Preparation of a Corticotropin-Releasing Factor Antagonist by Nucleophilic Aromatic Substitution and Copper-Mediated Ether Formation

Abstract

Several synthetic approaches to a corticotropin-releasing factor (CRF) antagonist containing a tetrasubstituted pyridine were evaluated. In particular, nucleophilic aromatic substitutions on 2,4-dichloropyridine derivatives were attempted using 2,6-dimethyl-4-chlorophenol (4), (S)-2-aminobutanol (7), and several sulfur nucleophiles. It was found that a copper-mediated coupling of a phenoxymesylate (26) was preferred for preparation of the diarylether followed by nucleophilic aromatic substitution to introduce the amine side chain, affording the desired drug candidate (1) in two steps from the commercially available methyl 2,4-dichloro-6-methylnicotinate (2).