Cesium carbonate → (+/-)-5-{[4-(6-Methylpyridin-3-yl)phenyl]methyl}-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one

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Reaction Steps

(±)-5-[(4-Iodophenyl)methyl]-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one [(Example 10, Step 3), 50 mg, 0.10 mmol], 2-methyl-5-pyridinylboronic acid (35 mg, 0.26 mmol, 2.5 equiv), palladium(II) acetate (4.6 mg, 0.21 mmol, 0.2 equiv), 1,1′-bis(diphenylphosphino)ferrocene (11 mg, 0.21 mmol, 0.2 equiv), copper(I) chloride (10 mg, 0.10 mmol, 1 equiv) and cesium carbonate (84 mg, 0.26 mmol, 2.5 equiv) were combined in degassed N,N′-dimethylformamide (3 mL) and placed in a preheated oil bath at 100° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (20 mL, aqueous saturated) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound as a deep red solid: 1H-NMR (hydrochloride salt, 400 MHz, CDCl3) δ 8.78 (2H, br s), 8.59 (1H, d, J=6.8 Hz), 8.39 (1H, br s), 7.72 (3H, br s), 7.55 (3H, br s), 6.02 (2H, s), 4.67 (1H, br s), 4.03-3.95 (2H, m), 3.79-3.70 (1H, m), 3.51-3.45 (1H, m), 3.02 (3H, br s), 2.36-2.06 (2H, m), 1.90-1.80 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 453.2039 [(M+H)+; calculated for C26H25N6O2: 453.2034].

Provenance & Evidence