To a 250 mL round-bottom flask was added 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (10.8 g, 37.4 mmol), DMAP (228 mg, 1.87 mmole), and THF (80 mL). The solution was stirred with gentle heating until all the material was fully dissolved. The reaction mixture was then concentrated under vacuum to achieve a final volume of approximately 20 mL. After cooling to room temperature, 4-fluoro-1-isothiocyanato-2-methyl-benzene (9.36 g, 56.0 mmole) was added in one portion, and stirring was continued at room temperature for 12 hours, after which time all the diamine had been converted to the corresponding thiourea as determined by TLC analysis. To the reaction mixture was then added mercuric oxide (12.15 g, 56 mmole) and the resulting slurry stirred at room temperature. The slurry rapidly became black, indicating the formation of mercuric sulfide. After 1 hour, the reaction was complete as determined by TLC analysis. Silica gel was added to the mixture and the resulting thick slurry was filtered through a pad of celite, washing with several volumes of EtOAc. The clear filtrate was concentrated to produce a dark gray solid. To the solid was added diethylether, and the insoluble material was isolated by filtration to provide 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (8.25 g, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.46-7.42 (m, 2H), 7.14 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.06 (td, 1H, J1=2.7 Hz, J2=8.6 Hz), 6.87 (d, 1H, J=8.6 Hz), 4.28-4.19 (m, 2H), 3.95 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.81 (s, 3H), 1.23 (t, 3H, J=7.4 Hz); ESMS (m/z): 423 (M+1)+.
