Improved chemical synthesis, identification and evaluation of prospective centrally active oxime antidotes for the treatment of nerve agent exposure

Valdez, Carlos A.; Lam, Doris; Lao, Victoria; Subramanian, Alagu; Enright, Heather A.; Malfatti, Michael A.; Be, Nicholas A.; Dreyer, Mark L.

doi:10.1016/j.tet.2023.133598

Improved chemical synthesis, identification and evaluation of prospective centrally active oxime antidotes for the treatment of nerve agent exposure

Journal Article · Wed Aug 09 00:00:00 EDT 2023 · Tetrahedron

DOI:https://doi.org/10.1016/j.tet.2023.133598· OSTI ID:2204940

Valdez, Carlos A. ^[1]; Lam, Doris ^[1]; Lao, Victoria ^[1]; Subramanian, Alagu ^[1]; Enright, Heather A. ^[1]; Malfatti, Michael A. ^[1]; Be, Nicholas A. ^[1]; ^[1]

Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

In this study, an improved method for the synthesis of hydroxyiminoacetamide-based oximes, compounds rhat hold great promise as centrally-active nerve agent antidotes, is described. The method involves the coupling of hydroxyiminoacetic acid to various amines in the presence of HOBT or HATU and diisopropylcarbodiimide. The optimized protocol was found to work effectively for the coupling with amines to the activated form of the hydroxyiminoacetic acid with yields ranging between 84 and 90% for primary amines, 65–75% for α-substituted and cyclic amines, while producing decent 41–48% yields for the sterically hindered α,α-substituted amines, that can not be obtained using the previously established method.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); Defense Threat Reduction Agency (DTRA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 2204940

Alternate ID(s):: OSTI ID: 1995829

Report Number(s):: LLNL--JRNL-851875; 1078118

Journal Information:: Tetrahedron, Journal Name: Tetrahedron Journal Issue: 7 Vol. 144; ISSN 0040-4020

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Amide-coupling
Blood brain barrier
Nerve agent
Oximes
Reactivators

Improved chemical synthesis, identification and evaluation of prospective centrally active oxime antidotes for the treatment of nerve agent exposure

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