N-PHOSPHORYLATED NITROGEN MUSTARDS - PREPARATION OF 2-CHLOROETHYL-AMIDES AND BIS(2-CHLOROETHYL)-AMIDES WITH THE BENZODIAZAPHOSPHORINONE RING-SYSTEM

The reaction of isatoic acid anhydride 1 with NaH/BrCH2CH2Cl furnished the N-(2-chloroethyl) substituted derivative 2, which was allowed to react with methylamine to form N-(2-chloroethyl)-N'-methylanthranilami de 3. Treatment of 3 with PCl3 furnished the 1,3,2-diazaphosphorin-4-o ne 4, which reacted with bis(2-chloroethyl) amine hydrochloride to for m the P-bis(2-chloroethyl)amino derivative 5 by substitution at phosph orus. Oxidation of 5 with the hydrogen peroxide/urea 1:1 adduct led to the phosphoryl species 6. The sigma(4)P-derivative 7 was formed by hy drolysis of 4 with small amounts of water. Treatment of the P-chloro d erivative 8 with (CH3)(3)SiOCH3 furnished the methoxy-substituted comp ound 9, which formed the phosphoryl derivative 10 upon reaction with S O2Cl2. The previously known bis(2-chloroethyl)amino-substituted 1,3,2- benzodiazaphosphorin-4-on-2-oxide 11 was synthesized by reaction of 10 with bis(2-chloroethyl)amine hydrochloride/triethylamine. The P-2-chl oroethylamino-substituted derivative 12 was obtained by treatment of 8 with 2-chloroethylamine hydrochloride/triethylamine. The structures o f 3, 4 and 5 were confirmed by single crystal X-ray structure determin ation. In 3 the molecules are linked into chains by hydrogen bonds of the form N-H ... O=C between amide gaups. The heterocycles of 4 and 5 display half-boat conformation with the P atom out of plane.