Nucleophilic Aromatic Substitutions of 2-Halo-5-(sulfamoyl)benzoic Acids and N,O-Bis-alkylation via Phase Transfer Catalysis: Synthesis of RoRγ Inverse Agonist GSK2981278A

GSK2981278A ( 1 ) is a RORγ inverse agonist used as a potential topical nonsteroidal therapy for psoriasis. New synthesis of 1 was developed based on a S N Ar reaction of (tetrahydro-2 H -pyran-4-yl)methanol with an aryl halide intermediate, prepared from 2-halobenzoic acids. The dianion underwent in situ N, O -bis-isobutylation, followed by a reduction to provide 1 . The new route eliminated a genotoxic tosylate of (tetrahydro-2 H -pyran-4-yl)methanol and a difficult reductive amination from the original synthesis starting from methyl salicylate. A primary version of the route has been scaled up to deliver 125 kg of 1 . However, the heating of a strong base in DMSO for an extended period during the bis-alkylation was found to be a safety concern for manufacturing. A safer and greener process was then developed utilizing a facile N, O -bis-alkylation, which was conducted under phase transfer conditions with mild bases such as potassium carbonate and in green solvents such as water. The concise four stage sequence from 2-halobenzoic acids to GSK2981278A ( 1 ) had an overall yield of 41%.