Dimethylformamide → 2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide

Participants

Reaction Conditions

Reaction Steps

A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Example 109, Step 1, 0.25 g, 0.47 mmol) in acetonitrile (10 mL, 0.048M) was treated with cesium carbonate (0.31 g, 0.95 mmol) and 1H-indol-4-ol (75.4 mg, 0.56 mmol). The resulting reaction mixture was stirred at 25° C. for 3.5 h. At this time, the reaction was treated with N,N-dimethylformamide (1.0 mL) and the reaction was heated at 80° C. overnight. The reaction mixture was then concentrated in vacuo and partitioned between water (75 mL) and ethyl acetate (75 mL). The emulsified bilayer was filtered through filter paper and rinsed with water and ethyl acetate. The layers were separated, and the organics were washed with a saturated aqueous sodium chloride solution (50 mL). The combined aqueous layers were acidified with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 24 g, 1-10% methanol/methylene chloride) afforded 2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (207.1 mg, 81%) as a viscous brown/black oil as a mixture of diastereomers.

Provenance & Evidence