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).

Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes

“…The desired product 73 was obtained in only 16% yield after column chromatographic purification. In order to identify the regioselective conditions for the preparation of 73 128 The medicinal route leveraged N-oxide to direct selectivity during the S N Ar coupling of 77 and 78 to afford the desired diaryl ether 80 in 70% yield over the two steps of S N Ar and reduction of the N-oxide intermediate 79. However, process safety evaluation of the N-oxide intermediate 77 revealed an exothermic decomposition event with an onset temperature of 98 °C and total energy release of −806 J/g, which presented potential safety risks for large-scale practice.…”

When SMILES Smiles, Practicality Judgment and Yield Prediction of Chemical Reaction via Deep Chemical Language Processing

“…O RGANIC reaction including addition reactions [1], elimination reaction [2], substitution reactions [3]- [5], pericyclic reactions [6], rearrangement reactions [7], [8], redox reaction [9] have been studied for hundreds of years. Owing to the development of organic methodology [10], hundreds of millions of reactions have been practiced, and more and more compounds have been produced.…”

A Practical, One-Pot Synthesis of Sulfonylated Pyridines

“…As shown in eq , simply heating chloropyridine 1 with sulfinate 2 in the presence of a catalytic amount TBACl in DMAc at 100 °C for 3 h afforded pyridine 3 in 93% isolated yield . In the absence of TBACl, conversion was <20% at the same time point . We speculated that the significant rate increase in the presence of TBACl could be explained by the formation of n -Bu 4 NSO 2 Tol from TBACl and NaSO 2 Tol. , In order to probe this possibility, we prepared n -Bu 4 NSO 2 Tol and subjected it to the reaction with 1 .…”