3,17-二氧代甾体的硝甲基化和硝乙基化研究

雌二醇对肿瘤部位有特别的亲和力 ,例如以雌二醇为载体苯丁酸氮芥就能够选择性地聚集在肿瘤部位并显示强抗肿瘤作用。在报道过的雌二醇载体中 1 甲基 3 羟基 1 ,3,5 ( 1 0 ) ,9( 1 1 ) 雌甾四烯 1 7 酮( 1 )的特点是对肿瘤部位的亲和力高和雌激素活性低。为了满足对雌二醇载体的需求 ,通过 1 1 α 羟基雄甾 1 ,4 二烯 3,1 7 二酮 ( 2 )和雄甾 1 ,4,9( 1 1 ) 三烯 3,1 7 二酮 ( 3)的硝甲基化和硝乙基化制备重要的雌二醇载体。用乙二胺作催化剂回流 2和硝基甲烷 ,使硝甲基化选择性地发生在 1 7位羰基以 60 %收率生成1 1α 羟基 1 7 硝基甲烯雄甾 1 ,4 二烯 3 酮 ,3位羰基不参与反应。采用相同的操作使 2和硝基乙烷以 2 3%收率生成 1 1α ,1 7β 二羟基 1 7α 乙基雄甾 1 ,4,8( 1 4) 三烯 3 酮 ,3和 1 7位羰基都不参与反应。在对甲苯磺酰氯存在下使 2以 94%收率转化为 1 1α 对甲苯磺酰氧基雄甾 1 ,4 二烯 3,1 7 二酮 ( 4 )。 90℃在醋酸钾和醋酐存在下使 4发生消除反应 ,以 80 %收率生成 3。发现 3和硝基甲烷回流 ,期间蒸去至少 1 0 %硝基甲烷 ,残留物再用乙二胺处理 ,然后回流 1h可以以 96%收率得到 1。若将 3、硝基甲烷及乙二胺的混合物简单回流 ,则以 45 %收率得到 1 7 硝基甲烯 雄甾 1 ,3,1 1

Nitormethylation and Nitroethylation of 3,17-Dioxo-steroids

Some investigations discovered that estradiol has specific affinity to the tumor sites. With estradiol as the carrier chlorambucil can accumulate specifically t o the tumor sites and exhibit a strong antitumor effect. Among the reported estr adiol carriers 1-methyl-3-hydroxy-1,3,5(10),9(11)-estratetraene-17-one (1) is characterized by high affinity to the tumor sites and low estrogenic activity, and thus exhibits promising use. In the present pa per nitormethylation and nitroethylation of 11-α-hydroxyandrosta-1,4-diene-3,17-dione (2) and 1,4,9(11)-androstatriene-3,17-d ione (3) were investigated. With ethylenediamine as the catalyst refluxing 2 and nitromethane the condensation s electively occurred at the 17-carbonyl and gave 11α-hydroxy-17-nitromethyl-ideneandrosta-1,4-diene-3-one in 60% yield no any reaction occurred at 3-carbonyl. With the same procedure the condensation of 2 and nitroethane exclus ively gave 11α,17β-dihydroxy-17α-ethylandrosta-1,4,8(14)-triene-3-one in 23% yield neither 17-nor 3-carbonyl nitroethylation product was obtained. In the presence of tosyl chloride and pyridine 2 was co nverted into 11α-p-to luenesulfonyloxyandrosta-1,4-diene-3,17-dione (4) in 94% yield. At 90 ℃ in the presence of potassium acetate and acetic anhydrid e 4 was eliminated and 3 was obt ained in 80% yield. Refluxing the mixture of nitromethane and 3 for 1 h, removing at least 10% of nitromethane via distillatio n, treating the residue with ethylenediamine, and refluxing the mixture for anot her 1 h gave specifically 1 in 96% yield. Refluxing the mixture of 3, notromethane and ethylenediamine the cond ensation gave 17-nitrome thylidene-1,3,11(12)-androstatriene-3-one (5) in 45% yield. Under the same conditions and increasing the amount of ethylenediamine t he simultaneously nitromethylation of 3-and 17-carbonyl of 3 resulted in 1 and 5 in 50% and 40% yield, respectively. Refluxing the mixture of 3, notroethane and ethylenediamine the condensation gave 17β-hydroxy-17α-ethyl-androsta-1,4,8(14),9(11)-tetraene-3-one in 17% yield.