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Stage #1: 3-(6-bromo-3-nitro-pyridin-2-yl)-2-oxo-propionic acid ethyl ester With ammonium chloride In tetrahydrofuran; ethanol; water at 20℃; for 0.5h;
Stage #2: With iron In tetrahydrofuran; ethanol; water Reflux;
84.2
To a solution of 3-(6-bromo-3-nitro-pyridin-2-yl)-2-oxo-propionic acid ethyl ester (500 mg, 1.6 mmol) in tetrahydrofuran (16 mL) and ethanol (8 ml) is added saturated aqueous NH4Cl solution (8 ml). The resulting solution is vigorously stirred at room temperature for 30 minutes. Iron powder (528 mg, 9.5 mmol) is added portion wise, and the suspension is heated to reflux for 2 hours. After cooling, the mixture is filtrated through a celite plug, and washed with warm tetrahydrofuran. The filtrate is concentrated in vacuo to give an aqueous suspension, that is extracted with dichloromethane (200 ml). The organic layer is washed with water, brine, and dried over Na2SO4. After the solvent is filtrated and evaporated, the crude product is purified on silica with hexanes / ethyl acetate as the eluent to give the product as a white solid 295 mg, 70%, LC/MS ESI m/z (M+H)+ = 269.3.
sodium (S)-6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridine-2-sulfinate[ No CAS ]
ethyl (S)-5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With palladium diacetate; potassium carbonate; tricyclohexylphosphine In 1,4-dioxane at 150℃; for 14h; Inert atmosphere; Sealed tube;
Intermediate 71: Route C; ethyl (S)-5-(6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-1H-pyrrolo[3.2-b]pyridine-2-carboxylate
Intermediate 43 sodium (S)-6-(3-ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H- pyran-4-yl)pyridine-2-sulfinate (127 mg, 0.245 mmol), palladium(II) acetate (5.01 mg, 0.022 mmol), tricyclohexyl phosphine (12.51 mg, 0.045 mmol), ethyl 5-bromo-1H-pyrrolo[3,2-b]pyridine-2- carboxylate (60 mg, 0.223 mmol, Advanced Chemblocks) and K2C03 (46.2 mg, 0.334 mmol) were placed in dry 1,4-Dioxane (2500 mI) and the resulting mixture was degassed under a flow of nitrogen for 5 min, sealed, and heated to 150 °C for 14h. The reaction mixture was cooled down and filtered through a Celite cartridge (2.5 g) and eluted with EtOAc (20 ml_). The resulting solution was concentrated under reduced pressure to give a residue that was purified by column chromatography on silica using the elution gradient EtOAc in Cyclohexane 0-100%, to give ethyl (S)-5-(6-(3- ethylmorpholino)-4-(4-(methylsulfonyl)tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-1H-pyrrolo[3,2- b]pyridine-2-carboxylate (95 mg, 0.175 mmol, 79% yield) as a off-white solid. LCMS (System B, UV, ESI): Rt = 0.88 min, [M+H]+ 543