Potassium Carbonate → 5-(4-(1-Acetylpiperidin-4-yl)phenyl)-6-chloro-1H-indazole-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (110 mg, 0.32 mmol), oven dried potassium acetate (139 mg, 1.41 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (26 mg, 0.032 mmol), and 1-(4-(4-bromophenyl)piperidin-1-yl)ethanone (86 mg, 0.30 mmol) in 1,4-dioxane (3.1 mL) was degassed with N2 for 10 minutes, and subjected to microwave irradiation at 115° C. for 1 hour. The cooled reaction mixture was filtered through cotton and concentrated in vacuo to give a dark solid. To the dark solid was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (68.9 mg, 0.25 mmol), 2N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (20.4 mg, 0.025 mmol). The reaction mixture was diluted with degassed toluene (0.8 mL) and EtOH (0.8 mL), sealed in a pressure tube and heated at 100° C. for 1 hour then 75° C. for an additional 16 hours. The cooled reaction mixture was concentrate in vacuo, and the residue was partitioned between 0.5N HCl (14 mL) and EtOAc (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×8 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting reddish solid was purified by reverse phase HPLC Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 85.0% H2O/15.0% MeCN linear to 65.0% H2O/35.0% MeCN in 10.5 min, 65.0% H2O/35.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to give the title compound (14.4 mg, 15% yield). MS (ES+) 398.2 (M+H)+. Retention time=2.55 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Provenance & Evidence