Water → HCID 67959729, compound

Participants

Reaction Conditions

Reaction Steps

A 75 mL threaded pressure vessel was flushed with argon and was charged with a stir bar, bis(4-(di-tert-butylphosphino)-N,N-dimethyl-benzenamine) palladium dichloride (0.061 g, 0.086 mmol) and (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (1.00 g, 1.711 mmol). (2,6-Difluorophenyl)zinc(II) bromide 0.5 M in THF (Rieke metals) (5.13 mL, 2.57 mmol) was added, the reaction was sealed, and the slurry was heated to 70° C. After ˜10 min, a clear solution resulted. After 3 h the reaction was cooled and judged complete by LCMS. The reaction was treated with sodium 2,2′-(2-((carboxylatomethyl)(2-hydroxyethyl)amino)ethylazanediyl)diacetate hydrate 10 wt % in water (10.23 mL, 2.82 mmol) (10% aqueous EDTA-H) and DCM. An additional 2-3 mL of 10% EDTA-H solution was added to break up emulsion. The layers were separated, and the aqueous layer was extracted 3×DCM. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) eluting with 0-40% EtOAc/hexane. The product-containing fractions were concentrated to afford (4R)-tert-butyl 4-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (1.10 g, 1.781 mmol, quant.) as a light-yellow foam: MS (ESI, pos. ion) m/z: 618 (M+1)

Provenance & Evidence