Cesium carbonate → 1,1-Dimethylethyl 4-methoxybenzeneacetate

Participants

Reaction Conditions

Reaction Steps

2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile A mixture of tert-butyl 3-(3-amino-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate (21-D), (163 mg, 0.500 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (186 mg, 0.525 mmol), DPPF (27.7 mg, 0.050 mmol), Cs2CO3 (326 mg, 1.001 mmol), XANTPHOS (29.0 mg, 0.050 mmol), and palladium(f1) acetate (33.7 mg, 0.150 mmol) in a microwave vial in dioxane (4.5 mL) was evacuated and backfilled with nitrogen for three times, and then was heated in an oil bath at 100° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through celite to remove insoluble material. The filtrate was washed with water, and brine. After drying with sodium sulfate, the solvents were removed and the product was purified by ISCO column (4 g) chromatography, eluting with hexane containing 0 to 35% EtOAc to afford 167 mg of the Boc-PMB-protected product which was dissolved in DCM (6 ml), added TFA (3 ml), and left stirring at room temperature for 30 min. Removal of the solvent. The crude was applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with a mixture of 2 N solution of ammonia in methanol and DCM (1:1). Removal of the solvents left 2-((2-chloro-5-cyano-3-(3-fluoroazetidin-3-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (143 mg) as a solid which was used on next step as such.

Provenance & Evidence