5194 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 16
Verhoest et al.
1
(463 mg, 98%). H NMR (400 MHz, DMSO) δ 8.39 (d, J=
stirred 1 h at ambient temperature and solvent evaporated. The
reaction mixture was partitioned between methylene chloride and
saturated sodium bicarbonate. The layers were separated and the
organic layer dried with magnesium sulfate, filtered, and concen-
trated. Preparative HPLC chromatography provided the title
compound (major isomer) as a clear oil (0.97 g, 56%). 1H NMR
(400 MHz, CDCl3) δ 8.44 (d, J=5.0 Hz, 2 H), 8.17 (d, J=8.7 Hz,
1 H), 8.05 (d, J=8.3 Hz, 1H), 7.81 (d, J=7.9 Hz, 1 H), 7.70 (m,
1 H), 7.66 (d, J=8.7 Hz, 1H), 7.54 (s, 1H), 7.53 (m, 1H), 7.37 (d, J=
8.7 Hz, 2H) 7.15 (d, J=5.0, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.38
(s, 2H), 3.93 (s, 3H). MS: (MþH m/z=393.3). The free base was
dilute in ethyl acetate, and a suspension of succinic acid (1 equiv) in
ethyl acetate was added. The mixture was stirred overnight,
then filtered and washed with ether to provide the succinate salt.
1H NMR (500 MHz, methanol-d4) δ ppm 2.57 (s, 4 H) 3.96 (s, 3 H)
5.41 (s, 2 H) 7.11 (d, J=8.79 Hz, 2 H) 7.30 (d, J=6.35 Hz, 2 H) 7.36
(d, J=8.79 Hz, 2 H) 7.59-7.65 (m, 1 H) 7.75 (d, J=8.54 Hz, 1 H)
7.80 (ddd, J=8.48, 6.89, 1.46 Hz, 1 H) 7.95 (d, J=1.22 Hz, 1 H)
8.02 (s, 1 H) 8.06 (d, J=8.54 Hz, 1 H) 8.36 (dd, J=4.76, 1.59 Hz,
2H) 8.40(d, J=8.54 Hz, 1 H) MS: (MþHm/z=510.6). Anal. Calcd
8.3 Hz, 1 H), 7.99 (m, 2 H), 7.81 (m, 2H), 7.76 (dt, J=8.3, 1.7 Hz,
1 H), 7.64 (d, J=8.3 Hz, 1 H), 7.60 (dt, J=7.9, 1.3 Hz, 1 H), 7.12
(M, 2 H), 5.41 (s, 2 H). MS: (MþH m/z=280.2).
N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide (6).
To a solution of 4-(quinolin-2-ylmethoxy)-benzoic acid 5 (25.98 g,
93 mmol) was added 250 mL of thionyl chloride under N2. The
reaction mixture stirred 3 h, and the excess thionyl chloride was
removed under vacuum. The acid chloride was dissolved in
tetrahydrofuran (450 mL), and triethylamine (50 mL, 4 equiv)
was slowly added. O,N-Dimethyl hydroxyl amine hydrochloride
(27 g, 3 equiv) was added and the reaction stirred for 18 h. The
reaction mixture was placed on a rotovap to remove the solvent,
partitioned between 1 N NaOH and methylene chloride, sepa-
rated, dried with magnesium sulfate, filtered, and concentrated.
The crude product was filtered through silica gel eluting with 30-
70% ethyl acetate/hexane to proved the title compound as a
1
brown oil (26.26 g, 87%). H NMR (400 MHz, CDCl3) δ 8.17
(d, J=8.7 Hz, 1 H), 8.06 (d, J=8.3 Hz, 1 H), 7.81 (d, J=8.3 Hz,
1H), 7.67 (m, 3 H), 7.63 (d, J=8.3 Hz, 1 H), 7.52 (m, 1 H), 7.01 (M,
2 H), 5.39 (s, 2 H), 3.52 (s, 3 H) 3.31 (s, 2H). MS: (MþH m/z=
323.2).
for C24H18N4O C4H6O4: C, 68.22%; H, 5.13%; N, 10.97%.
Found: C, 68.05%; H, 4.99%; N, 10.87%.
3
2-Pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (7).
To a solution of lithium diisopropyl amide (1.0M) in tetrahydro-
furan was added 4-picoline dropwise (7.55 mL, 5 equiv) at 0 °C
under N2. After 30 min, the anion was cooled to -78 °C. In a
separate round-bottom flask, N-methoxy-N-methyl-4-(quinolin-
2-ylmethoxy)-benzamide 6 (5.0, 15.5 mmol) was dissolved in
tetrahydrofuran (77 mL, 0.2M) and cooled to -78 °C under N2.
Then 1.2 equiv of the 4-picoline anion was added dropwise to the
amide solution. After 45 min, 1 equiv more of the 4-picoline anion
was added. After an additional 30 min, acetic acid (40 mL) was
added dropwise and the reaction was slowly warmed to ambient
temperature. The solid product (acetate salt) was filtered and
partitioned between saturated sodium bicarbonate and dichloro-
methane. The layers were separated, dried with magnesium sulfate,
filtered, and concentrated to provide the title compound as a tan
solid (4.41 g, 80%). 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=
5.8 Hz, 2 H), 8.19 (d, J=8.7 Hz, 1 H), 8.07 (d, J=8.7 Hz, 1H), 7.93
(m,2 H), 7.82 (d, J=8.3 Hz, 1 H), 7.75 (m, 1 H), 7.61 (d, J=8.3 Hz,
1 H), 7.54 (dt, J=7.9, 1.0 Hz, 1 H), 7.23 (m, 2 H) 7.07 (m, 2H), 5.42
(s, 2H), 4.19 (s, 2H). MS: (MþH m/z=355.2).
2-[4-(2-Methyl-4-pyridn-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-
quinoline (10). To a solution of 3-dimethylamino-2-pyridin-4-
yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenone 8 (1.72 g) in
ethanol (20 mL) was added methyl hydrazine (3.5 mL, 1.5 equiv)
and concentrated sulfuric acid (0.1 mL). The reaction mixture was
stirred 1 h at ambient temperature followed by solvent evapora-
tion. The reaction mixture was partitioned between methylene
chloride and saturated sodium bicarbonate. The layers were
separated and the organic layer dried with magnesium sulfate,
filtered, and concentrated. Preparative HPLC chromatography
provided the title compound (minor isomer) as a white solid
(0.30 g, 17%). 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J =
5.4 Hz, 2 H), 8.21 (d, J=8.7 Hz, 1 H), 7.80 (d, J=8.3 Hz, 1H),
7.77 (s, 1 H), 7.66 (m, 3 H), 7.53 (m, 1H), 7.19 (d, J=8.7 Hz, 2 H),
7.11 (d, J=8.7 Hz, 2 H), 7.01 (d, J=6.2 Hz, 2H) 5.40 (s, 2H), 3.69
(s, 3H). MS: (MþH m/z=393.3). HPLC purity, column 4: RT
2.764, 96.76%.
2-[4-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
quinoline (11). Following the procedure for the preparation of
2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
quinoline 9 but substituting ethyl hydrazine provided the title
compound (37%). 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 2H),
8.19 (d, J=8.3 Hz, 1 H), 8.07 (d, J=9.1 Hz, 1 H), 7.82 (d, J=
7.9 Hz, 1H), 7.73 (t, J=8.3 Hz, 1H), 7.67 (d, J=8.3 Hz, 2 H), 7.62
(s, 1H), 7.55 (t, J=7.9 Hz, 1 H), 7.37 (d, J=9.1 Hz, 2H), 7.21 (bs,
2 H), 7.01 (d, J=8.7 Hz, 2H) 5.39 (s, 2H), 4.24 (q, J=7.5 Hz, 2H),
1.56 (t, J=7.5 Hz, 3H). MS: (MþH m/z=407.3). HPLC purity,
column 4: RT 3.007, 95.73%.
3-Dimethylamino-2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-
phenyl]-propenone (8). To 2-pyridin-4-yl-1-[4-(quinolin-2-
ylmethoxy)-phenyl]-ethanone 7 (4.0 g, 11.3 mmol) was added
dimethoxymethyl-dimethyl amine (10 mL) and the reaction
mixture was heated at reflux for 1 h. The reaction mixture was
concentrated to give a quantitative yield of the title compound,
which was used without purification in the next step. LC/MS:
RT=1.4 min. MS: (MþH m/z=410.2).
2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline
(3). To a solution of 3-dimethylamino-2-pyridin-4-yl-1-[4-(qui-
nolin-2-ylmethoxy)-phenyl]-propenone 8 (9.57 g, 27 mmol) in
methanol was added hydrazine hydrate (3.33 g, 40.5 mmol) and
the reaction mixture was heated at reflux for 1 h. The solvent was
evaporated to yield a white solid. The solid was washed with
water and ethyl ether. The solid was recrystallized from hot
ethanol/ethylacetate (10 mL/g) to give 8.34 g of the title com-
pound (82%). 1H NMR (400 MHz, DMSO) δ 8.41 (m, 3 H), 8.16
(s, 1 H), 7.97 (m, 2H), 7.86 (s, 1 H), 7.75 (t, J=7.9 Hz, 1 H), 7.68
(d, J=8.3 Hz, 1 H), 7.60 (t, J=7.5 Hz, 1 H), 7.33 (m, 2 H), 7.18
(m, 2 H) 7.15 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 5.38 (s,
2H). MS: (MþH m/z=379.2). Anal. Calcd for C24H18N4O: C,
76.17%; H, 4.79%; N, 14.81%. Found: C, 75.82%; H, 4.73%;
N, 14.71%.
2-[4-(2-Ethyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-
quinoline (12). Following the procedure for the preparation of
2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
quinoline 9 but substituting ethyl hydrazine provided the title
compound (33%). 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 2H),
8.23 (d, J=8.3 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1 H), 7.85 (d, J=
7.4 Hz, 1H), 7.83 (s, 1 H), 7.74 (m, 2 H), 7.57 (t, J=7.9 Hz, 1H),
7.21(d, J=8.7 Hz, 2 H), 7.14 (d, J=9.1 Hz, 2 H), 7.04 (m, 2H) 5.42
(s, 2H), 4.03 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.5 Hz, 3H). MS:
(MþH m/z=407.3). HPLC purity, column 4: RT 2.977, 99.00%.
2-{4-[-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-
phenoxymethyl}-quinoline (13). Following the procedure for the
preparation of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-
phenoxymethyl]-quinoline 9 but substituting (2,2,2-trifluoro-
ethyl)-hydrazine provided the title compound (58%). MS:
(MþH m/z=461.2). The free base was diluted in ethyl acetate,
and a suspension of succinic acid (1 equiv) in ethyl acetate was
added. The mixture was stirred overnight, then filtered to
provide the hemisalt. 1H NMR (500 MHz, methanol-d4)
δ ppm 2.57 (s, 2 H) 5.01 (q, J = 8.54 Hz, 3 F) 5.40 (s, 2 H)
2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
quinoline (9). To a solution of 3-dimethylamino-2-pyridin-4-
yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenone 8 (1.72 g) in
ethanol (20 mL) was added methyl hydrazine (3.5 mL, 1.5 equiv)
and concentrated sulfuric acid (0.1 mL). The reaction mixture was