肿瘤的化学治疗——ⅩⅩⅩⅨ.2-甲基-5-双(β-氯乙基)氨基苯丙氨酸及2-双(β-氯乙基)氨甲基-5-硝基苯丙氨酸的合成

本文报道在间位溶肉瘤素氮芥基的对位引入一个甲基,合成了2-甲基-5-双(β-氯乙基)氨基苯丙氨酸(Ⅳ,AT-1420),希望甲基的引入,通过其推电子效应,增加氮芥基中氯原子的活泼性,从而增加抗癌效力。药理试验结果表明,化合物Ⅳ对艾氏癌实体型有明显的抑制作用。从合成化合物Ⅳ的中间体(Ⅶ)出发,为抗癌新药消瘤芥(AT-1258,Ⅴ)提供了一条有用的工艺生产路线。

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.