An Efficient Process for the Large-Scale Synthesis of a 2,3,6-Trisubstituted Indole

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• 作者：Anthony D. Alorati ; Andrew D. Gibb ; Peter R. Mullens ; Gavin W. Stewart
• 刊名：Organic Process Research & Development
• 出版年：2012
• 出版时间：December 21, 2012
• 年：2012
• 卷：16
• 期：12
• 页码：1947-1952
• 全文大小：307K
• 年卷期：v.16,no.12(December 21, 2012)
• ISSN：1520-586X

文摘

The efficient synthesis of a key trisubstituted indole intermediate 1 is described. The synthetic route required the use of an aryl Grignard reagent which was not commercially available, and the large-scale formation of this fragment and the thermal evaluation for this step is presented. The key step in the sequence was a Truce鈥揝miles rearrangement to provide an advanced ketone intermediate which, upon reduction, cyclized to the desired indole 1. Design of experiment (DoE) optimization of this reduction is also presented. In total >50 kg of target indole 1 were synthesized in 55% overall yield over five steps using this new route.