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

Participants

Reaction Conditions

Reaction Steps

Sodium tert-butoxide (805 mg, 8.38 mmol) was added to a suspension of 2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride (498 mg, 2.33 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-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (300 mg, 0.93 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (86 mg, 0.15 mmol) were added and the resulting suspension was purged with nitrogen. tris(dibenzylideneacetone)dipalladium(0) (68.2 mg, 0.075 mmol) was added and the mixture 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 mixture was evaporated and the residue 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 solution was washed with CH2Cl2 (100 mL), filtered and then evaporated. The residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL) and the resulting solid filtered and then washed with a 1:1 mixture of CH2Cl2/MeOH. The combined filtrates were evaporated to leave 2-[4-[[5-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid (250 mg, 63% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.96 (2H, t), 3.06 (3H, s), 3.57 (2H, t), 4.71 (2H, s), 6.81 (1H, s), 6.89 (1H, d), 7.40 (1H, s), 7.43-7.50 (2H, m), 7.90 (1H, d), 8.01 (1H, s), 8.86 (1H, s), 11.23 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=427.33 and 429.29.

Provenance & Evidence