Trifluoroacetic acid → 6-(3-Cyano-5-(trifluoromethyl)phenylamino)-8-(isopropylamino)imidazo[1,2-b]pyridazine-3-carbonitrile

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Reaction Conditions

Reaction Steps

A solution of 3-amino-5-(trifluoromethyl)benzonitrile (0.078 g, 0.42 mmol) in DMA (1 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was purged with argon. 10A (0.100 g, 0.281 mmol), cesium carbonate (0.366 g, 1.124 mmol), copper(I) iodide (0.027 g, 0.141 mmol), Xantphos (0.033 g, 0.056 mmol), and Pd2(dba)3 (0.026 g, 0.028 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was then heated to 125° C. for 45 min. The solids were removed via filtration through CELITE® and washed with THF. The dark brown filtrate was concentrated under reduced pressure and then diluted with water and ethyl acetate. The layers were separated, and the aqueous phase extracted with ethyl acetate (2×10 mL). The organics were combined, washed with water and brine, dried over sodium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (SiO2, hexanes to 40% EtOAc/hexanes, 12 g column, 30 mL/min., 20 min. gradient, monitoring at 254 nm). The fractions were concentrated, dissolved in DCM (1 mL), and treated with triethylsilane (0.45 mL, 2.8 mmol), and TFA (0.3 mL) at room temperature. After 20 min., the volatiles were removed via a stream of nitrogen. The residue was triturated with MeOH, forming a white precipitate. The solid was isolated via filtration, washed with MeOH, and suspended in 1:1 1N HCl/MeCN and lyophilized, affording Example 10, (0.081 g, 68.3% yield) as a white solid. HPLC: Rt=4.35 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=386.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (1H, s), 8.52 (1H, s), 8.24 (1H, s), 8.19 (1H, s), 7.82 (1H, s), 7.48 (1H, d, J=8.03 Hz), 5.94 (1H, s), 2.52-2.55 (1H, m), 1.28 (6H, d, J=6.27 Hz).

Provenance & Evidence