Unusual (+/-)-electrospray ionization induced fragmentation: Structural elucidation of an in-process synthetic intermediate of doravirine (MK-1439) using liquid chromatography/high-resolution tandem mass spectrometry and two-dimensional nuclear magnetic resonance.
BACKGROUND
During the development of a novel synthetic route to doravirine (1), a human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI), an unanticipated reaction intermediate, methyl (Z)-2-(3-chloro-5-cyanophenoxy)-5-(3-(3-chloro-5-cyanophenoxy)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-ethoxy-3-(trifluoromethyl)pent-2-enoate (2), was isolated. Moreover, an unusual electrospray ionization (ESI)-induced fragmentation was observed for 2. Hence, efforts were made towards the understanding of the structure of 2, which was crucial for the understanding of the reaction mechanism.


METHODS
The isolated impurity was fully characterized by liquid chromatography coupled with high-resolution tandem mass spectrometry (LC/HRMS/MS), hydrogen/deuterium (H/D) exchange, and an ensemble of two-dimensional nuclear magnetic resonance (2D-NMR) techniques. Density functional theory (DFT) calculations were also conducted.


RESULTS
An unusual ESI-induced fragmentation was observed for intermediate 2, giving an ion for half of the molecule in the positive ion mode, with the other half of the molecule affording an ion in the negative ion mode.


CONCLUSIONS
To the best of our knowledge, this unique ESI-induced fragmentation has not been previously reported in the literature. The underlying mechanism was explored and is supported by DFT calculations, which could greatly help the structural characterization of unknown impurities with similar structural features using ESI-MS in the future. Copyright © 2017 John Wiley & Sons, Ltd.
Analytical Research & Development, Merck Research Laboratories, Rahway, NJ, 07065, USA.
Huaming
http://orcid.org/0000-0001-8134-411X
H
Sheng
Process Research & Development, Merck Research Laboratories, Rahway, NJ, 07065, USA.
Katrina W
KW
Lexa
Analytical Research & Development, Merck Research Laboratories, Rahway, NJ, 07065, USA.
Li-Kang
LK
Zhang
Analytical Research & Development, Merck Research Laboratories, Rahway, NJ, 07065, USA.
Rong-Sheng
RS
Yang
Chemical Engineering Research & Development, Merck Research Laboratories, Rahway, NJ, 07065, USA.
Timothy J
TJ
Wright
Process Research & Development, Merck Research Laboratories, Rahway, NJ, 07065, USA.
Benjamin D
BD
Sherry
Analytical Sciences, Merck Research Laboratories, Rahway, NJ, 07065, USA.
Roy
R
Helmy
Analytical Research & Development, Merck Research Laboratories, Rahway, NJ, 07065, USA.
Gary E
GE
Martin