New quinoline derivatives
A compound and alkyl technology, applied in the field of new quinoline derivatives, can solve problems such as no description of quinoline derivatives
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Embodiment 1
[0945] N-[(4S)-3,4-dihydro-2H-benzopyran-4-yl]-4-(3,6-dihydro-2H-pyran-4-yl)-8-(2 ,3,5-trifluorophenyl)quinoline-3-carboxamide
[0946]
[0947] Under argon, add 4-chloro-N-[(4S)-3,4-dihydro-2H-benzopyran-4-yl]-8-(2,3,5- Trifluorophenyl) quinoline-3-carboxamide (Example 3A) (500 mg, 1.07 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin Cyclopentan-2-yl)-3,6-dihydro-2H-pyran (246 mg, 1.17 mmol), potassium carbonate (295 mg, 2.13 mmol), 1,1'-bis(diphenylphosphine base) ferrocene-palladium(II) dichloride dichloromethane complex (43.5 mg, 53 μmol) and a degassed 5:1 mixture of dioxane / water (4 ml). The vessel was capped and heated at 80°C overnight with stirring. The mixture was filtered through celite and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The residue (650 mg) was purified by flash chromatography on silica (50 g) with cyclohexane / ethyl acetate (8-40%).
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Embodiment 2
[0952] N-[(4S)-3,4-dihydro-2H-benzopyran-4-yl]-4-(tetrahydro-2H-pyran-4-yl)-8-(2,3,5 -Trifluorophenyl)quinoline-3-carboxamide
[0953]
[0954] Procedure 1:
[0955]N-[(4S)-3,4-dihydro-2H-benzopyran-4-yl]-4-(3,6-dihydro-2H-pyran-4-yl) -8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (Example 1) (500 mg, 0.97 mmol) was dissolved in ethyl acetate / ethanol (2:1, 15 ml) . 10% palladium / carbon (125 mg) catalyst was added, argon was replaced by hydrogen, and the mixture was stirred under hydrogen pressure for 18h. The reaction mixture was filtered through celite, rinsed with ethyl acetate and concentrated in vacuo. The residue (560 mg, crude mixture of different reduction products) was dissolved in DMSO (4.5 ml) and treated with ceric ammonium nitrate (2 M solution in water, 1.9 ml, 3.8 mmol) to give a tan suspension which was dissolved in Stir overnight at ambient temperature. The mixture was dissolved by adding more DMSO, acetonitrile and some 5 M formic acid and direct...
Embodiment 3
[0964] N-[(4S)-3,4-dihydro-2H-benzopyran-4-yl]-7-fluoro-4-(tetrahydro-2H-pyran-4-yl)-8-(2 ,3,5-trifluorophenyl)quinoline-3-carboxamide
[0965]
[0966] The title compound was prepared from ethyl 8-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (Example 8A) in a similar manner as described eg in 4A, 5A, 6A and Example 2, Procedure 2 .
[0967] LC-MS (Method 2): R t = 1.14 min; MS (ESI+): m / z = 537 [M+H] +
[0968] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.679 (4.00), 1.713 (6.39), 1.737 (3.34), 2.033 (2.47), 2.052 (2.85), 2.067 (3.55), 2.211 (2.97) , 2.220 (3.09), 2.229 (2.93), 2.243 (2.14), 2.328 (0.95), 2.367 (2.64), 2.388 (4.62), 2.401 (5.48), 2.420 (5.36), 2.432 (5.24), 2.449 (2.76) , 2.464 (2.06), 2.670 (0.95), 2.710 (0.91), 3.444 (1.32), 3.471 (3.63), 3.499 (4.04), 3.523 (3.09), 3.543 (4.29), 3.574 (2.23), 3.737 (3.01) , 4.016 (7.26), 4.036 (6.06), 4.197 (2.06), 4.219 (4.21), 4.225 (4.91), 4.246 (4.41), 4.270 (4.74), 4.286 (4.16), 5.275 (2.27), 5.288 (5.07) , 5.30...
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