3836 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15
Mewshaw et al.
in CH2Cl2) gave 1.57 g (90.6%) of product as a brown oil that
was immediately used to prepare compound 20.
N-[2-(2-Am in o-3-n it r op h en oxy)et h yl]-N-[3-(5-flu or o-
1H-in d ol-3-yl)p r op yl]-2,2-d im eth ylp r op ion a m id e (80). A
solution of 75 (0.56 g, 1.5 mmol) and di-tert-butyl dicarbonate
(0.5 g, 2.25 mmol) in THF (30 mL) was stirred at room
temperature for 1.5 h. The mixture was poured into the water
and extracted with CH2Cl2. The organic layer was washed with
water, dried over anhydrous Na2SO4, and filtered, and the
solvent was removed under vacuum. Chromatography (2%
MeOH-CH2Cl2) afforded 0.94 g (100%) of product as a red
oil: 1H NMR (400 MHz, DMSO-d6) δ 1.30 (br, 9H), 1.82 (m,
2H), 2.59 (t, J ) 7.7 Hz, 2H), 3.60 (m, 2H), 4.10 (m, 2H), 6.55
(t, J ) 8.6 Hz, 1H), 6.82-6.88 (m, 3H), 7.15-7.18 (m, 2H),
7.27 (dd, J ) 8.8, 4.4 Hz, 1H), 7.5 (d, J ) 8.8 Hz, 1H), 10.82
(br s, 1H); HRMS (ESI) m/e 473.2189 (M + H+), C24H29FN4O5
requires 473.2195.
3-{2-[3-(5-F lu or o-1H-in d ol-3-yl)p r op yla m in o]eth oxy}-
ben zen e-1,2-d ia m in e (78). A mixture 75 (0.65 g, 1.7 mmol)
and 10% palladium on carbon in ethanol was hydrogenated
for 3 h. The catalyst was filtered off, and the solvent was
removed under vacuum. Chromatography (10% MeOH-CH2-
Cl2) afforded 0.49 g (82%) of product as a light-brown oil: 1H
NMR (400 MHz, DMSO-d6) δ 1.79 (m, 2H), 2.66 (m, 4H), 2.88
(t, J ) 5.28 Hz, 2H), 3.92 (t, J ) 5.28 Hz, 2H), 4.44 (br, 1H),
6.7-6.20 (m, 2H), 6.33 (t, J ) 7.92 Hz, 1H), 6.88 (m, 1H), 7.18
(m, 1H), 7.25 (dd, J ) 10.1, 2.64 Hz, 1H), 7.30 (dd, J ) 8.8,
4.64 Hz, 1H), 10.8 (br s, 1H); HRMS (ESI) m/e 365.1770 (M +
Na+), C19H23FN4O requires 365.1748.
3-{2-[3-(5-F lu or o-1H-in d ol-3-yl)p r op yla m in o]eth oxy}-
ben zen e-5-ch lor o-1,2-d ia m in e (79). A mixture 76 (0.65 g,
1.7 mmol) and 5% platinum on sulfide carbon in ethanol was
hydrogenated for 1 h. The catalyst was filtered off, and the
solvent was removed under vacuum. Chromatography (15%
MeOH-CH2Cl2 plus NH4OH) afforded 0.59 g (80%) of product
as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 1.92 (m, 2H),
2.71 (t, J ) 7.4 Hz, 2H), 2.91 (m, 2H), 3.15 (m, 2H), 4.06 (t, J
) 4.6 Hz, 2H), 4.80 (br 2H), 6.23 (d, 2.2 Hz, 1H), 6.27 (d, J )
2.2 Hz, 1H), 6.89 (dd, J ) 9.4, 2.4 Hz, 1H), 7.22 (m, 1H), 7.28-
7.34 (m,2H), 10.9 (br s, 1H); HRMS (ESI) m/e 377.1535 (M +
H+), C19H22ClFN4O requires 377.1539.
N-[2-(2,3-Dia m in op h en oxy)eth yl]-N-[3-(5-flu or o-1H-in -
d ol-3-yl)p r op yl]-2,2-d im eth ylp r op ion a m id e (81). A solu-
tion of 80 (0.94 g, 2.0 mmol) and 10% palladium on carbon in
ethanol was heated at 50 °C for 10 min, then hydrazine
monohydrate (3 g) in ethanol (10 mL) was slowly added to
above mixture. The resulting mixture was stirred for 1 h,
followed by filtration of the catalyst through Celite that was
washed with ethanol (100 mL). The organic solvent was
removed under vacuum. Chromatography (5% MeOH-CH2-
Cl2) afforded 0.83 g (88%) of product as a clear oil: 1H NMR
(400 MHz, DMSO-d6) δ 1.30-1.37 (m, 9H), 1.83 (m, 2H), 2.59
(t, J ) 7.5 Hz, 2H), 3.13 (d, J ) 5.3 Hz, 2H), 3.52 (m, 2H),
3.90 (br, 2H), 6.16 (m, 1H), 6.19 (d, J ) 7.0 Hz, 1H), 6.32 (t, J
) 7.9 hz,1H), 6.85 (td, J ) 8.7, 2.6 Hz, 1H), 7.16-7.20 (m,
2H), 7.27 (dd, J ) 8.8, 4.6 Hz, 1H), 10.81 (br s, 1H); HRMS
(ESI) m/e 443.2440 (M + H+), C24H31FN4O3 requires 443.2453.
[2-(3H-Ben zoim id a zol-4-yloxy)eth yl]-[3-(1H-in d ol-3-yl)-
p r op yl]a m in e (20). A solution of 77 (0.75 g, 2.3 mmol)
dissolved in 15 mL of formic acid (98%) was heated to 104 °C
for 6 h. The excess formic acid was removed by vacuum
distillation, and water (100 mL) and EtOAc (100 mL) were
added. The EtOAc layer was separated, washed with water
(50 mL) and brine (75 mL), and dried over anhydrous MgSO4.
Concentration of the solvent gave 0.7 g of product as a brown
solid. Purification by chromatography (2 N ammonia in
MeOH-CH2Cl2, 20:1.5) and crystallization from EtOAc-
ethanol) afforded 0.34 g (45%) of product as a white solid: mp
121-124 °C (dec). The HCl salt was prepared in ethanol: mp
256-258 °C (dec); 1H NMR (400 MHz, DMSO-d6) δ 2.17 (m, 2
H), 2.80 (t, J ) 7.4 Hz, 2 H), 3.11 (m, 2H), 3.37 (m, 2H), 4.51
(t, J ) 5.1 Hz, 2H), 6.96 (ddd, J ) 7.9, 7.0, 1.0 Hz, 1H), 7.06
(ddd, J ) 7.6, 7.6, 1.2 Hz, 1H), 7.14 (d, J ) 7.4 Hz, 1H), 7.18
(d, J ) 2.2 Hz, 1H), 7.34 (d, J ) 8.1 Hz, 1H), 7.43 (d, J ) 8.0
Hz, 1H), 7.49 (t, J ) 8.0 Hz, 1H), 7.55 (d, J ) 7.9 Hz, 1H),
9.39 (bs, 2H), 9.56 (s, 1H), 10.85 (s, 1H). Anal. (C20H22N4O‚
2HCl‚0.25H2O) C, H, N.
N-[3-(5-F lu or o-1H -in d ol-3-yl)p r op yl]-2,2-d im et h yl-N-
[2-(qu in oxa lin -5-yloxy)-eth yl]p r op ion a m id e (82). A solu-
tion of 81 (0.5 g, 1.12 mmol) and glyoxal (40% in water, 0.4
mL) in ethanol (20 mL) was heated to reflux for 1 h. The
reaction was quenched with water and extracted with CH2-
Cl2. The organic portion was washed with water and dried over
anhydrous Na2SO4. The solvent was removed under vacuum.
Chromatography (5% MeOH-CH2Cl2) afforded 0.38 g (72%)
of product as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ
1.30 (s, 9H), 1.88 (m, 2H), 2.60 (t, J ) 7.5 Hz, 2H), 3.40 (m,
2H), 3.66 (t, J ) 5.7 Hz, 2H), 4.28 (m, 2H), 6.86 (td, J ) 9.2,
2.4 Hz, 1H), 7.13-7.20 (m, 2H), 7.27 (t, J ) 4.2 Hz, 1H), 7.31
(d, J ) 8.1 Hz, 1H), 7.62 (d, J ) 7.9 Hz, 1H), 7.34 (t, J ) 8.1
Hz, 1H), 10.83 (br s, 1H); HRMS (ESI) m/e 465.2297 (M + H+),
C
26H29FN4O3 requires 465.2296.
[3-(5-F lu or o-1H-in d ol-3-yl)p r op yl]-[2-(qu in oxa lin -5-yl-
[2-(3H -Ben zoim id a zol-4-yloxy)et h yl]-[3-(5-flu or o-1H -
in d ol-3-yl)]p r op yl]a m in e (21). A solution of 78 (0.49 g) in
formic acid (30 mL) was allowed to reflux for 4 h. The mixture
was poured into NaOH (1 N, 150 mL) and extracted with
EtOAc (3 × 100 mL). The organic layer was dried over
anhydrous MgSO4 and filtered. Chromatography (10% MeOH-
CH2Cl2) afforded 0.25 g (50%) of product as a off-white solid:
oxy)eth yl]a m in e (16). To a solution of 82 (0.27 g, 0.58 mmol)
and anisole (0.5 mL, 4.6 mmol) in CH2Cl2 (20 mL) was added
TFA (1 mL) slowly at 0 °C. The resulting mixture was slowly
warmed to room temperature and stirred for 4 h. The mixture
was quenched with saturated Na2CO3 and extracted with CH2-
Cl2. The organic layer was washed with water and dried over
anhydrous Na2SO4, and the solvent was removed under
vacuum. Chromatography (10% MeOH-CH2Cl2) afforded 47
mg (23%) of product as a clear oil: 1H NMR (400 MHz, DMSO-
d6) δ 1.79 (m, 2H), 2.69 (m, 4H), 3.04 (t, J ) 5.5 Hz, 2H), 4.26
(t, J ) 5.7 Hz, 2H), 6.86 (td, J ) 9.2, 2.6 Hz, 1H), 7.18 (m,
1H), 7.23 (dd, J ) 10.1, 2.4 Hz, 1H), 7.28 (t, J ) 4.2 Hz, 1H),
7.31 (d, J ) 7.0 Hz, 1H), 7.56 (d, J ) 8.1 Hz, 1H), 7.63 (d, J )
8.6 Hz, 1H), 8.87 (m, 1H), 8.92 (M, 1H), 10.83 (br, 1H); MS
ESI m/e 365 (M + 1)+.
7-Meth oxybezofu r a n (84). A solution of 7-methoxy-2-
benzofuran-2-carboxylic acid (5 g, 0.026 mol) and copper (0.2
g) in quinoline (30 mL) was heated at reflux for 2 h. The
mixture was filtered through Celite and washed with EtOAc.
The solvent was removed under vacuum followed by chroma-
tography (25% EtOAc-hexanes) to afford 2.45 g (64%) of
product as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 4.02 (s,
3H), 6.76 (d, J ) 1.96 Hz, 1H), 6.80 (dd, J ) 7.4, 1.3 Hz, 1H),
7.14-7.21 (m, 2H), 7.62 (d, J ) 2.2 Hz, 1H); MS EI m/e 148
(M+).
1
mp 93-95 °C; H NMR (400 MHz, DMSO-d6) δ 1.77 (m, 2H),
2.61-2.89 (m, 4H), 2.93 (t, J ) 5.68 Hz, 2H), 4.22 (t, J ) 5.5
Hz, 2H), 6.70 (d, J ) 7.8 Hz, 1H), 6.86 (m, 1H), 7.06 (t, J )
7.92 Hz, 1H), 7.16 (m, 2H), 7.23 (dd, J ) 10.12, 2.64 Hz, 1H),
7.29 (dd, J ) 9.0, 4.84 Hz, 1H), 8.08 (s, 1H), 10.8 (br s, 1H).
The oxalate salt was prepared in ethanol: mp 185-187 °C.
Anal. (C20H21FN4O‚2C2H2O4) C, H, N.
[2-(6-Ch lor o-1H-ben zoim id a zol-4-yloxy)eth yl]-[3-(5-flu -
or o-1H-in d ol-3-yl)]p r op yl]a m in e (22). This compound was
prepared in a similar fashion described for 21 by replacing
3-{2-[3-(5-fluoro-1H-indol-3-yl)propylamino]ethoxy}benzene-
1,2-diamine(78)with 3-{2-[3-(5-fluoro-1H-indol-3-yl)propylamino]-
ethoxy}benzene-5-chloro-1,2-diamine (79) to give the product
in 76% yield (0.22 g) as a white solid: mp 96-99 °C; 1H NMR
(400 MHz, DMSO-d6) δ 1.81 (m, 2H), 2.67-2.74 (m, 4H), 3.00
(t, J ) 5.3 Hz, 2H), 4.29 (t, J ) 5.3 Hz, 2H), 6.78 (d, J ) 1.3
Hz, 1H), 6.84 (td, J ) 9.4, 2.6 Hz, 1H), 7.19 (m, 1H), 7.23-
7.26 (m, 2H), 7.29 (dd, J ) 8.8, 4.6 Hz, 1H), 8.16 (s, 1H), 10.8
(br s, 1H). The oxalate salt was prepared in ethanol: mp 185-
187 °C. Anal. (C20H20FN4O‚2C2H2O4‚2H2O) C, H, N.
7-Hyd r oxybezofu r a n (85). To a solution of 84 (1 g, 6.7
mmol) in anhydrous CH2Cl2 (25 mL) was carefully added a