6-Bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole

1231930-29-2

1231930-33-8

The general procedure for the synthesis of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[D]imidazole using (E)-N-(4-bromo-2,6-difluorophenyl)-N'-isopropylacetamidine as starting material was as follows: potassium tert-butanolate (6.9 kg) was added batchwise to a (E)-N-(4-bromo-2,6-difluorophenyl)-N'-isopropylacetamidine (16.2 kg) N-methylformamide (76 kg) solution while controlling the reaction temperature below 30°C. The reaction mixture was heated to 70-75°C until the completion of the reaction was monitored by HPLC. The reaction solution was then cooled to 20-30°C and the reaction was quenched by addition of water (227 kg). Extraction was carried out with methyl tert-butyl ether (37 x 4 kg) and the combined organic phases were washed with brine (49 x 2 kg). The organic phase was concentrated to 25-30 L, n-hexane (64 kg) was added and the resulting slurry was filtered to give 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[D]imidazole (11 kg). Mass spectrum (ES+): m/z = 272 (M + H)+. For further purification, the crude product was dissolved in dichloromethane, filtered through silica gel and Celite pads, and finally recrystallized from a mixed solvent of methyl tert-butyl ether/hexane.