7874 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26
Boschelli et al.
between 10% methanol in ethyl acetate and water. The organic layer
was dried over magnesium sulfate, filtered and concentrated in
Vacuo. Diethyl ether was added to the residue and the solid was
collected by filtration to provide 130 mg (41% yield) of the
intermediate aldehyde derivative as a yellow-orange solid.
8.30 (s, 1H), 8.44 (s, 1H), 9.81 (s, 1H); MS 539.1 (M + H)+. Anal.
(C27H24Cl2N4O4‚0.50H2O) C, H, N.
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-
[(dimethylamino)methyl]-3-furyl}-3-quinolinecarbonitrile (22).
Compound 22 was prepared from 9 according to the route used to
prepare 10: mp 133-138 °C; 1H NMR (DMSO-d6) δ 2.20 (s, 6H),
3.49 (s, 2H), 3.87 (s, 3H), 4.07 (s, 3H), 7.03 (s, 1H), 7.38 (s, 1H),
7.76 (s, 1H), 7.95 (s, 1H), 8.13 (s, 1H), 8.30 (s, 1H), 8.45 (s, 1H),
9.82 (s, 1H); MS 497.1 (M + H)+; HRMS calcd, 497.11418; found,
497.11291 (M + H)+. Anal. (C25H22Cl2N4O3‚1.50H2O) C, H. N:
calcd, 10.68; found, 10.11.
A mixture of this aldehyde (106 mg, 0.26 mmol) and 1-meth-
ylpiperazine (0.15 mL, 1.35 mmol) in 4 mL of dichloromethane
and 1 mL of 1-methyl-2-pyrrolidinone was cooled to 0 °C. Sodium
triacetoxyborohydride (300 mg, 1.42 mmol) was added, followed
by a few drops of acetic acid. The resulting mixture was stirred at
0 °C for 10 min and then at room temperature for 2 h. The mixture
was partitioned between ethyl acetate and water. The organic phase
was dried over magnesium sulfate, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography,
eluting with a gradient of 10% methanol in ethyl acetate to 1%
ammonium hydroxide in 25% methanol in ethyl acetate. Trituration
with diethyl ether provided 48 mg (38% yield) of 17 as a light
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-{5-
[(4-phenylpiperazin-1-yl)methyl]-3-furyl}-3-quinolinecarboni-
trile (23). Compound 23 was prepared from 9 according to the
1
route used to prepare 10: mp 201-203 °C; H NMR (DMSO-d6)
δ 2.52-2.62 (br s, 4H), 3.09-3.19 (br s, 4H), 3.34 (s, 2H), 3.87
(s, 3H), 4.07 (s, 3H), 6.77 (t, J ) 7 Hz, 1H), 6.92 (d, J ) 8 Hz,
2H), 7.09 (s, 1H), 7.20 (t, J ) 8 Hz, 2H), 7.38 (s, 1H), 7.76 (s,
1H), 7.95 (s, 1H), 8.14 (s, 1H), 8.32 (s, 1H), 8.45 (s, 1H), 9.83 (s,
1H); MS 614.1 (M + H)+; HRMS calcd, 614.17203; found,
614.17153 (M + H)+. Anal. (C33H29Cl2N5O3‚0.50H2O) C, N. H:
calcd, 4.85; found, 4.37.
1
yellow solid, mp 183-186 °C; H NMR (DMSO-d6/TFA) δ 2.84
(s, 3H), 3.06-3.62 (br s, 8H), 4.13 (s, 2H), 7.19 (s, 1H), 7.61 (dd,
J ) 8, 2 Hz, 1H), 7.68 (d, J ) 8 Hz, 1H), 7.90 (d, J ) 2 Hz, 1H),
8.12 (s, 1H), 8.16 (d, J ) 9 Hz, 1H), 8.64 (s, 1H), 8.69 (d, J ) 9
Hz, 1H), 9.01 (s, 1H); MS 492.0 (M + H)+. Anal. (C26H23-
Cl2N5O‚1.20H2O) C, H, N.
4-(2-Methoxy-5-nitrophenyl)-2-furaldehyde (24). To a mixture
of 2-iodo-4-nitroanisole (565 mg, 2.02 mmol) and 4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-2-furancarboxaldehyde (670
mg, 3.03 mmol) in 20 mL of ethylene glycol dimethyl ether and
12 mL of aqueous saturated sodium bicarbonate was added 80 mg
of tetrakis(triphenylphosphine)palladium(0). The mixture was heated
to reflux overnight then allowed to cool to room temperature. An
attempt to partition the reaction mixture between 10% methanol in
ethyl acetate and water led to a large amount of insoluble material.
These solids were collected by filtration and washed with water
and ethyl acetate to provide 259 mg (52% yield) of 24 as a light
1-[(4-Bromo-2-furyl)methyl]-4-methylpiperazine (19). To a
solution of 4-bromo-2-furaldehyde (500 mg, 2.86 mmol) in 20 mL
of dichloromethane was added 1-methylpiperazine (1.58 mL, 14.3
mmol). The solution was cooled to 0 °C, and sodium triacetoxy-
borohydride (3.03 g, 14.3 mmol) was added in portions, followed
by 0.07 mL of acetic acid. The reaction mixture was stirred at room
temperature overnight. Saturated aqueous sodium bicarbonate was
added, and the mixture was stirred for 2 h. The reaction mixture
was extracted with dichloromethane, and the organic phase was
washed with brine and dried over sodium sulfate. Filtration and
concentration in vacuo, followed by flash column chromatography,
eluting with a gradient of methanol in dichloromethane (0% to
20%), with a second flash column chromatography, eluting with a
gradient of methanol in ethyl acetate (0% to 15%) to 1%
concentrated ammonium hydroxide in 20% methanol in ethyl
1
brown solid; H NMR (DMSO-d6) δ 4.07 (s, 3H), 7.37 (d, J ) 9
Hz, 1H), 8.20-8.29 (m, 2H), 8.55 (d, J ) 3 Hz, 1H), 8.69 (s, 1H),
9.68 (s, 1H); MS 247.1 (M - H)-.
1-{[4-(2-Methoxy-5-nitrophenyl)-2-furyl]methyl}-4-methylpip-
erazine (25). A mixture of 24 (230 mg, 0.93 mmol) and 1-meth-
ylpiperazine (0.90 mL, 8.1 mmol) in 20 mL of dichloromethane
and 2 mL of 1-methylpyrrolidinone was cooled to 0 °C. Sodium
triacetoxyborohydride (1.21 g, 5.7 mmol) was added in portions,
followed by a few drops of acetic acid. The resulting mixture was
stirred at 0 °C for 10 min then at room temperature for 1.5 h. The
mixture was partitioned between ethyl acetate and saturated aqueous
sodium bicarbonate. The organic phase was dried over magnesium
sulfate, filtered, and concentrated in vacuo. The residue was purified
by flash column chromatography, eluting with a gradient of 20%
methanol in ethyl acetate to 1% ammonium hydroxide in 20%
methanol in ethyl acetate. Trituration with diethyl ether and hexane
provided 57 mg (18% yield) of 25 as a light yellow solid; 1H NMR
(DMSO-d6) δ 2.14 (s, 3H), 2.25-2.36 (br s, 4H), 2.38-2.46 (br s,
4H), 3.52 (s, 2H), 4.04 (s, 3H), 6.96 (s, 1H), 7.31 (d, J ) 8 Hz,
1H), 8.14-8.20 (m, 2H), 8.38 (d, J ) 3 Hz, 1H); MS 332.1 (M +
H)+. Anal. (C17H21N3O4) C, H, N.
1
acetate, provided 426 mg of 19 (58% yield) as a yellow oil; H
NMR (DMSO-d6) δ 2.13 (s, 3H), 2.29 (br s, 4H), 2.54 (br s, 4H),
3.46 (s, 2H), 6.48 (s, 1H), 7.82 (s, 1H); MS 259.0 (M +H)+.
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-{5-[(4-methyl-1-
piperazinyl)methyl]-3-furyl}-3-quinolinecarbonitrile (20). A mix-
ture of 19 (135 mg, 0.52 mmol), hexamethylditin (170 mg, 0.52
mmol), and tetrakis(triphenylphosphine)palladium(0) (42 mg) in 6
mL of 1,4-dioxane was heated at 103 °C for 3 h. To the reaction
mixture was added 1828 (200 mg, 0.47 mmol) and tetrakis-
(triphenylphosphine)palladium (0) (16 mg). The temperature was
increased to 110 °C, and the reaction mixture was kept at this
temperature for 20 h. After cooling to room temperature, the
reaction mixture was partitioned between dichloromethane and
saturated aqueous sodium bicarbonate. The organic phase was dried
over sodium sulfate, filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography, eluting with a
gradient of dichloromethane to 10% methanol in dichloromethane.
The resultant oil was purified by preparative thin layer chroma-
tography, developing with 10% methanol in dichloromethane.
Trituration with hexane and ethyl acetate provided 24 mg of 20
(10% yield) as a yellow solid, mp 192-195 °C; 1H NMR (DMSO-
d6/TFA) δ 2.89 (s, 3H), 3.21-3.72 (br s, 8H), 3.91 (s, 3H), 4.43
(s, 2H), 7.32 (s, 1H), 7.62 (s, 1H), 7.92 (s, 1H), 8.09 (d, J ) 8 Hz,
1H), 8.43 (d, J ) 8 Hz, 1H), 8.58 (s, 1H), 8.99 (s, 1H), 9.22 (s,
1H); MS 522.1 (M + H)+. Anal. (C27H25Cl2N5O2‚1.30H2O) C, H,
N.
(4-Methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}-
phenyl)amine (26). To a solution of 25 (396 mg, 1.19 mmol) in
20 mL of methanol was added 10% palladium on carbon (40 mg).
The resulting mixture was treated with hydrogen in a Parr shaker
until hydrogen uptake ceased. The reaction mixture was filtered
through Celite and the filtrate concentrated in vacuo to give 358
1
mg (100% yield) of 26 as a brown oil; H NMR (DMSO-d6) δ
2.14 (s, 3H), 2.29 (br s, 4H), 2.40 (br s, 4H), 3.49 (s, 2H), 3.72 (s,
3H), 4.61 (s, 2H), 6.47 (d, J ) 8 Hz, 1H), 6.58 (s, 1H), 6.78 (d, J
) 9 Hz, 1H), 6.80 (s, 1H), 7.91 (s, 1H); MS 302.1 (M + H)+.
Alternative Preparation of 4-[(2,4-Dichloro-5-methoxyphen-
yl)amino]-6-methoxy-7-{5-[(4-methylpiperazin-1-yl)methyl]-3-
furyl}-3-quinolinecarbonitrile (10). To a suspension of 11 (261
mg, 1.01 mmol) in 5 mL of iso-propanol was added triethylortho-
formate (0.504 mL, 3.03 mmol). The mixture was heated to reflux
and 26 (320 mg, 1.06 mmol) in 9 mL of iso-propanol was added
dropwise. This mixture was heated at reflux for 25 h. The mixture
4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[5-
(morpholin-4-ylmethyl)-3-furyl]-3-quinolinecarbonitrile (21). Com-
pound 21 was prepared from 9 according to the route used to
prepare 10: mp 164-166 °C; 1H NMR ((DMSO-d6) δ 2.39-2.46
(br s, 4H), 3.50-3.60 (complex m, 6H), 3.87 (s, 3H), 4.06 (s, 3H),
7.05 (s, 1H), 7.36 (s, 1H), 7.75 (s, 1H), 7.94 (s, 1H), 8.12 (s, 1H),