Acetic Acid → [2-(4-Chloro-2-methyl-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid

Participants

Reaction Conditions

Reaction Steps

N-benzyl-2-[2-(4-chloro-2-methyl-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetamide (3.8 g, 6.508 mmol) were dissolved in 49.3 ml (521.9 mmol) acetic acid anhydride and 24.7 ml (431.5 mmol) acetic acid. The dark brown solution was cooled to 0-5° C. and 2.245 g (32.54 mmol) sodium nitrite were added in four portions within 10 min. After 30 min. the reaction mixture was allowed to warm to room temperature. The reaction mixture was then evaporated, taken up with toluene and evaporated again. The residue was extracted twice ethyl acetate, saturated aqueous sodium bicarbonate solution, water and brine. The organic layers were separated, dried over magnesium sulfate, filtered and evaporated. The crude intermediate was then dissolved in a mixture of tetrahydrofuran and water. To the dark brown solution slowly a solution of lithiumhydroxide monohydrate in 30% aqueous hydrogen peroxide was added dropwise over 20 min (gas evolution, exothermic). The mixture was stirred until all starting material had disappeared. The reaction mixture was then evaporated and the pH of the residue was adjusted to 4 with acetic acid. Ethyl acetate was added, the phases separated and the aqueous layer extracted another time with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated. The residue was taken up in toluene, stirred at 0-5° C. for 15′, the solid was filtered off, washed with cold toluene and dried in vacuum to give the desired compound as a beige solid (54%). MS (ESI): 418.87 (M+).

Provenance & Evidence