M-Phenylenediamine → 6-(3-Aminophenylamino)-8-(cyclopropyl(4-methoxybenzyl)amino) imidazo[1,2-b]pyridazine-3-carbonitrile

Participants

Reaction Conditions

Reaction Steps

A 1-dram vial was charged with 1-methoxy-2-(2-methoxyethoxy)ethane (1.5 mL) and purged for 10 min with argon. The vessel was then charged with 1G (0.100 g, 0.28 mmol), benzene-1,3-diamine (0.037 g, 0.34 mmol), cesium carbonate (0.368 g, 1.13 mmol), copper(I) iodide (0.027 g, 0.14 mmol), Xantphos (0.033 g, 0.057 mmol), and Pd2(dba)3 (0.026 g, 0.028 mmol) in one portion. The resulting suspension was heated to 125° C. overnight. The suspension was filtered through a medium-porosity frit, and the solid was washed with THF. The filtrate was diluted with EtOAc and water, and the layers were separated. The aqueous phase was extracted three times with EtOAc. The organics were then combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was dissolved in DMF and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm), 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min, monitoring at 220 nm. Rt=53.697 min. The appropriate fractions were concentrated and lyophilized to dryness, affording 3A (11 mg, 9% yield). HPLC: Rt=3.68 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=426.0 [M+H]+.

Provenance & Evidence