Isopropyl 4-[(6-chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylate → Isopropyl 4-((5-methoxy-6-((2-methyl-6-(methylsulfonyl)pyridin-3-yl)amino)pyrimidin-4-yl)oxy)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

Bis[(2-diphenylphosphino)phenyl] ether (0.021 g, 0.04 mmol) was added in one portion to Palladium(II) acetate (4.33 mg, 0.02 mmol) in toluene (1 mL) (degassed by bubbling N2 through it for 30 minutes) at 20°C under nitrogen. After a few minutes a yellow suspension had formed. This added in one portion by pipette to a mixture of isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (0.318 g, 0.96 mmol), 2-methyl-6-(methylsulfonyl)pyridin-3-amine (0.180 g, 0.96 mmol) and Sodium tert-butoxide (0.177 mL, 1.45 mmol) in toluene (3 mL) at 60°C under nitrogen. The resulting mixture was degassed using N2 / vacuum six times. The resulting suspension was stirred at 60 °C for 18 hours. Work up was by diluting with water (10 ml) and DCM (10 ml) then filtering through a pad of celite and washing through well with DCM (6 x 10 ml). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography (40g column), elution gradient 0 to 100% EtOAc in heptane (material applied in DCM). Pure fractions were evaporated to dryness to afford isopropyl 4-(5-methoxy-6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate (0.231 g, 50.0 %) as a slightly off white foam. Trituration with Et2O (10 ml) and sctratching gave a free flowing white suspension. The solvent was removed under reduced pressure to give a white powder.

Provenance & Evidence