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With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In 1,4-dioxane; water at 100℃; for 16h; Inert atmosphere;
35.b Step b.
To a solution of tert-butyl 3-(5-bromoindoline-l-carbonyl)-3-fluoropyrrolidine-l-carboxylate (0.2 mmol), l-benzyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.2 mmol) and CS2CO3 (0.6 mmol, 3eq) in 1,4-dioxane (1 ml) and water (0.2 ml) was added Pd(PPh3)4 (0.2eq) at rt under nitrogen. The reaction mixture was stirred at 100°C for 16 h. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by prep-TLC (PE:EtOAc=l: l) yielding tert- butyl 3 -(5 -( 1 -benzyl- 1 H-pyrazol-5 -yl)indoline- 1 -carbonyl)-3 -fluoropyrrolidine- 1 -carboxylate, which was used for next step directly without further purification.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); cesium fluoride In 1,4-dioxane at 140℃; for 1h; Microwave irradiation;
Preparation of N-[2-(1-benzyl-1H-pyrazol-5-yl)phenyl]-8-fluoroquinolin-3-amine (compound I- 096)
In a 5 mL micro-wave tube, 100 mg (0.32 mmol) of N-(2-bromophenyl)-8-fluoro-quinolin-3-amine, 108 mg (0.38 mmol) of 1-benzyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole, 14.4 mg (0.016 mmol) of tris(dibenzylideneacetone)dipalladium, 13 mg (0.032 mmol) of 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (SPhos) and 120 mg (0.79 mmol) of cesium fluoride were added in 3 mL of dry 1 ,4- dioxane. The resulting mixture was heated at 140°C for 1 h in micro-wave. The reaction mixture was cooled to room temperature, and then diluted with water and extracted with ethyl acetate. Combined organic layers were washed with brine, then dried over ChemElut cartridge and concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel (gradient n- heptane/ethyl acetate) to yield 98 mg (78%) of N-[2-(1-benzyl-1 H-pyrazol-5-yl)phenyl]-8-fluoroquinolin- 3-amine as solid. LogP = 3.49 [Method A]. Mass (M+H) = 395. Purity= 98% (LC-210nm).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 80℃; for 0.5h; Inert atmosphere;
29.03 N-((1-aminoisoquinolin-6-yl)methyl)-5-(1-benzyl-1H-pyrazol-5-yl)nicotinamide M th l 5-(1-be zyl-1H- y azol-5-yl)nicotinate
A stirred solution of methyl 5-bromonicotinate (250 mg, 1.16 mmol), 1-benzyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (460 mg, 1.62 mmol) and potassium carbonate (320 mg, 2.31 mmol) in THF (5 mL) and water (100 mL) was degassed with N2 and then Pd(PPh34 (134 mg, 0.12 mmol) was charged and degassed again with N2. Reaction mixture was heated in the microwave at 80 °C for 30 min. Purification was performed by flash chromatography (0-100 % EtOAc in isohexane) to afford the title compound (265 mg, 55% yield) as a pale yellow-green viscous oil. [M+H]+ = 294.0
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