Hydrochloric Acid → [2-(6-Chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexylacetic acid

Beteiligte Stoffe

Reaktionsschritte

To a solution of (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (1.0 g, 4.1 mmol) in methanol (15 mL) were added cyclohexanecarbaldehyde (0.82 mL, 6.14 mmol, 1.5 equiv.), 6-chloro-nicotinic acid (0.665 g, 4.1 mmol, 1.0 equiv.) and isocyanomethyl-benzene (0.48 mL, 10.24 mmol, 1.0 equiv.) and stirred at rt for 16 h. A solution of 4 M HCl in dioxane (10 mL) was added and the reaction mixture stirred at rt for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was dissolved in a mixture of acetic anhydride (40 ml) and acetic acid (20 ml) and cooled to 0° C. Sodium nitrite (7.4 g, 107 mmol) were added in portions. After the addition the reaction was warmed to rt and stirred for 3 h. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with ethyl acetate. The resulting brown oil was taken up in a mixture of THF:water (3:1, 20 mL) and a pre-prepared solution of LiOH (2.1 g, 48.7 mmol) in hydrogen peroxide (10 mL, 30% solution in water) was added drop wise. The mixture was stirred at rt for 30 min. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 4 by addition of acetic acid and the aqueous layer extracted with ethyl acetate. The intermediate was not further purified but used as crude material for further modification. MS (ES−): 404 (M−H).

Herkunft & Nachweise