A mass spectral study of cyclophosphamide with special reference to differences in isomeric structures

Abstract

Mass spectrometric fragmentation of cyclophosphamide (CP) has been studied in detail using linked field scanning, isotope labelling, low energy ionization and accurate mass measurements. The molecular ion is of low abundance and it favours loss of HCl and .CH,CI to form the base peak at m / z 211. All the other ions are formed by sequential fragmentation processes. The direct bond rupture between phosphorus and the N-chloroethyl group produces two ions m/z 120 and m / z 92. The ion m / z 56 is a triplet. Many of the ions in the spectrum are produced by several competing pathways. Several of the rearrangement mechanisms involve a single hydrogen transfer.Quantitative differences between two commercial C P preparations were observed in the linked field scanning spectra. Differences in the abundances of the metastable ions strongly suggest that there is an intense isomeric competition in the decomposition pathways. The experimental evidence supports the conclusion that the two CP preparations differ in their isomeric composition and these differences are related to their stereoisomers. The rates of the individual fragmentation pathways are dependent upon the isomeric structure of the parent molecule and might also be reflected by different rates of metabolism of the isomers of the drug in uiuo.

Electron ionization mass spectra of phosphorus‐containing heterocycles. II. 1,2,3,4,4a,5,6,7,8,8a‐decahydro‐1,3,2‐benzodiazaphosphinine 2‐oxides

“…In addition to the common primary fragments already discussed, compounds 14 – 17 (as reported earlier for cyclophosphamide and its derivatives3, 15, 16 and their 3,1,2‐O,N,P analogs1) gave the ions [M–CH 2 Cl] + , [M–HClCH 2 Cl] + and [M–HCl] + . with variable abundances (Table 4), the first of these often being the most abundant; this is comparable with the situation for the 1,4,4a,5,6,7,8,8a‐2 H ‐3,1,2‐benzoxazaphosphinine 2‐oxides, which practically did not give the second ion at all 1.…”

“…Comparisons are also made with the results on the corresponding 3,1,2‐O,N,P derivatives discussed earlier 1. While the ring system in the 1,3,2‐N,N,P compounds is of pharmacological importance, as revealed by their anticancer2 and immunosuppressant3 properties, the 1,3,2‐N,N,P analogs of cyclophosphamide do not possess significant anticancer activity 4…”

Molecular Evolution Using Intramolecular Acyl Migration on myo‐Inositol Benzoates with Thermodynamic and Kinetic Selectors

“…at m/z 345 and [M–R 1 PO 2 H] + at m/z 294 were observed. The [M–R 1 PO 2 H] + fragment ion of compounds 1 – 4 is already known from the mass spectra of the 1,3,4,2‐oxadiazaphosphinane 2‐oxides and 3,1,2‐O,N,P‐heterocycles,27b and other simple cyclophosphamides 17. This kind of elimination is important for stereochemical reasons and will be discussed later.…”

“…The mass spectral fragmentation of substituted pyrimido[6,1‐ a ]isoquinolin‐2‐ones14 and oxazino[4,3‐ a ]isoquinolines15 under electron ionization (EI) were studied in detail by the analysis of metastable ions, by the collision‐induced dissociation technique and by exact mass measurements. The EI‐induced fragmentation of N,N ‐ bis (2‐chloroethyl)‐substituted 1,3,2‐oxazaphoshorine‐2‐amine‐2‐oxide and 1,3,2‐oxazaphospholo‐2‐amine‐2‐oxide16 were examined by high‐resolution mass spectrometry and metastable ion analysis 17–19. The fragmentation of phenyl‐ and phenoxy‐substituted 5,5‐dimethyl‐2‐oxo‐1,3,2‐dioxaphosphorines was studied in detail on the basis of the mass spectra of deuterated compounds and high mass resolution studies 20, 21.…”

“…As already mentioned ( vide supra ), the mass spectra of these classes of compounds (especially the cyclophosphamides and hetero‐isoquinoline derivatives)12–22 have previously been studied in detail. Therefore, in the present study, special attention was paid to the influence of the size (five‐ or six‐membered) of the condensed heterocyclic ring moiety, to the effect of changing [4,3‐ a ]‐ to [3,4‐ b ]‐connectivity and to the effect of changing P(O)‐R 1 for SO [R 1 = Ph or N(CH 2 CH 2 Cl) 2 ] substitution on the initial losses in the fragmentation patterns of 1 – 17 .…”