Journal of Medicinal Chemistry
ARTICLE
7-Methoxy-4-(3-phenylpiperidin-1-yl)-6-propoxyquinazoline (7).
Azadicarboxylic acid di-tert-butyl ester (280 mg, 1.2 mmol) in THF
(5 mL) at 23 °C was treated with triphenylphosphine (395 mg, 1.49
mmol) and was stirred for 10 min. Compound 5 (200 mg, 0.6 mmol)
was then added, followed by 1-propanol. After it was stirred for 24 h, the
reaction mixture was diluted with ethyl acetate, was washed with
saturated sodium bicarbonate solution, water, and brine, was dried over
MgSO4, was filtered, and was concentrated in vacuo. The residue was
purified by silica gel chromatography with ethyl acetate/methanol
(100 MHz, CDCl3) δ (ppm) = 25.9, 32.1, 42.7, 51.0, 56.5, 72.6, 77.5,
106.3, 107.7, 111.6, 119.1, 126.9, 127.0, 127.4, 127.8, 128.1, 128.8, 129.0,
130.1, 137.5, 143.8, 147.0, 147.8, 149.1, 153.4, 154.8, 157.5, 164.2. MS
(AP/CI): 477.3 (M þ H)þ.
Compounds 12ꢀ15, 19, and 20. All were prepared using a
procedure analogous to that used to prepare compound 16 via Mitsu-
nobu alkylation of compound 5 with the appropriate alkyl alcohol
7-Methoxy-6-(2-phenylethoxy)-4-(3-phenylpiperidin-1-yl)quinazo-
line (12). The title compound was obtained in 85% yield (75 mg). 1H
NMR (400 MHz, CDCl3) δ (ppm) = 8.65 (s, 1H), 7.4ꢀ7.2 (m, 11H),
7.13 (s, 1H), 4.33ꢀ4.19 (m, 4H), 3.99 (s, 3H), 3.28 (t, J = 7.5 Hz, 2H),
3.19ꢀ2.97 (m, 3H), 2.11 (m, 1H), 1.95ꢀ1.77 (m, 3H); 13C NMR (100
MHz, CDCl3) δ (ppm) = 164.32, 154.99, 153.38, 149.29, 147.78,
143.60, 137.79, 129.31, 128.89, 128.83, 127.31, 127.00, 111.77,
107.80, 104.97, 70.03, 57.33, 56.41, 50.42, 43.25, 35.84, 32.33, 25.97.
MS (AP/CI): 440.2 (M þ H)þ.
1
(100:1) to give 214 mg (95% yield) of the title compound. H NMR
(400 MHz, CDCl3) δ (ppm) = 8.64 (s, 1H), 7.35ꢀ7.22 (m, 6H), 7.13
(s, 1H), 4.27ꢀ4.21 (2H, m), 4.1ꢀ4.0 (m, 2H), 3.98 (s, 3H), 3.15ꢀ3.02
(m, 3H), 2.16 (d, J = 11.9 Hz, 1H), 1.96ꢀ1.87 (m, 4H), 1.82 (m, 1H),
1.06 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) =
164.28, 154.99, 153.29, 149.15, 143.67, 128.81, 127.32, 126.99, 111.84,
107.70, 104.62, 70.79, 57.13, 56.37, 50.62, 43.29, 32.40, 26.00, 22.50,
10.67. MS (ESþ): 378.6 (M þ H)þ.
7-Methoxy-4-(3-phenylpiperidin-1-yl)-6-(2-pyridin-2-ylethoxy)-
quinazoline (13). The title compound was obtained in 80% yield
(70 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.63 (s, 1H), 8.57
(m, 1H), 7.63 (m, 1H), 7.23ꢀ7.15 (m, 9H), 4.5 (m, 2H), 4.2 (m, 2H),
3.96 (s, 3H), 3.80 (m, 2H), 3.05 (m, 3H), 2.1 (m, 1H), 1.9 (m, 2H), 1.8
(m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 26.0, 32.2, 37.9, 43.2,
50.6, 56.4, 57.3, 68.5, 105.3, 107.7, 111.8, 122.0, 124.1, 126.9, 127.4,
128.8, 136.7, 143.7, 147.8, 149.3, 149.7, 153.3, 155.0, 158.2, 164.3. MS
(AP/CI): 441.1 (M þ H)þ.
7-Methoxy-4-(3-phenylpiperidin-1-yl)-6-(pyridin-2-ylmethoxy)-
quinazoline (8). A mixture of compound 5 (100 mg, 0.3 mmol),
2-picolyl chloride hydrochloride (74 mg, 0.45 mmol), and cesium
carbonate (293 mg, 0.9 mmol) in DMSO (2 mL) was stirred at 23 °C
for 6 h. The mixture was diluted with 5% n-butanol in ethyl acetate and
was washed with water and then brine, was dried over MgSO4, was
filtered, and was concentrated in vacuo. Purification by silica gel chro-
matography (200:1:2 CHCl3ꢀMeOHꢀNH4OH (aq)) gave 109 mg
(85%) of the title compound. 1H NMR (400 MHz, CDCl3) δ (ppm) =
8.6 (s, 1H), 8.5 (d, J = 4.6 Hz, 1H), 7.58 (m, 1H), 7.48 (d, J = 7.9 Hz,
1H), 7.2 (m, 5H), 7.08 (m, 1H), 5.4 (d, J = 14.0 Hz, 1H), 5.3 (d, J = 13.7,
1H), 4.1 (dd, J = 1.7, 11.2 Hz, 1H), 4.0 (s, 3H), 3.96 (m, 1H), 3.0 (m,
3H), 2.07 (d, J = 12.0 Hz, 1H), 1.8 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) = 164.24, 156.67, 154.85, 153.45, 149.47, 149.34,
146.95, 143.75, 137.08, 128.77, 127.44, 126.88, 123.03, 121.49, 111.62,
107.85, 106.18, 71.82, 56.62, 56.44, 50.88, 42.97, 32.22, 25.89. MS (AP/
CI): 427.3 (M þ H)þ.
7-Methoxy-4-(3-phenylpiperidin-1-yl)-6-(2-pyridin-3-ylethoxy)-
quinazoline (14). The title compound was obtained in 70% yield
(62 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.63 (s, 1H), 8.58
(s, 1H), 8.5 (d, J = 4.1 Hz, 1H), 7.65 (m, 1H), 7.3ꢀ7.2 (m, 7H),
4.3ꢀ4.15 (m, 4H), 3.97 (s, 3H), 3.18 (m, 2H), 3.07 (m, 2H), 2.98 (m,
1H), 2.12 (m, 1H)1.95ꢀ1.72 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm) = 164.22, 155.01, 153.32, 150.62, 149.22, 148.46, 147.58, 143.55,
136.88, 133.63, 128.84, 127.27, 127.04, 123.68, 111.54, 107.76, 105.24,
69.35, 57.12, 56.40, 50.51, 43.21, 33.05, 32.32, 25.95. MS (AP/CI): 441
(M þ H)þ.
Compounds 9ꢀ11. All were prepared in a manner analogous to
compound 8 via alkylation of compound 5 with the appropriate alkyl
halide.
7-Methoxy-4-(3-phenylpiperidin-1-yl)-6-(2-pyridin-4-ylethoxy)-
quinazoline (15). The title compound was obtained in 64% yield (56
mg). 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.63 (s, 1H), 8.53 (d, J =
5.8 Hz, 1H), 7.3ꢀ7.2 (m, 9 H), 7.10 (s, 1H), 4.3ꢀ4.2 (m, 4H), 3.96 (m,
3H), 3.17 (m, 2H), 3.07 (m, 2H), 2.98 (m, 1H), 2.13 (m, 1H), 1.95ꢀ
1.75 (m, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm) = 164.20, 155.02,
153.36, 150.16, 149.27, 147.50, 147.10, 143.54, 128.84, 127.26, 127.04,
124.61, 111.51, 107.81, 105.50, 68.76, 57.11, 56.39, 50.49, 43.19, 35.11,
32.36, 25.94. MS (AP/CI): 441.3 (M þ H)þ.
7-Methoxy-4-(3-phenylpiperidin-1-yl)-6-(pyridin-3-ylmethoxy)-
quinazoline (9). The title compound was obtained in 84% yield (107
mg) following silica gel chromatography. 1H NMR (CDCl3, 400 MHz)
δ (ppm) = 8.68 (d, J = 1.2 Hz, 1 H), 8.62 (s, 1H), 8.5 (m, 1H), 7.75 (ddd,
J = 1.7, 2.1, 7.9 Hz, 1H), 7.25 (m, 8H), 7.11 (s, 1H), 5.20 (s, 2H), 4.16
(m, 1 H), 4.04 (d, J = 13.7 Hz, 1 H), 3.98 (s, 3H), 3.0 (m, 3H), 2.1 (m,
1H), 1.8 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ (ppm) = 164.21,
155.06, 153.60, 149.91, 149.60, 148.99, 146.90, 143.65, 135.27, 131.99,
128.85, 127.36, 127.01, 123.82, 111.45, 108.05, 106.69, 68.92, 56.68,
56.42, 50.82, 43.07, 32.31, 25.93. MS (AP/CI): 427.2 (M þ H)þ.
7-Methoxy-4-(3-phenylpiperidin-1-yl)-6-(pyridin-4-ylmethoxy)-
quinazoline (10). The title compound was obtained in 85% yield (108
mg) following silica gel chromatography. 1H NMR (CDCl3, 400 MHz)
δ (ppm) = 8.62 (s, 1H), 8.57 (d, J = 1.7 Hz, 2H), 7.3 (m, 5H), 7.24 (m,
4H), 7.04 (s, 1H), 5.21 (d, J = 2.1 Hz, 2H), 4.18 (dt, J = 1.7, 12.9 Hz,
1H), 4.02 (s, 3H), 3.95 (m, 1H), 3.06 (m, 1H), 2.95 (m, 2H), 2.1 (m,
1H), 1.75 (m, 3H). 13C NMR (CDCl3, 100 MHz), d (ppm) = 164.20,
154.96, 153.62, 150.42, 149.56, 146.74, 145.58, 143.61, 128.86, 127.32,
127.03, 121.45, 111.40, 108.10, 106.51, 69.50, 56.47, 50.97, 42.98, 32.33,
25.97. MS (AP/CI): 427.3 (M þ H)þ.
7-Methoxy-4-(3-phenylpiperidin-1-yl)-6-(2-quinolin-2-ylethoxy)-
quinazoline (16). Di-tert-butyl azodicarboxylate (92 mg, 0.4 mmol) was
mixed with triphenylphosphine (131 mg, 0.5 mmol) in THF (2 mL) at
room temperature for 10 min. Compound 5 (67 mg, 0.2 mmol) was
added followed by 2-(quinolin-2-yl)ethanol (138 mg, 0.8 mmol), and
the solution was stirred at room temperature for 24 h. The reaction
mixture was diluted with ethyl acetate, was washed with aqueous sodium
bicarbonate, water, and then brine, was dried over MgSO4, was filtered,
and was concentrated in vacuo. The residue was dissolved in methylene
chloride and was applied to a column packed with silica-bound p-toluene
sulfonic acid. The column was eluted by gravity with 2 column volumes
(cv) of methylene chloride, 3 cv of methanol to remove reaction
byproduct, then was eluted with 4 cv of 1 N triethylamine in methanol
to remove the product. The solvent from the triethylamine elution was
removed in vacuo and the resulting residue was purified by silica gel
chromatography (50ꢀ1ꢀ0 to 50ꢀ1ꢀ1 chloroform/methanol; 50ꢀ1
chloroform/triethylamine) to afford the title compound in 30% yield.
1H NMR (400 MHz, CDCl3) δ (ppm) = 8.63 (s, 1H), 8.10 (d, J = 8.3
Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.7 (m, 1H),
7.51(t,J=7.47Hz,1H), 7.43(d, J=8.3Hz, 1H), 7.2(m, 7H), 4.6(m, 2H),
7-Methoxy-4-(3-phenylpiperidin-1-yl)-6-(quinolin-2-ylmethoxy)-
quinazoline (11). The title compound was obtained in 80% yield (115
mg) following silica gel chromatography. 1H NMR (400 MHz, CDCl3)
δ (ppm) = 8.57 (s, 1H), 8.1 (m, 2H), 7.76 (m, 1H), 7.72 (m, 1H), 7.65
(d, J = 8.7 Hz, 1H), 7.25 (m, 6H), 7.18 (s, 1H), 5.59 (d, J = 13.7 Hz, 1H),
5.54 (d, J = 14.1 Hz, 1H), 4.16 (m, 1H), 4.03 (s, 1H), 3.8 (m, 2H),
3.0ꢀ2.8 (m, 3H), 2.02 (m, 1H), 1.7 (m, 2H), 1.5 (m, 1H); 13C NMR
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dx.doi.org/10.1021/jm2001508 |J. Med. Chem. 2011, 54, 4536–4547