Hydrochloric Acid → 6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

Participants

Reaction Conditions

Reaction Steps

To 1-bromo-2,4,6-trifluorobenzene (0.02 ml, 0.16 mmol) in diethyl ether (0.52 mL) at −78° C. was added n-butyllithium (0.12 mL, 0.18 mmol, 1.6 M in hexanes). After 30 minutes, tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.10 mmol) in diethyl ether (1 mL) was added drop-wise to the reaction. After 60 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (3.5 mL) was added hydrochloric acid (0.35 mL, 1.4 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (40-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a white solid.

Provenance & Evidence