TUMOUR CHEMOTHERAPY ⅩⅩⅩⅣ. STUDIES ON HEXAMETHYLENETETRAMINE SALT OF p-BIS-(2-CHLORO-ETHYL)-AMINO-ω-BROMOACETOPHENONE (AT-584) Ⅲ. SYNTHESIS OF HEXAMETHYLENETETRAMINE SALT OF p-BIS (2-CHLOROETHYL) -AMINOMETHYL-ω-BROMOACETOPHENO

In a previous paper of this series we reported that the hexamethylenetetramine salt of p-bis-(2-chloroethyl)-amino-ω-bromoacetophenone (Ⅰ, AT-584) had pronounced inhibitory action with long-acting efficacy on the growth of several experimental tumoturs, and that the antiturnout property was due to the mustard group-and the long-acting efficacy was probably related to the quarternary structure. Since nitrogen mustards of aliphatic type usually possess more effective action than those of aromatic ones, the hexamethylenetetramine salt of p-bis-(2-chloroethyl)-aminomethyl-ω-bromoacetophenone (Ⅱ) was synthesized.The starting material for the synthesis of compound Ⅱ was p-bis-(2-chloroethyl) aminomethyl-benzoic acid hydrochloride (Ⅷ), which was prepared from ethyl p-toluate or p-tolunitrile via bromination with NBS, condensation with diethanolamine, Chlorination with thionyl chloride and hydrolysis with hydrochloric acid successively. Gompound Ⅷ was chlorinated by thionyl chloride in dry benzene to give its acid chloride (Ⅸ), which without being isolated, was treated with diazomethane to yield the corresponding diazoketone(Ⅹ). The latter, without being isolated in pure state was decomposed in dioxane by hydrobromic acid to give p-bis (2-chloroethyl) aminomethyl-ω-bromoacetophenone (Ⅺ). Finally, the desired product (Ⅱ) was obtained by treating Ⅺ with hexamethylenetetramine in chloroform.Preliminary pharmacological tests showed that compound Ⅱ did not possess significant inhibitory action against sarcoma 180 in mice.