Bromide ion → benzyl 4-((5-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate

Participants

Reaction Steps

benzyl 4-((5-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate (Intermediate B38, 903 mg, 1.790 mmol) was dissolved in 20 ml of dry then tribromophosphine 1M in DCM (2684 μl, 2.68 mmol) was slowly added. The mixture was stirred at r.t. The reaction was quenched by addition of 60 ml of NaHCO3 sat. sol. and extracted with DCM (100 ml). Phases were separated to leave a milky organic phase. 30 ml of ACN were added and the solution became clear. The mixture was concentrated to dryness to leave an off white solid. In a separate 30 ml vial, 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 510 mg, 1.969 mmol) and potassium carbonate (742 mg, 5.37 mmol) were suspended in 10 ml DMF and the mixture heated at 60 C for 15 min prior addition of the bromide dissolved in 5 ml of dry DMF. The reaction was stirred for a further hour at r.t. then the reaction was quenched with NaHCO3aq (40 ml) and extracted with DCM (80 ml) then concentrated to leave a brown solid that was purified by chromatography eluting with DCM:MeOH to give benzyl 4-((5-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophen-2-yl)methyl)piperazine-1-carboxylate (460 mg, 0.617 mmol, 34.5% yield) as a brown solid.

Provenance & Evidence