The synthesis of some N-substituted phosphoramidic and thiophosphoramidic diesters



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Eight new 2-inethoxyethyl amine, 3-methoxypropyl amine and 3-methylthiopropylamine derivatives of N-substituted phosphoramidic diesters, as well as six new thiophosphoramidie diesters, were prepared. The diethyl ester of N-(3-methoxy-l-propyl)phosphoramidic acid was prepared by the direct reaction of one mole of diethyl chlorophosphate and two moles of 3-methoxypropylamine. The reaction of one mole of dialkyl chlorophosphate or dialkyl chlorothiophosphate with one mole of amine, in the presence of one mole of triethylamine as a hydrogen chloride acceptor, formed the corresponding phosphoramidate or thiophosphoramidate. By use of this method the dimethyl and diethyl esters of N-(3-methoxy-l-propyl)phosphoramidic acid, the diethyl ester of N-(2-methoxy-l-ethyl)phosphoramidic acid, the dimethyl and dipropyl esters of N-(3-methoxy-l-propyl) thiophosphoramidic acid, the dimethyl, diethyl and dipropyl esters of N-(2-methoxy-l-ethyl)thiophosphoramidic acid, and the diethyl ester of N-(3-methylthio-l-propyl)phosphoramidic acid were prepared. One mole of dialkyl phosphite reacted with two moles of amine in the presence of carbontetrachloride formed phosphoramidates, such as diisopropyl N-(3-methoxyl-propyl)phosphoramidate and dimethyl N-(2-methoxy-l-ethyl)phosphoramidate. By the replacement of one mole of amine by one mole of triethylamine the reaction was more satisfactory, especially in the preparation of 2-methoxyethylamine derivatives. By this method the diisopropyl and dibutyl diesters of N-(2-methoxy-l-ethyl)phosphoramidic acid were prepared. These fourteen compounds have been submitted to the Cancer Chemotherapy National Service Center, Bethesda, Maryland, to be screened for possible oncolytic activity. The results of the screening test will be reported later.