反应详情

In other embodiments, the present invention provides methods of preparing N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamide-dibenzo[b,d]furan-1-carboxamide, as shown in FIG. 1. For example, 4-difluoromethoxy-3-hydroxybenzaldehyde may be reacted with 2-bromo-1-fluoro-4-nitrobenzene in a first solvent comprising potassium fluoride to produce 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde (scheme I). In a second step, the 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde may be cyclized in a second solvent comprising a catalyst to produce 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran (scheme II). In a third step, the 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran may be oxidized in a third solvent comprising an oxidizing agent to produce 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid (scheme III). In a fourth step, 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid may be reacted in a fourth solvent comprising an inorganic acid halide, 4-amino-3,5-dichloropyridine and a first base to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (scheme IV). In a fifth step, N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide may be reduced in the presence of a reducing agent to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide. Suitable reducing agents include, but are not limited to, zinc, indium, iron, tin, Raney-nickel and sodium borohydride. In a sixth step, the N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide may be reacted in a fifth solvent comprising methanesulfonyl chloride and a second base to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide)dibenzo[b,d]furan-1-carboxamide.

1. customIn other embodiments, the present invention provides