Development of a Catalytic Cuprate 1,6-Conjugate Dienone Addition Process for the Manufacture of Fulvestrant EAS, a Key Intermediate in the Synthesis of Fulvestrant
Development of a Catalytic Cuprate 1,6-Conjugate Dienone Addition Process for the Manufacture of Fulvestrant EAS, a Key Intermediate in the Synthesis of Fulvestrant
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DOI：
10.1021/op1001319
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发表时间：
2010-07
影响因子：
3.4
通讯作者：
P. J. Hogan;Lyn Powell;G. Robinson
中科院分区：
文献类型：
--
作者：
P. J. Hogan;Lyn Powell;G. Robinson
本文描述了抗癌药芙仕得的活性药物成分氟维司群中关键甾体中间体的工艺开发。中间体的合成，在阿斯利康称为氟维司群EAS，涉及铜催化的格氏试剂与甾体二烯酮的1，6-共轭加成。反应温度以及试剂的添加顺序和速率对所需化合物的总产率有显着影响。开发的一个新方面是监测与催化循环相关的瞬时颜色变化，作为工艺优化的重要辅助手段。
The paper describes the development of a process to a key steroidal intermediate in fulvestrant, the active pharmaceutical ingredient of the anticancer agent Faslodex. Synthesis of the intermediate, known within AstraZeneca as fulvestrant EAS, involves the copper-catalysed 1,6-conjugate addition of a Grignard reagent to a steroidal dienone. The reaction temperature and the order and rate of addition of the reagents have a dramatic effect on the overall yield of the desired compound. A novel aspect of the development was the monitoring of transient colour changes associated with the catalytic cycle as an important aid to process optimisation.