1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) → 2-[4-[[5-Fluoro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid

関与物質

反応条件

反応手順

Reaction performed in 2 batches: sodium tert-butoxide (778 mg, 8.09 mmol) was added to a suspension of 2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride (481 mg, 2.25 mmol) in 1,4-dioxane (15 mL) at 22° C. under an atmosphere of nitrogen. The mixture was stirred and sonicated for 5 minutes and then 8-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (275 mg, 0.90 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (84 mg, 0.15 mmol) were added and the resulting suspension purged with nitrogen. Tris(dibenzylideneacetone)dipalladium (66 mg, 0.072 mmol) was added and the mixture was purged with nitrogen. The mixture was heated at 150° C. for 60 minutes in a microwave reactor and then allowed to cool to room temperature. The two batches were combined and the mixture was evaporated. The residue was partitioned between CH2Cl2 (150 mL) and a 0.1N solution of NaOH (150 mL). The aqueous layer was separated, washed with CH2Cl2 (100 mL) and then adjusted to pH4 with 2N HCl solution. The aqueous mixture was washed with CH2Cl2 (100 mL), filtered and then evaporated. The residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL). The mixture was filtered and the residue washed with a 1:1 mixture of CH2Cl2/MeOH. The combined filtrates were evaporated to give 2-[4-[[5-fluoro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid (400 mg, 54% yield); Mass spectrum: m/z (ESI+) (M+H)+ =411.37.

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