694-03-1Relevant articles and documents
The partitioning of phosphoramide mustard and its aziridinium ions among alkylation and P-N bond hydrolysis reactions
Shulman-Roskes, Ellen M.,Noe, Dennis A.,Gamcsik, Michael P.,Marlow, Allison L.,Hilton, John,Hausheer, Frederick H.,Colvin, O. Michael,Ludeman, Susan M.
, p. 515 - 529 (2007/10/03)
NMR (1H and 31P) and HPLC techniques were used to study the partitioning of phosphoramide mustard (PM) and its aziridinium ions among alkylation and P-N bond hydrolysis reactions as a function of the concentration and strength of added nucleophiles at 37 °C and pH 7.4. With water as the nucleophile, bisalkylation accounted for only 10-13% of the product distribution given by PM. The remainder of the products resulted from P-N bond hydrolysis reactions. With 50 mM thiosulfate or 55-110 mM glutathione (GSH), bisalkylation by a strong nucleophile increased to 55- 76%. The rest of the PM was lost to either HOH alkylation or P-N bond hydrolysis reactions. Strong experimental and theoretical evidence was obtained to support the hypothesis that the P-N bond scission observed at neutral pH does not occur in the parent PM to produce nornitrogen mustard; rather it is an aziridinium ion derived from PM which undergoes P-N bond hydrolysis to give chloroethylaziridine. In every buffer studied (bis-Tris, lutidine, triethanolamine, and Tris), the decomposition of PM (with and without GSH) gave rise to 31P NMR signals which could not be attributed to products of HOH or GSH alkylation or P-N bond hydrolysis. The intensities of these unidentified signals were dependent on the concentration of buffer.
Chemistry of N-phosphorylated nitrogen mustards: The effect of a second nitrogen substituent at phosphorus on the stability of the system
Wan, Huijie,Modro, Tomasz A.
, p. 155 - 168 (2007/10/03)
Methyl N,N-diethyl-N′N′-bis(2-chloroethyl)phosphoramidate was prepared as a precursor for the corresponding phosphordiamidate anion, a model for the phosphoramidate mustard, biologically active degradation product of cyclophosphamide drug. Demethylation of the precursor led to a highly unstable ion which underwent spontaneous fragmentation. In the absence of an external nucleophile, the ion decomposed yielding metaphosphoramidate and N-substituted ethyleneimine as primary intermediates. In the presence of pyridine, bis-alkylation of two pyridines took place yielding bis [2-(N-pyridinio)ethyl]amine dication, in addition to some 1,3,2-oxazaphospholidine derivative, formed via the competitive 1,5-cyclization of the demethylated anion. Incubation of the precursor in the presence of thiophenol/triethylamine resulted in two parallel nucleophilic displacements: (i) the O-demethylation followed by bisalkylation of two molecules of thiophenol, together with some 1,5-cyclization; (ii) initial direct displacement of the chlorine at the β-carbon of the precursor, followed by the fragmentation of the system. It is concluded that the electron-rich ionic phosphoramidate substituent, -O(R2N)P(O), highly activates the N-(2-chloroethyl) functional group in alkylation reactions.
