Pyridazinone compound and its application for preparing medicine for treating cystic fibrosis
A compound and medicine technology, applied in the application field of pyridazinone compound and medicine for preparing cystic fibrosis
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Embodiment 1
[0381] Embodiment 1: Synthesis of N-ethyl-N-(4-ethylphenyl)-2-(1-oxo-4-phenylphthalazin-2(1H)-yl)acetamide become
[0382]
[0383] 2-Bromo-N-ethyl-N-(4-ethylphenyl)acetamide
[0384]
[0385] 4-Ethylaniline (5.13 mL, 41.3 mmol) in THF (44 mL) was cooled to 0 °C and washed with acetaldehyde solution (2.55 mL, 45.4 μM) and H 2 SO 4 (3.09 mL, 12.38 mmol) was treated in THF (117 mL). A white slurry was obtained, which was stirred for 10 min and then washed with NaBH 4 (1.03 g, 27.2 mmol) worked up. After 4 hours, add additional NaBH 4 (0.390 g, 10.32 mmol) and stirring was maintained overnight. in saturated NH 4 The reaction was annealed in Cl and washed with Et 2 O extraction. The organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness. The resulting crude product was purified by silica gel chromatography (10-20% ethyl acetate / hexanes) to yield 3.0 g (48%) of N,4-diethylaniline. N,4-diethylaniline (0.5 g, 2.95 mmol), DMAP (...
Embodiment 25
[0415] Example 25: N-ethyl-N-(4-ethylphenyl)-2-(1-oxo-4-(pyridin-3-ylmethyl)phthalazine-2(1H)- base) acetamide:
[0416]
[0417] At 0°C, a solution of 4-(pyridin-3-ylmethyl)phthalazin-1(2H)-one (35 mg, 0.148 mmol) in dimethylformamide (369 μl) was treated containing Vials of NaH (60%) (6.49 mg, 0.162 mmol) and DMF (738 μl). After 10 minutes, 2-bromo-N-ethyl-N-(4-ethylphenyl)acetamide (39.9 mg, 0.148 mmol) in dimethylformamide (369 μl) was added and incubated at room temperature The reaction was stirred overnight under conditions. Sat NH4Cl was added and the product was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and evaporated. The crude product was purified by chromatography (0-5% methanol / ethyl acetate) to yield N-ethyl-N-(4-ethylphenyl)-2-(1-oxo-4-(pyridin-3-ylmethyl yl)phthalazin-2(1H)-yl)acetamide (20mg), (MS:ESI+ve, 427[M+H])
[0418] The following compounds can be prepared in a similar manner to Exampl...
Embodiment 28 and Embodiment 29
[0432] Example 28 and Example 29: N-ethyl-N-(4-ethylphenyl)-2-(7-methyl-1-oxo-4-(pyridin-3-yl) Methyl)phthalazin-2(1H)-yl)acetamide and N-ethyl-N-(4-ethylphenyl)-2-(6-methyl-1-oxo-4-(pyridine-3 -base Methyl)phthalazin-2(1H)-yl)acetamide:
[0433]
[0434] 7-Methyl-4-(pyridin-3-yl-methyl)-phthalazin-1(2H)-one and 6 - A solution of methyl-4-(pyridin-3-yl-methyl)-phthalazin-1(2H)-one (0.5 g, 1.9 mmol) in THF (15 mL), then maintained at 0 °C 30 minutes. A solution of 2-bromo-N-ethyl-N-(4-ethylphenyl)acetamide (0.537 g, 1.9 mmol) in THF (5 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature And keep it overnight. with saturated NH 4 The reaction was diluted with Cl (25 mL) and extracted with ethyl acetate (2x50 mL). The organics were washed with brine (50 mL), dried over sodium sulfate and concentrated to give a crude product which was purified by preparative HPLC to give separable isomers, Example 28: N-Ethyl-N -(4-Ethylphenyl)-2-...
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