Synthesis of [3H,33P]-phosphoramide and -isophosphoramide mustards and metabolites [3H]-chloroethylaziridine and -aziridine for studies of DNA alkylation

Autor: O. Michael Colvin, Susan M. Ludeman, James B. Springer
Rok vydání: 2007
Předmět:
Zdroj: Journal of Labelled Compounds and Radiopharmaceuticals. 50:79-84
ISSN: 1099-1344
0362-4803
Popis: Reduction of diethyliminodiacetate with [ 3 H]-LiAlH 4 and then reaction with SOCl 2 gave bis(2-chloro-2-[ 3 H] ethyl)amine hydrochloride. This compound, together with [ 33 P]-phosphorus oxychloride, provided for the synthesis of [ 3 H, 33 P]-phosphoramide mustard (as its cyclohexylammonium salt) in three steps over 2 days. Similarly, 2-[ 3 H]-ethanolamine was reacted with SOCl 2 to give 2-chloro-2-[ 3 H]-ethylamine hydrochloride which, along with [ 33 P]-POCl 3 , was used to synthesize [ 3 H, 33 P]-isophosphoramide mustard in two steps over 1 day. 1 H NMR studies were carried out to determine optimal times for in situ formation and storage of chloroethylaziridine and aziridine. A solution of 10 mM bis(2-chloroethyl)amine hydrochloride in 0.1M phosphate/D 2 O, pD 7.9 at 37°C for 3h gave chloroethylaziridine without contamination by starting material or hydrolysis products. For aziridine, the disappearance of 0.2 M 2-chloroethylamine hydrochloride in 2 M NaOD/D 2 O at pD 14, 37°C, gave κ = 0.00455 min -1 (R 2 = 1.000) and τ 1/2 = 2.55 h; no hydrolysis product was observed over the course of the NMR experiment (4 h). It was concluded that ∼ 13 h (5 half-lives) of reaction time would yield a solution of aziridine which was relatively free of contaminants. Using these reaction conditions, 3 H-labeled chloroethylamines were used to synthesize 1-(2-chloro-2-[ 3 H]-ethyl)-2-[ 3 H]-aziridine and 2-[ 3 H]-aziridine in situ.
Databáze: OpenAIRE
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