Selective Olefin Reduction in Thebaine Using Hydrazine Hydrate and O2 under Intensified Continuous Flow Conditions

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• 作者：Bartholomäus Pieber ; D. Phillip Cox ; C. Oliver Kappe
• 刊名：Organic Process Research & Development
• 出版年：2016
• 出版时间：February 19, 2016
• 年：2016
• 卷：20
• 期：2
• 页码：376-385
• 全文大小：470K
• ISSN：1520-586X

文摘

Hydrocodone, a high value active pharmaceutical ingredient (API), is usually produced in a semisynthetic pathway from morphine, codeine or thebaine. The latter alkaloid is an attractive precursor as it is not used as a remedy itself. The key step in this production route is a selective olefin reduction forming 8,14-dihydrothebaine which can be subsequently hydrolyzed to yield hydrocodone. Unfortunately, standard hydrogenation procedures cannot be applied due to severe selectivity problems. A transfer hydrogenation using in situ generated diimide is the only known alternative to achieve a selective transformation. The most (atom) economic generation of this highly unstable reducing agent is by oxidizing hydrazine hydrate (N<sub>2sub>H<sub>4sub>·H<sub>2sub>O) with O<sub>2sub>. In the past, this route was “forbidden” on an industrial scale due to its enormous explosion potential in batch. A continuous high-temperature/high-pressure methodology allows an efficient, safe, and scalable processing of the hazardous reaction mixture. The industrially relevant reduction was achieved by using four consecutive liquid feeds (of N<sub>2sub>H<sub>4sub>·H<sub>2sub>O) and residence time units, resulting in a highly selective reduction within less than 1 h.