Triazene drug metabolites. Part 14. Kinetics and mechanism of the acid-catalysed hydrolysis of 3-alkoxymethyl-3-alkyl-1-aryltriazenes

Triazene: vielseitige Verbindungen für die organische Synthese

“…Die Arbeitsgruppen von Vaughan [40,41] und Rosa [42,43] haben eine Vielzahl von Hydroxymethyltriazen-Derivaten hergestellt und hinsichtlich der Entwicklung von Wirkstoffvorstufen untersucht. Rosa und Mitarbeiter entwickelten eine allgemeine Synthesemethode f¸r diese Stoffklasse.…”

“…Rosa und Mitarbeiter entwickelten eine allgemeine Synthesemethode f¸r diese Stoffklasse. [43] In den meisten F‰llen erh‰lt man die Produkte problemlos und in hoher Ausbeute. [44] Die Verwendung von DMF als Lˆsungsmittel verbessert die Ausbeuten und ermˆglicht den Einsatz weniger best‰ndiger Alkohole.…”

“…Dabei wird durch Abspaltung von Wasser in saurer Lˆsung das Iminiumion gebildet, das von einem Alkohol nucleophil angegriffen wird. [43] [43] In den meisten F‰llen erh‰lt man die Produkte problemlos und in hoher Ausbeute.…”

The Mechanism of Hydrolysis of Aryl Ether Derivatives of3‐Hydroxymethyltriazenes

“…[6] Among the derivatives of 2 studied are esters, [7,8] particularly more recently the "cascade release molecules" that concomitantly target DNA and epidermal growth factor receptor tyrosine kinase, [9] and alkyl ethers. [10,11] Our investigations of the hydrolysis of 3-alkyloxymethyl-3-alkyl-1-aryl-tion of the protonated intermediate proceeds via a triazenyliminium ion that can be trapped by methanol. The generalacid-catalysed process exhibits an SDIE of 1.43 and Hammett ρ values of 0.49, 0.84 and 1.0 for reactions catalysed by chloroacetic, formic and acetic acids, respectively.…”

“…triazenes 4 showed these compounds to behave like acetals of formaldehyde, hydrolysing in aqueous buffers by forma-tion of a triazenyliminium ion intermediate by a specificacid-catalysed pathway. [11] However, in general, the alkoxymethyltriazene derivatives 4 are too stable toward hydrolysis and metabolism [12] to be considered satisfactory prodrugs. Acetals that contain a phenolic or other weakly basic leaving group undergo hydrolysis more readily; for such compounds, as well as the specific-acid-catalysed reaction observed for the alkyl analogues, general acid catalysis and pH-independent processes have been observed.…”