Trimethylphosphine → HCID 131734133, compound

Participants

Reaction Steps

tert-butyl ((2S,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (first eluting diastereomer) and tert-butyl ((2R,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (second eluting diastereomer). PMe3 (0.86 mL of 1.0 M solution in THF, 0.86 mmol) was added drop wise to a solution of 3-(azidomethyl)-6-(3-fluoropyridin-2-yl)pyridazine (Preparation XXVIII, 190 mg, 0.82 mmol) in THF (2 mL) at RT. After the reaction mixture stirred for 15 min at RT, it was treated with a suspension of tert-butyl ((3S)-1-(3-isothiocyanatopyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (Preparation XLIX, 288 mg, 0.82 mmol) in THF (2.5 mL) at RT. The resulting mixture was stirred at RT for 15 min; then concentrated to half of its volume. The solution purified by silica gel chromatography (50-100% EtOAc in hexanes followed by 1-3% MeOH in EtOAc) to provide tert-butyl ((3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate as an orange amorphous solid. MS (ESI, pos. ion) m/z: 519.1 (M+1). LCMS indicated the presence of 2 peaks with the same mass at about 1:3 ratio. The above obtained orange amorphous solid was dissolved in 10 mL of DMSO and purified on a preparative reverse-phase HPLC (using Prep HPLC method 3) to provide tert-butyl ((2S,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (first eluting diastereomer) and tert-butyl ((2R,3S)-1-(3-((2-(3-fluoropyridin-2-yl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (second eluting diastereomer).

Provenance & Evidence