摘要
以金鸡纳碱衍生物为催化剂,采用不对称Mannich反应,在催化剂3-((3,5-二(三氟甲基)苯基)氨基)-4-(((1S)-6-甲氧基喹啉-4-基)((1S,4S,5R)-5-乙烯基奎宁-2-基)甲基)氨基)-3-环丁烯-1,2-二酮(Ⅴe)摩尔分数为10%,溶剂为甲苯,温度为60℃的最佳反应条件下一锅法合成了9个手性含1,3,4-噻二唑的丙二酸酯衍生物(Ⅳa~i),具有较高的收率(70%~89%)和优异的对映选择性(e.e.值最高>99%)。生物活性测试结果表明:该类衍生物对烟草花叶病毒具有一定的活性,其中,手性化合物(–)-Ⅳf〔(–)-二乙基-2-((3,4-二氯苯基)((5-(2,4-二氯苯基)-1,3,4-噻二唑-2-基)氨基)甲基)丙二酸酯〕的治疗活性和保护活性分别为50.8%和42.6%,与对照商品化药剂病毒唑相当。
Nine chiral malonate derivatives containing 1,3,4-thiadiazole moiety(Ⅳa~i) were synthesized by one-pot asymmetric Mannich reaction using cinchona alkaloid squaramide catalyst. High yields(70%~89%)and excellent enantioselectivities [up to>99%, enantiomeric excess(e.e.)] were obtained in toluene in the presence of 10 mol% catalyst 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((1 S)-(6-methoxyquinolin-4-yl)((1 S,4 S,5 R)-5-vinylquinuclidin-2-yl)methyl)amino)cyclobut-3-ene-1,2-dione(Ⅴe) at 60 ℃ which were the optimum reaction conditions. The bioassay results showed that these derivatives possessed good activities against tobacco mosaic virus(TMV). Especially, chiral compound(-)-Ⅳf exhibited high curative and protective activities against TMV in vivo(50.8% and 42.6%, respectively), equivalent to that of commercially available antiviral agent ribavirin.
引文
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