Hydrochloric Acid → Trifluoroacetic acid

Participants

Reaction Steps

A vial was charged with copper (I) chloride (1.7 mg, 0.017 mmol), cesium carbonate (55.0 mg, 0.169 mmol), 4-chlorophenol (21.7 mg, 0.169 mmol), and the title compound from Example 5 Step A (50.0 mg, 0.084 mmol). 2,2,6,6-Tetramethyl-3,5-dione (0.007 mL, 0.034 mmol) was added and the mixture was flushed with nitrogen. Degassed N-methylpyrrolidinone (0.170 mL) was added, and the vial was capped and placed in a pre-heated oil bath (120° C.). After 15 h, the mixture was allowed to cool to ambient temperature, then was filtered through a short plug of silica gel with DCM and concentrated in vacuo: LCMS m/z 594.3 [M+H]+. To a solution of the unpurified coupling product in 1,4-dioxane (1 mL) was added lithium hydroxide (0.5 mL, 2.0 M in water, 1.00 mmol), and the resulting mixture was stirred at 50° C. After 30 min, the reaction mixture was rendered acidic by addition of aqueous hydrochloric acid, then was diluted with dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (50 to 100% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 564.4 [M−H]−; 1H NMR (500 MHz, d6-DMSO) δ 8.27 (s, 1H), 8.15-8.09 (m, 2H), 7.74 (dd, J=8.0, 2.0 Hz, 1H), 7.70 (dd, J=7.5, 1.0 Hz, 1H), 7.47-7.42 (m, 4H), 7.29 (d, J=8.0 Hz, 2H), 7.12-7.09 (m, 2H), 7.04-7.00 (m, 3H), 5.22 (s, 2H).

Provenance & Evidence