항암제인 Cyclophosphamide의 중간체인 $^{15}N$과 $^{17}O$-phosphoramide Mustards의 합성

The Study of Cyclophosphamide Metabolite $^{15}N$ and $^{17}O$ Phosphoramide Mustards

Each nitrogen and oxygen site isotope enriched the cyclophosphamide metabolite phosphoramide mustard was synthesized. Reaction of N,N-bis(2-chloroethyl)phosphoramidic dichloride$[Cl_2P(O)N(CH_2CH_2Cl)_2]$ with benzyl alcohol and ammonia gave N,N-bis(2-chloroethyl)phosphorodiamidic acid phenylmethyl ester $[BzO(H_2N)P(O)N(CH_2CH_2Cl)_2]$. Catalytic hydrogenation of this benzyl ester followed by the addition of cyclohexylamine provided PM. Incorporation of $^{15}NH_3$ into this general scheme gave PM with a $^{15}NH_2$ moiety. Glycine-$^{15}N$ was converted to bis(2-chloroethyl)amine-$^{15}N$ hydrochloride which, in turn, provided for N,N-bis(2-chloroethyl)phosphorodiamidic-$^{15}N$ dichloride. Use of this compound in the general synthetic pathway yielded PM CHA with $^{15}N$ in the mustard moiety. $^{17}O$-Enriched PM was generated through the use of benzyl alcohol-$^{17}O$. To obtain the alcohol, labelled benzaldehyde was made by exchange with $^{17}OH_2$ and was then reduced with sodium borohydride.