title: NMR strategies to support medicinal chemistry workflows for primary structure determination.
abstract: Central to drug discovery is the correct characterization of the primary structures of compounds. In general, medicinal chemists make great synthetic and characterization efforts to deliver the intended compounds. However, there are occasions which incorrect compounds are presented, such as those reported for Bosutinib and TIC10. This may be due to a variety of reasons such as uncontrolled reaction schemes, reliance on limited characterization techniques (LC-MS and/or 1D 1H NMR spectra), or even the lack of availability or knowledge of characterization strategies. Here, we present practical NMR approaches that support medicinal chemist workflows for addressing compound characterization issues and allow for reliable primary structure determinations. These strategies serve to differentiate between regioisomers and geometric isomers, distinguish between N- versus O-alkyl analogues, and identify rotamers and atropisomers. Overall, awareness and application of these available NMR methods (e.g. HMBC/HSQC, ROESY and VT experiments, to name only a few) should help practicing chemists to reveal chemical phenomena and avoid mis-assignment of the primary structures of compounds.
authors.affiliation: Université du Québec, INRS-Institut Armand-Frappier, 531, Boulevard des Prairies, Laval H7V 1B7, Canada; NMX Research and Solutions Inc., 500 Cartier Ouest, Laval H7V 5B7, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Oguadinma
authors.affiliation: Université du Québec, INRS-Institut Armand-Frappier, 531, Boulevard des Prairies, Laval H7V 1B7, Canada; NMX Research and Solutions Inc., 500 Cartier Ouest, Laval H7V 5B7, Canada.
authors.forename: Francois
authors.initials: F
authors.lastname: Bilodeau
authors.affiliation: Université du Québec, INRS-Institut Armand-Frappier, 531, Boulevard des Prairies, Laval H7V 1B7, Canada; NMX Research and Solutions Inc., 500 Cartier Ouest, Laval H7V 5B7, Canada. Electronic address: stevenrlaplante@gmail.com.
authors.forename: Steven R
authors.initials: SR
authors.lastname: LaPlante
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000814:Aniline Compounds; D009570:Nitriles; D011804:Quinolines; C471992:bosutinib
keywords: Medicinal chemistry; NMR methods; Primary structure; Regioisomers; Rotamers