4000
K. T. Nguyen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3997–4000
Curr. Top. Med. Chem. 2006, 6, 687; (c) McCauley, J. A.
chem. Int. 2005, 46, 453; (b) Mosser, S. D.; Gaul, S. L.;
Bednar, B.; Koblan, K. S.; Bednar, R. A. J. Assoc. Lab.
Automat. 2003, 8, 54.
Expert Opin. Ther. Patents 2005, 15, 389; (d) Nikam, S. S.;
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Chenard, B. L.; Menniti, F. S. Curr. Pharm. Design 1999,
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14. Experimental procedure for the preparation of compound
29: A solution of 2-methyl-4-(trifluoromethoxy)benzamide
(2.0 g, 9.13 mmol) in POCl3 (20 mL) was heated at 70 °C
for 1 h and then concentrated. The residue was dissolved
in EtOAc, washed with aqueous saturated NaHCO3,
water, brine, dried over Na2SO4, filtered and concentrated.
The crude product was chromatographed on silica gel,
eluting with 5–20% ether/hexanes, to give 2-methyl-4-
7. Chenard, B. L.; Bordner, J.; Butler, T. W.; Chambers, L.
K.; Collins, M. A.; DeCosta, D. L.; Ducat, M. F.;
Dumont, M. L.; Fox, C. B.; Mena, E. E.; Menniti, F. S.;
Nielsen, J.; Pagnozzi, M. J.; Richter, K. E. G.; Ronau, R.
T.; Shalaby, I. A.; Stemple, J. Z.; White, W. F. J. Med.
Chem. 1995, 38, 3138.
8. Fischer, G.; Mutel, V.; Trube, G.; Malherbe, P.; Kew, J.
N. C.; Mohacsi, E.; Heitz, M. P.; Kemp, J. A. J. Pharm.
Exp. Ther. 1997, 283, 1285.
9. Claiborne, C. F.; McCauley, J. A.; Libby, B. E.; Curtis, N.
R.; Diggle, H. J.; Kulagowski, J. J.; Michelson, S. R.;
Anderson, K. D.; Claremon, D. A.; Freidinger, R. M.;
Bednar, R. A.; Mosser, S. D.; Gaul, S. L.; Connolly, T.
M.; Condra, C. L.; Bednar, B.; Stump, G. L.; Lynch, J. J.;
Macaulay, A.; Wafford, K. A.; Koblan, K. S.; Liverton,
N. J. Bioorg. Med. Chem. Lett. 2003, 13, 697.
10. Borza, I.; Kolok, S.; Ignacz-Szendrei, G. Bioorg. Med.
Chem. Lett. 2005, 15, 5439.
11. Bednar, B.; Cunningham, M. E.; Kiss, L.; Cheng, G.;
McCauley, J. A.; Liverton, N. J.; Koblan, K. S. J.
Neurosci. Methods 2004, 137, 247.
(trifluoromethoxy)-benzonitrile (1.74 g, 95% yield). A
mixture of 2-methyl-4-(trifluoromethoxy)-benzonitrile
(1.3 g, 6.5 mmol), NBS (1.7 g, 9.7 mmol) and AIBN
(5 mg) in carbon tetrachloride (25 mL) was heated at
reflux for 7 h and then filtered and concentrated. The
residue was chromatographed on silica gel, eluting with 5–
25% EtOAc/hexanes, to give 2-(bromomethyl)-4-(triflu-
oromethoxy)benzonitrile (1.3 g, 70% yield). 1H NMR
(400 MHz, CDCl3)d 7.73 (d, 1H), 7.41 (s, 1H), 7.27 (d,
1H), 4.62 (s, 2H) ppm. To a stirred solution of 2-methoxy-
benzylamine (88 mg, 0.64 mmol) in ethanol (0.5 mL), at
80 °C, was added a solution of 2-(bromomethyl)-4-(triflu-
oromethoxy)-benzonitrile (150 mg, 0.56 mmol) in ethanol
(0.5 mL). The reaction mixture was stirred at 80 °C for
1 h, then concentrated and crystalized in ether to give
compound 31 as an HBr salt (136 mg, 93% yield). 1H
NMR (400 MHz, MeOH-d4) d 8.19 (d, 2H), 7.63 (s, 1H),
7.58 (d, 1H), 7.43 (t, 1H), 7.36 (dd, 1H), 7.09 (d, 1H), 7.03
(t, 1H), 4.98 (s, 2H), 4.72 (s, 2H), 3.87 (s, 3H) ppm; LRMS
(FT/ICR) m/z 337.0 [(M+H)+; calcd for C17H16F3N2O2:
337.1].
12. Basicity was calculated using pKa/ACD/Labs application
by Advanced Chemistry Development Inc. For more
13. For NR2B binding assay protocol see: (a) Kiss, L.; Cheng,
G.; Bednar, B.; Bednar, R. A.; Bennett, P. B.; Kane, S. A.;
McIntyre, C. J.; McCauley, J. A.; Koblan, K. S. Neuro-