TUMOUR CHEMOTHERAPY ⅹⅹⅪⅩ Synthesis of 2-Methyl-5-bis (β-Chloroethyl) Aminophenylalanine and 2-bis (β-Chloroethyl)-Aminomethyl-5-Nitrophenylalanine

m-Bis (β-chloroethyl) aminophenylalanine (Ⅱ, m-Melphalane) was reported to possess significant antitumour activities. In view of the fact that electropositive groups, such as methyl group, can activate the chlorine atom of the mustard, thus possibly increase the antitumour activity, the authors synthesized 2-methyl-5-bis (β-chloroethyl) aminophenylalanine (Ⅳ, AT-1420) in which a methyl group was introduced into the benzene ring of m-melphalane. Preliminary pharmacological examination revealed that Ⅳ possessed a strong inhibitory action against S-180 in mice with a rate of above 95%. On the bacis of synthesis of AT-1420 a more practical route of synthesis of the known anticancer drug Nitrocaphane (Ⅴ, AT-1258) was described by use of diethyl acetamidomalonate instead of diethyl formamidomalonate.2-Methylnitrobenzyl chloride(Ⅵ) was condensed with diethyl acetamidomalonate to give diethyl 2-methyl-5-nitrobenzyl acetamidomalonate(Ⅶ), which was readily converted to the corresponding amino compound (Ⅷ) by catalytic reduction with Pd-C. Treatment of Ⅷ with ethylene oxide in 40% acetic acid solution at room temperature afforded 2-methyl-5-bis (β-chloroethyl) aminobenzyl acetamidomalonate(Ⅸ), which was then chlorinated with thionyl chloride to give the chloride (Ⅹ), and the desired product(Ⅳ) was obtained by hydrolysis of Ⅹ with concentrated hydrochloric acid.