A mass spectral study of cyclophosphamide concerning a thermally induced rearrangement reaction

Abstract

The electron impact mass spectra of cyclophosphamide (1) are very sensitive towards experimental conditions in view of the kind of sample handling, the type of mass spectrometer used and the temperature of evaporation. The reason for this phenomenon is the elimination of HCl from the molecular ion by a specific 1,5-hydrogen transfer yielding an ion at m/z 224 which is structurally related to the bicyclic compound 4 with its typical fragment ions at m/z 175 and 147. Thermal excitation of the sample increases the intensity of this fragmentation pathway. The fragmentation pattern of 1 and the thermally induced rearrangement reaction has been elucidated by means of isotopic labelling, high-resolution data, metastable ion analysis and some tandem mass spectrometric experiments. Various samples of 1 monohydrate and its commercially available preparations, which are triturates with sodium chloride, differing in the crystal size distribution, showed nearly identical mass spectra on two different magnetic mass spectrometers, provided that the materials were introduced as solids under careful control of the evaporation temperature. The fragmentation via m/z 224 prevails in case of non-crystalline, pre-dissolved samples on one of the instruments used which might be explained by a differing construction of the ion source and the sample cup holder. The conclusions of Mruzek et al. concerning different proportions of stereoisomers in pharmaceutical preparations of 1 lack any analytical evidence.

Selective Gas Adsorption and Unique Structural Topology of a Highly Stable Guest‐Free Zeolite‐Type MOF Material with N‐rich Chiral Open Channels

“…, or, if they are present, they have very low RA s. In the linear and angular isoquinoline derivatives, the ionization occurs on the aromatic moiety (Scheme ). Compounds 8 ( n = 2, R  N(CH 2 CH 2 Cl) 2 ) behaved as expected on the basis of the earlier findings,7, 8, 22–24 with the exception that the cyclophosphamide derivatives discussed here exhibited relatively abundant M + . ( 8a : m/z 315/317 RA = 17/11% and 8b : 8/5%) ions and very weak [M–CH 2 Cl] + ( 8a : m/z 266/268, RA = 2/0.7% and 8b : 0.7/0.1%) ions.…”

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.…”

Tandem mass spectrometric analysis of cyclophosphamide, ifosfamide and their metabolites

“…The molecular ion was seldom observed due to the presence of the N‐mustard. Busker et al 6. studied the fragmentations of CP under EI conditions, and found that the initial fragment ion at m/z 224 was formed by 1,5‐elimination of HCl followed by loss of chloromethylene to generate the most abundant fragment ion at m/z 175.…”