Triethylamine → N-(4-(1-(4-methoxybenzyl)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Participants

Reaction Conditions

Reaction Steps

A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (25 mg, 0.036 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (10 mg, 0.072 mmol; obtained from Example 7, Step D), copper(I)iodide (0.3 mg, 0.002 mmol), triethylamine (0.25 mL, 1.8 mmol), and THF (0.5 mL) was sparged with N2 for 2 minutes, then tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) was added. The sealed reaction was heated to 50° C. for 18 hours. Additional 1-methyl-4-(prop-2-ynyl)piperazine (10 mg, 0.07 mmol), copper(I)iodide (0.3 mg, 0.002 mmol), and tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) were added and heating was continued at 80° C. for 5 hours. After cooling to room temperature, the entire reaction mixture was loaded directly on to a preparative TLC plate, eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was obtained as a waxy solid (10 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.30 (d, J=6 Hz, 1H), 8.25 (s, 1H), 7.77 (m, 1H), 7.45 (m, 2H), 7.34 (d, J=9 Hz, 2H), 7.24 (m, 2H), 7.06 (m, 2H), 6.82 (d, J=9 Hz, 2H), 6.25 (d, J=6 Hz, 1H), 5.60 (s, 2H), 3.76 (s, 3H), 3.55 (s, 2H), 2.68 (m, 4H), 2.39 (m, 4H), 2.23 (s, 3H), 1.81 (m, 2H), 1.62 (m, 2H).

Provenance & Evidence