Degradation products of cyclophosphamide synthesis and structural studies

Article abstract of DOI:10.1080/10426509608545193

The degradation of cyclophosphamide in neutral or slightly acidic aqueous solution starts with an intramolecular alkylation leading to an intermediary bicyclic compound which hydrolyses immediately and exclusively to a nine-membered heterocycle. Subsequent acid-catalyzed hydrolysis of the P-N-bond leads to a phosphoric acid monoester. In strongly acidic solutions (1 N HCl) cyclophosphamide decomposes exclusively to bis(2-chloroethyl)-amine and to the corresponding phosphoric acid monoester H₂N(CH₂)₃OP(O)(OH)₂. In solid samples of cyclophosphamide, heated up to its melting point, the first pathway predominates over the second one. The structures of the phosphorus compounds were established by ¹H and ³¹p NMR spectroscopy, and synthesis. The structure of the bicyclic compound 2 is confirmed by a single crystal X-ray diffraction study which allows an explanation for the selective and immediate hydrolysis with formation of a nine-membered heterocycle and for the absence of the isomer with a six-membered ring.

Full text of DOI:10.1080/10426509608545193

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Phosphorus, Sulfur, and Silicon and
the Related Elements
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Degradation Products of
Cyclophosphamide Synthesis and
Structural studies
Ulf Niemeyer , Bernhard Kutscher , Jürgen Engel , Ion
Neda , Axel Fischer , Reinhard Schmutzler , Peter G.
Jones , Marie-C. Malet-Martino , Véronique Gilard &
Robert Martino
a ASTA Medica AG, D-60314 Frankfurt, Germany
b ASTA Medica AG, D-60314 Frankfurt, Germany
c ASTA Medica AG, D-60314 Frankfurt, Germany
d Institut für Anorganische und Analytische Chemie
der Technischen Universität, Postfach 3329, D-38023
Braunschweig, Germany
e Institut für Anorganische und Analytische Chemie
der Technischen Universität, Postfach 3329, D-38023
Braunschweig, Germany
f Institut für Anorganische und Analytische Chemie
der Technischen Universität, Postfach 3329, D-38023
Braunschweig, Germany
g Institut für Anorganische und Analytische Chemie
der Technischen Universität, Postfach 3329, D-38023
Braunschweig, Germany
h Université Paul Sabatier, 31062 Toulouse, France
i Université Paul Sabatier, 31062 Toulouse, France
j Université Paul Sabatier, 31062 Toulouse, France
Published online: 06 Aug 2008.
To cite this article: Ulf Niemeyer , Bernhard Kutscher , Jrgen Engel , Ion Neda , Axel
Fischer , Reinhard Schmutzler , Peter G. Jones , Marie-C. Malet-Martino , Vronique Gilard &
Robert Martino (1996) Degradation Products of Cyclophosphamide Synthesis and Structural
studies, Phosphorus, Sulfur, and Silicon and the Related Elements, 109:1-4, 473-476, DOI:
10.1080/10426509608545193
To link to this article: http://dx.doi.org/10.1080/10426509608545193

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