6-Bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine → 4-{5-[2-Amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile

Participants

Reaction Steps

6-Bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (Int. 2, 100 mg, 0.27 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 115 mg, 0.25 mmol) were dissolved in THF (5 mL) and degassed then bis(triphenylphosphine)palladium (II) dichloride (18 mg, 0.025 mmol) was added. The reaction mixture was stirred at reflux temperature for 21 hrs then allowed to cool before washing with cesium fluoride (saturated aqueous solution) and extracting with EtOAc (2×30 mL). The combined organic extracts were filtered and the filtrate was concentrated in vacuo. The resultant residue was subjected to preparative C18 HPLC, eluting with a gradient 40-90% MeCN in water (+0.1% formic acid) to afford 51 mg of an impure title compound (containing 25% starting material) which was dissolved in THF (3 mL) with 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 4.72 g, 0.103 mmol) and degassed before addition of bis(triphenylphosphine)palladium (II) dichloride (10 mg, 0.014 mmol). The reaction mixture was heated at 75° C. for 6.5 h then purified using an SCX-2 cartridge (loading in MeOH/eluting with 2 N NH3 in MeOH). The resultant residue was taken up in MeOH (5 mL) and treated with 3-mercaptopropylethyl sulfide silica (PhosphonicS SPM 32, 0.5 eq by weight) and stirred at 50° C. for 1 hr then filtered and evaporated. The resultant residue was dissolved in DCM then filtered and evaporated in vacuo before further purification by preparative C18 HPLC, eluting with a gradient 40-90% MeCN in water (+0.1% formic acid) to give the title compound as a white solid (25 mg).

Provenance & Evidence