title: Labeled oxazaphosphorines for applications in mass spectrometry studies. 2. Synthesis of deuterium-labeled 2-dechloroethylcyclophosphamides and 2- and 3-dechloroethylifosfamides.
abstract: The prodrugs cyclophosphamide (CP) and ifosfamide (IF) each metabolize to an active alkylating agent through a cytochrome P450-mediated oxidation at the C-4 position. Competing with this activation pathway are enzymatic oxidations at the exocyclic α and α' carbons, which result in dechloroethylation of CP and IF. The incidence of oxidation at one position relative to another is believed to be at least one factor underlying the high degree of interpatient variability in both CP and IF pharmacokinetics. As standards for the mass spectrometry quantification of dechloroethylation, the following were synthesized: (1) [4,4,5,5-(2) H4 ]-2-dechloroethylcyclophosphamide (equivalent to [4,4,5,5-(2) H4 ]-3-dechloroethylifosfamide); (2) [α,α,4,4,5,5-(2) H6 ]-2-dechloroethylcyclophosphamide (equivalent to [α,α,4,4,5,5-(2) H6 ]-3-dechloroethylifosfamide); and (3) [α,α,4,4,5,5-(2) H6 ]-2-dechloroethylifosfamide. The common precursor to all of the target compounds was [2,2,3,3-(2) H4 ]-3-aminopropanol. A one-pot reaction of this compound with POCl3 and unlabeled or labeled 2-chloroethylamine hydrochloride gave the d4 and d6 labeled 2-dechloroethylcyclophosphamides. The construction of the 2-dechloroethylifosfamide from the aminopropanol required five discreet steps. Optimization of the synthetic pathways and stability studies are discussed.
authors.affiliation: Duke Comprehensive Cancer Center and Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Springer
authors.forename: O Michael
authors.initials: OM
authors.lastname: Colvin
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ludeman
mesh_terms: D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D003903:Deuterium / Q000737:chemistry*; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D007553:Isotope Labeling; D013058:Mass Spectrometry / Q000379:methods
chemical_list: C064445:dechloroethylcyclophosphamide; D003520:Cyclophosphamide; D003903:Deuterium; C038007:dechloroethylifosfamide; D007069:Ifosfamide
keywords: dechloroethylcyclophosphamide; dechloroethylifosfamide; deuterium; synthesis