A two-step synthesis of the anti-cancer drug (R,S)-bicalutamide

Article abstract of DOI:10.1055/s-2002-28508

A short, efficient synthesis of the non-steroidal antiandrogen (R,S)-bicalutamide is presented. This new route generates bicalutamide in only two steps with an overall yield of 73%. The key step is a 1,2 addition of a methyl sulfone to a keto-amide.

Full text of DOI:10.1055/s-2002-28508

850
SHORT PAPER
A Two-step Synthesis of the Anti-cancer Drug (R,S)-Bicalutamide
A
Two-stepSynth
e
e
sis of the
A
n
nti-cancer
D
n
rug
(
R
,
S
)-Bi
e
calutamideth D. James,* Nnochiri N. Ekwuribe
Department of Innovation, Nobex Corporation, 617 Davis Drive; Durham, NC 27713, USA
Fax +1(919)4749407; E-mail: kjames@nobexcorp.com; E-mail: nekwuribe@nobexcorp.com
Received 3 February 2002
compound would be reserved until the end of the synthe-
sis. However, we reasoned that the yield of coupling could
be significantly improved if steric interactions were mini-
mized by having an sp2 center adjacent to the carboxyl
group. We found that when thionyl chloride was added
with pyruvate to a solution of 2 in DMA, the -keto-amide
3 was generated (Scheme 1). When eight equivalents of
pyruvate and thionyl chloride were used, the product was
obtained in 81% yield after chromatography and crystalli-
zation. Stoichiometry was found to be important in the re-
action; when only four equivalents of pyruvate and
thionyl chloride were used, yields were approximately
65%.
Abstract: A short, efficient synthesis of the non-steroidal antian-
drogen (R,S)-bicalutamide is presented. This new route generates
bicalutamide in only two steps with an overall yield of 73%. The
key step is a 1,2 addition of a methyl sulfone to a keto-amide.
Key words: addition reaction, aldol reaction, antiandrogen, antitu-
mor agent, keto-amide
The non-steroidal antiandrogen (R,S)-bicalutamide (1),
which is sold under the name Casodex®,1 is the leading an-
tiandrogen used for the treatment of prostate cancer (Fig-
ure). The published synthetic route for this compound
provides the enantiomeric mixture after four steps in an
overall yield of approximately 50%.2 We now report a
more efficient synthetic route (Scheme 1), which provides
(R,S)-bicalutamide in two steps with an overall yield of
73%.
With the use of the methyl sulfone 4, carbanion addition
to the carbonyl would generate bicalutamide in only one
more step. Our first approach utilized sodium hydride in
an effort to deprotonate 4, which was then transferred to a
solution of the keto-amide 3 with the goal of forming bi-
calutamide (1). Instead, the dimer 6 was the only observed
product. This compound likely resulted from deprotona-
tion of the methyl ketone 3 to form the enolate 5, which
underwent an aldol reaction with another keto-amide
(Scheme 2). We switched to a stronger base on the
premise that the sulfone was not being deprotonated.
Adapting the work by Fournier, et al.,5 we successfully
synthesized 1 following the above procedure while using
either pentyl magnesium bromide or n-butyllithium as the
base.
O
S
OH
O
H
CF3
CN
N
O
F
1
Figure
With two strongly electron-withdrawing groups attached,
the aniline derivative 2 is a relatively poor nucleophile.
When we performed couplings of such anilines with sub-
stituted -hydroxy acids, the yields have generally been When 1:1 ratios of sulfone to keto-amide were used,
rather modest. Similar results have been reported by yields of bicalutamide were approximately 45%. The low
Tucker, et al.2,3 and by Ohnmatch, et al.4 Since the aniline yield was due to a side reaction, which generated a prod-
is expensive, we initially considered routes in which this uct with a mass corresponding to 6. It seemed likely that
O
O
CN
H
SOCl2
DMA
CF3
CN
N
OH
H2N
CF3
O
O
2
3
O
S
O
OH
O
H
1. BuLi
CF3
S
N
2. 3
O
O
THF
F
CN
F
4
1
Scheme 1
Synthesis 2002, No. 7, 21 05 2002. Article Identifier:
1437-210X,E;2002,0,07,0850,0852,ftx,en;M00502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

SHORT PAPER
A Two-step Synthesis of the Anti-cancer Drug (R,S)-Bicalutamide
851
H
O
H
O
H
N
CN
CF3
NC
F3C
N
O
O
5
O
OH
O
H
H
F3C
NC
N
N
CF3
CN
O
6
Scheme 2
N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sul-
fonyl]-2-hydroxy-2-methylpropanamide (1)
the alkoxide of the desired reaction product might have
been serving as a general base, deprotonating any unreact-
ed keto-amide and thus catalyzing the undesired reaction.
We reasoned that if the keto-amide present in the reaction
mixture were always exposed to excess quantities of the
deprotonated sulfone, then the side reaction would be
minimized. When a solution of the keto-amide was added
slowly to three equivalents of the deprotonated sulfone,
bicalutamide was generated in yields of 90% and higher.
BuLi (13.0 mmol) was added to a stirring soln of 4-fluorophenyl
methyl sulfone (2.49 g, 14.3 mmol) in 13 mL of anhyd THF. After
1 h, a soln of 3 (1.11 g, 4.34 mmol) in 40 mL of anhyd THF was
added slowly over the course of 30 min to the stirring reaction. After
20 min, the reaction was brought to neutral pH with 1 M HCl. The
contents were diluted with EtOAc (250 mL) and extracted with 1 M
HCl (75 mL) and sat brine (75 mL). The aq layers were combined
and extracted with EtOAc (2 50 mL). The organic layer was dried
with MgSO4 and concentrated by rotary evaporation. After purifica-
We believe that the ease and speed of this synthetic route, tion by silica gel chromatography (CH2Cl2 EtOAc, 4:1), the prod-
uct was crystallized from EtOAc–PE. Yield 1.67 g (90%); mp
187 °C.
IR (KBr): 3432, 3338, 3106, 2921, 1699, 1586, 1525 cm–1.
coupled with the cost effectiveness of the approach, will
be of great utility in the production of this antineoplastic.
1H NMR (300 MHz, CDCl3): = 9.1 (s, 1 H, NH), 8.0 (s, 1 H, Ar-
H), 7.9 (m, 2 H, Ar-H), 7.8 (m, 2 H, Ar-H), 7.2 (m, 2 H, Ar-H), 5.0
(s, 1 H, OH), 4.0 (d, J = 14.5, 1 H, CH2), 3.5 (d, J = 14.5, 1 H, CH2 ),
1.6 (s, 3 H, CH3).
19F NMR (282.3 MHz, CDCl3): = –62.7 (CF3), –101.5 (Ar-F).
MS-FAB: (m/z)= 431 (M + 1), 453 (M + Na+).
UV (CH3CN): max = 216, 270 nm.
Unless otherwise stated, all reagents were purchased from Aldrich
and were used without further purification. All solvents were glass-
distilled. Pyruvate and 4-fluorophenyl methyl sulfone (4) were pur-
chased from Lancaster. 4-Cyano-3-trifluoromethyl-aniline (2) was
purchased from Maybridge. Chemical shift values for fluorine at-
oms are expressed in ppm relative to an external standard of CFCl3.
Coupling constants are reported in Hertz. All melting points are un-
corrected. Petroleum ether is abbreviated as PE.
Anal. Calcd for C18H14F4N2O4S: C, 50.23; H, 3.28; N, 6.51. Found:
C, 50.35; H, 3.16; N, 6.35.
N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-oxopropanamide (3)
Pyruvate (3.0 mL, 43 mmol) and SO2Cl2 (3.1 mL, 43 mmol) were
added simultaneously via syringes over the course of 10 min to a
stirring soln of 4-cyano-3-trifluoromethyl-aniline (1.00 g, 5.38
mmol) in 20 mL of dry DMA at r.t. After 10 min, the reaction mix-
ture was diluted with Et2O (200 mL), extracted with sat. NaHCO3
(3 50 mL) and with cold sat. brine (4 100 mL). The organic lay-
ers were combined, dried with MgSO4, and concentrated by rotary
evaporation. The product was purified by silica gel chromatography
(EtOAc hexanes, 1:1) and crystallized from the same solvents.
Yield 1.11 g (81%); mp 147–148 °C.
N,N -Bis[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-me-
thyl-4-oxopentanediamide (6)
Mp 165–168 °C.
IR (KBr): 3292, 2234, 1705, 1688, 1524 cm–1.
1H NMR (300 MHz, CDCl3–DMSO): = 10.5 (s, 1 H, NH), 10.3 (s,
1 H, NH), 8.2 (s, 1 H, Ar-H), 8.1 (s, 1 H, Ar-H), 8.0 (d, 1 H, J = 8.4,
Ar-H), 7.9 (d, 1 H, J = 8.2, Ar-H), 7.7 (d, 1 H, J = 8.4, Ar-H), 7.7
(d, 1 H, J = 8.2, Ar-H), 5.6 (s, 1 H, OH), 2.6 (d, 1 H, J = 14.0, CH2),
2.4 (d, 1 H, J = 14.0, CH2’), 1.5 (s, 3 H, CH3).
IR (KBr): 3330, 3112, 3065, 1719, 1540 cm–1.
13C NMR (75.4 MHz, CDCl3/DMSO): = 176.2, 170.3, 169.4,
142.0, 141.2, 135.7, 135.4, 133.2, 132.9, 127.5, 122.9, 122.8, 122.6,
118.3, 115.6, 115.3, 106.7, 104.3, 90.0, 73.1, 48.5, 25.0.
19F NMR (282.3 MHz, CDCl3–DMSO): = –62.3 (CF3), –62.5
(CF3’).
HRMS-FAB: (m/z) [M + H]+ calcd for C22H14F6N4O4, 513.0997;
found, 513.1001.
1H NMR (300 MHz, CDCl3): = 9.1 (s, 1 H, NH), 8.2 (s, 1 H, Ar-
H), 8.0 (d, J = 8.5, 1 H, Ar-H), 7.8 (d, J = 8.5, 1 H, Ar-H), 2.6 (s, 3
H, CH3).
13C NMR (75.4 MHz, CDCl3): = 195.7, 157.7, 140.3, 135.9,
134.2, 122.0, 121.9, 117.4, 115.1, 105.6, 23.9.
19F NMR (282.3 MHz, CDCl3): = –62.8.
MS-FAB: (m/z) = 257 (M + 1).
UV (CH3CN): max = 267 nm, min = 231 nm.
UV (CH3CN): max = 214, 248, 288 nm.
Anal. Calcd for C22H14F6N4O4: C, 51.57; H, 2.75; N, 10.94. Found:
C, 51.48; H, 2.61; N, 10.65.
Anal. Calcd for C11H7F3N2O2: C, 51.57; H, 2.75; N, 10.94. Found:
C, 51.69; H, 2.81; N, 10.86.
Synthesis 2002, No. 7, 850–852 ISSN 0039-7881 © Thieme Stuttgart · New York

852
K. D. James, N. N. Ekwuribe
SHORT PAPER
(4) Ohnmacht, C. J.; Russell, K.; Empfield, J. R.; Frank, C. A.;
Gibson, K. H.; Mayhugh, D. R.; McLaren, F. M.; Shapiro, H.
S.; Brown, F. J.; Trainor, D. A.; Ceccarelli, C.; Lin, M. M.;
Masek, B. B.; Forst, J. M.; Harris, R. J.; Hulsizer, J. M.;
Lewis, J. J.; Silverman, S. M.; Smith, R. W.; Warwick, P. J.;
Kau, S. T.; Chun, A. L.; Grant, T. L.; Howe, B. B.; Neilson,
K. L. J. Med. Chem. 1996, 39 , 4592.
References
(1) Chem. Abstr. 1986, 101, 54739.
(2) (a) Tucker, H.; Crook, J. W.; Chesterson, G. J. J. Med.
Chem. 1988, 31, 954. (b) Overall yield was calculated from
the reported yields of individual or representative reactions
in the synthesis
(3) Tucker, H.; Chesterson, G. J. J. Med. Chem. 1988, 31, 885.
(5) Fournier, J. P.; Loiseau, P.; Moreau, R. C.; Narcisse, G.;
Choay, P. Eur. J. Med. Chem. 1982, 17, 53.
Synthesis 2002, No. 7, 850–852 ISSN 0039-7881 © Thieme Stuttgart · New York