Synthesis of some fluorine-containing pyridinealdoximes of potential use for the treatment of organophosphorus nerve-agent poisoning

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• 作者：Christopher M. Timperley^a ; ^{cmtimperley@dstl.gov.uk"" rel=""nofollow} ; R. Eric Banks^b ; ¹ ; Ian M. Young^b ; ¹ ; Robert N. Haszeldine^b ; ¹
• 关键词：Fluoropyridines ; Fluorinated pyridinecarboxaldehydes ; Nerve agent ; Oximes ; 2-PAM ; Sarin
• 刊名：Journal of Fluorine Chemistry
• 出版年：2011
• 出版时间：August 2011
• 年：2011
• 卷：132
• 期：8
• 页码：541-547
• 全文大小：820 K

文摘

Fluoroheterocyclic aldoximes were screened as therapeutic agents for the treatment of anticholinesterase poisoning. 2-Fluoropyridine-3- and -6-aldoxime, and 3-fluoropyridine-2- and -4-aldoxime, were synthesised. Attempts to obtain 3,5,6-trifluoropyridine-2,4-bis(aldoxime) and -2-aldoxime, however, proved unsuccessful. Pentafluorobenzaldoxime was prepared by oximation of pentafluorobenzaldehyde. Acid dissociation constants (pK_a) and second-order rate constants (k_ox−) of the fluorinated pyridinealdoximes towards sarin were measured. 2,3,5,6-Tetrafluoropyridine-4-aldoxime had the best profile: its k_ox− approached that of the therapeutic oxime P2S (310 vs. 120 l mol⁻¹ min⁻¹), but its higher pK_a (9.1 vs. 7.8) fell short of the target figure of 8 required for reactivation of inhibited acetylcholinesterase in vivo. N-alkylation of the fluorinated pyridine-aldoximes may reduce their pK_a nearer to 8 and enhance their therapeutic potential.