Dimethylformamide → 4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl]-piperidine-1-carboxylic acid tert butyl ester

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Reaction Steps

To a round bottom flask, 7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ol (0.593 g, 0.00277 mol), DIEA (1.50 mL, 0.0086 mol) and DMF (25 mL, 0.32 mol) were added. The mixture was stirred at room temperature and N-Phenylbis(trifluoromethanesulfonimide) (1.14 g, 0.00320 mol) was added. The mixture was stirred at room temperature for 1 h then 4-(4-Amino-phenyl)-piperidine-1-carboxylic acid tert butyl ester (0.995 g, 0.00361 mol) was added and the mixture stirred at 60° C. for 4 h. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with a 2:1 Hexane/DCM and Methanol as eluant (0 to 10% Methanol). The collected fractions gave 4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl]-piperidine-1-carboxylic acid tert butyl ester as a pale solid (˜2:1 P: SM by NMR). LCMS (E/I+) 472 (M+H). ii) To a round bottom flask, Palladium Acetate (0.083 g, 0.000368 mol) and Triphenylphosphine (0.144 g, 0.000551 mol) and THF (6 mL, 0.070 mol) were added and purged under an atmosphere of Nitrogen for 10 minutes. A solution of 4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl]-piperidine-1-carboxylic acid tert butyl ester (70% pure, 1.24 g, 0.00184 mol) in THF (4 mL, 0.050 mol) was added and the reaction was stirred for a further 10 minutes. 4-(Methylsulfonylphenyl)boronic acid (0.735 g, 0.00368 mol), Ethanol (10 mL, 0.20 mol) and 0.90 M Sodium carbonate in Water (6.12 mL, 0.00551 mol) were added and the mixture was heated at 80° C. overnight. The reaction was partitioned with aqueous Sodium Carbonate and EtOAc. The organic was separated, washed with Brine, and dried over Sodium Sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and MeOH as eluant (0 to 10%). The collected fractions afforded 4-{4-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl}-piperidine-1-carboxylic acid tert butyl ester as a yellow solid (0.762 g, 75% pure by NMR). LCMS (E/I+) 570 (M+Na).

Provenance & Evidence