反应详情

温度

125 °C

A mixture of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine (210 mg, 0.42 mmol), 2-isopropoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (145 mg, 0.55 mmol) (CombiPhos Catalysts Inc., Cat#BE177), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (16 mg, 0.034 mmol, Strem), Pd2(dba)3 (15 mg, 0.017 mmol, Strem), and potassium phosphate (271 mg, 1.27 mmol) in dioxane (4 mL) and H2O (1 mL) in a sealed glass tube was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 125° C. for 20 min. The mixture was partitioned between 2 mL of 0.5 N NaOH and 10 mL of EtOAc. The organic layer was filtered through a pad of Celite and concentrated to give crude 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine that was used in next step without further purification. MS (ESI, pos. ion) m/z: 504.1 (M+1). A mixture of 5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine and KOH (49 mg, 0.88 mmol) in 2 mL of dioxane and 1 mL of H2O was heated in a microwave at 105° C. for 15 min. It was partitioned between 15 mL of EtOAc and 3 mL of H2O. The organic layer was concentrated and purified on a reverse phase HPLC, using a gradient of 10-90% [0.1% TFA in AcCN] in [0.1% TFA in H2O] to afford 5-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine 2,2,2-trifluoroacetate (51 mg, 27% overall for 2 steps) as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 350.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, br.), 8.99 (1H, s), 8.19 (1H, d, J=2.6 Hz,), 7.66 (2H, m), 7.56 (1H, d, J=8.6 Hz), 7.42 (1H, d, J=7.4 Hz), 6.52 (1H, d, J=8.0 Hz), 5.49 (1H, m), 4.06 (1H, br.), 2.89 (3H, s), 1.44 (6H, d, J=6.1 Hz).

1. customThe mixture was partitioned between 2 mL of 0.5 N NaOH and 10 mL of EtOAc
2. filtrationThe organic layer was filtered through a pad of Celite
3. concentrationconcentrated