engleski

New Method for Preparation of N-Substituted 2-(Hydroxyimino)Acetamides

Current therapy in case of poisoning with organophosphorus (OP) nerve agents and pesticides includes an antimuscarinic drug (e.g., atropine), an anticonvulsant drug (e.g., diazepam), and an acetylcholinesterase (AChE) reactivator of the quaternary pyridinium aldoxime family (pralidoxime, trimedoxime, obidoxime, HI-6, Hlö-7). However, commonly used quaternary pyridinium aldoximes do not cross the blood-brain barrier (BBB) due to their permanent positive charge, thus preventing reactivation of central nervous system (CNS) inhibited AChE. Recently attempts have been made to develop efficient uncharged reactivators, including N-substituted 2-(hydroxyimino)acetamides. Here, we describe method susceptible for preparation of highly functionalized and structurally diverse N-substituted 2-(hydroxyimino)acetamides. The preparation starts with commercially available (E)-3-phenylprop-2-en-1-ol which is easily converted in the 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU) catalyzed reaction into corresponding allyl trichloroacetimidate. The allyl trichloroacetimidate is subsequently submitted to thermal Overman rearrangement to give 2, 2, 2-trichloro-N-(1-phenylallyl)acetamide which is hydrolized under alkaline conditions to 1-phenylprop-2-en-1-amine. Amine group was protected using di-tert-butyl dicarbonate to give tert-butyl (1-phenylallyl)carbamate. Subsequently alkene group underwent hydroboration with 9-borabicyclo[3.3.1]nonane (9-BBN) followed by oxidation of the resulting organoborane with hydrogen peroxide to form anti-Markovnikov alcohol tert-butyl (3-hydroxy-1-phenylpropyl)carbamate. Alcohol moiety was converted to the azide moiety with diphenyl-phosphoryl azide (DPPA) in the presence of DBU. Treatment of the resulting N-protected amine with triflouroacetic acid (TFA) gave 3-azido-1-phenylpropan-1-amine. Finally, amidation of ethyl glyoxylate oxime with 3-azido-1-phenylpropan-1-amine yielded the final product N-(3-azido-1-phenylpropyl)-2-(hydroxyimino)acetamide. The prepared N-(3-azido-1-phenylpropyl)-2-(hydroxyimino)acetamide can be further structurally modified since azide moiety can undergo extremely reliable Cu(I) catalyzed Huisgen dipolar cycloaddition of azides and alkynes, thus enabling implementation of various structural elements with different functional groups. This is of utmost importance in order to develop new efficient uncharged AChE reactivators.

acetylcholinesterase; 2-(hydroxyimino)acetamides; Overman rearrangement

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