Hydrogen Bromide → 2-(2,6-Difluorophenyl)-1-[(2,6-difluorophenyl)methyl]benzimidazol-4-amine

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Reaction Steps

FIG. 9 provides a schematic approach for the preparation of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole substituted with chloro, bromo, nitro, amino, acetylamino, dimethylamino groups at the C-4 position of the benzimidazole ring. In this Figure, “a” comprises 2,6-difluorobenzoyl chloride, pyridine:THF (1:1); “b” comprises AcOH reflux; “c” comprises 2,6-F2-BnBr, NaH,THF; “d” comprises SnCl2, AcOH, HCl; “e” comprises Ac2O, THF; “f” comprises H2CO, NaBH4, H2SO4; and “g” comprises NaNO2, HBr or HCl. As shown in this Figure, reduction of the 4-nitro group of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (Example 83) was accomplished with tin (II) chloride, which gives 4-amino-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole 3300 (Example 85). Compound 3300 was used to prepare 4-bromo-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (Example 86) and 4-chloro-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (Example 87) via the Sandmeyer reactions (i.e., methods known in the art). Monoacylation of compound 3300 with acetic anhydride gave 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetamidobenzimidazole (Example 88), while treatment of 3300 with formaldehyde and sodium borohydride yielded the dimethylamino compound 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-N,N-dimethylaminobenzimidazole (Example 89).

Provenance & Evidence