Organic Process Research & Development
Technical Note
extracted with n-hexane (20 L).The pH of the aqueous layer
was adjusted to 7.5−8.0, using aqueous NaOH solution (10%
w/v). After stirring for 15−20 min and filtration, the solid was
washed with a mixture of 1:1 methanol/water (8 L) with drying
under vacuum at 60−65 °C for 15 h to give 2 (2.88 kg, 72%) as
a white solid. HPLC Purity: 99.87%. MS: m/z = 350.3 [M +
H]+. IR (KBr) (cm−1): 3236, 3062, 3031, 2931,1596, 1065,
803. 1H NMR (400 MHz, CDCI3): δ 8.61 (s, 1 H), 8.44−8.46
(d, 1 H), 7.63−7.65 (d, 1 H), 7.20−7.23 (dd, 1 H), 5.993−
5.996 (d, 1 H), 5.38−5.99 (d, 1 H), 3.48−3.54 (m, 1 H), 2.24−
2.32 (m, 3H), 1.97−2.10 (m, 3H), 1.47−1.86 (m, 10H), 1.04−
1.10 (s, 8H). 13C NMR (CDCl3): δ 16.58, 19.34, 20.88, 30.45,
31.52, 31.63, 31.81, 35.27, 36.71, 37.20, 42.32, 47.34, 50.37,
57.56, 71.62, 121.28, 123.03, 129.24, 132.99, 133.70, 141.21,
147.79, 147.88, 151.68
Abiraterone Acetate (1). To a stirred solution of 2 (2 kg,
0.0057 kmol) and DMAP (60 g) in dichloromethane (12 L)
was added acetic anhydride (0.876 kg, 0.086 kmol) at 25−30
°C over a period of 15 min. The stirring was continued for 60
min at 25−30 °C and the reaction monitored by HPLC. After
completion of reaction, water (8 L) was added and stirred for
10 min. The organic layer was separated, water (8 L) was
added, and the pH was adjusted to 6−7 with aqueous NaOH
(10% w/v). The organic layer was separated, washed with water
(4 L), and then concentrated. To the residue was added IPA (4
L) and was concentrated at 70−75 °C. IPA (16 L) was added
to the residue at 55−50 °C; the mixture was heated to reflux
and treated with activated carbon (0.1 kg). The solution was
filtered hot, and the bed was washed with IPA (4 L). The
filtrate was heated to reflux and added water (12 L) at reflux
temperature in 1 h. The resulting mixture was then cooled to
15−20 °C and stirred for 2 h at this temperature. The resulting
solid was filtered and washed with IPA/water (4 L, 1:1) and
dried under vacuum at 60−65 °C for 12 h to give 1 in 81%
yield (1.8 kg). HPLC Purity: 99.72%, Assay: 98.8% (HPLC, w/
w). MS: m/z = 392.7 [M + H]+. IR (KBr) (cm−1): 3047, 2936,
1735, 1244, 1035, 801, 714. 1H NMR (400 MHz, DMSO-d6): δ
8.58 (s, 1 H), 8.43−8.42 (d, 1 H), 7.76−7.74 (d, 1 H), 7.34−
7.31 (dd, 1 H), 6.11 (s, 1 H), 5.38 (s, 1 H), 4.44 (m, 1H),
2.19−2.50 (m, 3H), 1.98−2.08 (m, 6H), 1.39−1.85 (m, 9H),
1.03−1.11 (m, 8H). 13C NMR (CDCl3): δ 170.4, 151.6, 147.9,
147.8, 140.0, 133.6, 132.9, 129.1, 122.9, 122.2, 73.8, 57.4, 50.2,
47.3, 38.1, 36.9, 36.7, 35.1, 31.7, 31.4, 30.3, 27.7, 21.4, 20.8,
19.2, 16.5.
Analytical Division of Ranbaxy Research Laboratories for their
analytical and spectral support.
REFERENCES
■
18.
(1) Rehman, Y.; Rosenberg, J. E. Drug Des. Dev. Ther. 2012, 6, 13−
(2) Shah, S.; Ryan, C. J. Drugs Future 2009, 34, 873−880.
(3) (a) Barrie, S. E.; Jarman, M.; Potter, G. A.; Hardcastle, I. R. U.S.
Patent 5,618,807, 1997. (b) Barrie, S. E.; Jarman, M. Potter, G. A.;
Hardcastle, I. R. U.S. Patent 5,604,213, 1997. (c) Potter, G. A.; Barrie,
S. E.; Jarman, M.; Rowlands, M. G. J. Med. Chem. 1995, 38, 2463−
2471.
(4) (a) Hunt, N. J. U.S. Patent 8,076,474, 2011. (b) Bury, P. S. U.S.
Patent 8,389,714, 2013.
(5) Potter, G. A.; Hardcastle, I. R.; Jarman, M. Org. Prep. Proced. Int.
1997, 29, 123−134.
(6) Perez-Encabo, A.; Toriel-Hernandez, J. A.; Gallo-Nieto, F. J.;
Lorente B. A.; Sandoval-Rodriguez, C. M. PCT Int. Appl. WO/2013/
030410, 2013.
(7) Zhiquan, Z.; Hongbo, W. China patent CN102617681, 2012.
(8) Marom, E.; Rubnov, S.; Mizhiritskii, M. PCT Int. Appl. WO/
2014/016830, 2014.
(9) Li, W.-S.; Torun, L.; Morrison, H. Can. J. Chem. 2003, 81, 660−
668.
(10) Handratta, V. D.; Vasaitis, T. S.; Njar, V. C O.; Gediya, L. K.;
Kataria, R.; Chopra, P.; Newman, D., Jr.; Farquhar, R.; Guo, Z.; Qiu,
Y.; Brodie, A. M. J. Med. Chem. 2005, 48, 2972−2984.
(11) Qingquan, F.; Jian, Y. L.; Ping, Z.; Qiang, L.; Bo, L.; First, Z. M.;
Yan, Q. China Patent CN102816201, 2012.
ASSOCIATED CONTENT
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S
* Supporting Information
1H, 13C, IR spectral data, and HPLC chromatogram of
compounds. This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Author
4011832.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We are grateful to Dr. Hashim Nizar, Associate Director, and
Dr. Neera Tewari, Director Chemical Research and Develop-
ment, for their valuable discussion and guidance. We also thank
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dx.doi.org/10.1021/op500044p | Org. Process Res. Dev. 2014, 18, 555−558