Hydrochloric Acid → 1-(6-(3-chloro-5-fluoro-4-hydroxyphenyl)-4-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone dihydrochloride

Participants

Reaction Conditions

Reaction Steps

To a suspension of 1-(6-bromo-4-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone (80 mg, 0.19 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (68 mg, 0.25 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80° C. for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded a residue that was dissolved in methanol (8 mL) and HCl (6 M in water, 1.0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (69.8 mg, 65%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.28 (s, 1H), 8.26-8.17 (m, 2H), 8.12 (s, 1H), 8.05-7.99 (d, J=8.8 Hz, 1H), 7.82-7.77 (m, 1H), 7.25 (s, 1H), 7.13 (d, J=11.3 Hz, 1H), 5.46-5.34 (m, 1H), 4.28-3.96 (m, 2H), 3.88-3.55 (m, 1H), 3.41-3.32 (m, 1H), 3.15 (s, 1H), 3.05 (s, 2H), 2.93-2.81 (m, 1H), 2.80 (s, 3H), 2.68-2.33 (m, 1H). ESI MS m/z 480 [C25H23ClFN5O2+H]+; HPLC>99% (AUC), tR=9.44 min.

Provenance & Evidence