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Unusual (+/-)-Electrospray Ionization Induced Fragmentation: Structural Elucidation of an In-process Synthetic Intermediate of Doravirine (MK-1439) Using LC/HRMS/MS and 2D-NMR.

Unusual (+/-)-Electrospray Ionization Induced Fragmentation: Structural Elucidation of an In-process Synthetic Intermediate of Doravirine (MK-1439) Using LC/HRMS/MS and 2D-NMR.
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Sheng H, Lexa KW, Zhang LK, Yang RS, Wright TJ, Sherry BD, Helmy R, Martin GE,


Sheng H, Lexa KW, Zhang LK, Yang RS, Wright TJ, Sherry BD, Helmy R, Martin GE, (click to view)

Sheng H, Lexa KW, Zhang LK, Yang RS, Wright TJ, Sherry BD, Helmy R, Martin GE,

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Rapid communications in mass spectrometry : RCM 2017 02 07() doi 10.1002/rcm.7833

Abstract
RATIONALE
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, the unusual 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 2D-NMR techniques. DFT calculation was also conducted.

CONCLUSIONS
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 ionization mode. To the best of our knowledge, this unique ESI-induced fragmentation had not been previously reported in the literature. The underlying mechanism was explored and is supported by DFT calculation, which could greatly help the structural characterization of unknown impurities with similar structural features using ESI-MS in the future.

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