950
C. L. Horchler et al. / Bioorg. Med. Chem. 15 (2007) 939–950
F.; Barr, C. L.; Schachar, R.; Roberts, W.; Malone, M.;
Tannock, R.; Basile, V. S.; Beitchman, J.; Kennedy, J. L.
Mol. Psychiatry 2003, 8, 98–102; (d) Smoller, J. W.;
Biederman, J.; Arbeitman, L.; Doyle, A. E.; Fagerness, J.;
Perlis, R. H.; Sklar, P.; Faraone, S. V. Biol. Psychiatry
2006, 59, 460–467.
4.6.4. 6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1-yl)-
quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)am-
ide (18c). To a 250 mL, round-bottomed flask equipped
with a nitrogen inlet and magnetic stirrer was added 21
(2.01 g, 6.3 mmol). The material was dissolved in DMF
(20 mL) and then 4-morpholinoaniline (1.35 g,
7.56 mmol) was added. To the stirred solution were
quickly added simultaneously TBTU (4.05 g,
12.6 mmol) and HOBt (1.7 g, 12.6 mmol). At this point,
DIEA (3.25 g, 4.11 mL, 25.2 mmol) was added via syr-
inge over 5 min. The reaction mixture was allowed to
stir at room temperature for 18 h. The DMF was re-
moved by concentration on a rotary evaporator under
high vacuum. The residue was triturated with methanol
and the crude solids were isolated by filtration. The
material was then dissolved in methylene chloride and
extracted with 10% sodium bicarbonate solution. The
organic layer was dried over MgSO4, filtered, and con-
centrated. The residues were purified by flash chroma-
tography using a gradient of 5–10% methanol in
methylene chloride as eluent. The obtained material
was crystallized from methanol to give the pure product
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1
as a yellow solid (2.83 g, 93%). H NMR (300 MHz,
CDCl3) d 10.05 (s, 1H, C(O)NH), 7.77 (s, 1H, ArH3),
7.71
(dd,
2H,
Jo = 7.0 Hz,
Jm = 2.0 Hz,
0
0
ArH2 and H6 ), 7.45 (dd, 1H, J = 9.3 Hz, Jm = 2.7 Hz
0
0
ArH7), 6.99 (d, 2H, Jo = 7.0 Hz, ArH3 and H5 ), 6.94
(dd, 1H, J = 10.8 Hz, Jm = 2.7 Hz, ArH5), 4.13 (s, 3H,
ArOCH3), 3.88 (t, 4H, J = 4.8 Hz, OCH2CH2N), 3.51
(br s, 4H, ArNCH2CH2N), 3.17 (t, 4H, J = 4.8 Hz,
OCH2CH2N), 2.83 (t, 4H, J = 4.7 Hz, ArNCH2CH2N),
2.47 (s, 3H, NCH3); 13C NMR (300 MHz, CDCl3) d
164.0, 163.9, 163.1, 161.9, 159.8, 151.5, 151.4, 148.2,
148.1, 138.6, 130.8, 124.3, 124.1, 120.5, 116.5, 107.9,
107.5, 99.2, 98.9, 98.2, 66.9, 56.3, 55.4, 52.1, 49.8, 46.3;
Mass Spec.: Calcd for [C26H30FN5O3 + H]+ Theor.
m/z = 480.2405;
Obs. = 480.2419.
Analysis
for
C26H30FN5O3Æ0.45HCl: Calculated C, 62.97; H, 6.19;
N, 14.12. Found C, 63.24; H, 5.88; N, 14.20.
10. (a) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046–
2067; (b) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000,
65, 1144–1157.
´
11. De la Cruz, A.; Elguero, J.; Goya, P.; Martınez, A.
Tetrahedron 1992, 48, 6135–6150.
Acknowledgments
12. Glennon, R. A.; Westkaemper, R. B. Drug News &
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13. Chapdelaine, M.; Davenport, T.; Haeberlein, M.; Horch-
ler, C.; McCauley, J.; Pierson, Ed.; Sohn, D.; WO
2003037872 A1, 2003.
The authors gratefully acknowledge the contributions of
Drs. M. Edward Pierson, Robert T. Jacobs, and Timo-
thy J. Blake.
14. Lazareno, S. In Methods in Molecular Biology; Walker, J.
M., Keen, M., Eds.; Humana Press: Totowa, New Jersey,
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2
2
2
2
˚
˚
˚
˚
˚
86.4 A , 7i 77.2 A , 10a 73.4 A , 10b 82.2 A , 10c
2
64.2 A ..
17. Girault, G.; Coustal, S.; Rumpf, P. Bull. Soc. Chim. Fr.
1972, 7, 2787–2798.
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