3β-乙酰氧基雄甾-5,15-二烯-17-酮的合成

Synthesis of 3β-acetoxyandrosta-5,15-dien-17-one

以醋酸去氢表雄酮为原料,经C17保护,C16溴代,C15和C16间脱溴化氢及C17脱保护4步反应法合成了3β 乙酰氧基雄甾 5,15 二烯 17 酮。探讨了影响缩酮化反应、溴代反应、消除反应及去保护反应的主要因素,测试了各步产物的物理常数,并用高效液相色谱,红外光谱,质谱,氢核磁共振等对产物进行了表征。研究结果表明:缩酮化反应中催化剂对甲苯磺酸与甾体的量比为0.066时比较适宜,过量会产生油状物;溴代反应中,溴化试剂C5H5N·HBr·Br2的性能优于Br2的性能;溴代反应中间体偕二溴代物中,脱溴试剂NaI的性能优于KI的性能,KI的性能优于Zn粉的性能;消除反应中反应速度与叔丁醇钾的用量成正比,溶剂二甲亚砜优于二甲苯;升高温度不利于去保护反应的进行。上述4步反应的收率分别为93.4%,81.8%,88.8%和96.7%,总收率为65.6%。

3β-acetoxyandrosta-5,15-dien-17-one was prepared from 3β-acetoxyandrost-5-en-17-one (dehydroepiandrosterone acetate) by 4 steps of ketal formation, bromination, elimination and deprotection with overall yield of 65.6%. The influence of main factors such as reaction temperature, kind and dosage of reagents and solvent on the four reactions was analysed. The products are characterized by high performance liquid chromatography(HPLC), infrared spectrum(IR), mass spectrum(MS) and hydrogen nuclear magnetic resonance(~1HNMR). The results show that the advantage of new method lies in raising of the yield and shortening of the synthetic experiment steps; the excessive catalyst p-toluence sulfonic acid is unfavorable to ketal formation; in brominating reaction, C_5H_5N·HBr·Br_2 is better than Br_2 in terms of a brominating agent; (NaI) is better than KI and the latter is better than Zn dust in terms of a debrominating (agent) of the brominating intermediate o-dibromide. Good yield(81.8%) was obtained by using C_5H_5N·HBr·Br_2 as a brominating agent and NaI as a debrominating agent in the brominating reaction; the rate of dehydrobromination is direct ratio to the content of potassium (tert-butoxide) and to the concentration of steroid.