrated under reduced pressure to give 6.1 g of brown oil.
The oil was purified via column chromatography (petroleum
ether–ethyl acetate 15:1) to yield 5.17 g (86.9%) of slightly yellow
syrupy. FTIR (KBr, diffuse reflectance): cmax 2938; 1742 and 1725
(AC@O); 1662 and 1654 (conjugated AC@O); 1571; 1538; 1449;
1379; 1342; 1269; 1242; 1178; HRMS: calculated for C30H37NO4
475.6191, found: 475.6181. 1H NMR {400 MHz, CDCl3 (TMS), d
(ppm)}: 0.702 (s, 3H, CH3), 0.856–2.813 (m, 16H), 2.090 (s, 3H,
COCH3), 2.129 (s, 3H, COCH3), 2.935(s, 6H, NACH3), 4.278 (t, 1H,
J = 6.4, CH), 5.747 (s, 1H, @CH), 6.683 (d, 2H, J = 8.4, ArAH), 7.021
(d, 2H, J = 8.4, ArAH); 13C NMR {400 MHz, CDCl3 (TMS), d
(ppm)}: 21.184; 24.079; 25.688; 26.765; 27.791; 30.178; 30.988;
36.687; 36.791; 38.264; 39.271; 40.487; 46.957; 50.854; 66.979;
96.134; 112.695; 122.851; 127.234; 129.179; 131.442; 145.551;
148.537; 156.499; 170.554; 199.445; 203.731.
3. Discussion
3.1. The formation of the 11a,17a-isomer I
The synthesis of the drug substance was based on the very effi-
cient 1,4-addition (Scheme 5). The 5a,10a-epoxide was converted
into Ulipristal acetate smoothly. But there always had the 5b, 10b-
isomer in the starting material. After a series of reactions, the
5b,10b-isomer was transformed into the 11a,17a-isomer I
(Scheme 6). Especially, the contents of 15b was up to 45% in the
route reported by Dancsi et al. [8]. In this route, the ratio of 15a
and 15b was about 55:45, which was used directly in the next step
without further separation. And there were only three steps to

N
R R

Grignard addition
O O O Ulipristal acetate

O O OH
5α,10α
3a R= 17β−hydroxy, 17α-ethynyl 4a R= 17β− hydroxy, 17α- ethynyl

O O
15a R= 17 α−hydroxy, 17β - O 16a R= 17α− hydroxy, 17β - O
CH 3 CH 3

Scheme 5. Synthesis of Ulipristal acetate.

N
R R N
O
OAc
Grignard addition
O O O
O O OH O
5β,10β
11α,, 17α−
−isomer Ι
3b R= 17β− hydroxy, 17α - ethynyl 4b R= 17 β− hydroxy, 17 α-ethynyl

O O
15b R= 17α− hydroxy, 17β- O 16b R= 17α−hydroxy, 17β- O
CH3 CH 3

Scheme 6. Formation of 11a,17a-isomer I.

 Y. Zhao et al. / Steroids 95 (2015) 7–16 13

O
HC S
C O O
OH OH

1) CH3ONa/P(OCH 3)3
+
O O
2)1.0 M HCl O
O O O
17 18 19

5 steps 5 steps

Ulipristal acetate and 11β,, 17β-isomer III 11α,, 17β- isomer II and 11β,, 17β-isomer III

Scheme 7. Formation of compound 19.

O
HC S N O N O
N HO
C HO
1)P(OCH3) 3 /CH3ONa
+
2)1.0 M HCl
O O
O
20 21 14

Ac 2O
Ac 2O

Ulipristal acetate 11β,, 17β-isomer III

Scheme 8. Formation of compound 14.

O
HC S N O N O
N HO
C HO
1)P(OCH3) 3 /CH3ONa
+
2)1.0 M HCl
O O
O
6 7 8

Ac2O Ac2O

11α,, 17α -isomer I 11α,, 17β -isomer II

Scheme 9. Formation of compound 7 and 8.

obtain Ulipristal acetate. Thus, it was highly possible that the

11a,17a-isomer I was present in the final product. According to
HPLC-MS, we found two peaks with the same m/z value as Ulipri-
stal acetate. So, it was necessary to confirm the two peaks. At the
beginning, we tried to separate the 11a, 17a-isomer I from the
final product. However, the content of the title compound was
too low to fit the large scale. Then we attempted to directly get
the compound 15b or 16b. Unfortunately, 15a and 15b, or 16a
and 16b had the same Rf according to TLC. There was no way to
obtain 15b or 16b at a slightly large scale by the means of Dancsi’s
route [8].
Previously, we had published our work describing a synthetic
route to Ulipristal acetate [9]. Fortunately, in this route, it was
found the compound 2a and 2b could be separated on TLC easily,
where the Rf value of 2b was slightly larger than 2a. Thus, we
designed the above route to synthesize the 11a,17a-isomer I Fig. 3. ORTEP view of the key intermediate 5.
(Scheme 1 and 2). In this route, the contents of 2b was about
35% using hexachloroacetone as the catalyst, mCPBA as epoxida- concentrated in vacuo to yield a 42:58 mixture of the 2a and 2b.
tion reagents [9]. In order to improve the contents of 2b, the mix- The mixture was separated via column chromatography to give
ture of 2a and 2b was recrystallized firstly. Then, the filtrate was the 5b,10b-isomer 2b.
14 Y. Zhao et al. / Steroids 95 (2015) 7–16

Fig. 4. (a) The 1H NMR {400 MHz, CDCl3 (TMS)} of compound 7. (b) The NOEDS {400 MHz, CDCl3 (TMS)} of compound 7 at 0.89 ppm (arrow).

Fig. 5. (c) The 1H NMR {400 MHz, CDCl3 (TMS)} of compound 8. (d) The NOEDS {400 MHz, CDCl3 (TMS)} of compound 8 at 0.90 ppm (arrow).

Fig. 6. (e) The 1H NMR {400 MHz, CDCl3 (TMS)} of compound 14. (f) The NOEDS {400 MHz, CDCl3 (TMS)} of compound 14 at 0.39 ppm (arrow).

3.2. The formation of the 11a,17b-isomer II and 11b,17b-isomer III
Dancsi et al. used compound 1 as their starting material to syn-
thesize Ulipristal acetate [8]. The phenyl-sulfinyl compound 17
was obtained after two steps, then, reacted with sodium
methoxide and trimethyl phosphite to get 17a-hydroxy compound
18 (Scheme 7). Our previous work also used compound 1 as the
starting material to synthesize Ulipristal acetate [9]. After 5 steps,
the phenyl-sulfinyl compound 20 was afforded, then reacted with
sodium methoxide and trimethyl phosphite to yield 17a-hydroxy
 Y. Zhao et al. / Steroids 95 (2015) 7–16 15

Table 1
The differences in 11a,17a-isomer I, 11a,17b-isomer II and 11b,17b-isomer III and Ulipristal acetate.

Compound [a]20
D (c 1.0,CHCl3) 11-CH (ppm) 17-CH3 (ppm) 17-COCH3 (ppm) 17-OCOCH3 (ppm)
Ulipristal acetate +174° 4.365 0.355 2.137 2.099
11a,17b-Isomer I 82° 3.905 0.797 2.024 2.024
11a,17a-Isomer II 135° 3.850 0.979 1.609 2.072
11b,17a-Isomer III +124° 4.278 0.702 2.129 2.090

Fig. 7. HPLC chromatogram of the crude Ulipristal acetate which was synthesized by Dancsi’s route [8].

Fig. 8. HPLC chromatogram of the crude Ulipristal acetate which was synthesized by Yu’s route [9].

compound 21 (Scheme 8). Thus, most of the product was the 17a-
hydroxy compound 18 and 21. However, the 17b-hydroxy com-
pound 19 and 14 can also be generated according to collision the-
ory. Especially, when there was 11a-[4-(dimetnylamino)phenyl] in
the molecule of compound 6, the generation of 17b-hydroxy com-
pound 8 was easier than the 17b-hydroxy compound 19 and 14
(Scheme 9).
From above discussion, we can see that 11a,17a-isomer I,
11a,17b-isomer II and 11b,17b-isomer III might be all present in
the final product of Ulipristal acetate. Therefore, further study of
the isomers is highly desirable.
3.3. Structure confirmation
We tried to cultivate the single-crystal to research their struc-
ture. Fortunately the single-crystal of the key intermediate 5 was
cultivated by slow evaporation at room temperature successfully.
Its structure had been confirmed by the use of single-crystal
X-ray analysis (Fig. 3). It was clear that 4-N,N-dimethylaminophe-
nyl in the molecule of compound 5 was found out at the a-config-
uration which was not changed in the next reactions. The d (ppm)
of 11b-hydrogen was about 3.6–4.0, while 11a-hydrogen was
about 4.2–4.4 according to 1H NMR. Thus, the configurations of
4-N,N-dimethylaminophenyl in the molecule of compound I, II
and III were easily confirmed.
In order to confirm the configurations of 17-acetyl in the mole-
cule of compound I and II and III, we had tried to make NOEDS
tests of compound I, II and III. Unfortunately, it was found the
17-acetyl and 17-acetoxy affected each other. Then, we transferred
to make NOEDS tests of compound 7 and 8 and 14.
According to the 1H NMR and NOEDS of compound 7 and 8 and
14 (Figs. 4–6), the configuration of each compound can been easily
16 Y. Zhao et al. / Steroids 95 (2015) 7–16
confirmed. The position of each arrow is just the chemical shift of
13b-methyl. On the basis of the intensity of the signal of 17-acetyl,
it can be easily confirmed that the 17-acetyl is at the same side of
13b-methyl. Clearly, the 17-acetyl of compound 7 is at the b-con-
figuration, the 17-acetyl of compound 8 is at the a-configuration,
and the 17-acetyl of compound 14 is at the a-configuration.
Because the next step is acetylation, the configuration of 17-acetyl
was not changed. Thus, that is to say, the configuration of com-
pound I, II and III are the title compounds. The differences of these
three isomers are listed in Table 1.
4. Results
HPLC Analysis was carried out on a Agilent eclipse XDB-C18
(5 lm, 4.6  150 mm) eluded with 70% CH3OH in water at a flow
rate of 1 mL/min and at k = 260 nm. At last, it was found that
0.2% of 11a, 17a-isomer I was present in the Ulipristal acetate syn-
thesized by Dancsi’s route (Fig. 7), while 0.14% of 11b,17b-isomer
III was present in the Ulipristal acetate synthesized by our route
(Fig. 8). The 11a,17b-isomer II was not detected in any Ulipristal
acetate synthesized by above two routes.
5. Conclusion
We have developed an efficient and practical synthesis approach
to deliver 11a,17a-isomer I, 11a,17b-isomer II and 11b,17b-isomer
III for the first time. It is essential and important for comprehending
the complete stereoisomers profile of Ulipristal acetate and meeting
the stringent regulatory requirements of ICH. This study will provide
an access to the reference standard of these three stereoisomers and
also will be of immense help for organic chemists to obtain the pure
Ulipristal acetate.
Acknowledgement
This work was supported by the National Natural Science Foun-
dation of China (No. 81072532 & No. 81102324).
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