Citric Acid → 4,6-Difluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carboxylic acid

Participants

Reaction Steps

To a solution of 4,6-difluoro-5-[4-(1-hydroxy-cyclobutyl)-phenyl]-1H-indole-3-carbaldehyde (37.0 mg, 0.11 mmol) in a mixture of MeCN (2 mL), tert-butanol (1 mL) and water (2 mL) was added sodium phosphate monobasic hydrate (214.0 mg, 1.55 mmol), sodium chlorite (114.0 mg, 1.26 mmol) and 2-methyl-2-butene (1.0 mL, 6.85 mmol). The reaction mixture was stirred at room temperature for 24 hours, acidified with 1N aqueous citric acid solution (1 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting yellow gum was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 60% H2O/40% MeCN in 8.5 min, 60% H2O/40% MeCN linear to 0% H2O/100% MeCN in 0.5 min, HOLD at 0% H2O/100% MeCN to 10.0 min. Flow: 25 mL/min) to afford the title compound (9.4 mg, 24%). MS (ES+) 344.1 (M+H)+. Retention time=2.48 minutes (Waters Atlantis dC18 4.6×50, 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