Griggs L J, Jarman M
J Med Chem. 1975 Nov;18(11):1102-6. doi: 10.1021/jm00245a011.
Convenient syntheses are described of d4 analogs of cyclophosphamide and some of its metabolites, potential standards for the quantitative analysis of the drug and its metabolites in human body fluids by stable isotope dilution-mass spectrometry. Base-catalyzed H-D exchange on N-nitrosobis(2-hydroxyethyl)amine gave N-nitrosobis(1,1-dideuterio-2-hydroxyethyl)amine from which bis(2-chloro-1,1-dideuterioethyl)amine (nor-HN2-d4) was readily obtained. Established synthetic routes were then used to convert nor-HN2-d4 into d4 analogs of cyclophosphamide [2-[bis(2-chlorethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide], 4-ketocyclophosphamide [2[BIS(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorin-4-one 2-oxide], and carboxyphosphamide [2-carboxyethyl N-N-bis(2-chloroethyl)phosphorodiamidate], and these analogs were used in a preliminary investigation into the quantitation of the appropriate components in human plasma and urine. Also prepared were d4 analogs of phosphoramide mustard [N,N-bis(2-chloroethyl)phosphorodiamidic acid (cyclohexylammonium salt)] and 3-(2-chloroethyl)oxazolidone and the methyl and trideuteriomethyl esters of phosphoramide mustard.
本文描述了环磷酰胺及其一些代谢物的d4类似物的简便合成方法，这些类似物是通过稳定同位素稀释质谱法定量分析人体体液中该药物及其代谢物的潜在标准品。N-亚硝基双（2-羟乙基）胺在碱催化下进行H-D交换得到N-亚硝基双（1,1-二氘代-2-羟乙基）胺，由此可轻松制得双（2-氯-1,1-二氘代乙基）胺（去甲氮芥-d4）。然后利用已有的合成路线将去甲氮芥-d4转化为环磷酰胺[2-[双（2-氯乙基）氨基]四氢-2H-1,3,2-恶唑磷烷2-氧化物]、4-酮环磷酰胺[2[双（2-氯乙基）氨基]四氢-2H-1,3,2-恶唑磷-4-酮2-氧化物]和羧基磷酰胺[2-羧乙基N-N-双（2-氯乙基）磷二酰胺]的d4类似物，并将这些类似物用于人体血浆和尿液中相应成分定量分析的初步研究。还制备了磷酰胺芥[N,N-双（2-氯乙基）磷二酰胺酸（环己铵盐）]和3-（2-氯乙基）恶唑烷酮的d4类似物以及磷酰胺芥的甲基和三氘代甲酯。
