Dimethylformamide → HCID 71008483, compound

Participants

Reaction Conditions

Reaction Steps

Take up 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-chloro-pyridin-2-ylamino)-1H-pyrazole-4-carboxylic acid amide (prepared in example 23, above) (31 mg, 55.2 μmol), zinc cyanide (51.8 mg, 441 μmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6 mg, 14.6 μmol) in 1.5 ml of dry dimethylformamide in a small capacity microwave tube and thoroughly degas with argon. Add tris(dibenzylideneacetone)dipalladium(0) (7 mg, 7.6 μmol) and degas again. The mixture was heated in a microwave reactor at 150° C. for 60 minutes. The solvent was stripped (rotary evaporator/pump) and the remainder was taken up in ethyl acetate (25 ml) and water (25 mL) and shaken in a reparatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×20 ml). The organic phase was combined, dried from magnesium sulfate, filtered and stripped. The crude was purified by preparative thin layer chromatography (1 plate, eluting with 9.5% methanol in dichloromethane). The product band was collected, providing semi-pure desired product (21 mg, 91% pure). For greater purity the material was again loaded onto 1 preparative thin layer chromatography plate and eluted with 7% methanol in dichloromethane. Re-develop the plate with 7% and then 8.5% and finally 9% methanol in dichloromethane, at which point a more polar impurity was separated. The less polar product band was collected, providing the desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(5-cyano-pyridin-2-ylamino)-1H-pyrazole-4-carboxylic acid amide as an off-white solid (17 mg, 56%). LC/MS calc'd for C29H25FN8O3 (m/e) 552.57, obs'd 553 (M+H, ES+).

Provenance & Evidence