Hydrazine hydrate (1:1) → 6-[2-Amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine

Participants

Reaction Conditions

Reaction Steps

To 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (16.5 g, 66.6 mmol) and 4-chloro-6-(methylthio)-2-pyrimidinamine (11.7 g, 66.6 mmol) were added 1,4-dioxane (300 mL) and saturated aqueous NaHCO3 (150 mL) and the mixture was degassed with nitrogen gas for 15 minutes into a sealable tube. Pd(Ph3P)4 (2.3 g, 2.0 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100° C. The mixture was cooled to room temperature and poured onto water where a precipitate was formed. The mixture was filtered and the solid was transferred to a sealable tube. Dioxane (300 mL) was added followed by hydrazine monohydrate (32.7 mL, 666 mmol) and the reaction mixture was stirred overnight at 100° C. into the sealed tube. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was poured onto water and filtered again. The aqueous filtrate was poured onto a separatory funnel and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. To the resulting residue was added 1,4-dioxane (100 mL) and the mixture was sonicated for 30 minutes. The solids were filtered affording the crude title compound (11.5 g) as a yellow solid. The filtrate was concentrated and the resulting residue was dissolved in dioxane and purified via flash chromatography on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH) to afford the title compound (4.5 g) as a pale yellow solid. LC-MS (ES) m/z=273 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.53 (s, 3H), 5.41 (s, 2H), 6.70 (s, 2H), 7.06 (s, 1H), 7.58 (dd, J=8.5, 1.1 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.98 (s, 1H), 11.60 (s, 1H).

Provenance & Evidence