Hydrogen Bromide → 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide

Participants

Reaction Conditions

Reaction Steps

2-Amino-5-bromo-3-fluoro-N-methyl-benzamide; hydrobromide (1.76 g, 5.38 mmol) was placed in toluene (70.5 mL, 662 mmol) and ethanol (70.7 mL, 1210 mmol). Tetrakis(triphenylphosphine)palladium(0) (622 mg, 0.538 mmol) was added followed by 1.00 M of sodium carbonate in water (32.3 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.567 g, 7.531 mmol). The reaction was heated at 90° C. for 3 hours and then concentrated under reduced pressure. The residue was taken up in DCM (200 mL) and washed with 1.00 M Na2CO3 (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain a mixture containing 2-amino-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide. This mixture was dissolved in N-methylpyrrolidinone (15.0 mL, 156 mmol) and N,N-diisopropylethylamine (1.12 mL, 6.46 mmol) was added followed by 2,4,5-trichloro-pyrimidine (1.85 mL, 16.1 mmol). The reaction was heated at 100° C. overnight and then cooled to room temperature. The mixture was diluted with DCM (75 mL) and washed with water (4×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide as a yellow solid (967 mg, 45%). m.p.=220-221° C.; LCMS (m/e) 395 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.51 (s, 1H), 8.19 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.33-7.23 (m, 2H), 6.83-6.70 (m, 1H), 3.95 (s, 3H), 3.00 (d, 3H, J=3.6 Hz).

Provenance & Evidence