Patent GB-853044-A (GB)
Title: Novel phosphoric and thiophosphoric acid ester amides and the production thereof
IPC: C07F9/6584
Filed: 1958-12-03
Abstract: The invention comprises compounds of the general formula : <FORM:0853044/IV(b)/1> wherein X1 and X2 each represent a saturated or unsaturated aliphatic or cycloaliphatic residue containing from 2 to 6 carbon atoms which may be substituted by halogen, preferably by chlorine, at least one of X1 and X2 containing at least 3 carbon atoms, X3 is an oxygen or sulphur atom, <FORM:0853044/IV(b)/2> atom or an alkyl radical with a straight or branched chain and having from 1 to 6 carbon atoms, which if desired can carry one or more hydroxy, etherified hydroxy, carboxyl, carbalkoxy, amino, substituted amino or aldehyde groups or one or more further of the N,N-di-substituted phosphoramido or thiophosphoramido rings, and p  n is a whole number from 1 to 3.  Z is preferably a hydrogen atom, a methyl or ethyl radical, a radical of the sugar series, or the radical of a polyhydroxy compound having from 1 to 6 carbon atoms. They may be obtained by reacting a compound of the formula : <FORM:0853044/IV(b)/3> herein X1, X2, and X3 are as defined above and X4 is a halogen atom with a compound of the formula : <FORM:0853044/IV(b)/4> wherein a is a hydroxy or amino group or the group-NH-Z and the other radicals are as defined above in an inert solvent, e.g. dioxane or benzene, in the presence of an acid binding agent, e.g. triethylamine.  Several examples are given, typical products being : N,N-bis-(b -chloropropyl)-N1,O-ethylene-phosphoric acid ester diamide, N-b -chloroethyl-N-b -chloropropyl- N, 1O-propylene phosphoric acid ester diamide, N,N-bis (b -chloropropyl)-N1,O-[(3-methyl) - propylene]- phosphoric acid ester diamide, N,N-bis (b -chloropropyl)-O,O1-propylene-phosphoric acid ester amide, N.N-bis-(b -chloropropyl)-N1,O-propylene thiophosphoric acid ester diamide, N,N-bis-(b -chloropropyl)-O1, O-ethylenethiophosphoric acid ester amide and N-b -chloroethyl-N-b -chlorobutyl-N1,O-propylene phosphoric acid ester diamide.  The products have good cytostatic properties.  The preparation of the following stating materials is described : (1) bis-(b -chloropropyl) amine hydrochloride by reacting bis (b -hydroxypropyl) amine with thioyl chloride in benzene solution ; (2) N,N-bis-(b -chloropropyl)-phosphoric acid amide dichloride by reacting the hydrochloride of (1) with phosphorus oxychloride, (3) b -chloroethyl-b -chloropropyl amine hydrochloride by reacting b -hydroxy-ethyl-b -hydroxypropyl amine with thionyl chloride in benzene, (4) N-b -chloroethyl-N-b -chloropropyl phosphoric acid amide dichloride by reacting the hydrochloride of (3) with phosphorus oxychloride.  The following hydrochlorides are obtained similarly from the corresponding hydroxy amines and are converted to the corresponding N,N-disubstituted phosphoric acid amide dichlorides by reaction with phosphorus oxychloride b -chloroethyl-g -chloropropylamime hydrochloride, b -chloropropyl-g -chloropropylamine hydrochloride, N,N-bis-(d -chlorobutyl)-amine hydrochloride, and N-b -chlorethyl-N-b -chlorobutylamine hydrochloride. N,N-bis-(b -chloropropyl) - thiophosphoric acid amide dichloride is obtained by reacting N1N-bis (b -chloropropyl)-amine hydrochloride with phosphorus sulphochloride.