新的前列腺癌治疗剂17-(5′-异唑基)雄甾-4,16-二烯-3-酮合成方法的改进

17-(5′-异唑基)雄甾-4,16-二烯-3-酮(4,L-39)是最有希望的P45017α和5α-还原酶的双重抑制剂,对前列腺癌及前列腺肥大具有潜在的治疗作用.对其合成路线进行改进,收率极大提高.首先,Claisen缩合物2用羟胺在乙醇中环和得到纯5′-异唑3a,用Swern氧化反应直接氧化3a,然后在在酸中异构化后得到L-39(4).或者,化合物2在无水甲酸中与羟胺环和得到3-甲酯物(6),后者以改良奥氏氧化法直接氧化生成4-烯-3-酮物(4).

Improved synthesis of 17-(5′-isoxazolyl)androst-4,16-dien-3-one,a potential agent for the treatment of prostate cancer

17-(5′-isoxazolyl)androst-4,16-dien-3-one(4,L-39)is the most promising inhibitor of 17α-hydroxylase/C17,20-lyase(P45017α)and 5α-reductase(5α-R),and has potential uses in the treatment of prostate cancer and benign prostatic hypertrophy.Its synthesis has been improved with much higher yield in this paper.First,the Claisen condensate(2)was cyclized with hydroxylamine in ethanol to give pure 5′-isoxazole 3a,which could be oxidized directly by Swern oxidation and then isomerized in acid to give L-39(4).Second,2 was cyclized with hydroxylamine in anhydrous formic acid to give 3-formate(7),which was then oxidized directly by the modified Oppenauer oxidation to give 4-en-3-one(4).