Journal of Medicinal Chemistry
ARTICLE
1
142.1, 143.2, 148.5, 153.5 (d, JCꢀF = 239 Hz), 164.7. 19F NMR
(d, 1H, J = 8.1 Hz), 7.43 (m, 1H), 7.69 (td, 1H, 4JHꢀF = 1.7 Hz, J = 1.7,
4.9 Hz), 7.72 (dd, 1H, J = 1.2, 8.1 Hz), 7.82 (dd, 1H, J = 1.4, 7.7 Hz), 8.52
(s, 1H), 8.58 (dd, 1H, J = 1.3, 8.0 Hz), 12.33 (s, 1H). 13C NMR (50
MHz, CDCl3) δ 9.8 (3C, 1J119SnꢀC = 342 Hz, 1J117SnꢀC = 327 Hz), 12.0,
(CDCl3) δ ꢀ83.97. ESI-MS m/z 724.4 [M þ H]þ.
(N-[2-[N-Ethyl-N-[2-(2-fluoropyridin-3-yloxy)ethyl]amino]ethyl]-7-
iodophenazine-1-carboxamide (67). To a stirred solution of stannane
66 (270 mg, 0.37 mmol) in chloroform (7 mL) was added dropwise,
during 4 h, a solution of diiodine (192 mg, 0.76 mmol) in chloroform
(14 mL). The mixture was then stirred 14 h at room temperature before
addition of a saturated aqueous sodium carbonate solution (40 mL). The
solution was decanted, and the organic layer was washed with a 5%
aqueous sodium hydrogenosulfite solution (2 ꢁ 15 mL), dried on
magnesium sulfate, filtered, and evaporated under vacuum. The residue
was chromatographed (Al2O3, EtOAc/cyclohexane, 7/3, v/v) to give
compound 67 (112 mg, 0.20 mmol) as a yellow oil. Yield 54%; Rf
(Al2O3, EtOAc/cyclohexane, 7/3, v/v) 0.68. IR (CCl4) ν 1119, 1189,
1246, 1286, 1458, 1649, 2800ꢀ3000, 3246 cmꢀ1. 1H NMR (200 MHz,
CDCl3) δ 1.14 (t, 3H, J = 7.1 Hz), 2.86 (m, 4H), 3.05 (t, 2H, J = 5.5 Hz),
3.76 (q, 2H, J = 5.5 Hz), 4.10 (t, 2H, J = 5.5 Hz), 6.80 (dd, 1H, J = 4.9, 7.9
Hz), 6.97 (m, 1H), 7.53 (m, 1H), 7.83 (dd, 1H, J = 1.4, 9.2 Hz), 7.93 (m,
2H), 8.25 (dd, 1H, J = 1.5, 8.7 Hz), 8.60 (brs, 1H), 8.92 (dd, 1H, J = 1.5,
7.2 Hz), 10.92 (m, 1H). 13C NMR (50 MHz, CDCl3) δ 12.1, 38.3, 49.0,
52.2, 53.4, 68.5, 97.7, 121.5 (d, 4JCꢀF = 4 Hz), 122.3 (d, 3JCꢀF = 4 Hz),
13.7 (3C), 27.2 (3C, 2J
SnꢀC = 42 Hz), 29.2 (3C, 3J
=
119Sn/117SnꢀC
119Sn/117
20 Hz), 37.5, 48.2, 52.2, 52.4, 68.2, 117.2, 117.5, 119.5, 121.0, 121.8 (d,
4JCꢀF = 4 Hz), 123.0 (d, 3JCꢀF = 4 Hz), 123.1, 131.4, 131.7, 134.7, 135.0,
137.8 (d, 3JCꢀF = 13 Hz), 140.3, 141.0, 141.4 (2J
SnꢀC = 35 Hz),
119Sn/117
142.0 (d, 2JCꢀF = 25 Hz), 153.8 (d, 1JCꢀF = 238 Hz), 168.5, 178.1. 19
NMR (CDCl3) δ ꢀ83.85. ESI-MS m/z 739.3 [M þ H]þ.
F
N-[2-[N-Ethyl-N-[2-(2-nitropyridin-3-yloxy)ethyl]amino]ethyl]-
phthalimide (71). To a solution of compound 22 (11.3 g, 43.1 mmol) in
anhydrous tetrahydrofuran (400 mL) were added successively, under
argon, triphenylphosphine (11.3 g, 43.1 mmol), commercial 2-nitro-3-
hydroxypyridine (6.02 g, 43.0 mmol), and dropwise diisopropyl azodicar-
boxylate (8.70 mL, 44.2 mmol). The mixture was stirred at room
temperature for 60 h, and the solvent was evaporated under vacuum.
Unreacted 2-nitro-3-hydroxypyridine was removed by chromatography
(Al2O3, EtOAc/cyclohexane, 9/1, v/v). After evaporation, the residue
containing the desired product was dissolved in dichloromethane
(200 mL) and pentane (600 mL) was added. The mixture was stirred at
room temperature for 5 min, and the precipitate was filtered and dried under
vacuum to give compound 71 (12.7 g, 33.0 mmol) as a yellow solid. Yield
77%; Rf (Al2O3, EtOAc/cyclohexane, 9/1, v/v) 0.76; mp 124ꢀ126 °C. IR
(KBr) ν 1274, 1397, 1536, 1702, 1767, 2830 cmꢀ1. 1H NMR (200 MHz,
CDCl3) δ 0.96 (t, 3H, J = 7.1 Hz), 2.63 (q, 2H, J = 7.1 Hz), 2.81 (t, 2H, J =
6.4 Hz), 2.94 (t, 2H, J = 5.8 Hz), 3.76 (t, 2H, J = 6.4 Hz), 4.10 (t, 2H, J = 5.8
Hz), 7.50 (m, 2H), 7.60 (m, 2H), 7.75 (m, 2H), 8.05 (dd, 1H, J = 2.5, 3.4
Hz). 13C NMR (50 MHz, CDCl3) δ 12.0, 36.3, 48.5, 51.4, 51.8, 68.8, 122.7
(2C), 123.6, 128.6, 131.9 (2C), 133.8 (2C), 138.8, 147.1, 148.6, 168.3
(2C). ESI-MS m/z 385.0 [M þ H]þ.
3
129.4, 129.8, 130.7, 133.6, 135.7, 137.3 (d, JCꢀF = 13 Hz), 138.6, -
2
140.1, 140.2, 140.9, 142.0 (d, JCꢀF = 26 Hz), 143.2, 143.4, 153.6 (d,
1JCꢀF = 239 Hz), 164.6. 19F NMR (CDCl3) δ ꢀ83.95. ESI-MS m/z
560.0 [M þ H]þ.
N-[2-[N-Ethyl-N-[2-(2-fluoropyridin-3-yloxy)ethyl]amino]ethyl]-
6-(tributylstannyl)imidazo[1,2-a]pyridine-2-carboxamide (69). To a
stirred solution of compound 50 (200 mg, 0.40 mmol) in anhydrous
toluene (9 mL), beforehand degassed under argon, were successively
added hexabutylditin (638 μL, 1.20 mmol) and freshly prepared
tetrakis(triphenylphosphine)palladium(0)32 (20 mg). The resulting
solution was refluxed for 12 h under argon. After cooling to room
temperature, the mixture was filtered through Celite 545, washed with
toluene (2 ꢁ 10 mL), and the filtrate was evaporated under vacuum. The
residue obtained was then chromatographed (Al2O3, EtOAc/cyclohex-
ane, 8/2, v/v) to give compound 69 (246 mg, 0.37 mmol) as a yellow oil.
Yield 93%; Rf (Al2O3, EtOAc/cyclohexane, 8/2, v/v) 0.40. IR (CCl4) ν
N-(2-Aminoethyl)-N-ethyl-N-[2-(2-nitropyridin-3-yloxy)ethyl]amine
(72). The title compound was synthesized according to the procedure
described for amine 24, starting from compound 71 (2.00 g, 5.20 mmol).
Reaction time under reflux: 12 h. The purification was performed using
column chromatography (Al2O3, CH2Cl2/EtOH, 95/5, v/v) to give
compound 72 (1.01 g, 3.97 mmol) as a yellow oil. Yield 76%; Rf (Al2O3,
CH2Cl2/EtOH, 95/5, v/v) 0.36. IR (CCl4) ν 1116, 1289, 1505, 1548,
1608, 2874, 2934, 2970 cmꢀ1. 1H NMR (200 MHz, CDCl3) δ 1.11 (t,
3H, J = 7.1 Hz), 2.72 (m, 8H), 2.99 (t, 2H, J = 5.6 Hz), 4.28 (t, 2H, J = 5.6
Hz), 7.63 (dd, 1H, J = 4.3, 8.4 Hz), 7.71 (dd, 1H, J = 1.5, 8.4 Hz), 8.13
(dd, 1H, J = 1.5, 4.3 Hz). 13C NMR (50 MHz, CDCl3) δ 12.0, 39.6, 48.5,
52.1, 56.6, 68.9, 123.7, 128.6, 139.1, 147.2, 150.3. ESI-MS m/z 255.0
[M þ H]þ.
1250, 1340, 1378, 1465, 1507, 1565, 1670, 2854, 2873, 2927, 2959 cmꢀ1
.
1H NMR (200 MHz, CDCl3) δ 0.85 (t, 9H, J = 7.1 Hz), 1.03 (m, 6H),
1.26 (m, 9H), 1.51 (m, 6H), 2.66 (q, 2H, J = 7.1 Hz), 2.75 (t, 2H, J = 6.2
Hz), 2.92 (t, 2H, J = 6.1 Hz), 3.50 (q, 2H, J = 6.2 Hz), 4.06 (t, 2H, J = 6.1
Hz), 6.87 (ddd, 1H, 5JHꢀF = 0.7 Hz, J = 4.8, 7.9 Hz), 7.17 (m, 2H), 7.40
(d, 1H, J = 8.9 Hz), 7.58 (td, 1H, 4JHꢀF = 1.6 Hz, J = 1.6, 4.8 Hz), 7.71
(m, 1H), 7.92 (s, 1H), 8.01 (s, 1H). 13C NMR (50 MHz, CDCl3) δ 9.8
(3C, 1J119SnꢀC = 349 Hz, 1J117SnꢀC = 334 Hz), 11.9, 13.6 (3C), 27.1 (3C,
N-[2-[N-Ethyl-N-[2-(2-nitropyridin-3-yloxy)ethyl]amino]ethyl]-6-
iodoquinoxaline-2-carboxamide (73). The title compound was
synthesized starting from amine 72 (600 mg, 2.36 mmol) and ethyl
6-iodoquinoxaline-2-carboxylate22a (774 mg, 2.36 mmol) according to
the general procedure for the synthesis of amides described above.
Reaction time under reflux: 12 h. The purification was performed using
column chromatography (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give
compound 73 (902 mg, 1.68 mmol) as a light-sensitive brown oil. Yield
71%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.46. IR (CCl4) ν 1117,
1289, 1526, 1549, 1683, 2800ꢀ3000, 3410 cmꢀ1. 1H NMR (200 MHz,
CDCl3) δ 1.08 (t, 3H, J = 7.1 Hz), 2.70 (q, 2H, J = 7.1 Hz), 2.83 (t, 2H,
J = 6.1 Hz), 2.99 (t, 2H, J = 5.3 Hz), 3.57 (q, 2H, J = 6.1 Hz), 4.17 (t, 2H,
J = 5.3 Hz), 7.36 (dd, 1H, J = 4.2, 8.4 Hz), 7.43 (dd, 1H, J = 1.7, 8.4 Hz),
7.61 (d, 1H, J = 8.8 Hz), 7.94 (dd, 1H, J = 1.7, 4.2 Hz), 7.99 (dd, 1H, J =
1.8, 8.8 Hz), 8.29 (m, 1H), 8.53 (d, 1H, J = 1.8 Hz), 9.57 (s, 1H). 13C
NMR (50 MHz, CDCl3) δ 12.4, 37.8, 48.9, 52.3, 53.3, 69.4, 98.1, 123.3,
128.6, 130.9, 138.6, 139.2, 139.5, 139.8, 144.1, 144.5, 144.7, 147.3, 149.0,
163.1. ESI-MS m/z 536.9 [M þ H]þ.
3
2J
= 64 Hz), 28.9 (3C, J
= 21 Hz), 37.2, 48.7,
119Sn/117SnꢀC
119Sn/117SnꢀC
52.3, 53.4, 68.4, 113.1, 117.5 (3J
SnꢀC = 34 Hz), 121.4 (d, 4JCꢀF
=
119Sn/117
4 Hz), 122.8 (d, 3JCꢀF = 4 Hz), 123.3, 130.7 (2J
SnꢀC = 51 Hz),
119Sn/117
132.2 (3J
SnꢀC = 24 Hz), 137.0 (d, 3JCꢀF = 13 Hz), 139.4, 142.2 (d,
119Sn/117
2JCꢀF = 25 Hz), 144.4, 153.8 (d, JCꢀF = 239 Hz), 162.9. 19F NMR
1
(CDCl3) δ ꢀ86.21. ESI-MS m/z 662.3 [M þ H]þ.
N-[2-[N-Ethyl-N-[2-(2-fluoropyridin-3-yloxy)ethyl]amino]ethyl]-
7-(tributylstannyl)acridone-4-carboxamide (70). The title compound
was synthesized according to the procedure described for stannane 69,
starting from compound 51 (0.40 g, 0.70 mmol). Reaction time under
reflux: 12 h. The purification was performed using column chromatog-
raphy (Al2O3, EtOAc/cyclohexane, 8/2, v/v) to give compound 70 (208
mg, 0.28 mmol) as a yellow oil. Yield 40%; Rf (Al2O3, EtOAc/
cyclohexane, 8/2, v/v) 0.43. IR (CCl4) ν 1465, 1510, 1608, 1652,
2220, 2854, 2873, 2927, 2959 cmꢀ1. H NMR (200 MHz, CDCl3) δ
1
0.88 (m, 12H), 1.09 (m, 6H), 1.32 (sex, 6H, J = 7.2 Hz), 1.55 (m, 6H),
2.70 (q, 2H, J = 7.1 Hz), 2.84 (t, 2H, J = 5.9 Hz), 2.96 (t, 2H, J = 5.2 Hz),
3.57 (q, 2H, J = 5.9 Hz), 4.08 (t, 2H, J = 5.2 Hz), 7.00 (m, 1H), 7.03
(t, 1H, J = 7.7 Hz), 7.18 (ddd, 1H, 4JHꢀF = 10.1 Hz, J = 1.6, 7.9 Hz), 7.34
tert-Butyl N-[2-[N-Ethyl-N-[2-(2-fluoropyridin-3-yloxy)ethyl]amin-
o]ethyl]carbamate (74). To a solution of amine 29 (500 mg, 2.20
2761
dx.doi.org/10.1021/jm101574q |J. Med. Chem. 2011, 54, 2745–2766