Synthesis of (+)-ambrisentan via chiral ketone-catalyzed asymmetric epoxidation

Article abstract of DOI:10.1021/jo201927m

The synthesis of optically pure (+)-ambrisentan has been achieved from 3,3-diphenylacrylate in four steps with 53% overall yield and >99% ee at the >100 g scale without column purification. The chiral epoxide intermediate was prepared via asymmetric epoxi

Full text of DOI:10.1021/jo201927m

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pubs.acs.org/joc
Synthesis of (+)-Ambrisentan via Chiral Ketone-Catalyzed
Asymmetric Epoxidation
Xianyou Peng,† Peijun Li,† and Yian Shi*,†,‡
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
ABSTRACT: The synthesis of optically pure (+)-ambrisentan has been achieved from 3,3-diphenylacrylate in four steps with
53% overall yield and >99% ee at the >100 g scale without column purification. The chiral epoxide intermediate was prepared via
asymmetric epoxidation with a fructose-derived diacetate ketone as catalyst.
(+)-Ambrisentan (1), under the brand names Letairis in the
United States and Volibris in Europe, is an endothelin-1 (ET-1)
receptor antagonist and clinically used for the treatment of
pulmonary arterial hypertension.1,2 The reported synthesis of
ambrisentan usually involves the epoxide formation via Darzens
reaction with benzophenone and methyl chloroacetate, acid-
catalyzed epoxide ring-opening with MeOH, nucleophilic
substitution with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine
(5), and hydrolysis of ambrisentan methyl ester (6b) (Scheme
1).1−3 The synthesis of optically pure ambrisentan mainly relied
on resolution with various chiral amines.1b,2,3 During our
studies on chiral ketone-catalyzed asymmetric epoxidation,4 we
found that diacetate ketone 8 prepared in one pot from readily
available ketone 7 can also epoxidize electron-deficient olefins
such as α,β-unsaturated esters (Figure 1).5−7 Herein, we wish
to report the application of this epoxidation to the synthesis of
enantiomerically enriched (+)-ambrisentan.
sentan in ethyl acetate and water and was separated from
(+)-ambrisentan by simple filtration. (+)-Ambrisentan (1)
(120.1 g) was obtained in 53% total yield and >99% ee in four
steps from ethyl 3,3-diphenylacrylate (2) (Scheme 1).
In summary, optically pure (+)-ambrisentan was synthesized
at the 120 g scale (53% overall yield, >99% ee) in four steps
from ethyl 3,3-diphenylacrylate (2). The chiral epoxide
intermediate was prepared via asymmetric epoxidation with a
fructose-derived diacetate ketone as catalyst. No column
purification was required for the entire process. The optical
purity of (+)-ambrisentan was readily enhanced by taking
advantage of the poor solubility of the racemic form. All these
features make the current process practical for the large-scale
preparation of (+)-ambrisentan.
EXPERIMENTAL SECTION
General Methods. All commercially available reagents were used
■
Asymmetric epoxidation of ethyl 3,3-diphenylacrylate (2)8
was carried out at the 0.6 mol scale with 0.32 equiv of diacetate
ketone 8 under the standard epoxidation conditions.6b The
corresponding epoxide (3) was obtained with 90% conversion
and 85% ee (Scheme 1). The crude epoxide was treated with
BF3·Et2O (1.3 mol %) in MeOH to give alcohol 4 (84% ee),
which was directly reacted with 4,6-dimethyl-2-
(methylsulfonyl)pyrimidine (5) and K2CO3 in DMF to give
ester 6a in 83% ee. The crude ester was hydrolyzed with 3.8 N
aqueous NaOH solution to give ambrisentan Na salt. The
aqueous solution was washed with ether to remove any organic
impurities9 and then acidified to pH ≈ 1 with concentrated
HCl to precipitate ambrisentan. To our delight, it was found
that ( )-ambrisentan is much less soluble than (+)-ambri-
without further purification. Column chromatography was performed
1
on silica gel (200−300 mesh). H NMR spectra were recorded on a
400 MHz NMR spectrometer and 13C NMR spectra were recorded on
a 100 MHz NMR spectrometer. IR spectra were recorded on a FT-IR
spectrometer. Melting points were uncorrected. Ethyl 3,3-diphenyla-
crylate was prepared according to the reported procedure.8
(S)-3,3-Diphenyloxirane-2-carboxylic Acid Ethyl Ester (3).
To a vigorously stirred solution of ethyl 3,3-diphenylacrylate (2)
(151.4 g, 0.60 mol) in CH3CN (3.0 L) and aqueous Na2(EDTA) (1 ×
10−4 M) (3.0 L) at 0 °C was added (n-Bu)4NHSO4 (12.2 g, 0.036
mol). A mixture of Oxone (1.85 kg, 3.0 mol) and NaHCO3 (0.78 kg,
9.3 mol) was pulverized, and a small portion of this mixture was added
Received: September 17, 2011
Published: November 18, 2011
© 2011 American Chemical Society
701
dx.doi.org/10.1021/jo201927m | J. Org. Chem. 2012, 77, 701−703

The Journal of Organic Chemistry
Note
Scheme 1
for 30 min (the mixture became dark green), 4,6-dimethyl-2-
(methylsulfonyl)pyrimidine (5) (154.7 g, 0.83 mol) was added in
one portion at rt. Upon stirring at 90 °C for 15 h, the reaction mixture
was cooled to rt and diluted with ethyl acetate (2.5 L) and water (1.0
L). The organic layer was washed by 2 N citric acid (0.5 L) and brine
(1.0 L), dried over MgSO4, filtered, and concentrated to give crude
ester 6a as red oil (284.0 g, crude yield >99%), which was directly used
for the next step. For the analysis, small amounts of ester 6a were
purified by column chromatography (silica gel, petroleum ether/ethyl
acetate = 5:1). Colorless oil: [α]D20 = +82.9 (c 1.0, CHCl3) (83% ee);
IR (film) 1750, 1596 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J
= 7.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.33−7.19 (m, 6H), 6.70 (s,
1H), 6.12 (s, 1H), 4.01−3.85 (m, 2H), 3.50 (s, 3H), 2.38 (s, 6H), 0.93
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 168.7,
163.9, 142.5, 141.3, 128.5, 128.03, 127.97, 127.94, 127.5, 127.4, 115.0,
83.8, 79.2, 60.7, 53.9, 24.0, 13.9; Anal. Calcd For C24H26N2O4: C,
70.92; H, 6.45; N, 6.89. Found: C, 70.72; H, 6.47; N, 6.83.
(S)-2-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-di-
phenylpropanoic Acid (Ambrisentan) (1). To a stirred solution of
the above ester (6a) (∼0.6 mol) in 1,4-dioxane (1.4 L) was added an
aqueous solution of NaOH (3.8 N) (110.0 g, 2.76 mol) in distilled
water (0.72 L) at rt. Upon stirring at 90 °C overnight (ester 6a
disappeared by TLC), the reaction mixture was concentrated to
remove the organic solvent and washed with ethyl ether (0.5 L × 2) to
remove any organic impurities.9 The aqueous layer was acidified with
concentrated HCl to pH ≈ 1.0 (large amounts of white solid
appeared) and extracted with ethyl acetate (2.0 L). At this point, some
solid stayed at the interface of the organic and aqueous layer. The
whole mixture was filtered by suction. The filter cake (24.9 g) was
found to be ambrisentan in nearly racemic form (<10% ee). The layers
of the filtrate were separated. The aqueous layer was extracted with
ethyl acetate (1.0 L × 2). The combined organic layers were dried over
Na2SO4, filtered, and concentrated. The resulting residue was stirred
with ethyl acetate (0.5 L) and filtered with suction to give
(+)-ambrisentan as white solid (100.0 g, 99% ee) (the ee was
determined after it was converted to the methyl ester with
TMSCHN2). The mother liquid was concentrated, stirred with ethyl
acetate (0.1 L), and filtered to give another batch of white solid (20.1
Figure 1. Chiral ketone catalysts.
to the reaction mixture to bring the pH to >7.0. Then, a solution of
ketone 8 (57.8 g, 0.19 mol) in CH3CN (1.5 L) was added. The
remainder of the Oxone and NaHCO3 was added to the reaction
mixture portionwise over a period of 4.5 h. Upon stirring at 0 °C for
additional 20 h, the reaction mixture was diluted with water, extracted
with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and
concentrated to give crude epoxide 3 as orange oil (∼190.0 g, 90%
1
conversion by H NMR, crude yield >99%), which was directly used
for the next step. For the analysis, small amounts of the epoxide were
purified by column chromatography (silica gel, eluent: petroleum
ether/ethyl acetate = 1:0 to 20:1). Colorless oil: [α]D20 = +27.4 (c 1.0,
CHCl3) (85% ee); IR (film) 1757, 1726 cm−1;10 1H NMR (400 MHz,
CDCl3) δ 7.48−7.43 (m, 2H), 7.39−7.29 (m, 8H), 4.07−3.94 (m,
2H), 3.98 (s, 1H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.0, 139.0, 135.6, 128.7, 128.5, 128.3, 128.1, 127.0, 66.6,
62.1, 61.4, 14.0; HRMS Calcd for C17H16O3 (M+) 268.1099; found
268.1104.
(S)-2-Hydroxy-3-methoxy-3,3-diphenylpropionic Acid Ethyl
Ester (4). To a stirred solution of the above epoxide (3) (∼0.6 mol)
in MeOH (120 mL) at 0 °C was added BF3·Et2O (1.0 mL, 8.0 mmol).
Upon stirring at 0 °C overnight (the epoxide was consumed as judged
by TLC), the reaction mixture was quenched with water (5.0 mL) and
concentrated. The resulting yellow oil was dissolved in ethyl acetate
and washed with brine. The organic layer was dried over MgSO4,
filtered, and concentrated to give crude alcohol 4 as yellow oil (∼190.0
g, crude yield >99%), which was directly used for the next step. For the
analysis, small amounts of the alcohol were purified by column
chromatography (silica gel, petroleum ether/ethyl acetate = 20:1).
Colorless oil: [α]D20 = +3.3 (c 1.0, CHCl3) (84% ee); IR (film) 3496,
1729 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.44−7.27 (m, 10H), 5.15
(d, J = 8.8 Hz, 1H), 4.14−4.04 (m, 2H), 3.18 (s, 3H), 2.94 (d, J = 8.8
Hz, 1H), 1.15 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.5, 141.1, 140.3, 129.0, 128.7, 128.0, 127.81, 127.76, 127.6, 85.0,
73.9, 61.8, 52.6, 14.1. Anal. Calcd For C18H20O4: C, 71.98; H, 6.71.
Found: C, 71.96; H, 6.72.
g, 99% ee). A total 120.1 g of (+)-ambrisentan was obtained (53%
20
combined yield in four steps from ethyl 3,3-diphenylacrylate): [α]D
=
+170.0 (c 0.5, MeOH), lit.2d [α]D = +183.37 (c 0.5, MeOH); IR
(film) 3434, 1731, 1599 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.49 (d,
J = 8.0 Hz, 2H), 7.39−7.20 (m, 8H), 6.70 (s, 1H), 6.33 (s, 1H), 3.35
20
1
(s, 3H) 2.37 (s, 6H); H NMR (400 MHz, DMSO) δ 12.51 (s, 1H),
(S)-2-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-di-
phenylpropionic Acid Ethyl Ester (6a). To a stirred solution of
the above ethyl ester (4) (∼0.6 mol) in DMF (945 mL) was added
K2CO3 (26.1 g, 0.19 mol). After the reaction mixture was stirred at rt
7.37−7.19 (m, 10H), 6.94 (s, 1H), 6.16 (s, 1H), 3.39 (s, 3H) 2.34 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 171.6, 169.7, 163.6, 140.6,
139.6, 128.62, 128.56, 128.1, 128.04, 127.95, 127.87, 115.3, 84.4, 77.8,
702
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The Journal of Organic Chemistry
Note
53.5, 23.9; 13C NMR (100 MHz, DMSO) δ 169.0, 163.2, 142.6, 141.4,
127.8, 127.7, 127.6, 127.2, 127.0, 114.7, 83.1, 77.6, 53.0, 23.3.
155. (c) Takada, A.; Hashimoto, Y.; Takikawa, H.; Hikita, K.; Suzuki,
K. Angew. Chem., Int. Ed. 2011, 50, 2297.
(S)-2-[(4,6-Dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-di-
phenylpropionic Acid Methyl Ester (6b).2d To a stirred solution
of (+)-ambrisentan (0.19 g, 0.50 mmol) in THF/MeOH (2:1) (3.0
mL) was added TMSCHN2 (2 M in hexane) (0.5 mL, 1.0 mmol) at rt.
Upon stirring at rt for 30 min, the reaction mixture was concentrated
and purified by column chromatography (silica gel, petroleum ether/
ethyl acetate = 20:1) to give ambrisentan methyl ester (6b) as white
(8) Ethyl 3,3-diphenylacrylate (2) was prepared from benzophenone
and ethyl 2-(diethoxyphosphoryl)acetate in the presence of sodium
hydride: Le Tadic-Biadatti, M.-H.; Callier-Dublanchet, A.-C.; Horner,
J. H.; Quiclet-Sire, B.; Zard, S. Z.; Newcomb, M. J. Org. Chem. 1997,
62, 559.
(9) It was found that the ambrisentan Na salt dissolved well in ethyl
acetate. Thus, ether was used to extract out organic impurities such as
unreacted olefin 2, ester 6a, and 4,6-dimethyl-2-(methylsulfonyl)
pyrimidine 5.
solid (0.16 g, 81%): [α]D = +139.0 (c 0.5, MeOH) (99% ee), lit.2d
20
25
[α]D = +135.8 (c 0.5, MeOH); mp 132−135 °C; IR (film) 1754,
1596 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.6 Hz, 2H),
7.37 (d, J = 7.2 Hz, 2H), 7.34−7.20 (m, 6H), 6.70 (s, 1H), 6.15 (s,
1H), 3.45 (s, 3H), 3.42 (s, 3H), 2.38 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 169.6, 169.3, 163.8, 142.2, 141.1, 128.6, 128.2, 128.0, 127.9,
127.57, 127.55, 115.1, 83.9, 79.1, 53.7, 51.7, 24.0.
(10) (a) Alickmann, D.; Frohlich, R.; Maulitz, H. A.; Wurthwein, E.-
̈
̈
U. Eur. J. Org. Chem. 2002, 1523. (b) House, H. O.; Blaker, J. W. J. Am.
Chem. Soc. 1958, 80, 6389.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra, X-ray structure of (+)-ambrisentan (1), and
HPLC data for the determination of ee values. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yian@lamar.colostate.edu.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Basic Research
Program of China (973 Program, 2011CB808600) and the
Chinese Academy of Sciences for the financial support.
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