1516 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 7
Hashimoto et al.
tion in vacuo, and separation by silica gel flash chromatogra-
phy (n-hexane/AcOEt ) 4/1) gave 16.06 g (74%) of N-tert-butyl-
2-fluoro-4-methylbenzenesulfonamide as a white solid: 1H
NMR (CDCl3) δ 1.22 (s, 9H), 2.42 (s, 3H), 4.68 (s, 1H), 6.99 (d,
J ) 11 Hz, 1H), 7.05 (d, J ) 7.5 Hz, 1H), 7.77 (t, J ) 7.8 Hz,
1H).
Step 2: P r ep a r a tion of 4-Cycloh exyl-5-(3-flu or op h en -
yl)-2-eth yloxa zole (20a ). Com p ou n d 20a was prepared from
19a using the procedure described for 9d (step 3) in 84% yield
as a colorless oil: 1H NMR (CDCl3) δ 1.2-1.4 (m, 4H), 1.36 (t,
J ) 7.6 Hz), 1.6-1.9 (m, 6H), 2.8 (m, 1H), 2.82 (q, J ) 7.6 Hz,
1H), 6.99 (dt, J ) 2.2, 8.3 Hz, 1H), 7.22-7.41 (m, 3H).
St ep s
3 a n d 4: P r ep a r a t ion of 4-(4-Cycloh exyl-2-
To a suspension of the sulfonamide obtained above (15.00
g, 61.15 mmol) in CCl4 (150 mL) was added N-bromosuccin-
imide (10.00 g, 56.18 mmol) and AIBN (0.50 g, 3.04 mmol).
The solution was heated at reflux temperature for 3 h. After
cooling, the insoluble material was removed by filtration. The
filtrate was concentrated in vacuo to give a crude solid, which
was purified by silica gel flash chromatography (n-hexane/
AcOEt ) 4/1) to give 11.14 g (59%) of 16d as a white solid: 1H
NMR (CDCl3) δ 1.24 (s, 9H), 4.45 (s, 2H), 4.72 (s, 1H), 7.22-
7.28 (m, 2H), 7.88 (d, J ) 7.8 Hz, 1H). Anal. (C11H15BrFNO2S)
C, H, N.
eth yloxazol-5-yl)-2-flu or oben zen esu lfon am ide (21a). Com-
pound 21a was prepared from 20a using the procedure
described for 9d (steps 4 and 5) in 51% yield: mp 154-155
1
°C; H NMR (CDCl3) δ 1.37 (t, J ) 7.8 Hz, 3H), 1.3-1.4 (m,
3H), 1.6-1.9 (m, 7H), 2.8 (m, 1H), 2.84 (q, J ) 8.7 Hz, 3H),
5.10 (s, 2H), 7.37-44 (m, 2H), 7.94 (t, J ) 7.8 Hz, 1H). Anal.
(C17H21FN2O3S) C, H, N.
4-(4-Cycloh exyl-2-isop r op yloxa zol-5-yl)-2-flu or ob en -
zen esu lfon a m id e (21b). Compound 21b was prepared from
3d using the procedure described for 21a in 15% yield. In this
case, 2-methylpropionic acid potassium salt was used instead
of propionic acid potassium salt in step 1: mp 193-194 °C;
1H NMR (CDCl3) δ 1.38 (d, J ) 6.9 Hz, 6H), 1.3-1.4 (m, 3H),
1.7-1.9 (m, 7H), 2.79 (m, 1H), 3.13 (heptad, J ) 6.9 Hz, 1H),
5.08 (s, 2H), 7.36-44 (m, 2H), 7.94 (t, J ) 7.8 Hz, 1H). Anal.
(C18H23FN2O3S) C, H, N.
N-ter t-Bu tyl-4-[2-m eth yl-4-(5-m eth ylth ien -2-yl)-oxa zol-
5-yl]ben zen esu lfon a m id e (17a ). Compound 17a was pre-
pared from 16a using the procedure described above for 9d
(steps 1-3) in 11% yield: 1H NMR (CDCl3) δ 1.24 (s, 9H), 4.45
(s, 2H), 4.72 (s, 1H), 7.22-7.28 (m, 2H), 7.88 (d, J ) 7.8 Hz,
1H).
Refer en ces
N-ter t-Bu t yl-2-flu or o-4-[2-m et h yl-4-(5-m et h ylt h ien -2-
yl)-oxa zol-5-yl]ben zen esu lfon a m id e (17d ). Compound 17d
was prepared from 16d using the procedure described above
for 9d (steps 1-3) in 20% yield: 1H NMR (CDCl3) δ 1.25 (s,
9H), 2.53 (S, 3H), 2.55 (S, 3H), 4.73 (s, 1H), 6.74 (d, J ) 3 Hz,
1H), 7.16 (d, J ) 3 Hz, 1H), 7.55 (d, J ) 11.7 Hz, 1H), 7.63 (d,
J ) 8.4 Hz, 1H), 7.89 (t, J ) 8.4 Hz, 1H).
(1) A part of this work was presented earlier: Hashimoto, H.;
Imamura, K.; Haruta, J .; Wakitani, K. Potent and Selective
COX-2 Inhibitors. The 214th National Meeting of the American
Chemical Society, Las Vegas, NV, September 1997; MEDI 90.
(2) Xie, W.; Chipman, J . G.; Robertson, D. L.; Erikson, R. L.;
Simmons, D. L. Expression of a Mitogen-response Gene Encoding
Prostaglandin Synthesis is Regulated by mRNA Splicing. Proc.
Natl. Acad. Sci. U.S.A. 1991, 88, 2692-2696.
(3) Kujubu, D. A.; Fletcher, B. S.; Varnum, B. C.; Lim, R. W.;
Herschman, H. R. TIS10, a Phorbol Ester Tumor Promotor-
inducible mRNA from Swiss 3T3 Cells, Encodes a Novel Pros-
taglandin Synthase/ Cyclooxygenase Homologue. J . Biol. Chem.
1991, 266, 12866-12872.
(4) Hla, T.; Neilson, K. Human Cyclooxygenase-2 cDNA. Proc. Natl.
Acad. Sci. U.S.A. 1992, 89, 7384-7388.
(5) Vane, J . Towards a better aspirin. Nature 1994, 367, 215-216.
(6) Masferrer, J . L.; Zweifel, B. S.; Manning, P. T.; Hauser, S. D.;
Leahy, K. M.; Smith, W. G.; Isakson, P. C.; Seibert, K. Selective
inhibition of inducible cyclooxygenase 2 in vivo is antiinflam-
matory and nonulcerogenic. Proc. Natl. Acad. Sci. U.S.A. 1994,
91, 3228-3232.
(7) For a review, see: Reitz, D. B.; Seibert, K. Selective Cyclooxy-
genase Inhibitors. Annu. Rep. Med. Chem. 1995, 30, 179-188.
(8) For a review, see: Prasit, P.; Riendeau, D. Selective Cyclooxy-
genase-2 Inhibitors. Annu. Rep. Med. Chem. 1997, 32, 211-220.
(9) Tally, J . J . Selective Inhibitors of COX-2. In Progress in
Medicinal Chemistry 36; King, F. D., Oxford, A., Eds.; Elsevier:
Amsterdam, 1999; pp 201-234.
(10) For a review, see: Dannhardt, G.; Kiefer, W. Cyclooxygenase
inhibitors - Current status and future prospects. Eur. J . Med.
Chem. 2001, 36, 109-126.
2-F lu or o-4-[2-m et h yl-4-(5-m et h ylt h ien -2-yl)-oxa zol-5-
yl]ben zen esu lfon a m id e (18d ). A solution of 17d (500 mg,
1.22 mmol) in CF3COOH was heated at 50 °C for 4 h. The
solution was concentrated in vacuo, and the residue was
dissolved in AcOEt. The solution was washed with saturated
aqueous NaHCO3 and brine and was dried over Na2SO4.
Filtration, concentration in vacuo, and purification by silica
gel flash chromatography (n-hexane/AcOEt ) 2/1) gave 385
1
mg (90%) of 18d as a white solid: mp 190-192 °C; H NMR
(CDCl3) δ 2.52 (d, J ) 1.2 Hz, 3H), 2.55 (S, 3H), 5.08 (s, 2H),
6.73 (m, 1H), 7.16 (d, J ) 3 Hz, 1H), 7.58 (dd, J ) 1.5, 11 Hz,
1H), 7.63 (dd, J ) 1.5, 8.4 Hz, 1H), 7.89 (dd, J ) 7.2, 8.4 Hz,
1H). Anal. (C15H13FN2O3S2) C, H, N.
4-[2-Meth yl-4-(5-m eth ylth ien -2-yl)-oxazol-5-yl]ben zen e-
su lfon a m id e (18a ). Compound 18a was prepared from 17a
using the procedure described for 18d in 85% yield: mp 164-
1
165 °C; H NMR (CDCl3) δ 2.51 (d, J ) 1.1 Hz, 3H), 2.55 (S,
3H), 4.86 (s, 2H), 6.71 (m, 1H), 7.14 (d, J ) 3.7 Hz, 1H), 7.86
(d, J ) 8.8 Hz, 1H), 7.93 (d, J ) 8.8 Hz, 1H). Anal.
(C15H14N2O3S2) C, H, N.
(11) Penning, T. D.; Tally, J . J .; Bertenshaw, S. R.; Carter, J . S.;
Collins, P. W.; Doctor, S.; Graneto, M. J .; Lee, L. F.; Malecha, J .
W.; Miyashiro, J . M.; Rogers, R. S.; Rogier, D. J .; Yu, S. S.;
Anderson, G. D.; Burton, E. G.; Cogburn, J . N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.;
Zhang, Y. Y.; Isakson, P. C. Synthesis and Biological Evaluation
of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors:
Identification of 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-
pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib). J . Med.
Chem. 1997, 40, 1347.
(12) Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charleson, S.;
CromLish, W.; Ethier, D.; Evans, J . F.; Ford-Hutchinson, A. W.;
Gauthier, J . Y.; Gordon, R.; Guay, J .; Gresser, M.; Kargman, S.;
Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J .; O′Neill, G. P.;
Ouellet, M.; Percival, M. D.; Perrier, H.; Riendeau, D.; Rodger,
I.; Tagari, P.; Therien, M.; Vikers, P.; Wong, E.; Xu, L.-J .; Young,
R. N.; Zamboni, R.; Boyce, S.; Rupniak, N.; Forrest, M.; Visco,
D.; Patrick, D. The discovery of rofecoxib, [MK 966, Vioxx, 4-(4′-
methylsulfonylphenyl)-3-phenyl-2 (5H)-furanone], an orally ac-
tive cyclooxygenase-2 inhibitor. Bioorg. Med. Chem. Lett. 1999,
9, 1773.
4-(4-Cycloh exyl-2-et h yloxa zol-5-yl)-2-flu or ob en zen e-
su lfon a m id e (21a ). Step 1: P r ep a r a tion of 2-Cycloh exyl-
1-(3-flu or op h en yl)-2-oxoeth yl P r op ion a te (19a ). To a so-
lution of 3d (5.00 g, 22.7 mmol) in toluene (30 mL) was added
a solution of Br2 (3.6 g, 22.5 mmol) in CHCl3 (5 mL) dropwise
at room temperature. The solution was stirred for 30 min and
poured in saturated aqueous NaHCO3. AcOEt was added to
the solution, and the organic layer was separated. The organic
layer was washed with saturated aqueous NaHCO3 again and
brine and was dried over Na2SO4. Evaporation of the solvent
in vacuo gave 6.95 g of R-bromoketone as a crude oil. The
R-bromoketone was dissolved in EtOH (60 mL). A total of 3.82
g (34.1 mmol) of propionic acid potassium salt was added to
the solution. The solution was heated at reflux temperature
for 2 h. The solution was concentrated in vacuo, and the
residue was dissolved in AcOEt. The solution was washed with
water and brine and was dried over Na2SO4. Filtration,
concentration in vacuo, and purification by silica gel flash
chromatography (n-hexane/AcOEt ) 9/1) gave 1.88 g (28%) of
19a as an colorless oil: 1H NMR (CDCl3) δ 1.19 (t, J ) 7.5 Hz,
3H), 1.1-1.4 (m, 5H), 1.6-1.8 (m, 4H), 2.0 (m, 1H), 2.3-2.4
(m, 1H), 2.45 (q, J ) 7.5 Hz, 2H), 6.06 (s, 1H), 7.05-7.15 (m,
2H), 7.19 (d, J ) 7.7 Hz, 1H), 7.37 (dt, J ) 6.1, 7.7 Hz, 1H).
(13) J ackson, L. M.; Hawkey, C. J . Gastrointestinal effects of COX-2
Inhibitors. Expert Opin. Invest. Drugs 1999, 8, 963-971.
(14) Scrip 2000, 2554, 20.
(15) Haruta, J .; Hashimoto, H.; Matsushita, M. Patent J P-8325249,
1996.
(16) Haruta, J .; Hashimoto, H.; Matsushita, M. Patent WO9619463,
1996.