Patent GB-812651-A (GB)
Title: Novel cyclic phosphoric acid ester amides and the production thereof
IPC: C07F9/6584
Filed: 1957-01-30
Abstract: The invention comprises cyclic phosphoric acid ester amides of the formula: <FORM:0812651/IV (b)/1> in which Y is an -O- or <FORM:0812651/IV (b)/2> group and each Z which may be the same or different is a hydrogen atom, a carboxyl, carbalkoxy, or hydroxy group, or an alkyl radical with a straight or branched chain and having 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 N,N-bis-(b -chloroethyl)-phosphoramido rings, and n is a whole number from 1 to 3.  The products may be obtained by reacting a compound of the formula: <FORM:0812651/IV (b)/3> in which each X1 is a halogen atom, preferably chlorine, with a compound of the formula: <FORM:0812651/IV (b)/4> in which each Z which may be the same or different and n are as defined above and a is a hydroxy group or the group -NH-Z in an inert solvent, e.g. dioxane or benzene, in the presence of an acid-binding agent, e.g. triethylamine, at low or elevated temperature.  Suitable starting materials of the last given formula are alkanolamines or glycols but it is also possible to use functional derivatives of such compounds, e.g. N-acyl derivatives of alkanolamines, the aryl group being split off during the process. Other suitable starting materials of the last given formula are hydroxy amino acids and compounds which introduce the radicals of carbohydrates, e.g. sugars, or other polyhydroxy compounds.  When polyhydroxy derivatives are used it is possible for two or three of the phosphamide rings to be introduced by using suitable proportions of the reactants, e.g. to form a compound of the formula: <FORM:0812651/IV (b)/5> in which X is a chlorine atom.  In examples, N,N - bis - (b  - chloroethyl) - phosphoric acid amide dichloride is reacted with: (1) ethanolamine to form N,N-bis-(b -chloroethyl)-N1-O-ethylene phosphoric acid diamide; (2) with ethylene glycol to form N,N-bis-(b -chloroethyl) - O,O1 - ethylene phosphoric acid amide; (4) with isopropanolamine to form N,N-bis-(b - chloroethyl) - N1,O - isopropylene phosphoric acid diamide; (5) with b -hydroxyethyl methylamine to form N,N-bis-(b -chloroethyl)-N1,O - ethylene - N1 - methyl phosphoric acid diamide; (6) with 1,2-propylene glycol to form N,N - bis - (b  - chloroethyl) - O,O1 - isopropylene phosphoric acid amide; (8) with glycerine to form N,N-bis-(b -chloroethyl)-O,O1-(b  - oxypropylene) - phosphoric acid amide; (9) with D-sorbitol to form N,N-bis-(b -chloroethyl) - O,O1 - sorbitol - phosphoric acid amide; (10) with pentaerythritol to form N,N-bis-(b -chloroethyl) - O,O1 - [b  - bis - (oxymethyl) - propylene] - phosphoric acid amide; (11) with DL-serine-methyl ester hydrochloride to form N,N - bis - (b  - chloroethyl) (O,N1 - dl - serinemethyl ester)-phosphoric acid amide; (12) with 1,3-propanolamine to form N,N-bis-(b -chloroethyl)-N1,O-propylene phosphoric acid diamide; (13) with 1,4-butanolamine to form N,N-bis-(b -chloroethyl) - N1,O - butylene phosphoric acid diamide; (14) with diethanolamine to form N,N - bis - (b  - chloroethyl) - N1,O - ethylene-N1 - b  - oxyethyl - phosphoric acid diamide; (15) with 1,3 propylene glycol to form N,N-bis-(b  - chloroethyl) - O,O1 - propylene - phosphoric acid amide; and (16) with tetramethylene glycol to form N,N-bis-(b -chloroethyl)-O,O1-butylene phosphoric acid amide.  In two other examples, (3) and (7), N,N-bis-(b -chloroethyl)-phosphoric acid amide phenyl ester chloride is reacted with 1,2-ethanolamine and b -hydroxyethyl - methylamine respectively to form N,N - bis - (b  - chloroethyl) - N1,O - ethylene-phosphoric acid diamide and N,N - bis - (b -chloroethyl) - O,N1 - ethylene - N1 - methyl phosphoric acid diamide respectively.  The products are stated to have therapeutic effect as cytostatics.