Advanced Synthetic Strategies for Progesterone: Combining trans-Hydrogenation and Rupe’s Rearrangement of 4-Androstenedione for Enhanced Yield

Progesterone, a steroid hormone, plays an important role in the human body, especially in the reproductive system. A unique, minimal, cost-effective and high yielding organic synthesis protocol for the synthesis of progesterone has been established. The proposed economical route utilizes low-cost and easily available hormone intermediate 4-androstenedione and acetylene gas, offering unique pathway to synthesize progesterone, which can be further scaled to the commercial level. The process starts with the synthesis of a propargylic alcohol intermediate from 4-androstenedione, yielding 93% through an improved procedure. Subsequently, this intermediate undergoes Rupe’s rearrangement, catalyzed by copper over an alumina catalyst, to form an enyne intermediate, which is then rehydrated to produce an enone with a 77% yield. The final step involves the selective reduction of an olefin bond via palladium-catalyzed trans-hydrogenation reaction, resulting in progesterone with a 75% yield. The final product is of pharmaceutical-grade purity as confirmed by HPLC analysis.