Practical Large-Scale Synthesis of 6-Bromo-2-naphthylmethanesulfonamide Using Semmler–Wolff Reaction

Abstract

A practical, scalable synthetic process for a sulfonamide was developed featuring a Semmler–Wolff aromatization as the key step. The optimized reaction conditions using HCl in HOAc give directly the desired naphthylamine in high yield as opposed to a naphthylacetamide commonly formed in the Semmler–Wolff reactions. One little known byproduct of anomalous rearrangement, ketoamine, was observed and a mechanism proposed to explain its formation. Employing the optimized process, 360 kg was prepared to support drug development.

Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor

“…18 As a result, a second route to 19 employing Semmler− Wolff chemistry was developed. 19 Although significantly longer, this reaction sequence was not corrosive to the reactor components.…”

“…While this chemistry led to the shortest route conceivable for 19 , the highly corrosive nature of the reaction rendered it untenable for long-term use . As a result, a second route to 19 employing Semmler–Wolff chemistry was developed . Although significantly longer, this reaction sequence was not corrosive to the reactor components.…”

Recent Advances in Molecule Synthesis Involving C-C Bond Cleavage of Ketoxime Esters

“…Ketone-derivated oxime esters have been widely used in the field of organic synthesis [ 10 , 11 , 12 , 13 ]. Among them, one of the most important aspects is the application in the construction of nitrogen heterocyclic compounds [ 14 , 15 ].…”