Thus, treatment of a mixture of methacrylamide 2 and
4-fluoro-2-trifluorobenzonitrile 3 in DMF with 2.6 equiv
of NaH afforded smoothly compound 4 in 97% yield after
quenching the reaction and isolating the product by
filtration. Under these reaction conditions, the potential
side reaction at the methyl group was not detected. More
importantly, the potential base promoted polymerization
of the resulted product 4 was not observed due presum-
ably to an immediate deprotonation of the aryl amide
proton in 4 by excess base once it is formed, which
deactivated the R,â-unsaturated carbon-carbon double
bond and prevented it from undergoing nucleophilic
addition.
Nu cleop h ilic Ar om a tic Su bstitu tion of
Meth a cr yla m id e An ion a n d Its Ap p lica tion
to th e Syn th esis of th e An tica n cer Dr u g
Bica lu ta m id e
Bang-Chi Chen,* Rulin Zhao, Stacey Gove, Bei Wang,
J oseph E. Sundeen, Mark E. Salvati, and
J oel C. Barrish
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical
Research Institute, Princeton, New J ersey 08543
bangchi.chen@bms.com
The N-arylmethacrylamide 4 was next oxidized to the
corresponding epoxide 5 using a combination of hydrogen
peroxide and trifluoroacetic anhydride instead of the
previously reported m-CPBA.6 The desired epoxide 5 was
isolated in 98% yield. Epoxide ring opening with 4-fluo-
rothiophenol followed by oxidation of the resulted sulfide
with the combination of hydrogen peroxide and trifluo-
roacetic anhydride afforded (R,S)-bicalutamide in 97%
isolated yield.
In summary, a new nucleophilic aromatic substitution
reaction of methacrylamide anion with electron deficient
aryl fluoride has been successfully demonstrated. This
new reaction made it possible to use the much less
expensive 4-fluoro-2-trifluoromethylbenzonitrile as a start-
ing material for the synthesis of the important anti-
cancer drug (R,S)-Bicalutamide.
Received September 19, 2003
Abstr a ct: The anticancer drug (R,S)-biscaltamide was
prepared in three steps in >90% overall yield. A key step in
the new synthesis involved a new nucleophilic aromatic
substitution reaction of methacrylamide anion.
(R,S)-Bicalutamide, sold under the name Casodex, is
the leading nonsteroidal antiandrogen used for the
treatment of prostate cancer.1-5 Two methods have been
previously reported for the synthesis of (R,S)-bicaluta-
mide, both starting from an expensive material, 4-amino-
2-trifluoromethylbenzonitrile.6,7 The overall yields were
approximately 50-70% and chromatographic separations
of products were required.6,7 We now describe a new
synthesis of (R,S)-biscaltamide which uses a much less
expensive starting material, 4-fluoro-3-trifluoromethyl-
benzonitrile, and is featured by a new nucleophilic
aromatic substitution reaction involving methacrylamide
anion.
Nucleophilic aromatic substitution of aryl fluorides
with amino nucleophiles including anions generated from
simple amides is an important method for the prepara-
tion of aniline derivatives.8 Such a reaction with acryla-
mides as nucleophiles has not, however, been reported.
We envisioned that the nitrogen anion generated from
methacrylamide 2 would react with electron-deficient
aryl fluorides such as 3 to give the desired coupling
product 4 (Scheme 1).9
Exp er im en ta l Section
N-(4-Cya n o-3-tr iflu or op h en yl)m eth a cr yla m id e 4. To a
solution of methacrylamide (2, 153.0 g, 1.80 mol) in 800 mL of
DMF was added 4-cyano-3-trifluoromethylphenyl fluoride (3,
200.0 g, 1.06 mol) at room temperature. The solution was cooled
in a methanol/dry ice bath to -20 °C. To this cooled solution
was added sodium hydride (102.0 g, 2.70 mol), portionwise, while
keeping the reaction temperature below 70 °C. The reaction
mixture was allowed to cool to room temperature and stirred
for 4 h under a nitrogen atmosphere. Water (915 mL) was added
followed by 18% HCl (250 mL) and hexane (970 mL). The
resulted slurry was allowed to stir overnight. The solid was
filtered and washed with water (3 × 150 mL) and and hexane
(100 mL). The solid was dried at 60 °C overnight to give the
titled compound 4 (260.0 g, 97%): mp 137-139 °C (lit.6b mp 137-
139 °C); 1H NMR (CDCl3) δ 7.87 (d, J ) 1.9 Hz, 1H), 7.80 (dd, J
) 1.9, 8.5 Hz, 1H), 7.69 (bs, 1H), 7.62 (d, J ) 8.5 Hz, 1H), 5.69
(s, 1H), 5.44 (t, J ) 1.5 Hz, 1H), 1.90 (s, 3H); 13C NMR (CDCl3)
δ 18.9, 104.2, 116.2, 118.0, 121.2, 122.1, 122.6, 123.9, 126.6,
133.8, 136.2, 140.3, 142.9, 167.6. Anal. Calcd for C12H9F3N2O:
C, 56.70; H, 3.57; F, 22.42; N, 11.02. Found: C, 56.53; H, 3.36;
F, 22.52; N, 10.96.
N-(4-Cya n o-3-tr iflu or op h en yl)m eth a cr yla m id e Ep oxid e
5. To a stirred solution of N-[4-cyano-3-(trifluoromethyl)phenyl]-
methacrylamide (1.8 g, 7.08 mmol) and dichloromethane (10 mL)
was added hydrogen peroxide (1.22 mL, 42.5 mmol). The flask
was then put in a water bath at room temperature. Trifluoro-
acetic anhydride (5 mL, 35.40 mmol) was added slowly. The
reaction was stirred and checked by HPLC. After 1 h and 40
min, the reaction mixture was transferred to a separation funnel
using dichloromethane (35 mL). The organic layer was then
washed with distilled water (15 mL), saturated aqueous sodium
bisulfite (4 × 15 mL), saturated sodium bicarbonate (3 × 15 mL),
and brine (15 mL), dried over magnesium sulfate, filtered,
(1) Schellhammer, P. Exp. Opin. Invest. Drugs 1999, 8, 849.
(2) Goa, K. L.; Spencer, C. M. Drugs Aging 1998, 12, 401.
(3) Dalton, J . T.; Mukherjee, A.; Zhu, Z.; Kirkovsky, L.; Miller, D.
D. Biochem. Biophys. Res. Commun. 1998, 244, 1.
(4) Furr, B. J . A. Eur. Urol. 1996, 29 (Suppl 2), 83. Furr, B. J . A.;
Tucker, H. Urology 1996, 47 (Suppl 1A), 13.
(5) Maucher, A. von Angerer, E. J . Cancer Res. Clin. Cocol. 1993,
119, 669.
(6) (a) Tucker, H.; Crook, J . W.; Chesterson, G. J . J . Med. Chem.
1988, 31, 954. (b) Tucker, H. EP 100172 A1, February 8, 1984; Chem.
Abstr. 1984, 101, 54739.
(7) J ames, K. D.; Ekwuribe, N. N. Synthesis 2002, 850.
(8) Spange, S.; Seifert, A.; Mueller, H.; Hesse, S.; J aeger, C. Angew.
Chem., Int. Ed. 2002, 41, 1729. Norris, D.; Chen, P.; Barrish, J . C.;
Das, J .; Moquin, R.; Chen, B.-C.; Guo, P. Tetrahedron Lett. 2001, 42,
4297. Fleming, I.; Loreto, M. A.; Wallace, I. H. M.; Michael, J . P. J .
Chem. Soc., Perkin Trans. 1 1986, 349.
(9) For recent reports on amidation of aryl halides including the
copper catalyzed preparation of N-aryl R,â-unsaturated amides, see:
Klapars, A.; Huang, X.; Buchwald, S. L. J . Am. Chem. Soc. 2002, 124,
7421 and references therein.
10.1021/jo035377c CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/02/2003
J . Org. Chem. 2003, 68, 10181-10182
10181