title: Structure Elucidation of Poly-Faldaprevir: Polymer Backbone Solved Using Solid-State and Solution Nuclear Magnetic Resonance Spectroscopy.
abstract: A large-scale synthesis of the hepatitis C virus drug Faldaprevir revealed precipitation of an unknown insoluble solid from methanol solutions of the drug substance. The unknown impurity was determined to be a polymer of Faldaprevir based on analytical methods that included size exclusion chromatography in combination with electrospray ionization mass spectrometry, solution nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization-time of flight, ultracentrifugation, elemental analysis, and sodium quantitation by atom absorption spectroscopy. Structure elucidation of the polymeric backbone was achieved using solid-state NMR cross-polarization/magic angle spinning (CP/MAS), cross polarization-polarization inversion, and heteronuclear correlation (HETCOR) experiments. The polymerization was found to occur at the vinyl cyclopropane via a likely free radical initiation mechanism. Full proton and carbon chemical shift assignments of the polymer were obtained using solution NMR spectroscopy. The polymer structure was corroborated with chemical synthesis of the polymer and solution NMR analysis.
authors.affiliation: Material and Analytical Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877. Electronic address: nina.gonnella@boehringer-ingelheim.com.
authors.forename: Nina C
authors.initials: NC
authors.lastname: Gonnella
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Busacca
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
authors.forename: Anjan
authors.initials: A
authors.lastname: Saha
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
authors.forename: Jiang-Ping
authors.initials: JP
authors.lastname: Wu
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
authors.forename: Guisheng
authors.initials: G
authors.lastname: Li
authors.affiliation: Material and Analytical Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
authors.forename: Mark
authors.initials: M
authors.lastname: Davis
authors.affiliation: Material and Analytical Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
authors.forename: Thomas
authors.initials: T
authors.lastname: Offerdahl
authors.affiliation: Information Technology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
authors.forename: Paul-James
authors.initials: PJ
authors.lastname: Jones
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Herfurth
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Reddig
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Niemann
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Werthmann
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Grupe
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Roos
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: Gaby
authors.initials: G
authors.lastname: Reckzügel
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ding
mesh_terms: D000621:Aminoisobutyric Acids; D007930:Leucine / Q000031:analogs & derivatives; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D015394:Molecular Structure; D009842:Oligopeptides / Q000032:analysis / Q000737:chemistry*; D011108:Polymers / Q000032:analysis / Q000737:chemistry*; D011392:Proline / Q000031:analogs & derivatives; D011804:Quinolines; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013844:Thiazoles / Q000032:analysis / Q000737:chemistry*
chemical_list: D000621:Aminoisobutyric Acids; D009842:Oligopeptides; D011108:Polymers; D011804:Quinolines; D013844:Thiazoles; C552340:faldaprevir; D011392:Proline; D007930:Leucine
keywords: NMR spectroscopy; mass spectrometry; polymers; solid-state NMR; structure