Regioisomerism in the Synthesis of a Chiral Aminotetralin Drug Compound: Unraveling Mechanistic Details and Diastereomer-Specific In-Depth NMR Investigations

Abstract

During chemical process development of a novel 2-aminotetralin derivative intended for use as an antidepressant, scrutiny of the byproduct present in the drug molecule revealed a set of regioisomers. Detailed studies showed that this impurity issue originated from an early synthetic step in which a brominated tetralone motif was generated in a ring-closing protocol. It was found that this reaction was accompanied by a migration of the aromatic bromo substituent via different bromonium species along two discrete pathways. This example of the halogen dance reaction resulted in the formation of a series of tetralone impurities with a bromine distributed across all available aromatic positions of the tetralin nucleus. Subsequently, when subjected to reductive amination conditions, each of these tetralones gave rise to pairs of aminotetralins in a diastereomeric relationship. NMR investigations revealed that the alicyclic portion of the compounds thus formed displayed very complex signal patterns, which required further in-depth studies using a variety of sophisticated techniques. As a result, a deep insight into the structural features of the current 2-aminotetralin family was obtained, which is emphasized by the definition of a novel "0.2 ppm rule" allowing the absolute configuration at tetralin C-2 to be determined.

Rapid Detection and Identification of Impurities in Ten 2-Naphthalenamines Using an Atmospheric Pressure Solids Analysis Probe in Conjunction with Ion Mobility Mass Spectrometry

“…these ten naphthalenamines were separately synthesised and each was the main compound in the individual samples. 19 Each sample also contained minor related impurities. the ten target compounds were isomerised either at the position of the bromo and methyl functions or R/S diastereomers of naphthalenamine, such as five (S,S)-BMPNA and five (R,S)-BMPNA regio-isomers.…”

Modeling a halogen dance reaction mechanism: A density functional theory study

“…Halogen dance (HD) reactions are intermolecular rearrangements of halogen substituents on aromatic rings. The reaction class is a useful tool in the synthesis of materials for a range of applications from organic semiconductors to chiral drug scaffolds . HD reactions have been observed for diverse substrates including thiophene, phenyl, furan, thiazole, oxazole, and pyridine units.…”